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Home , Aloxiprin, Chondritis, Diacerein, Erythromelalgia, Kveim test, Oligoarthritis

Jozef Rovenský and Juraj Payer (eds.)

Dictionary of

With contributions by Roy B. Clague, Manfred Herold, Milan Bayer, Helena Tauchmannová, Miroslav Ferenčík, Zdenko Killinger

SpringerWienNewYork Jozef Rovenský National Institute of Rheumatic , Piestany, Slovak Republic Juraj Payer 5th Department of Internal Medicine, Medical Faculty of Comenius University Faculty Hospital Bratislava-Ruzinov, Slovak Republic

Roy B. Clague – Nobles Hospital, Isle of Man, UK Manfred Herold – Medical University of Innsbruck, Austria Milan Bayer – Faculty of Medicine in Hradec Kralove, Charles University Prague, Czech Republic Helena Tauchmannová – National Institute of Rheumatic Diseases, Piestany, Slovak Republic Miroslav Ferenčík – Institute of Neuroimmunology, Slovak Academy of Sciences and Institute of Immunology, Faculty of Medicine Comenius Universtiy, Bratislava, Slovak Republic Zdenko Killinger – 5th Department of Internal Medicine, Medical Faculty of Comenius University Faculty Hospital Bratislava-Ruzinov, Slovak Republic

With financial support by Bundesministerium für Wissenschaft und Forschung in Wien, Austria. Sponsors, who thankfully granted the translation from Slovak into English: Eli Lilly Slovakia s.r.o., Bratislava; Servier Slovensko, spol. s.r.o., Bratislava; Novartis Slovakia s.r.o., Bratislava; Roche Slo- vensko, s.r.o., Bratislava; sanofi-aventis Pharma Slovakia, Bratislava. The printing was sponsored by: Teva Pharmaceutical, Bartislava, Slovakia; Novartis Slovakia s.r.o., Bratislava; Mayor of Piešťany, Slovakia. Parts of the book were translated from Rovenský et al. “Revmatologický výkladový slovník” GRADA Publishing, 2006 and Payer et al. “Lexikón osteoporózy” SAP, 2007.

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machines or similar means, and storage in data banks. Product Liability: The publisher can give no guarantee for all the information contained in this book. This does also refer to information about drug dosage and application thereof. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. This publication is compiled primarily from the publications Revmatologický výkladový slovník, Grada Publi- shing 2006 and Lexikón osteoporózy, Slovak Academic Press, 2007, together with latest findings. Project management, translation and compilation work: Language Sense Ltd. (John Boyd), Bratislava © 2009 Springer-Verlag/Wien Printed in Germany SpringerWienNewYork is a part of Springer Science + Business Media springer.at Typesetting: Composition & Design Services, Minsk 220027, Belarus Printing: Strauss GmbH, 69509 Mörlenbach, Germany Printed on acid-free and chlorine-free bleached paper SPIN: 11953708 Library of Congress Control Number: 2008940520 ISBN 978-3-211-68584-6 SpringerWienNewYork Preface

This dictionary of rheumatology has tionary, we have taken into account the been prepared as a quick reference source fact that an integral part of prevention for the clinical, diagnostic and therapeu- and treatment of rheumatological dis- tic aspects of rheumatic disorders and eases includes rehabilitation. We there- related immunology. Rheumatology is a fore provided guidelines on how to pre- well-recognised specialty of medicine. vent the onset of functional damage and Recently, due to many factors (the envi- its progression towards increased dis- ronment, new viral diseases, genetics, ability. We believe this dictionary will increased life expectancy, improved di- serve not only rheumatologists, but also agnostic tests) an increase in the inci- the many related specialists, trainee doc- dence and prevalence of rheumatological tors, health professionals and nurses in- disorders has been witnessed. Rheuma- volved in the management of patients tology has close relationships with a num- with disorders of the human musculo- ber of medical specialties and health pro- skeletal system. fessionals, such as orthopaedic surgery, sports medicine, neurology, immunology, The early diagnosis and treatment of as well as clinical rheumatol- rheumatological disorders can help to ogy nurses, physiotherapists and occupa- improve their prognosis and we hope tional therapists, so we have endeavoured that this modest monograph will con- to collate some basic knowledge from tribute to a successful therapeutic man- these fields. When compiling this dic- agement.

Jozef Rovenský On behalf of the collective authors A

α1-antitrypsin A serum glycoprotein in- cellular processes that exert their action hibiting proteolytic , such as trypsin, mainly in blood coagulation, and chymotrypsin and elastase. It also acts as an . α2M and protease complexes acute-phase protein. Its serum level rises in are proteolytically inactive and are eliminated inflammatory diseases. The coding gene is quickly (in minutes) from the circulation. Its located on the 14th chromosome, where it serum levels are increased especially in neph- can occur in form of 25 alleles. Some of them rotic syndrome, , code for physiological products (PiMM phe- mellitus and -. notype), while others are related to patho- logical states, e.g. PiZZ phenotype, which is Abatacept Abatacept (Orencia®) is an in- often associated with emphysema, cirrhosis, jectable, synthetic (man-made) soluble fusion and cholelithiasis, where its serum levels are protein that consists of the extracellular do- diminished (α1-antitrypsin deficiency). main of human cytotoxic T-lymphocyte-as- sociated antigen 4 (CTLA-4) linked to the α-fetoprotein An oncofetal antigen that modified Fc portion of human immunoglob- can be found in small concentrations in nor- ulin G1 (IgG1). Abatacept is produced by re- mal human serum. Its level is high in the fetal combinant DNA technology in a mammalian serum, where presumably thanks to its im- cell expression system. munosuppressive effect, it participates in Abatacept belongs to a new class of drugs neonatal immunological tolerance. The called costimulation modulators, shown to α-fetoprotein level is also increased in sera of inhibit T cell activation by binding to CD80 pregnant women when fetal development is and CD86, thereby blocking interaction with defective ( defects, im- CD28. Blockade of this interaction has been munodeficiency syndromes, gastrointestinal shown to inhibit the autoimmune T-Cell acti- or other abnormalities). An increased serum vation that has been implicated in the patho- level can be found in patients with certain genesis of rheumatoid Abatacept at- neoplastic disorders, especially hepatic can- taches to a protein on the surface of T-lym- cer and can be used as a marker of hepatocel- phocytes and blocks both the production of lular carcinoma. new T-lymphocytes and the production of the chemicals that destroy tissue and cause

α1-microglobulin (α1M) A protein syn- the symptoms and signs of arthritis. Abata- thesised in the liver and present in blood, se- cept slows the damage to joints and rum and urine. Complexes of α1M with mo- and relieves the symptoms and signs of ar- nomeric immunoglobulin A (IgA) participate thritis. in renal IgA nephropathy where the serum Abatacept is indicated for reducing signs level of α2M is also usually increased. and symptoms, inducing major clinical re- sponse, slowing the progression of structural

α2-macroglobulin (α2M) A serum glyco- damage, and improving physical function in protein working as inhibitor of a number of adult patients with moderately to severely ac- proteases including , plasmin, kal- tive who have had an in- likrein, trypsin, chymotrypsin, elastase, col- adequate response to one or more DMARDs, lagenase and cathepsin B and G. α2M is pro- such as or TNF antagonists. duced mainly by macrophages and regulates Abatacept may be used as monotherapy or the proteolytic balance in a number of extra- concomitantly with DMARDs other than abduction 2

A TNF antagonists, but has not yet been ap- neus, separated from it by the Achilles bursa. proved by NICE. Tendonitis can be part of the clinical picture Approval of abatacept was supported by of spondyloarthritis, especially ankylosing five randomized, double-blind, placebo-con- spondylitis. It can remain thickened (by fi- trolled clinical trials. In all five studies, sub- brosis) after the inflammation has subsided jects received treatments with abatacept or and nodules may be palpable. placebo at weeks 0, 2, and 4, then every 4 weeks thereafter. Studies have found that Achillodynia of the Achilles tendon, abatacept can reduce the especially of its insertion, most frequently af- of rheumatoid arthritis. It can also reverse ter a trauma or sporting overload. some signs of joint damage. Abatacept/MTX slowed the progression of structural damage and hypochondro- compared to placebo/MTX alone (Furst et al. plasia An autosomal dominant hereditary 2007). syndrome characterized by a small stature Abatacept is infused over 30 minutes. The with short extremities, in most cases caused initial dose of abatacept is followed by doses by a mutation of the fibroblast growth factor two and four weeks later with further doses receptor-3 (FGFR-3). It belongs to the most every 4 weeks thereafter. Patients weighing frequent dysplasias with an incidence of 1 to <60 kg should receive a 500 mg dose, weigh- 15.000–77.000 births, depending on race. ing 60–100 kg a 750 mg dose and weighing The mutation of FGFR-3 results in a defect of >100 kg a 1000 mg dose. chondrocyte proliferation in the growth car- The most common side effects of abatacept tilage of long . include: back pain, , dizziness, head- Clinical symptoms and signs: Some chil- ache, high , nausea, rash, up- dren have difficulties/obstructive per infection, and urinary sleep apnoea, episodes of or chronic tract infection. Administration of abatacept respiratory insufficiency. Specific develop- in patients with chronic obstructive pulmo- mental abnormalities lead to the above-men- nary (COPD) has been associated tioned clinical picture: Hypoplasia of the with exacerbation and increased incidence of middle part of the face with a tendency of ob- COPD symptoms. Patients suffering from struction of the upper airways; dysplastic both rheumatoid arthritis and COPD who changes of the craniovertebral junction with elect to have abatacept therapy should moni- a tendency towards of the foramen tor symptoms carefully, and in collaboration magnum and compression of medulla oblon- with their physicians. Concurrent administra- gata; constriction of the chest. The condition tion of a TNF inhibitor with abatacept has can lead to a picture of “respiratory distress been associated with an increased risk of seri- syndrome in achondroplasia”. Problems can ous infections and no significant additional be divided into three groups. The mildest efficacy over use of the TNF antagonists alone. type is accompanied only by obstructive sleep Concurrent therapy with abatacept and TNF apnoea (most probably related to hypertro- antagonists is therefore not recommended. phy of adenotonsillar tissue); a more severe The long-term effects of abatacept aren’t course includes episodes of apnoea and up- yet known, as it hasn’t been studied over an per airway obstruction persisting even after extended period. adenotonsillectomy, often accompanied by the formation of hydrocephalus; severe dis- Abduction Movement of extremities of the tress progressing to cardio respiratory failure body away from the body’s midline. with oxygen dependency, eventually with co- incidental gastroesophageal reflux. Achilles tendon The common insertion of soleus and both gastrocnemii muscles ten- Acquired immunodeficiency syndrome dons. It inserts on the posterior side of calca- An infectious disease due to the HIV retrovi- 3 acupuncture (AC) rus (human immunodeficiency virus). Two with rapid course (Kaposi sarcoma – approx- A types of virus exist: HIV-1 and HIV-2. Both imately 1/3 of all patients). Dementia and cause serious defects. The changes of psychomotor functions, which are present pandemics are predominantly due to very likely due to direct HIV infection of glial HIV-1, which is more pathogenic. It is trans- cells in the brain, occur in approximately 2/3 mitted by homosexual or heterosexual inter- of all patients. The typical clinical picture of course, transfusion of infected blood and its AIDS does not develop in certain patients; derivates, IV drug administrations using in- however, these patients suffer from a group of fected needles, organ transplant from an in- symptoms referred to as ARC (AIDS related fected donor, or from an infected mother complex) in which infections and tumours during labour or breast-feeding. are not present. ARC may or may not prog- HIV infects cells that possess differential ress to full blown AIDS. antigen CD4 on their surface (particularly T The diagnosis of AIDS consists of serologi- lymphocytes and macrophages). Non-specif- cal assessment, immunological assessment ic symptoms occur at an early stage after in- (determination of CD4+-lymphocytes, or the fection. Subfebrile temperatures, , CD4+/CD8+ ratio in peripheral blood), clini- sweating, , myalgia, headache, di- cal assessment and relevant medical history. arrhoea, lymphadenopathy and also certain Contemporary treatment is only partial and neurological symptoms may occur. Such generally it allows inhibition of HIV replica- symptoms last for several days to two weeks. tion in infected cells (azidothymidine, zido- In the majority of infected individuals, these vudine) and thereby prolongs the period free symptoms may not be apparent. Approxi- of any clinical symptoms. However, after de- mately two weeks after virus transmission, velopment of the symptoms, treatment can- the viral antigens (p24, gp41) can be detected not cure the disease. in the blood of the infected individual. Later on these antigens disappear and antibodies ACR classification criteria for diagno- against certain HIV antigens (anti-p24 and sis of rheumatoid arthritis 1987 → see anti-gp41) can be detected in the blood of the Rheumatoid arthritis (RA) – classification infected individual at two to three months, criteria which is diagnostic confirmation of infec- tion. The disease now often enters a latent Electrical activity in the period without any clinical symptoms, except nerve or muscle fibre according to the for possible lymphadenopathy. Such a period “all or nothing” type, when the membrane po- may last up to 12 years and it terminates by tential polarity ceases or is restored abruptly. activation of the disease, which in untreated cases, leads to death in 6 to 30 months. Acupuncture (AC) Used in rheumatology Activation of the disease is manifested by for pain relief. Metallic needles are inserted decreasing antibodies against the HIV anti- into specific body points by rotation move- gens (anti-p24) and concurrent reoccurrence ment. Acupuncture should induce a balance of these antigens in the blood. Such an event between “yang” (spirit) and “yin” (blood) is referred to as seroconversion. The number principles that run in 14 meridians compris- of T lymphocytes in peripheral blood de- ing 361 acupuncture points. AC has been creases. If the number of T lymphocytes is considered as a form of neuromodulation. Its less the 0.2 x 109/l, then the infected individ- effects have been explained by the gate theory ual is considered to have severe AIDS, even of pain relief, and also by a presumption that though the patient may be asymptomatic. the insertion of the needle acts as a noxa, in- AIDS symptoms include infections due to ducing the production of endogenous opiate- normal, non-pathogenic micro-organisms like substances (). The locations of (pneumonia due to Pneumocystis carinii – in acupuncture points often overlap myofascial 50% of all patients) and certain malignancies trigger points and painful muscle points. acute febrile neutrophilic dermatosis (sweet’s syndrome) 4

A Electro-acupuncture refers to the stimula- coding APPs, whereas glucocorticoids and in- tion of the acupuncture points with needles sulin inhibit the transcription. plugged into a source of electrical current or by the application of small electrodes on Acute phase reactants → see Acute phase those points. Similarly, laserpuncture and proteins magnetopuncture is used. Acupressure refers to a method when acu- Acute prolapse of cervical interverte- puncture points are influenced by pressure bral disc Protrusion of the intervertebral from the fingers or rounded sticks. disc with intact annulus fibrosus and prolapse of the intervertebral disc with nucleus pulpo- Acute febrile neutrophilic dermatosis sus prolapse through the perforated annulus (Sweet’s syndrome) A rare disease of un- fibrosus are the consequence of degenerative known aetiology characterised by marked changes in intervertebral disc tissues. Pro- inflammatory neutrophilic infiltrates. lapse of the disc is usually directed posteri- Symptoms and signs: orly through a weak dorsal longitudinal liga- • painful nodules and red-violet maculae on ment. the skin of the shoulders, torso or head; ul- Symptoms and signs: Medial protrusion ceration usually doesn’t occur, of the disc can cause compression of the spi- • lesions generally heal without scarring, nal cord and lead to development of spastic • concomitant high , paraparesis, dorsal column syndrome and • leukocytes with polymorph nuclear pre- urinary bladder dysfunction. More frequent- , ly posterolateral prolapse of the disc causes • tendency to relapse. isolated compression of the corresponding spinal nerve. In most patients the symptoms Acute phase proteins (APPs) Glycopro- include pain projecting into corresponding tein mediators whose production is signifi- dermatome, movement limitation of the cer- cantly modified after activation of the inflam- vical spine and spasm of the paravertebral matory response or any other kind of tissue muscles. Initially the neck pain can be pro- damage. That is why they are also referred to voked by ambulation and later manifests it- as acute-phase (of inflammation) reactants. self by a typical radicular syndrome. They are produced mainly by hepatocytes, but also by monocytes, endothelial cells, fibro- Acute shoulder pain Pain caused by irri- blasts and other cells. They are divided into tation of the phrenic nerve and recognised as positive and negative APPs. The concentration shoulder pain (Eiselsberg´s phenomenon; of positive APPs increases in the course of in- first described by the Viennese surgeon Anton flammation, whilst the concentration of nega- von Eiselsberg, Vienna, 1860–1939). This in- tive APPs decreases. Albumin is an example cludes pain in pectoris, myocardial for a negative APP. The increase of the major infarction, gall bladder disorders, trauma of APPs can be greater than a thousand fold, the spleen, neoplasms, diseases of while the concentration of other positive APPs gland, pleuritis. Also bursitis calcarea, im- increases only by less than three fold. C-reac- pingement syndrome of one of the rotator tive protein (CRP) and serum amyloid A cuff tendons, most frequently the supraspina- (SAA) are the most strongly reactive positive tus muscle, may radiate to the shoulder. APPs in humans. Their main biological func- Acute shoulder pain without movement tions include direct neutralisation of inflam- limitation may be caused by radicular syn- matory reactions, minimising the damage due drome of C5, herpes zoster (shingles), dis- to inflammation, involvement in reparatory eases of the bones around the shoulder, Pag- mechanisms and regeneration of damaged tis- et-Schroetter syndrome, subclavian, axillary sues. TNF-α, IL-1, IL-6, IL-11 and other cytok- or brachial leading to ines stimulate the transcription of genes en- livid oedema of the hand. 5 agammaglobulinaemia

Limitation of active movement (passive Adhesive molecules Glycoproteins or A movements are unlimited) is caused by com- lectins taking part in interactions between plete disruption of the rotator cuff usually immune system cells, especially during colo- following trauma, overload, mechanical fric- nisation of primary and secondary lymphatic tion or trauma to the rotator tendons with organs and within inflammatory reactions. break up or rupture. Commonly the supraspi- They belong to several families, such as selec- natus muscle tendon is affected. In the case of tins, , members of the immuno- complete rupture, active abduction to the ex- globulin super family (ICAM-1, VCAM-1, tent of 0 to 30 degrees is impossible and the PECAM) and cadherins. anterior tip of the acromion is tender upon palpation. Sooner or later the supraspinatus Adjuvant A supplemental agent that in- muscle atrophies. In some cases, the X-ray creases the effect of the main drug. In immu- shows calcification in the supraspinatus mus- nology, it is an agent of organic or inorganic cle tendon. Ultrasound or magnetic reso- origin that is capable of potentiating the im- nance imaging can confirm disruption of the mune response to a concomitantly adminis- tendon. tered antigen (e.g.: Freund’s adjuvant). Treatment includes bed rest, extremity po- sitioning, , physiotherapy and sur- Adson’s test Test to examine for impinge- gical reconstruction. ment of the subclavian . During the ex- amination, the patient is upright with the up- Adduction Movement of extremities of the per extremity extended to 40 degrees and his/ body towards the midline. her head rotated to the examined side. When inspiring and elevating the chin, there is a Adenosine deaminase (ADA) An en- diminution of the radial pulse on the side of zyme in humans and mammals catalysing the the extended upper extremity, which indi- deamination of adenosine and deoxyadenos- cates evidence of impingement of the subcla- ine to inosine and deoxyinosine, respectively. vian artery. In the case of deficiency, the metabolism of DNA is impaired, resulting in severe disrup- Agammaglobulinaemia A condition in tion of T-lymphocyte function (adenosine which the total serum immunoglobulin level in deaminase deficiency). the individual is lower than 1g/L (immunode- ficiency). It is caused by genetically conditioned Adhesion Abnormal union of parts that are insufficient production of immunoglobulins. normally separate. Increased tissue adhesion, There are two forms: Bruton’s or Swiss type. caused in rheumatology most frequently by Bruton’s type is congenital, sex-linked agam- inflammation, is expressed by limited recip- maglobulinaemia in boys. The clinical picture rocal movement of tissues. is dominated by pyogenic infections. No anti- bodies are produced after vaccination. Adhesive capsulitis (frozen shoulder) Treatment: Infusion of intravenous prepa- This is characterised by pain and gradual rations of Ig (IVIg). progressive limitation in shoulder move- The Swiss type of idiopathic agammaglob- ments due to contraction of the glenohumer- ulinaemia with lymphopenia is a severe com- al capsule. There is often partial or complete bined immunodeficiency (SCID). The clini- resolution over months to years. It is com- cal picture is dominated by systemic fungal monest in later life and can be associated with infections, mainly candidiasis, together with neurodystrophy, for example in the “shoul- bacterial infections such as in Bruton’s type. der-hand” syndrome, following , met- The mere repletion of immunoglobulins is abolic disorders (especially insulin-depen- rarely therapeutically successful, so mar- dent diabetes mellitus) etc. row transplantation should be considered (im- munoglobulin deficiency). agonist 6

A Agonist The principal acting muscle (prime skin that is glossy and sweaty. The aim of mover) responsible for the movement in the physical therapy is to improve local blood required direction. The antagonist acts in the perfusion without increased afferentation opposite direction to the agonist. The syner- from the affected region. Diadynamic cur- gist co-acts in the direction of the agonist. rents and pulse ultrasound are advisable or interferential currents in doses Albers-Schönberg Disease → see Osteo- (Transcutaneous Nerve Stimulator). Vacu- petrosis um-compressive therapy (cautiously), pas- sive positioning of the extremity, and ac- Alendronate A bisphosphonate licensed tive exercise of the fingers. for the treatment and prevention of osteo- • dystrophic phase This begins 2 to 4 weeks porotic fractures (vertebral and nonvertebral) after the or damage. The skin goes in postmenopausal women, patients with glu- pale, the oedema decreases and a spotty or cocorticoid-induced osteoporosis and men diffuse osteoporosis of the whole affected with osteoporosis. The drug is taken on an region occurs on the X-ray image. In this empty stomach washed down with a cup of stage Basset currents or vacuum/compres- water in an upright posture and remaining sive treatment is advisable. Passive exercise upright for the next 30 minutes. It is taken in of the extremity, beginning with antigravi- a dose of 70 mg once weekly or (rarely nowa- ty exercises. days) 10 mg daily. and D • atrophic phase This is characterised by per- supplements are normally prescribed con- sisting trophic changes in the skin and der- currently to aid its effect. mis, limitation of passive and active move- ments up to . Functional changes Alexander technique → see Exercise tech- in this stage are very difficult to influence; niques application of pulse, low-frequency mag- netotherapy or distance electrotherapy Algodystrophic syndrome (ADS) ADS (Basset currents) may be applied. Intensive is characterised as a complex of symptoms locomotor treatment, exercise in a sling, elicited by a nociceptive stimulus. hydrokinesiotherapy, thermotherapy. Symptoms and signs: The clinical picture Prevention of ADS: early active mobilisation is characterised by severe burning pain, au- of the affected extremity focusing on func- tonomonic vasomotor dysfunction, skin tional training. changes and subsequent locomotor malfunc- tion of the affected extremity. Radiographi- Algometry (evaluation of pain thresh- cally, it is characterised by regional osteopo- old) rosis in the affected area. • Instrumental measurement of the pressure ADS – synonyms: algoneurodystrophy, re- on a joint or muscle already causing pain. flex sympathetic dystrophy, Sudeck’s atrophy, Using the Phyaction device (ultrasound + complex regional pain syndrome (CRPS), mid-frequency currents) one can, accord- shoulder–hand syndrome, causalgia. The ing to current density and ultrasound fre- complex of symptoms includes regional pain, quency, localise a painful trigger point. vasomotor disturbances, skin changes and Using thermovision, it is possible to loca- sensory disturbances. Any region on the up- lise tender or trigger points on the skin per and lower extremities may be affected. surface. The development of ADS can be divided • thermal by measuring thermal stimulus into: endurance • acute phase This begins usually 10 days af- • different types of visual analogue scales ter an injury. It is characterised by inten- (VAS; on a vector from 0 to 10, or 100 with sive, dull, roughly circumscribed pain, oe- plus values on the right side and minus val- dema with reddening to cyanosis of the ues on the left) horizontally and vertically 7 amyloid

• verbal e.g. Likert 5-degree scale Indications for hypouricaemic treatment A • pain evaluation using questionnaire sys- initiation: tems • recurrent acute attacks, • Melsack’s questionnaire where pain can be • occurrence of complications of hyperuri- expressed by 78 words divided into 4 cemia and gout, groups. Furthermore, the questionnaire • development of tophi, contains 3 indexes with a degree scale from • involvement of kidneys, 1 to 5: • patients with a uric acid level persistently – NWC – number of words chosen, >700 μmol/L who have already experienced – PRI – pain rating index, an attack, because they have a higher risk – PPI – present pain intensity. of developing complications. The evaluation of pain is an integral part of each evaluation system in rheumatology, e.g. Alphacalcidol (1-alpha-hydroxycholecal- HAQ, RADAI, WOMAC, Lequesne index, ciferol) is indicated in the treatment of the AIMS and others. postmenopausal osteoporosis and osteoporo- sis in patients with severe renal insufficiency. Alkalising agents Compounds used in cy- Alphacalcidol is rapidly metabolised in the tostatic treatment. They act as agents alkalis- liver to . Its principal mechanism of ing DNA, thereby blocking cell division, which action is to increase the circulating 1,25-di- is why they are used in the treatment of neo- hydroxycholecalciferol level, thus increasing plasms. Rarely some of them are used as im- the absorption of calcium and munosuppressants (). from the intestine. It is important in disor- ders where the hydroxylation process of vita- Alkaptonuria and ochronosis Alkapto- min D in the kidneys is disturbed, as in nuria is a rare inborn (autosomal recessive) chronic renal diseases. error of the metabolism of aromatic amino acids phenylalanine and tyrosine where, due Amyloid A family of fibrillar proteins de- to a defective activity of the called positing in different tissues in primary and homogentisic acid oxidase, there is no cleav- secondary . Their molecules have age of homogentisic acid (alkapton) causing a typical folded leaf structure (anti-parallel accumulation in the body and excretion in β-structure). Chemically they are composed urine. Its polymer – ochronotic pigment – of the two different types AL (amyloid light) impregnates the bradytrophic tissues. and AA (amyloid associated). The amyloid Symptoms and signs: AL fibres consist of light-chain immunoglob- • presence of homogentisic acid in the urine ulins or their fragments, whereas amyloid AA (turns dark when left standing), consists of non-immunoglobulin fibropro- • visible, black-grey pigmentation on eyes teins. The precursor of amyloid A is a serum and , amyloid P (SAP) which belongs to an impor- • degenerative changes of locomotor organs, tant group of acute phase proteins and is an especially the spine. integral part of high-density lipoproteins (HDL). Besides these two forms AL and AA, Allodynia Pain elicited by a stimulus nor- amyloid deposits comprise to a lesser extent mally insufficient to cause pain. the amyloid P (AP) component, whose pre- cursor is serum amyloid P. Allopurinol Acts as an inhibitor of xanthine Deposition of amyloid can result from an oxidase. The recommended starting dose is inflammatory, hereditary or neoplastic ori- 100 mg daily, with many patients requiring a gin. Primary (genetically predisposed) amy- dose of 300 to 400 mg daily, while with others loidosis is rare. Secondary and reactive amy- a dose of 100 mg a day is enough. 100 mg and loidosis is occasionally the consequence of a 300 mg tablets are available. number of chronic and recurrent diseases, anabolic steroids 8

A e.g. , tuberculosis, bronchiestasis, sys- the metabolism of lipids, etc.). Theoretically temic erythematosus, juvenile idio- it can be used in elderly women with low pathic arthritis and rheumatoid arthritis. It is bone turnover. In male osteoporosis second- characterised by extracellular deposition of ary to hypogonadism, testosterone deriva- insoluble protein fibres in a number of tis- tives are the treatment of choice. sues, including spleen, liver, kidneys and lymphatic nodes, leading eventually to death. Anaesthesia dolorosa Severe spontane- In the liver, the vessels of the portal system ous pain occurring in an anaesthetised re- are most affected; sometimes, in the advanced gion. stage, the space of Disse is filled with amy- loid. In the myocardium, the amyloid is de- Analgesia Painful stimulus does not elicit posited in the vessels and basal membranes of pain. It can be linked to a change of percep- cardiomyocytes, whilst in kidneys it is depos- tion of other modalities. ited in the mesangial loop and in the advanced stage in the perimeter of the glomeruli. Pri- ANCA Autoantibodies against the cytoplasm mary systemic amyloidosis is caused by the of neutrophils (Antineutrophil cytoplasmic overproduction and insufficient elimination antibodies). ANCA participate in the patho- of light-chain immunoglobulins (mainly genesis of systemic vasculitides and glomeru- lambda) and occurs in multiple myeloma (ap- lonephritis. These antibodies are directed proximately 20% of myelomas). Secondary against several enzymes or other proteins lo- amyloidosis is caused by deficient elimination cated, predominantly, in the azurophilic of acute phase protein cleavage products and granules of neutrophils. Using the indirect accompanies chronic autoimmune and sys- immunfluorescence method, it is possible to temic inflammatory processes. The deposits differentiate three types of ANCA during a consist of 85–90% of amyloid A and 10–15% reaction with the neutrophils: of amyloid P. It is therefore referred to as amy- 1. Diffuse fine granular cytoplasmic fluores- loidosis AA. The AP component can be found cence (cANCA) can be found in most also in other forms of amyloid plaques, includ- cases of Wegener’s granulomatosis, micro- ing those present in the brain in Alzheimer’s scopic polyarteritis and glomerulonephri- disease. Amyloidosis AL with fibrillar deposits tis. Proteinase-3 is the specific antigen. formed by light-chain immunoglobulins occurs 2. Perinuclear fluorescence is caused by frequently in multiple myeloma or Walden- pANCA which is shown in cases of micro- ström’s macroglobulinemia. Usually it affects scopic polyarteritis, crescent and segmen- the heart, gastrointestinal and respiratory sys- tal necrotizing and in tems, peripheral nerves and the tongue. Amy- Churg-Strauss syndrome. These are anti- loidosis can also occur due to age. bodies against myeloperoxidase (MPO), Symptoms and signs: but also against elastase, cathepsin G, lac- • latent course, toferrin and others. • prominent weakness, dyspnoea, oedema, 3. Atypical ANCA display nuclear fluores- , orthostatic collapse, macro- cence and certain atypical cytoplasmic glossia, patterns. The above-mentioned enzymes, • subsequently there are signs of nephrotic and also other as yet unidentified proteins, syndrome, cardiomyopathy, speech disor- are their antigens. ders and . Ankylosing → see Diffuse Anabolic steroids Anabolic steroids hav- Idiopathic Skeletal Hyperostosis (DISH; an- ing a generalised anabolic effect, but are no kylosing hyperostosis; Forestier’s disease) longer recommended in treating osteoporo- sis because of their adverse effects (virilisa- (AS; Bech- tion, hepatopathy, unfavourable influence on terev’s disease) A chronic systemic in- 9 antibodies against cyclic citrullinated peptides flammatory disorder belonging to the group play two major roles in the humoral immune A of seronegative spondylarthritides affecting system. The first is antibody specificity, the predominantly the axial skeleton, sacroiliac, essence of which represents the recognition apophyseal and costovertebral joints of the and binding to complementary antigen de- spine. Much of the pathology occurs at the terminants (recognising function). The sec- entheses. Secondary metaplasia of the in- ond role includes specific biological func- flamed tissue of anterior and lateral borders tions, which are referred to as effector func- of the vertebrae causes a gradual ossification tions. These represent the ability to bind to of the peripheral part of fibrous annulus of specific Fc-receptors of various cells, to acti- the intervertebral disc and adjacent liga- vate complement, to transfer through the pla- ments. Occasionally, peripheral joints are centa etc. All of these activities are induced also affected. The shoulder and hip joints are by interaction with specific antigen but dif- affected in up to 50%, with other joints af- ferent parts of immunoglobulin than the fected in about 20%. Extraspinal organ in- binding side are responsible for these func- volvement such as iritis and aortal valve dis- tions. Antibodies are present in serum and ease is less frequent than in rheumatoid ar- other body fluids, or inside the producing thritis, but inflammatory bowel disease can cells. They can be divided depending on their occur in 5–10% of patients. Pulmonary fibro- structure (different classes of immunoglobu- sis, amyloidosis and neurological signs of lins), how they are produced (conventional compression can be observed in late disease. and monoclonal antibodies) or depending on Symptoms and signs: their properties (anti-idiotypic, cytophilic, • pain with stiffness in the back of inflam- cytotoxic etc.). matory nature, • movement limitation of the spine in all Antibodies against cyclic citrullinated three planes, peptides (Anti-CCP antibodies; anti-cit- • a trend towards development of spinal de- rullinated peptide antibodies, ACPA) formity, Anti-CCP antibodies (ACPA) have a high • occasionally, peripheral arthritis, mostly of specificity and sensitivity for rheumatoid ar- hip and shoulder joints, and joints of the thritis (RA). They belong to the IgG class and lower extremities, have more than 56% sensitivity and more • extraspinal organ manifestations (ocular, than 90% specificity for RA, depending on skin, mucosal, cardiovascular, pulmonary, the assay used. They are directed against neurological, IgA-nephropathy and amy- peptides and proteins, which possess the un- loidosis), usual, non-standard amino acid citrulline. • radiological presence of sacroileitis, syn- Citrullinated proteins develop during enzy- desmophytes and peripheral enthesiopa- matic post-translation enzymatic deimina- thy, tion of arginine residues catalysed by pepti- • high association with HLA-B27 antigen. dylarginine deiminases in the presence of Ca2+. Such post-translational modification of nervosa A disorder character- proteins leads to loss of the positive charge of ised by low body weight (BMI usually under arginine residues with subsequent modifica- 17.5) with an intense wish to remain thin, tion of antigenicity of the proteins. Antiperi- amenorrhoea and relative hypercorticism. It nuclear factor, antikeratin antibodies (both most commonly affects adolescents. All these directed against citrullinated filaggrin), anti- factors cause a significantly decreased bone Sa antibodies (against citrullinated vimentin) density in women with anorexia nervosa. and cyclic citrullinated peptide antibodies (anti-CCP) are among the best-known citrul- Antibodies Immunoglobulins produced by linated reactive antibodies associated with plasma cells that originate from B lympho- RA. Recently, it has been shown that the basic cytes after specific antigen stimulation. They component of the antigenic epitope of filag- antibodies against ku antigen 10

A grin and vimentin is citrulline. The forma- against proteins complexed with small nuclear tion of citrullinated antigens is a dynamic RNA. Anti-Sm antibodies (antibodies against process that takes place in inflamed synovia Sm antigen or Smith antigen named in honour in the presence of peptidylarginine deimi- of the first patient with SLE where anti-Sm nases (PADs). Five subtypes (PAD 1, 2, 3, 4 antibodies were found) are very specific to and 6) are known. Expression of PAD4 iso- SLE. However, their sensitivity is low (10 to type with increased enzymatic activity is 30% of patients with SLE). Anti-Sm antibod- typical for RA. Anti-CP antibodies (ACPA) ies are almost always accompanied by the are produced in the area of inflammation and presence of anti-U1RNP antibodies, a con- pannus, probably by plasma cells and B cells. trary relationship does not apply. Apart from high specificity, antibodies The clinical correlation of anti-Sm is not against citrullinated peptides are typically significant, some studies report a more fre- present in the very early stage of RA. Their quent presence in central nervous system dis- presence is associated with the more active ease, nephritis, lung disease, pericarditis and and severe forms of the disease. A combina- their correlation with disease activity. In tion of these antibodies with rheumatoid fac- 1972, Sharp described antibodies against an tor increases the specificity and positive pre- extractable nuclear antigen (subsequently de- dictive value of these markers, and enables fined as U1RNP) and its association with early intervention. Currently, ELISA meth- mixed connective tissue disease (MCTD, ods are used to assess antibodies against cit- Sharp’s syndrome; first described 1972 by Gor- rullinated peptides and cyclic citrullinated don C. Sharp, American physician) (Sharp et peptide antibodies (anti-CCP). Measurement al. 1972). Antibody against U1RNP is also of ACPA is now the most frequent assay in found in SLE but usually with low titres. In- clinical practice. terestingly, many of the features of MCTD, particularly fibrosing alveolitis, myositis, ar- Antibodies against Ku antigen Ku anti- thritis and Raynaud’s phenomenon, were gen is a heterodimer of two peptides consist- found in these patients. ing of units with MW= 70 kDa and MW = 80 kDa, which are present in the nucleus and Anticardiolipin antibodies → see An- nucleolus. Ku protein is a component of tiphospholipid syndrome (APS) DNA-dependent protein kinase. Ku antigen binds the enzyme to DNA and helps in DNA Anticentromere antibodies → see Sys- repair. Anti-Ku antibodies were first found in temic sclerosis (SSc) patients with scleroderma-polymyositis over- lap syndrome in Japan. Apart from Japan, Anti-citrullinated peptide antibodies these antibodies are frequently found in pa- (ACPA) → see Antibodies against cyclic cit- tients with systemic lupus erythematosus or rullinated peptides mixed connective tissue disease. In addition, such antibodies have been found in some pa- Anti-dsDNA antibodies Anti-DNA anti- tients (23%) with primary pulmonary hyper- bodies form a heterogenous group directed tension. Anti-Ku antibodies induce macular against different antigen determinants of fluorescence of the nucleus with nucleolar DNA. Several groups are differentiated: fluorescence when cells are in the G1 phase of • Antibodies reacting only with the double the cell cycle. stranded DNA (dsDNA). These antibodies form the majority. 65% patient sera with Antibodies against U1RNP and Sm systemic lupus erythematosus (SLE) react antigen Antibodies present in systemic lu- with dsDNA. pus erythematosus (SLE) directed against • Antibodies cross-reacting with dsDNA small nuclear ribonucleoprotein particles and ssDNA (single stranded DNA). These (smRNP). They are usually autoantibodies antibodies are the most frequent in SLE. 11 antigen presentation

• Antibodies reacting solely with ssDNA. This is a complicated process in the course of A • Antibodies reacting with Z conformational which its molecule is fragmented within en- DNA (Z-DNA). dosomes of APC to immunogenic fragments Clinical importance of anti-dsDNA antibod- (peptides containing usually 12 to 20 amino ies: acids), which bind to a certain location (bind- • high levels of anti-dsDNA antibodies are ing channel) in the molecule of MHC (HLA associated especially with SLE, class II in humans) products (antigens). This • circulating anti-dsDNA can be found in complex is transferred to the surface of APC IgM, IgG and sometimes IgA classes, and recognised by T helper lymphocytes. The

• IgG antibodies are more significant than TH lymphocyte through its antigen receptor IgM; their presence correlates with the ac- (TCR) recognises only complexes in which tivity of the disease and severity of glom- immunogenic peptide is firmly bound in the erulonephritis, binding channel of HLA class II molecules.

• this correlation to glomerulonephritis can The TH lymphocyte does not recognise free be found mainly with complement fixating or weakly bound peptide fragments and this and activating antibodies especially IgG is the basis of the specificity of the subsequent anti-DNA, immune response. The binding of immuno- • IgG antibodies occur in four subgroups genic peptide to TCR is the first signal to ‘at-

with prevalence of IgG1 and IgG3, tract the attention’ of the specific TH cell • single-shot assessment of anti-dsDNA is clone. For their activation and initiation of

highly diagnostic, though for determining the immune response, TH lymphocytes must prognosis longitudinal follow-up is re- also obtain the second (confirming, co-stim- commended. In most cases a rise in anti- ulating) signal, which mediates interaction of dsDNA levels indicates an exacerbation of co-stimulation molecules (e.g. CD28 on the the SLE. surface of T lymphocyte and CD80 on the Mechanism of renal impairment by anti- surface of APC). dsDNA antibodies in SLE: Antigens originating from cells infected by • anti-dsDNA bind to histone complexes viruses or antigens associated with malignan- and DNA having affinity to sul- cies are subject to an endogenous pathway of phate of glomerular basement membrane, presentation. Moreover, in this case, the anti- • anti-dsDNA with the ability to cross-react gen is first degraded in the cytoplasm of the with several other antigens like A- and D- affected (target) cell in an organelle referred to peptides of small nuclear RNP or ribosom- as proteasome. Thereby immunogenic pep- al P-protein, can have a direct impairing tides, containing mainly 8 to 9 amino acid influence on renal cells by penetration into units, are formed and these peptides bind to cytoplasm and nucleus or by binding to the synthesised HLA class I molecules. This com- cell surface with subsequent binding of the plex is transferred to the surface of the cell complement and cytolysis. where it is recognised by cytotoxic T lympho- cytes, which initiate lysis of the ‘target’ cell.

Antigen presentation Modification of The capability of TH lymphocytes to recogn- antigen into a form that can be recognised by ise immunogenic peptide incorporated only

T lymphocytes and thus activate the immune into HLA class II molecules and TC lympho- response. Currently, most of the available in- cytes only into HLA class I molecules is re- formation relates to the presentation of pro- ferred to as immunologic restriction. A sig- tein antigens. The presentation of exogenous nificant majority of antigens undergo such a and endogenous protein antigens differs presentation. The exceptions are certain poly- slightly. In the exogenous pathway of antigen saccharide antigens, which can be recognised presentation, the antigen must first be phago- directly by B lymphocytes without TH lym- cytosed by antigen presenting cells (APC) phocytes, and superantigens that non-specif- where its further transformation takes place. ically activate a large number of TH lympho- antigen targets of antinuclear antibodies (ANA) 12

A cyte clones. Other exceptions are glycolipid of antibodies to particular classes and sub- and lipid antigens that are presented by CD1 classes of immunoglobulins, and are utilised molecules instead of HLA molecules. in the diagnostic assessment of their concen- trations in various immunochemical meth- Antigen targets of antinuclear anti- ods. bodies (ANA) in the cell (antibodies against intranuclear antigens) Anti-Jo-1 antibodies → see Antisynthetase • chromatin – essential components of the syndrome chromatin are DNA, histones and non- histone nuclear proteins, Anti-La antibodies → see Anti-SSA/Ro • nuclear membrane and pores, and anti-SSB/La antibodies • nucleolus, • RNA complex with the proteins (ribonu- Antimalarial drugs Misleading nomencla- cleoproteins; RNP), ture for drugs used in rheumatology as not all • matrix-fibrillar skeleton of the nucleus, preparations applied for the treatment of ma- • different components of cytoplasm, e.g. laria are used in rheumatology as well. It ap- enzymes, ribosomes or RNP. plies only to quinoline derivates, namely, only the two 4-aminoquinoline derivates chloro- Antihistone antibodies and antinu- quine and hydroxychloroquine that differ cleosome antibodies Histones are alka- from each other only by substitution of the line nuclear proteins containing a great hydroxyethyl group for the ethyl one on the amount of positively charged aminoacids tertiary nitrogen atom on the lateral chloro- (lysine, arginine). They are present in eucary- quine chain. otic cells associated with DNA. There are five Mechanism of action in autoimmune dis- main types of histones – H1, H2A, H2B, H3 eases and H4. Histones rich in H3 and H4 form a The exact mechanism of action of antima- tetramere, binding lysine-rich dimers of larial drugs is unknown. Possible mecha- H2A-H2B on both sides. These histones form nisms are shown in table 1. Probably inten- a central core encircled by two threads of a sive accumulation of chloroquine in the in- 146- long segment of DNA. This tracellular lysosomal system of lymphocytes, structure is called a nucleosome and individ- fibroblasts and polymorphonuclear cells is ual nucleosomes are interconnected by a seg- needed. This, in consequence, affects differ- ment of DNA with a bound H1 histone.

Anti-idiotypic antibodies Antibodies Table 1. Mechanism of action of antimalarial directed against idiotypic determinants of drugs in autoimmune diseases immunoglobulins (immunoglobulins, idio- Accumulation in lysosomes types). Antigenic determinants created by the • affects antigen processing, combining site of an antibody (= immun- • decreases antibody formation, globulin) are called idiotypes and antibodies • decreases activity of NK cells, directed against these idiotypes are anti-idio- • decreased release of IL-1, IL-2 and TNF-α, typic antibodies. • prevention of receptor-dependent lysosomal endocytosis Anti-immunoglobulin antibodies An- – decreases receptor formation at lower density, tibodies directed against antigenic determi- – decreases influenza and adenoviral nants, which are present on the surface of im- receptor internalisation, munoglobulin molecules. Basically they can • in Plasmodium malariae infection be divided into anti-isotypic, anti-allotypic or – decreases activity of lysosomal acidic anti-idiotypic antibodies. Antibodies against proteases and so the degradation of isotypic determinants define the competence haemoglobin-invaded erythrocytes. 13 antimalarial drugs ent functions of cellular functions, such as possible decrease in steroid dose in these pa- A protein glycosylation, membrane lipid diges- tients. Antimalarial drugs increase the num- tion and cell receptor development, which ber of LDL-receptors and decrease the cho- can be influenced by alkalisation of normally lesterol synthesis in the liver. The hypogly- acidic lysosomal pH, or by influencing the caemic effect of antimalarial drugs has not elimination and function of acidic proteases. been completely explained so far; it is likely Antimalarial drugs further inhibit multiple to be due to an increase in insulin binding to functions of phagocytes, including the release its receptor. of reactive oxygen species. Antimalarial drugs A combination of -sparing can also influence the antigen processing effect, hypoglycemic effect, lipid-lowering ef- ability of the monocyte-macrophage system, fect and anti-platelet aggregation effect, leads thus inhibiting the function of lymphocytes. to an overall decrease in cardiovascular events The release of interleukin-1 is also inhibited. with antimalarial drugs. Further action of antimalarial drugs – : Chloroquine and hy- decrease in lipidemia, anti-platelet aggre- droxychloroquine are rapidly absorbed after gation effects, hypoglycemic effects oral administration. The bioavailability var- The decrease in platelet aggregation with ies between 75% and 90%. The average time antimalarial drugs has been known for some needed for absorption of 50% of the prepara- time. Unlike the similar effect of salicylates, tion is 4.3 hours. no prolongation of bleeding time has been The biological half-life of antimalarial observed in antimalarial drugs. This led drugs is very long, up to 40 days, which means Charnley, (Johnson et al. 1977, 1979) other- a steady state is reached in 3 to 4 months. An- wise a pioneer in total hip joint replacements, timalarials accumulate predominantly in the to use antimalarial drugs as a prophylactic acidic environment of lysosomes. This ex- treatment against deep venous thromboses plains their high accumulation in the liver after implantation of hip joint prostheses. A that is rich in lysosomes, and low accumula- study was carried out involving 10,000 pa- tion in muscle, which have a low amount of tients who were administered 600 – 800 mg lysosomes. A significant accumulation can of hydroxychloroquine per day 1 to 2 weeks also occur in ocular tissues, especially those after surgery; a significant drop in the rate of containing melanin. The majority of the ab- thrombotic complications was observed. Ret- sorbed drug is excreted in urine in an unal- rospective and prospective studies showed a tered state; only 1/3 of the drug is metabo- lower incidence of venous, as well as arterial, lised through removing of ethyl group on the thrombotic complications in patients with terminal amino ethyl group of the lateral systemic lupus erythematosus (SLE) treated chain. The therapeutically effective serum with antimalarial drugs (Petri et al. 1994). concentration of chloroquine is thought to be Even in the group of patients at high risk with in the range 700 to 1200 ng/mL, but this has the presence of antiphospholipid antibodies, not been entirely confirmed. there was a decrease in the rate of thrombem- Dosage: The recommended daily dose of bolic events. In a study spread over 9 years, in chloroquine is 250 mg/day. The therapeutic a group of 54 patients treated with hydroxy- effect of antimalarial drugs takes up to 3 chloroquine, there were only 2 (4%) throm- months of continuous daily administration. bembolic events, whereas in the group with- In the course of treatment it is essential to out hydroxychloroquine this figure was 20% have regular eye checks, including ophthal- (Petri et al. 1992). mic examination, visual acuity and colour vi- In studies, it was also shown that antima- sion (every 12 months). In patients over 60 larial drugs decreased the total , years of age, it is advisable to have an ophthal- LDL-cholesterol and triglycerides by 10 to mic assessment prior to initiating treatment 15% in patients treated over the long term because of the stronger probability of devel- (Wallace 1990). This is indirectly related to a oping degenerative changes, especially with anti-mi-2anti-Mi-2 14

A coincident disorders (arterial Anti-Mi-2 → see Idiopathic inflammatory and diabetes mellitus). In recent years, hy- myopathies (IIM) droxychloroquine has been favoured more than chloroquine as it has a safer profile with Antineutrophil cytoplasmic antibod- far less ocular toxicity. It is commenced at 200 ies → see ANCA mg twice a day, then reduced to 200 mg daily after 3 months if effective. It is now often Anti-nuclear antibodies (ANA) Antinu- combined with methotrexate in moderate to clear antibodies (ANAs) were initially discov- severe rheumatoid arthritis. ered in the 1940s using the lupus erythemato- Clinical efficacy: The results of long-term sus (LE) cell test, but have now been replaced controlled clinical trials performed over the by serum testing for ANA. They are a useful last 40 years have shown that chloroquine and initial cost-effective screening test for pa- and hydroxychloroquine are effective in mild tients suspected of having a systemic autoim- rheumatoid arthritis (RA). When adminis- mune disease. However, false positive ANAs tered they have demonstrably better efficacy (can be found in women and in elderly pa- compared to placebo and can decrease the tients, but usually in low titer so results have to clinical activity of the inflammatory process be interpreted with the clinical picture. ANA is measured. Antimalarial drugs decrease the positive in most patients with SLE (>95%), activity of acute phase reactants, but have most patients with MCTD (90%), and com- failed to slow the rate of erosive progress on monly (>50%) found in patients with pauciar- X-rays in clinical trials. Its efficacy is compa- ticular juvenile idiopathic arthritis, Sjögren’s rable to D-penicillamine, but lower than sul- syndrome and polymyositis/. phasalazine and intra-muscular administra- It is also present in the serum of some patients tion of gold compounds. Antimalarial drugs with rheumatoid arthritis (40%), other auto- are indicated in rheumatoid arthritis with immune diseases (autoimmune hepatitis, au- mild clinical activity, especially in cases with- toimmune thyroid disease), and idiopathic out unfavourable prognostic signs. . Nowadays, more Furthermore, antimalarial drugs are used specific antibody testing can confirm a partic- in juvenile idiopathic arthritis, SLE and pso- ular connective tissue disease (e.g. anti-dsDNA riatic arthritis. for SLE, anti-histone antibodies for drug-in- Adverse effects related to treatment with duced lupus, anti-Scl-70 for scleroderma, etc.) chloroquine and hydroxychloroquine: • gastrointestinal: anorexia, nausea, vomit- Anti-PCNA/cyclin antibodies (prolifer- ing, epigastric pain, spasms, diarrhoea and ating cell nuclear antigen) DNA-poly- weight loss merase delta associated protein with a mo- • skin: rashes, pruritus, pigmentations of the lecular weight of 36 kDa. The antibodies are skin and nails, photosensitivity, exacerba- highly specific for systemic lupus - tion of , tosus, but they are rare (approximately in • neurological: headache, drowsiness, insom- 6%). One suggestion is that anti-PCNA posi- nia, irritability, tinnitus, proximal myopa- tive patients more frequently have diffuse thy, myasthenic syndrome, polyneuropa- proliferative glomerulonephritis and lymph- thy, lowered threshold for , adenopathy. Positive immunofluorescence of • haematological: toxic granulation of leuko- the nuclei occurs only in rapidly dividing cytes, leukopenia, agranulocytosis, aplastic cells because the amount of PCNA rises pro- anaemia, portionally to synthesis and cell growth. • ocular: accommodation disturbances, diplopia, corneal deposits, , Antiphospholipid syndrome (APS) A • other: arrhythmia, cardiomyopathy, por- syndrome with the following: phyria. symptoms and signs: Venous or arterial , or both, often multiple, repeated 15 antiphospholipid syndrome (APS) miscarriages and failures and mod- lungs: pulmonary , thrombo- A erate thrombocytopenia; all with the presence embolic pulmonary hypertension, of lupus (LA), elevated aCL (an- skin: , skin nodules, ticardiolipin antibodies), or both. chronic venous ulcers, superficial pur- Diagnostic criteria of primary/secondary pura resembling a , APS: eyes: of the retina • clinical signs: venous thrombosis, arterial • : thrombosis, repeated miscarriages (preg- limbs: ischaemia, gangrene, nancy failures), brain: • laboratory findings: thrombocytopenia, IgG- – major vessels: acute , transient aCL (moderate/high levels), IgM-aCL (mod- ischaemic attack, erate/high levels), and positive test for LA. – minor vessels: acute ischaemic en- Diagnostic criteria for APS: one clinical sign cephalopathy, multi-infarct demen- including thrombocytopenia and the pres- tia, ence of aCL (>20 GPL units) or presence of heart: LA; evidence of antiphospholipid antibodies – major vessels: , (aPL) on two occasions at least six weeks – minor vessels: acute – circulatory apart; up to 5-year follow-up of the patient to collapse, cardiac arrest, eliminate systemic lupus erythematosus chronic – cardiomyopathy, arrhyth- (SLE) or other . mia, bradycardia, In principle we distinguish primary APS, kidneys: i.e. it is impossible to show evidence of other – major vessels: renal artery thrombo- concomitant autoimmune disorder, especial- sis, ly SLE, over at least 5 years; and secondary – minor: thrombotic renal microan- APS when the patient, besides APS, also suf- giopathy, fers from SLE or drug induced lupus, or an- liver: infarction of the liver, other autoimmune disorder. aorta: Some authors broaden out the possible dis- – upper part: aortic arch syndrome, orders, likely related to the presence of aPL, – abdominal part: , into two basic groups: skin: gangrene of the fingers, 1. Disorders elicited by aPL without a direct eyes: thrombosis of arteries and arteri- connection to thrombosis oles of the retina, • neurological: Guillain-Barre syndrome, endocardium, valves: transversal , chorea, migraine, – acute: vegetations, “pseudoinfectious • obstetric: preeclamptic toxemia and ec- endocarditis”, lampsia, postpartum serositis, – chronic: valvular dysfunction (regur- • other: non-thrombogenic (idiopathic) gitation, stenosis), pulmonary hypertension, avascular Sneddon’s syndrome – coincidence of necrosis of the bone. stroke, hypertension and livedo reticu- 2. Disorders elicited by aPL with a direct laris. connection to thrombotic vascular signs A proposal of new classification criteria of APS :• veins:• (Sapporo, 1998): limbs: thrombophlebitis, Antiphospholipid antibodies – the pres- liver: ence of aPL (aCL or LA) demonstrated at – major vessels: Budd-Chiari syn- least twice at least 6 weeks apart with one or drome, more clinical signs. – hepatomegaly, increased concentra- Clinical symptoms and signs: tion of enzymes, • arterial or venous thrombosis (or both) adrenal glands: Addison’s disease, adre- demonstrated radiographically, by ultra- nal insufficiency, sound or histologically, anti-roanti-Ro antibodies antibodies 16

A • three or more consecutive miscarriages (up have antibodies to both Ro peptides, which is to 10th week) unexplained by other reasons, why this difference doesn’t have much clini- or one or more deaths of morphologically cal significance. normal foetus after the 10th week of preg- The presence of anti-SSA/Ro and anti-SSB/ nancy, or one or more still births after the La antibodies is clinically significant because 34th week of pregnancy accompanied by se- of their association with several SLE subtypes: rious pre-eclampsia or placental insuffi- subacute cutaneous lupus, neonatal lupus ciency, and SLE in C2 and C4 deficiencies. Likewise, • two or more episodes of reversible cerebral there exists an association between patients ischaemia, with pneumonitis and renal disturbance with • occurrence of multiple sclerosis like syn- the presence of anti-SSA/Ro antibodies in the drome or otherwise unexplainable focal serum. neurological deficit. There are certain differences among pa- Additional features, no criteria: tients with only anti-SSA/Ro or in combina- • thrombocytopenia below 100,000/mm3, tion with anti-SSB/La. • haemolytic anaemia with reticulocytosis Characteristics of patients with anti-SSA/ and positive Coombs test, Ro and anti-SSB/La antibodies • otherwise unexplainable transversal myel- • Anti-SSA/Ro Anti-SSA/Ro + opathy, Anti-SSB/La • livedo reticularis, • more frequent more frequent • otherwise unexplainable thickening of mi- HLA-DR2 HLA-DR3 tral or aortal valve and regurgitation dem- • young patients SLE in elderly onstrated on echocardiography, • frequent homozy- no relation with • unexplained chorea observed by a physi- gotes for C2 and complement cian, C4 deficiencies deficiency • migraine lasting one year with concomi- Association between the presence of anti- tant presence of aPL in the serum. SSA/Ro or anti-SSB/La and congenital heart block Anti-Ro antibodies → see Anti-SSA/Ro The risk of congenital heart block is prob- and anti-SSB/La antibodies ably highest when the mother’s serum con- tains a combination of anti-SSA/Ro and anti- Anti-SRP antibodies → see Idiopathic in- SSB/La, and in the case of antibodies against flammatory myopathies (IIM) Ro52 antigen.

Anti-SSA/Ro and anti-SSB/La antibo- Anti-SSB/La antibodies → see Anti-SSA/ dies Anti-La antibodies occur practically Ro and anti-SSB/La antibodies together with anti-SSA/Ro antibodies, but not vice versa as in the case of the relation be- Antisynthetase syndrome Myositis and tween anti-Sm and anti-U1RNP antibodies. interstitial with fever, ar- Anti-SSA/Ro can be found in primary Sjö- thritis, Raynaud’s phenomenon and thick- gren’s syndrome and systemic lupus ery- ened, fissured radial margins of index fingers thematosus (SLE). There are two Ro antigen on both hands (the so called car mechanics’ peptides (Ro60 and Ro52) differing from one hands). Typically, serum antibodies against another according to molecular weight. The cytoplasmic enzymes are present (aminoacyl- bond with Ro60 and Ro52 is in some cases tRNA synthetases), e.g. anti-Jo-1. distinct in SLE and systemic sclerosis (SSc). Approximately 40% of patients with SSc who Apoptosis Programmed cell death in multi- are anti-Ro positive have antibody only to cellular organisms. It can be regarded as the Ro52, and 20% of sera from SLE patients to opposite of mitosis. Multicellular organisms only Ro60. Other patients in both groups keep their integrity not only based on the 17 arthritis in chronic ability to form new cells as a replacement for Arthritis associated with erythema A those worn-down and withered, but also by nodosum in the course of infection regulated apoptosis. This is an active process (EN) is characterised by going on by continuously eliminating un- painful nodular subcutaneous infiltrates due wanted and unnecessary cells. It is applied, to an inflammation of the subcutaneous adi- for example, in disposing of those T-lympho- pose tissue. Its onset may be associated with cytes that are able to react with self antigens the use of certain drugs (penicillin, sulphon- and so cause an autoimmune response. It is, amides, contraceptives, etc.), sarcoidosis, ul- however, a common biological event and not cerative colitis, Crohn’s disease, systemic lu- unique to the immune system. Apoptosis is pus erythematosus, neoplasms, but most fre- regulated by growth factors, several quently it is associated with infection. Patho- and oncogenes. Cells undergoing apoptosis genically it is most probably a hypersensitive are mainly proliferating ones that failed to get reaction to a trigger factor. the necessary signalling ensured by growth Clinical picture: The red nodules are 1–10 factors during their development, or on the cm in size; they take the form of subcutane- contrary, got an apoptotic signalling. The sig- ous prominent infiltrates and are usually nalling is often produced by TNF, lymphoto- painful. They are localised most frequently xin or Fas-. In the cell, the apoptotic on the lower extremities. They are generally signalling causes water loss and an increase in of time-limited duration and often spontane- intracellular ionized calcium concentration. ously resolve in 6 to 8 weeks. In approximate- This leads to chromatin condensation and ly half of cases, joints (, arthritis) activation of the endonucleases that split the are affected. Acute in EN can be DNA to 50 – 300 kb fragments, leading to cell easily distinguished from chronic arthropa- death and its disintegration into smaller frag- thy in sarcoidosis with EN. In some cases the ments ingested by surrounding phagocytes occurrence of EN can be regarded as the without the development of an inflammatory symptom of a clinically well-defined disease reaction. Proteolytic enzymes mainly the so (e.g. post-Yersinia ). called caspases participate in this process. The second mechanism of terminating cells Arthritis impact measurement scale in a multicellular organism is necrosis. It is, (AIMS) → see Instruments of assessing (health however, morphologically and by its mecha- status measurements, outcome measurement) nism, distinct form apoptosis. Arthritis in brucellosis Infectious arthri- APS → see Antiphospholipid syndrome tis caused by Brucella (B) melitensis, B. abor- (APS) tus, B. suis and B. canis. Symptoms and signs: Brucellosis can be ARA Diagnostic criteria of SLE → see accompanied by arthralgia at any stage of the Systemic lupus erythematosus (SLE) disease. Besides other symptoms and signs, arthritis of peripheral joints can occur and A polyunsaturated fatty the sacroiliac joints and the spine can be af- acid found in the phospholipids of cell mem- fected. Rarely develops. branes from which it is released by the activ- ity of phospholipases A2 or C. The free arachi- Arthritis in chronic sarcoidosis In pro- donic acid has a short half-life and rapidly longed disease, a similar to metabolised by either or li- rheumatoid arthritis (RA) develops in 30– poxygenase. In the cyclooxygenase pathway, 40% of afflicted people. The course of the dis- , and thrombox- ease is relapsing and remitting, and the most ane occur, while the lipoxygenase pathway affected joints are the knees, ankles, wrists produces leukotrienes or lipoxins. and (symmetrically) small joints of the hand (MCP, PIP). Dactylitis can occur. multiplex congenita 18

A Laboratory diagnostics: Attention should Arthropathy in ochronosis This is prin- be drawn to a high erythrocyte sedimenta- cipally a degenerative process of known aeti- tion rate, eosinophilia, positive latex-fixation ology with a profound tendency to disability. test (that’s why this disease could be confused The core of clinical signs and symptoms in with RA), hypergammaglobulinaemia and ochronotic arthropathy affect the spine. negative tuberculin test (Kveim test is no lon- Symptoms begin at the end of the 3rd decade ger performed due to risk of transmitting vi- of life. The male to female ratio is 2:1. ruses such as Creuztfeld disease). A histologi- Objective signs include flattening of the cal picture is also characteristic (noncaseat- thoracic kyphosis and lumbar , a mild ing granulomas). rigidity with a tendency to worsening. Grad- ually in the advanced stages, an unevenness Arthrogryposis multiplex congenita of the contours of the spine appears with ir- This disease belongs to the congenital mus- regular prominence of spinous processes and cular syndromes. It is characterised by muscle complete ankylosis of the whole lumbar and weakness and fibrosis leading to joint con- thoracic spine. The cervical part of the spine tractures. preserves its mobility for quite a long time de- Clinical symptoms: Significant symmetri- spite considerable radiographic changes. In the cally deformed limbs in fixed flexion posi- advanced stages, extension and rotation move- tions with reduced movement are typical. ments are limited, with the head in a flexed po- The knees and hips are flexed in most cases, sition. Due to the degenerative changes in the and furthermore the hip joints are abducted. intervertebral discs, the intervertebral spaces Affected limbs are usually shortened. Crepi- narrow down causing a marked decrease in tus is audible during movement of the affect- body height over 20 years. ed limbs. Shortening of muscles and tendons Radiographic examination of the spine of unknown neurogenic or myogenic aetiol- shows characteristic calcification of the inter- ogy is the cause of limb deformity. The mus- vertebral discs. Osteolytic and hyperplastic cle of the affected extremities is very hy- changes and secondary new bone formation poplastic. Other abnormalities such as syn- occurs on the vertebral bodies. Osteophytes, dactyly, cleft palate and pigment defects are and sporadically massive bone bridging of frequently associated with the disease. the ankylosing hyperostosis type are formed.

Arthropathy in the course of inflam- Arthropathy in thyroid disease Auto- matory bowel diseases Arthropathy can immune thyroid diseases include Hashimo- be a systemic complication of regional enteri- to’s thyroiditis and Graves’ disease. These dis- tis (Crohn’s disease) or . Most eases can be associated with other rheumatic frequently it is a peripheral arthritis; with sa- disorders, such as rheumatoid arthritis, croileitis occurring less often. The incidence of Sjögren’s syndrome, systemic sclerosis, poly- arthropathy in the course of inflammatory myalgia rheumatica, giant cell and bowel disease is estimated at about 7.5 to 21%. . These disorders are The occurrence of sacroileitis is associated often interconnected and have a close rela- predominantly with the presence of HLA-B27 tion to HLA-B8 and HLA-DR3 haplotypes. antigen; there is no known association of HLA The presence of rheumatoid factor and anti with peripheral joint involvement. dsDNA antibodies is often seen in autoim- Symptoms and signs: Erythema nodosum, mune thyroiditis. Autoimmune diseases of but also pyoderma gangrenosum, can be im- the thyroid gland develop in patients with portant extraarticular manifestations. The systemic lupus erythematosus (SLE), which is course of the peripheral arthritis mirrors the often accompanied by the occurrence of anti- severity of underlying bowel disease; but has bodies against the thyroid gland. Autoimmune no influence on the progression of changes in thyroiditis has been reported in Sjögren’s syn- the axial skeleton drome. or giant cell 19 atrophy arteritis can be related to the development of lotransplants. This technique is particularly A autoimmune disease of the thyroid gland. used in young individuals after intra-articu- The occurrence of Hashimoto’s thyroiditis lar trauma. The area of damage is covered by with rheumatoid arthritis, SLE or other con- numerous autologous small transplants (mo- nective tissue diseases has also been reported. saic plasty) or by precisely turned and closely On the other hand, Hashimoto’s thyroiditis inserted osteochondral transplants to the alone can be characterised by a clinical pic- area of the damaged cartilage. ture of inflammatory polyarthritis not re- Frozen allogenic transplants are also used, sponding to thyroid hormone replacement, but they are associated with the risk of im- which can be erosive with the development of munological rejection. Periosteal and per- nodules. ichondral tissue is also used to cover defects Hyperthyroidism of the cartilage. The main problem with these The following rheumatic syndromes occur techniques is the fixation of the transplants to in hyperthyroidism: the area of the defect and their frequent calci- • thyroid acropachy, fication. More recently, as part of tissue engi- • proximal myopathy, neering, autologous cells, which are obtained • osteoporosis. by small biopsy, e.g. from nasal cartilage, are Hypothyroidism implanted directly into the subchondral In hypothyroidism, we often see an ar- bone. thropathy resembling rheumatoid arthritis, articular or synovitis of Articular cartilage → see Hyaline cartilage the flexors of the hand. There may be carpal tunnel syndrome and a proximal myopathy Aseptic necrosis of the navicular bone with muscle hypertrophy.. → see Köhler’s disease The following rheumatic syndromes occur in hypothyroidism: Atopic reactions Anaphylactic reactions • , occurring in atopic individuals (atopy). • carpal tunnel syndrome, Atopic individuals have a genetic predisposi- • myopathies. tion to the development of allergic diseases of hypersensitivity, such as bronchial , Arthroscopic joint washout and carti- allergic rhinitis, urticaria, eczema, certain lage Arthroscopic washout of a joint helps to gastrointestinal disorders, etc. Atopy is a ge- remove small fragments of cartilage that irri- netically conditioned feature, whereas ana- tate synovia. The washout can also be com- phylaxis is a reaction that occurs more fre- bined with arthroscopic debridement of the quently in atopic individuals than in common cartilage (‘shaving’). There is evidence that individuals. this combined approach provides pain relief and improves the joint function but does not Atrophy A decrease in cell volume and re- improve cartilage turnover. striction of cell functioning. Atrophy is often A number of microsurgical arthroscopic seen in regions with insufficient vascular techniques have been developed in an at- supply or chronic inflammation. It can be a tempt to improve cartilage turnover, e.g. consequence of decreased skeletal muscle ac- small holes are drilled into the subchondral tivity and can be regarded as an adaptive re- circulation to stimulate the growth of fibro- sponse to stress, whereby the cells decrease cartilaginous tissue into subchondral bone. their volume, restrict different functions Spongialisation, which is resection of the which leads to a decrease in energy consump- whole subchondral bone disc in chondromal- tion. As soon as the conditions in the affected acia patellae, also improves outcomes. region normalize, the atrophied cells restore The other method of improving cartilage their function and increase their volume. turnover is to use cartilaginous auto- or al- Their specific functions, such as protein syn- auranofin 20

A thesis or contractile muscle strength, also Cell ageing normalise. A process, which is independent of disease. Inactivity-induced atrophy The main cause of ageing of cells, especially This most common atrophy is subsequent those not replicating (heart, brain), is atrophy to decreased requirements for a function, e.g. of such cells. The volume of all parenchymal immobilisation of the limb after a fracture or organs in the body decreases with age. The in long-term confinement. Atrophy of muscle volume of important organs decreases in old cells and decrease in muscle strength occurs. age and in the very elderly a decrease in vol- Restoring the activity leads to normalisation ume of the heart can also be seen – senile at- of the volume, function and strength of the rophy. muscle. Insufficient oxygen supply Auranofin → see Gold salts A disturbance of blood supply to the tissues ends with ischaemia. Total ischaemia with in- Auto-antibodies Antibodies, whose for- terruption of oxygen supply to tissues leads to mation is induced by auto-antigens. cell death. A partial ischaemia or incomplete occlusion of the vessel or places with inade- Auto-antibodies assessed in systemic quately formed collateral circulation leads to lupus erythematosus (SLE) – other In chronic restriction of oxygen supply and as a approximately 30% of patients with SLE there consequence the life expectancy of the cells is are antibodies against the hnRNP (hetero- shortened. This process can be seen in regions genic nuclear) A1 protein. Clinically, it cor- of borderline ischaemia, e.g. necrosis (infarc- relates with the occurrence of Raynaud’s phe- tion) of heart, brain and kidneys. nomenon and disturbance of oesophagus motility. The antibodies against the RA-33 Starvation or malnutrition associated with antigen (hnRNP-A2) were originally regard- a chronic disease leads to cell atrophy, mainly ed as specific to rheumatoid arthritis. They in skeletal muscles. It is presumed that the have been observed also in patients with cell atrophy is caused by a partial ischaemia mixed connective tissue disease (MCTD) leading to undernutrition of the tissues. and SLE. In these cases they often appear to- Interruption of trophic signalling gether with anti-snRNP antibodies. The The function of a number of cells depends nuclear membrane contains laminins A, B on a signal transmitted by chemical media- and C, serving partly as a structural compo- tors (e.g. endocrine system or neuromuscular nent of the membrane and partly as a foot transmission). Elimination of the sources of holding of the chromosomes in the cells signalling (hormonal, transmission, etc.) de- during interphase. The antibodies against creases the requirements of cells of certain these structures induce a peripheral or mar- organs like adrenal glands, thyroid gland, ginal fluorescence on the nucleus of Hep-2 skeletal muscles and so on. This can happen cells; it was presumed that anti-dsDNA anti- in the case of endocrine gland removal or bodies were the main cause. Anti-laminin muscle denervation. antibodies were reported in systemic connec- Persistent cell damage tive tissue diseases including SLE, where they This is caused most often by a chronic in- are likely to be associated with the presence flammation associated with prolonged viral of lupoid or chronic active hepatitis. or bacterial infection. It’s not clear whether There were antibodies against heat shock an irritant agent, inflammatory process or proteins hsp90 (5–50% of SLE patients), ribo- both cause the cell damage. In any case, the nuclease P (25%), ubiquitine (80%), RNA- cells at the place of chronic inflammation of- polymerase II (9–14%) or ten atrophy. Physical damage, e.g. permanent inducible protein p16 (29%) found in SLE. pressure in an unsuitable locality, also induc- The diagnostic and clinical importance of all es atrophy. the mentioned antibodies is still not clear. In 21

30% of SLE patients, the antibodies belonging tigens that after binding to a corresponding A to p-ANCA, i.e. antibodies against neutrophil antigen activate complement and thereby cytoplasm were demonstrated. To be specific, cause haemolysis. Most of these anaemias can there are antibodies against elastase that oc- be divided into warm and cold antibody cur most frequently in drug-induced lupus. anaemia. Warm antibody haemolytic anae- mia is caused by IgG antibodies against Rh- Autoimmune diseases They occur as a antigens and the optimal reaction tempera- consequence of the overproduction of anti- ture is 37°C. Cold antibodies are aimed at bodies or autoreactive T-lymphocytes induc- antigens H and I, belonging to the IgM iso- ing a state of autoaggression, i.e. harm to one’s type, and an optimal interaction with eryth- own tissue and its structure. The presence of rocytes occurs at 4°C, but it is positive also at a small number of antibodies doesn’t neces- 25°C and 31°C. sarily mean it is a pathological process. To prove this it should be demonstrated that: 1) Autoimmune hepatitis This is referred to certain antibodies are formed regularly only as chronic active hepatitis. It affects mostly in the case of one specific disease, 2) the au- young women who present with fever, arth- toantigen inducing their formation can, after ralgia, jaundice and skin eruptions. The in- immunisation, provoke the development of flammatory changes can be seen predomi- the same pathological process in an experi- nantly in the periportal region where the in- mental animal model, and that 3) this experi- filtrating TH1-lymphocytes and other cells mental disease can be transmitted via the se- damage the hepatocytes. The disease is asso- rum or lymphocytes to a non-immunised ciated with HLA-A1, HLA-B8, HLA-DR3 animal (Witebsky’s criteria). The autoim- and HLA-DR4 antigens, and a familial pre- mune disorders may impair several organs disposition has been observed. There are an- (systemic) or only one specific organ (organ- tibodies against the smooth muscles, actin specific). and hepatocyte membranes. Autoantibodies Systemic autoimmune disorders include, against hepatocytes do not have a pathogenic for example, systemic lupus erythematosus, role. A polyclonal hypergammaglobulinae- rheumatoid arthritis, Sjögren’s syndrome and mia is present, mostly of the IgG class, and to systemic sclerosis. a lesser extent the IgM and IgA class. The dis- Organ-specific autoimmune disorders may order is associated with other immunopatho- impair: logical conditions such as systemic lupus ery- • endocrine system: Addison’s disease, Graves’ thematosus, Sjögren’s syndrome, autoim- disease, Hashimoto’s disease, juvenile dia- mune thyroiditis, insulin-dependent diabetes betes mellitus, mellitus etc. • haematopoetic system: autoimmune hae- molytic anaemia, autoimmune neutrope- Autoimmune neutropenia This is caused nia, paroxysmal cold haemoglobinuria, by increased destruction of neutrophils or by • gastrointestinal organs: ulcerative colitis, suppression of myeloid cell growth by au- Crohn’s disease, chronic active hepatitis, toantibodies not always detectable in the se- primary biliary cirrhosis, rum. It occurs as a primary condition or sec- • neuromuscular system: myasthenia gravis, ondary to other autoimmune disorders. Pa- multiple sclerosis, tients suffer form recurrent infections or can • skin: pemphigus vulgaris, be asymptomatic. • cardiopulmonary system: rheumatic fever, • genitourinary system: IgA-nephropathy, id- Autoimmunity Usually an immunopatho- iopathic membrane nephropathy. logical process with disregulated immune re- sponse to autoantigens (self antigens). This Autoimmune haemolytic anaemia It is response is inhibited in physiological states caused by antibodies against erythrocyte an- or has only a regulatory purpose, so its prod- autonomic nervous system (ANS) 22

A ucts cause no harm to one’s own tissue and thioprine nor 6-mercaptopurine is the drug of cells containing relevant autoantigens on first choice in the treatment of rheumatoid ar- their surface. The harmful autoimmune reac- thritis (RA) but they both remain a valuable tions appear in an overreaction of the im- therapeutic option for RA when complicated mune system caused by disturbances in im- by vasculitis, glomerulonephritis or when oth- mune homeostasis (the balance between er DMARDs are not tolerated. stimulating and inhibiting factors), and then Dosage: in RA is adminis- they are referred to as autoaggressive reac- tered orally in a daily dose from 1.5 to 2.5 mg/ tions. They induce autoimmune diseases. kg (75 to 200 mg daily). Its full effects take a couple of months. It is necessary to monitor Autonomic nervous system (ANS) The the blood count and liver function tests dur- autonomic part of the nervous system which ing treatment: every 14 days for the first two maintains homeostasis in the body and har- months, and subsequently every 6–8 weeks. monises activity of the visceral organs, mostly The occurrence of leukopenia is an indica- without the conscious participation of the in- tion for withdrawal of treatment. dividual. It is divided into the sympathetic Clinical efficiency: Several clinical trials and parasympathetic nervous system. show the comparable clinical efficiency of aza- thioprine with antimalarials, penicillamine, Autotolerance The ability of the body not parenteral gold, cyclophosphamide and cy- to stimulate immunocompetent cells into an closporin, but less when compared to metho- immune response to potential antigens that trexate in RA. are components of one’s own tissues and The therapeutic efficiency and toxicity of cells. azathioprine are dose dependent increase proportionally to the administered dose. of the lunate bone However, patients with a genetic deficiency → see Kienbock disease of thiopurine methyltransferase (TPMT) are at increased risk of severe myelosuppression Axon The prolonged sprout of the nerve cell and liver toxicity, so studies are looking at the transmitting impulses from the cell body. It efficacy of measuring the TMPT genotype can vary between 1 mm long or longer than 1 and/or enzyme activity in patients prior to m in length. treatment (Szumlanski et al. 1992). Azathio- prine is well tolerated in pregnancy and is not Azathioprine A nitroimidazole derivative associated with congenital malformations in of 6-mercaptopurine, a purine antagonist. It humans. In spite of data showing that only inhibits DNA synthesis, and so is used in the very small amounts transfer into breast milk, treatment of acute leukaemia and as an im- its administration during breast-feeding is munosuppressant for B-cell and T-cell re- not recommended. sponse. It decreases the number of circulating Adverse effects: Gastrointestinal symp- NK-cells, neutrophils and monocytes. It is toms such as nausea and vomiting, leukope- used in the treatment of various autoimmune nia and increased liver transaminases. Clini- disorders (systemic lupus erythematosus, cal symptoms resolve after withdrawal of Sjögren’s syndrome and rheumatoid arthri- treatment. Long-term treatment with azathi- tis). oprine is associated with a higher risk of ma- Azathioprine and 6-mercaptopurine belong lignancies, particularly haematopoietic and to purine analogues. Currently, neither aza- lymphoreticular malignancies. B

Baker’s cyst A palpable resistance or swell- infection from various infective agents. Pa- ing in the popliteal fossa, often communicat- tients with this syndrome suffer from oppor- ing with the joint cavity of the knee. It devel- tunistic and recurrent infections, chronic di- ops by enlargement of the gastrocnemius and arrhoea and eventually aplastic anaemia. semimembranosus muscles bursae. It is a fre- Laboratory findings include decreased levels quent finding in arthritides and in osteoar- of immunoglobulins, impaired specific im- throsis. A ruptured cyst mimics the signs of mune responses; decreased numbers of T deep venous thrombosis of the calf. lymphocytes (particularly CD4+) but the numbers of B lymphocytes are normal or Ballottement of the patella This is a slightly increased. clinical sign of increased fluid within the knee joint (synovitis, haemarthrosis). It is ex- Barthel’s index A clinical assessment tool amined by placing the palm of the hand on used to measure the activities of daily living the patella, pushing caudally and eliciting and mobility (functioning) of a patient. It is pressure on the patella with the fingers of the commonly used in evaluating functioning in other hand; when the fluid is increased, a different disorders, mainly neurological wobbling of the patella as in pushing on a bal- (multiple sclerosis, stroke). loon is felt. Bartter’s syndrome A group of disorders Balneophototherapy → see Tomesa (bal- with an autosomal recessive type of inheri- neophototherapy) tance characterised by disturbance or absence of salt transport in the thick ascending limb of Balneotherapy (BT) The use of natural the loop of Henle. The consequence is a loss of healing sources (thermal springs, peloids, salts in the urine, a drop in blood pressure, hy- mineral waters) for healing purposes. The pokalaemic, hypochloraemic metabolic alka- term “complex BT” refers to the additional losis and hypercalciuria with a variable degree use of other forms of physical therapy (ther- of risk of developing urine stones. At present motherapy, aquatherapy, electrotherapy, mas- there are 5 defined genes whose mutation sages), and above all therapeutic rehabilita- causes BS (types I–V). In the prenatal form of tion. In rheumatic disorders, health resorts the syndrome there is, among other things, (spas) with sulphur (S2–) content or with ra- an overproduction of E leading don content in the natural healing sources are to hypercalcaemia and increased bone re- recommended, together with complex treat- sorption. ment, in particular high-quality rehabilita- tion Basilar impression This occurs rarely as an isolated congenital anomaly. Usually it is Bare lymphocytes syndrome Autosom- associated with other inborn defects, such as al recessive primary immunodeficiency. The incomplete fusion of posterior arch of the at- fundamental of the syndrome is the absence las, Klippel-Feil deformity, atlanto-axial dis- of class I or II HLA antigens, or the absence location, as well as foramen magnum steno- of both classes of HLA antigens on the sur- sis. It accompanies disorders related to ossi- face of lymphocytes causing inefficient or de- fluence, such as Paget’s disease, , fective cooperation between immunocompe- and . The weight of tent cells. This leads to an increased risk of the head working on a soft cranial base causes bassett’s current 24

invagination of the axis through the foramen The manoeuvres are rated bilaterally; bilater- magnum. A basilar impression induced by al involvement with 2 points, the anteflexion B trauma usually has fatal consequences. with one point. Hypermobility has a score of 4 and more points; a generalized hypermobil- Bassett’s current A pulsatile, monophasic, ity has a score of 9. Hypermobility is assessed sinus, 72 Hz current used to stimulate bone also by the test of Janda. formation. It facilitates the influx of Ca2+ ions into cells. Selectively it acts on sen- Bence-Jones proteins (BJ-proteins) A sitivity towards parathormone and so in- monoclonal globulin protein found in blood creases the rate of bone tissue formation. Us- or urine, consisting of identical light chains of age: non-healing fractures, pseudoarthroses, immunoglobulins (kappa or lambda), which osteoporosis. are produced in the course of multiple my- eloma and malignant transformation of plas- Bath ankylosing spondylitis indices ma cells (gammopathy). Their daily secretion (BAS-indices) → see Instruments of assess- increases depending on disease intensity. ing (health status measurements, outcome They precipitate when heated to 40–60°C and measurement) redissolve at 90–100°C. According to their low molecular weight BJ-proteins are com- Bechterev’s disease → see Ankylosing pletely eliminated by kidneys. BJ-proteins spondylitis can first be detected in urine. BJ-protein in serum is only found if renal function rate is Behçet’s disease A vasculitis which affects disturbed or BJ-protein formation is greater skin, mucosa, eyes and the central nervous than the clearance rate. system. Significant clinical signs include re- current mouth ulcers appearing at least three Bicipital Tendinitis This is due to degen- times a year plus at least two of the following erative changes of the long head of the biceps signs: recurrent genital ulcers, ocular signs tendon, which may evoke , sub- (, ), cutaneous signs luxation or luxation and partial or total ten- (erythema nodosum, pseudofolliculitis, pap- don rupture. Pain over the anterior shoulder ulopustulous lesions or acneiform morphae area, pain provoked by pressure applied to and patergic phenomenon read by a physi- the biceps tendon, and sometimes on move- cian). Behçet’s disease is most prevalent (and ment of the tendon are typical. more virulent) in the Mediterranean region, Middle East, and Far East, with an estimated Bisphosphonates These are synthetic ana- prevalence of 1 case per 100.000 persons. logues of pyrophosphates that are resistant to the action of endogenous pyrophos- Beighton criteria → see Hypermobility phatases. They have a high affinity for the syndrome (HMS), Beighton-Horan score bone mineral of the skeletal surface and exert an inhibitory effect on several catalytic en- Beighton-Horan score The assessment of zymes, of which the most important is farne- the degree of joint hypermobility consists of syl diphosphate synthetase (FPPS), thus in- five manoeuvres: terfering with the mevalonate pathway of 1. passive hyperextension of the 5th MCP cholesterol formation. An insufficient preny- (metacarpophalangeal) joint over 90°, lation results with a consequent dysfunction 2. passive backwards belong of the thumb to leading to apoptosis of . Osteoab- the volar side of the forearm, sorption slows and, depending on the type of 3. hyperextension of the elbows over 10°, bisphosphonate, leads to disturbed remodel- 4. hyperextension of the knees 10°, ling, and prolongation of secondary minerali- 5. anteflexion without bending the knees, sation. The following are bisphosphonates the palms rest on the floor. used in the treatment of osteoporosis: alen- 25 birefringence (double refraction) dronate, ibandronate, risedronate, and zole- containing 75% human protein and 25% mu- dronate, with pamidronate, clodronate and rine protein; it is administered intravenously. etidronate used in some countries. The combination of and metho- B trexate has a significantly higher efficacy in Bioengineering technologies These suppressing clinical activity in resistant forms techniques represent the possibility of repair- of RA than methotrexate alone. Treatment ing tissue defects such as in cartilage. It may, with these antibodies is associated with an for example, lead to the successful transplan- increased incidence of septic complications, tation of autologous chondrocytes, allogenic especially mycobacterial infection. Despite chondrocytes, perichondral grafts and biode- their high clinical efficacy, they are currently gradable membranes. reserved for RA not responding well to monotherapy or combined treatment with Biolamp – bioptrone lamp The effect disease modifying anti-rheumatic drugs (biostimulation) is based on the use of polar- (DMARDs). Recently, they have been indi- ised light, but unlike a laser it is not mono- cated in early aggressive forms of RA. chromatic, nor coherent. In rheumatology Most of these agents are now licensed for used to treat painful conditions of soft tissue the treatment of severe juvenile idiopathic ar- structures (tendinitis, epicondylitis, and bur- thritis, and severely active and resistant forms sitis). It has practically no contraindications, of ankylosing spondylitis and psoriatic ar- but care must be taken not to expose to the thritis. As TNF-α undoubtedly participates in eyes. the development of osteoporotic changes in chronic , the agents improve Biologic drugs (BD) The research of BD bone mineral density in these patients. (short form of biotechnological produced Many newer biologic drugs have been or drugs, also called biologics or biologicals) to- are being developed. Rituximab is a B cell de- day is concentrating on the inhibition of a pleting monoclonal anti-CD20 antibody, li- number of functional antigens of B- and T- censed for severe SLE and RA. Anakinra is an cells, and adhesive molecules, but the best IL-1 agonist, but appears less potent than results are currently obtained by treatments TNF inhibitors in rheumatoid arthritis. influencing the activity of pro-inflammatory Abatacept is a soluble fusion protein causing cytokines. Of these, especially tumour necro- co-stimulation blockade by blocking CD28, sis factor-alpha (TNF-α) and interleukin-1 but is not yet licensed for clinical use. Other (IL-1), are associated with destruction of the biologic drugs are in development to block joints, erosions and development of deformi- other cytokines such as IL-6 (Tocilizumab), ties. The inhibition of TNF-α is rather well and many more. developed and there are several agents such as , adalimumab and infliximab Bioptrone lamp → see Biolamp – bioptrone that have been used in the treatment of severe lamp forms of rheumatoid arthritis (RA), either in- dividually or in combination with methotrex- Birefringence (Double refraction) Bi- ate. Etanercept is a recombinant soluble re- refringence, or double refraction, is the de- ceptor protein for TNF-α, which was found to composition of a ray of light into two rays have better efficacy in clinical trials with RA in when it passes through certain types of mate- combination with methotrexate than metho- rial depending on the polarisation of the trexate alone. Adalimumab is a fully hu- light. Through a double refracting material a manised monoclonal antibody against TNF-α line is seen as two parallel lines. Bifurcation and is administered subcutaneously. It has of a beam of light occurs during refraction good efficacy in treating RA with or without into an optically anisotropic environment. concomitant methotrexate. Infliximab is a Both beams are linearly polarised and pro- chimeric monoclonal antibody against TNF-α ceed in different directions. All crystals ex- polarisation of light through birefringence 26

cept the cubic system are characterised by tation of the oscillation plane. The principle their birefringence. The optical axis of the of the function of an analyser and polariser B crystal is a bisector leading through an arbi- can be explained by a simple observation. If trary point of the crystal in the direction in the slit of the polariser and analyser are paral- which birefringence does not occur. The lel, the light goes through it. If the slits are not plane containing the optic axis and the beam parallel, the light does not go through and the is the principal plane of the crystal. An ordi- analyser is dark. nary beam is polarised on the plane of the The polarising microscope is equipped principal section and an exceptional beam is with a polarisation device that enables the polarised in the plane perpendicular to the study of phenomena that are undetectable in principal section. Birefringence does not oc- normal unpolarised light. Generally the study cur with single axis crystals which only have can be divided into observation of light pass- a single direction beam. Crystals with two ing through and reflected light. Using the po- such directions are referred to as double-axis larisation device in the polarising micro- crystals. In most single-axis transparent crys- scope, one can also observe changes in the tals, the intensity of the ordinary and excep- colour of crystals. The colour is determined tional beams are the same. by the rate of light absorption. When the ab- The crystals are particles characterised by a sorption is weak across the whole range of the well-organised arrangement of their mole- visible spectrum, the material is glassy. When cules. They have, in general, three optic axes any part of the spectrum is absorbed, only that are identical to the length, width and that part of the spectrum that was not ab- depth of the particle. For the majority of ma- sorbed is seen by the eye. This phenomenon terials, the most significant descriptions of is seen in polarised light where the crystal ap- light are the length and width, and the refrac- pears variably coloured. The crystals of sodi- tion indices of these two axes are approxi- um urate (negatively) and calcium pyrophos- mately the same. Such materials are isotropic. phate (positively) can be clearly distinguished The majority of crystals have unequal refrac- by their different birefringence using the po- tion indexes in their longer axis compared to larisation device. the shorter one. Such material is referred to as anisotropic and demonstrates the properties Bobath method In adults it arises from of birefringence. three principles: 1. inhibition of developmentally lower loco- Polarisation of light through birefrin- motor reflexes and facilitation of greater gence In an optically isotropic environment postural reactions, the light radiates in all directions at the same 2. processing of superior postural reactions, velocity, but the crystals of certain substances hence improvement in targeted move- are anisotropic in terms of light propagation. ment, The velocity of light is different in different 3. influence of central motor control from directions. When the light strikes on such a the periphery. crystal, birefringence occurs. The beam of The Bobath method is also used as therapy light is divided at the interface of the crystal for children with cerebral palsy. into two beams: ordinary and exceptional beams. Both beams are linearly polarised. Po- Body mass index (BMI) A measure of a larised light is used in the investigation of op- person’s body weight scaled for their height. tically active substances; it does not differ BMI is calculated as dividing the body weight from natural light. To determine the orienta- (kg) by height in meters squared (m2). tion of the plane of polarised light, a device called the analyser is needed. The analyser Bone and Joint Decade – 2000–2010 complements the polarisation instrument The Decade is a global world campaign fo- and transmits light only with a certain orien- cusing the attention of the public on taking 27 bone mineral density measurement – evaluation care of people with bone and joint disorders. • quantitative ultrasound (QUS)-heel, ti- Supported by the UN and World Health Or- bia, ganisation (WHO), the idea of the Decade • peripheral quantitative computerised B developed on the basis of a consensus of ex- tomography, perts led by Prof L. Lidgren at a meeting in b) Central densitometry (DXA): Lund in 1998. The Decade was officially • standard measured areas: launched on the January 13, 2000 in the WHO – proximal femur and lumbar spine, headquarters in Geneva in the presence of the • complementary measurements: UN Secretary General Kofi Annan. – lateral lumbar spine, A stimulus for this initiative had been the – whole-body densitometry, great success of “The Decade of the Brain” in – densitometry in patients after joint the years 1990–2000 and a fact that research prosthesis implantation, in the field of musculoskeletal disorders in – morphometric measurements in the the recent decades led to high expectations lateral projection, that the start of a new millennium would c) Quantitative computerised tomography mean a significant improvement of the pa- QCT – measurement in the spinal region. tient care. The priorities of the Decade in- At present, DXA (previously DEXA) mea- cluded: joint diseases, osteoporosis, spinal surements in the lumbar spine in the AP pro- disorders, severe traumas and inherited dis- jection and in the area of proximal femur are eases of the locomotor system. The aims of considered the gold standard. The principle this initiative have been to increase public of DXA measurements is a detection of a dif- awareness of the growing burden of the mus- ference in the weakening of X-rays passing culoskeletal disorders on society, promoting through the measured bone and surrounding cost effective prevention and treatment strat- soft tissue. Appropriate software in the com- egies through research, improvement in the puter then evaluates the measured difference quality of life of these patients by implement- of X-ray weakening and gives the results as T- ing novel treatment procedures, encourage and Z-score, respectively, or in percentage. patients to a more active approach in deci- sion-making processes related to their health- Bone Mineral Density Measurement – care. evaluation The results of a bone mineral Reaching these aims demands a broad co- density (BMD) scan is normally expressed as operation of the public administration au- a the T-score, reflecting the number of stan- thorities, media, and scientific, professional dard deviations (SD) above or below the av- and lay communities. Towards the end of erage BMD in a group of individuals of the 2005, fifty-nine governments have entered same gender at the time of reaching the peak the Decade. The worldwide campaign is co- bone mineral density (normally 25–35 years ordinated by a controlling committee based of age). in Lund. There is a national action network The Z-score reflects the number of SD’s (NAN) in each country whose activities are above or below the average bone mineral coordinated by a national coordinator. density of a healthy population of the same gender, age and ethnicity. Bone Densitometry A bone densitometry The WHO classification of osteoporosis in scan measures the density of bone using vari- postmenopausal women is based mainly on ous methods. the results of the T-score. Types of densitometry: In interpreting the results, it is necessary to a) Peripheral densitometry: take into account the following: • single-energy X-ray absorptiometry 1. the error of measurement, especially in (SXA) – forearm, older patients with prominent degenera- • dual-energy X-ray absorptiometry tive changes within the spine and/or ver- (DXA) – forearm, tebral fractures, patients with ectopic cal- bone mineral density measurement – indications 28

cification in the scanned area (aorta, Bone Mineral Density Measurement – lymph nodes) or remnants of contrast individual areas At present, any part of the B (barium) medium after a gastrointestinal body skeleton can be measured. In practice, tract examination (false negative finding). however, only those sections for which we 2. site of measurement (lower density in re- possess a database of normative data and are gions where trabecular bone, which has a clinically relevant are measured. These are more rapid bone turnover, dominates), the following areas: L1 to L4 in PA and lateral 3. the method of measurement used and the projections, proximal femur, region of the database of normal values for that device great trochanter of the femur, femoral neck, and population. Ward’s triangle, distal forearm and the area measured at one site (for example called 1/3 forearm, heel and whole body den- measurement in the area with cortical bone sity. dominance – forearm, femoral neck) does The spinal region (in PA projection) and not exclude osteoporosis at another site. proximal femur are considered the gold stan- dard in BMD measurement, and according to Bone Mineral Density Measurement – the WHO criteria are suitable for establishing indications The indications vary between the diagnosis of osteoporosis. These areas are different countries, and are regularly re- the best for predicting the risk of fractures. viewed. Some variation occurs depending on Low bone mineral density established at any the availability of BMD machines. Indica- skeletal site, however, is associated with an tions for a scan include: increased risk of fractures in general. Normal a) oestrogen deficiency: premature meno- bone mineral density or osteopenia found at pause (< 45 years of age), prolonged sec- one skeletal site does not exclude the pres- ondary amenorrhoea (> 1 year), or pri- ence of osteoporosis at another site. There is a mary hypogonadism, significant correlation between sites that are b) corticoid treatment with prednisone at a measured most frequently. The differences dose of 5mg daily or more assuming the between individual areas are caused by the duration will be more than 3 months, different proportional representation of tra- c) family history of a , becular and cortical bone at the measured d) low body mass index (BMI < 19 kg/m2), areas, various velocity of bone loss in the in- e) all disorders associated with osteoporosis: dividual sections of the skeleton as well as the anorexia nervosa, , primary presence of coincident changes in the mea- , diffuse connective sured area (osteophytes, calcifications in the tissue disorders, rheumatoid arthritis, surrounding tissue, etc.). The bone turnover chronic inflammatory bowel diseases, in trabecular bone is markedly higher than in post-transplant syndrome, chronic renal cortical bone, therefore there is a more accel- insufficiency, hyperthyroidism, prolonged erated bone loss in trabecular bone in the immobilisation, Cushing syndrome, chron- postmenopausal period. The BMD measure- ic hepatopathies, myeloproliferative disor- ment in regions with dominance of trabecu- ders, genetic disorders and other meta- lar bone is therefore more sensitive and ca- bolic bone disorders, pable of detecting the postmenopausal bone f) osteopenia on plain radiographs or a find- loss earlier than the BMD measurement in ing of vertebral deformity, regions with a dominance of cortical bone. In g) fracture of the hip, , or forearm evaluating the results of a measurement, the after an inadequate trauma, sensitivity and specificity of the method of h) significant loss of height or thoracic measurement used for that area should be kyphosis, known. i) monitoring of antiresorptive treatment, j) prolonged use of certain drugs (heparin, Bone Mineral Density Measurement – anticonvulsants). least significant change (LSC) The min- 29 bone remodelling imally significant change of the bone mineral Generally, a statistically significant change in density scan. It is therefore important to en- the spinal region may be considered if there is sure good quality control by measurement of a change of more than approximately 3%. B a standard phantom. It enables evaluation as Assuming the annual loss of bone mass of to whether the measured change of density is 1–3%, the period between two measurements significant. LSC depends on the accuracy of should be at least 1–2 years. The majority of the device, the experience of the operator and authors recommend a 2- to 3-year interval. the measured segment. It should be deter- However, there are conditions where the an- mined at each densitometry session and for nual bone loss is substantially greater – osteo- each segment measured. The measured porosis with a high bone turnover and the change in bone mineral density, if lower than concomitant presence of several risk factors the determined LSC in the same session and in the postmenopausal woman. In these cas- segment of the skeleton, should be judged as es, it is possible to detect a statistically signifi- insignificant. See the entry “error of measure- cant change in in a shorter time ment”. period. For example, in glucocorticoid-treat- ed patients, it is recommended to repeat the Bone Mineral Density Measurement – bone densitometry scan 6 months after the measurement errors The error of mea- initiation of treatment. The same applies for surement should be taken into account when patients with long-term immobility. On the interpreting the BMD result. There are 2 pa- other hand, in patients with already docu- rameters to be distinguished: mented favourable response to the antire- Accuracy of measurement is the difference sorptive treatment, the scan may be repeated between the measured value and the true after 2 or more years. density of the measured bone. Precision or reproducibility of measure- Bone Mineral Density (BMD) Scans → ment indicates the difference between two or see Bone Mineral Density Measurement more measurements of the same portion of the skeleton. It is therefore important to check Bone remodelling There exists constant quality control by repeated measurement of a bone transformation – remodelling through- standard. It is necessary to declare whether out life. The constant renewing and repairing the measured change is statistically signifi- of impaired bone guarantees optimal bone cant when interpreting follow up measure- function. Bone remodelling proceeds in 4 ments. A parameter, called Least Significant main phases – activation, resorption, reversal Change (LSC), represents the minimally sig- phase and new formation. During the activa- nificant change in measurement of the differ- tion phase, osteoclasts appear at the site of ence between two BMD scans. future resorption, and then through the oste- olytic enzymes absorb the original bone Bone Mineral Density Measurement – thereby forming the so-called Howship’s la- repeat The following two factors should be cunae. After this phase lasting approximately considered when considering a repeat BMD 7 days, the reversal phase starts and lasts 5 to scan: 15 days. During the next osteoformation • The assumed bone loss velocity per year, phase, lasting 1 to 3 months, the resorption • The reproducibility bias of the measure- lacunae gradually fill in with osteoid pro- ment by the densitometer being used (pre- duced by . The completion of bone cision). mineralisation is done by deposition of hy- A BMD scan should only be repeated if the droxyapatite crystals into the osteoid. There is presumed change of BMD is expected to be a dynamic balance – coupling between the os- greater than the minimally significant change teoresorption and osteoformation processes. value established within the given depart- During , the degradation ment and measured area of the skeleton. products of collagen and lysosomal enzymes bone scan 30

of the osteoclasts are released into the circu- and placental (during pregnancy). The intes- lation, measurement of which can be used in tinal and placental forms are relatively easily B the assessment of bone resorption (a marker separable; telling apart the bone and liver of osteoresorption). Similarly, during the specific isoenzymes causes greater problems. process of osteoformation, the bone specific Various laboratory methods have been as- isoenzymes of and os- sessed for the selective assessment of bone teocalcin that are considered as markers of specific alkaline phosphatase; however none osteoblastic activity are released into the cir- of them has a sufficient sensitivity, specificity culation. Evaluation of the plasma levels of and reliability necessary for routine applica- these individual markers of bone remodelling tion. Newer methods using monoclonal anti- provides indirect information of the velocity bodies bind a small number of liver specific of bone turnover. Increased velocity of bone isoenzymes (5–15%) as well as bone specific turnover may predict the risk of an osteo- isoenzymes. porotic fracture, which is independent of The level of bone specific isoenzyme of al- bone mineral density. kaline phosphatase is significantly increased The velocity of bone turnover is substan- in hyperphosphataemia and decreased in hy- tially greater in trabecular bone. The site of pophosphataemia. It increases in hyperthy- bone remodelling is on bone surfaces which roidism, primary hyperparathyroidism and are abundant in trabecular bone. Up to 25% chronic renal insufficiency. In Paget’s disease, of trabecular bone is renewed annually, while it correlates with the activity of the bone dis- in the case of cortical bone, it is only 2–3% ease. In postmenopausal women, the activity per year. Total bone loss is therefore more of bone specific isoenzyme increases and de- rapid and greater in bones with predomi- creases with the effective antiresorptive treat- nance of trabecular bone. This has implica- ment. tions in decision-making about the sites of bone mineral density measurement and its Bouchard’s nodes → see – evaluation in the early diagnosis of osteopo- hands (Heberden and Bouchard type) rosis. Bragard’s sign If the Lassegue test does not Bone scan → see Nuclear Scintigraphy of cause pain on the examined side, the exami- the skeleton (bone scintigraphy or bone nation should be appended by performing scan) dorsiflexion of the ankle (Bragard’s sign). If pain is provoked by this manoeuvre, a radic- Bone (skeletal) Scintigraphy The role of ular irritation is suspected. bone scintigraphy lies mainly in the assess- ment of the velocity of bone turnover at dif- Brittle → see Osteogenesis ferent sites of the skeleton. It has a high sensi- Imperfecta (Brittle Bone Disease) tivity but a relatively low specificity. The pathological finding of increased bone activ- → see Osteomyelitis ity in certain regions of the skeleton estab- lished by scintigraphy therefore needs a dif- Brunkow’s method The basic principal of ferential diagnostic solution using alternative the method arises from the hypothesis that imaging techniques and suitable laboratory the way to normal movement is blocked investigations. somewhere. The aim is to remove the block- ade and restore the interrupted connection. Bone specific isoenzyme of alkaline After complete dissociation of the false con- phosphatase The total serum alkaline nection in the central nervous system, the phosphatase is less specific for bone. The hu- way to initiate normal movement is free. man serum contains various alkaline phos- phatase isoenzymes: bone, liver, intestinal 31 bursitis – trochanteric bursitis

Bursae Structures resembling vesicles filled chondrocalcinosis (crystals can be found in with synovial fluid. They are positioned in the aspirated fluid). regions with increased friction between mus- B cles, tendons and bones. Bursitis – subacromial (subdeltoid) bursitis Involvement of the bursa located in Bursitis – iliopectineal bursitis An in- the space between the deltoid muscle and flammation on the biggest bursa in the body shoulder joint capsule. The pain is manifested located under the iliopsoas muscle and anteri- predominantly on abduction (facial hygiene, or side of the joint capsule. It often communi- dressing, undressing). The involvement of cates with the hip joint cavity and may be an the bursa induces an inflammation of lesser accompanying phenomenon of coxitis. When bursae around the shoulder (coracoid b., su- enlarged it may be palpable in the groin. praspinatus b., coracobrachial b., etc.) Affec- tion of these bursae is a sign of the so called Bursitis – ischiogluteal bursitis Affec- “rotator cuff syndrome”, humeroscapular pe- tion of the bursa located between the ischial riarthritis and frozen shoulder syndrome. tuberosity and gluteus maximus muscle caus- ing pain mainly in the sitting position. It is Bursitis – trochanteric bursitis The bur- frequent particularly in professional truck sa lies between the major trochanter and glu- drivers and tractor operators, obviously as a teus maximus and tensor fasciae latae mus- consequence of irritation during sitting. cles, in the region of the fascia lata and ilio- tibial tract junction. Its affection provokes Bursitis – olecranon bursitis It starts severe pain, mainly over the greater trochan- most frequently after a trauma or microtrau- ter. Movement in the hip joint need not be ma (miner’s elbow). Often it occurs in the limited. It often forms calcification (X-ray ex- course of rheumatoid arthritis, gout and amination is necessary). C

C1 A component of complement (C), con- C3a receptor A binding receptor for C3a sisting of three subunits, C1q, C1r and C1s. fragment. It is localised on neutrophils (stimu- In the classical pathway of activating C, the lating aggregation, the release of lysosomal subunit C1q binds to an immune complex content and the formation of reactive oxygen containing an IgM or IgG antibody, which is species), macrophages (activation, stimula- a signal for the creation of the macromolecu- tion of IL-1 secretion) and mast cells (stimu- lar complex C1q-C1r-C1s stabilised by Ca2+ lating the release of anaphylaxis mediators). ion and initiation of the whole complement cascade. C3-convertases Enzymes cleaving C3 into C3a and C3b fragments. There are two en- C1-inhibitor This is a regulatory glycopro- zymes: C3-convertase of the classical pathway tein of the complement system that binds to – C4b-C2a complex and C3-convertase of the C1r and C1s, thereby blocking their activity alternative pathway – C3bBb complex. (C1). What’s more, it facilitates the dissocia- tion of the active C1 component complex and C4 A component of the complement system hampers further activation of complement. A cleaved by C1s of the activated C1 compo- hereditary angioedema develops in the C1- nent into C4a and C4b fragments. The C4a inhibitor deficiency. fragment belongs to anaphylatoxins, while the C4b fragment is a component of a C3- C2 A component of the complement system. It converting enzyme of the classical pathway is split into C2a and C2b fragments by the (C4b2b). C4 and C2 deficiency is often asso- C14b enzyme, which is formed after activation ciated with systemic lupus erythematosus or of C1 and C4 components. The C2b fragment glomerulonephritis. is a which participates in fur- ther complement activation. The C4b2b com- C4bp A protein binding C4b fragment, regu- plex is formed, which serves as C3-converting latory molecule of the complement system. It enzyme of the classical pathway. regulates the activity of C4b fragment.

C3 A component of the complement system C5 A glycoprotein composed of two polypep- that plays a central role in all pathways of com- tide chains. The C5-converting enzymes cleave plement activation. Two polypeptide chains it into C5a and C5b fragments. The C5a frag- form this glycoprotein. Its molecule has a ment has anaphylatoxic (anaphylatoxins) and unique thiolester bond whose hydrolysis is chemotactic activities towards professional fundamental for the alternative pathway of phagocytes. The C5b fragment couples with the complement activation. With the action of C3- C6 component, thereby creating a membrane- converting enzymes it is cleaved to C3a and attacking complex (complement, MAC). A very C3b fragments. The C3a fragment belongs to rare C5 deficiency manifests in increased sensi- anaphylatoxins, while the C3b fragment can tivity to Neisseria-induced infections. become either a component of C5-converting enzymes or can acquire an opsonising func- C5a receptor A receptor specifically bind- tion. The C3b fragment participates in immu- ing the C5a fragment. It is localised on mast noadherence reactions through its CR1 to CR4 cells and basophils (anaphylaxis), profession- receptors localised mainly on professional al phagocytes (chemotaxy, release of the con- phagocytes and certain other cells. tent of granules, stimulation of reactive oxy- 33 calcitriol gen species production) and thrombocytes above mentioned amino acids from proteins. (stimulation of the aggregation and release of This dephosphorylation of the proteins has a the content of granules). significant regulatory effect on their biologi- cal activities. In T-lymphocytes, calcineurin C6 A component of the complement system stimulates the transcription factor NF-AT, C that is a part of the membrane-attacking which activates the promotor region of the complex (complement, MAC). gene coding for IL-2. The immunosuppres- sive agents cyclosporin A and tacrolimus fuse C7 A component of the complement system in lymphocytes in the presence of immuno- that is a part of the membrane-attacking phillins and the resulting complex inhibits complex. calcineurin. This leads to an IL-2 deficiency and blocks T-lymphocyte activity. C8 A component of the complement system that is a part of the membrane-attacking Calcitonin It is a polypeptide belonging to complex. inhibitors of osteoclastic resorption of the bone. Calcitonin receptors are found on os- C9 A component of the complement system teoclasts. They inhibit its activity and de- that is a typical perforin. After binding to the crease the number of osteoclasts. The plasma C5b678 complex it polymerises and so creates level of calcitonin decreases with age, but it is a definitive structure of membrane-attacking not considered an important factor in the complex, which enables the formation of a pathogenesis of osteoporosis. Calcitonin was number of holes in the cytoplasmic membrane the first antiresorptive agent. Salmon calci- of target cells, and consequently, its lysis. tonin in the form of a nasal spray at a dose 200 IU reduces the risk of vertebral fractures. Calcaneal Spur A spur under the heel Particularly when given subcutaneously, it bone, which occurs particularly in older indi- has good painkilling effects for re- viduals, and may cause pain during walking lated to osteoporotic vertebral fractures. (plantar fasciitis). Treatment is based on the use of a special relieving insert. Calcitriol Several studies have confirmed the high prevalence of deficiency Calcific Tendinitis Deposition of calcium in the European population (Ovesen et al. in tendons, often leading to inflammation. 2003). An important portion of 1,25-dihy- Symptoms include chronic and relapsing droxy vitamin D3 deficiency is caused by pain. Acute painful inflammation develops chronic hepatic and renal disorders as well as when the calcification infiltrates the subacro- drugs influencing the metabolism of vitamin mial bursa referred to as bursitis calcarea. D or its clearance. In recent years the active metabolites of vitamin D3 (no need for an en- Calcifying , enthesopa- dogenous hydroxylation in the liver or kid- thies and periarthritis Calcific tendinitis, neys) are increasingly used in the treatment bursitis or enthesitis are characterised by the of osteoporosis. The beneficial effect of cal- presence of hydroxyapatite microcrystals (cal- citriol in the treatment of primary, as well as cium phosphate) at the point of the damaged secondary, osteoporosis has been demon- tendon and its insertion, which may penetrate strated by certain studies. (Payer et al. 2007) into the adjacent bursa in the form of crystals. The calcitriol deficiency has several causes In calcifying periarthritis, the crystals accu- and can be subdivided as follows: mulate in the periarticular fibrous tissue. • type I – primary deficiency due to low food intake or low sunlight exposure, Calcineurin A protein phosphatase specific • type II – insufficient effect of 1,25(OH)2D3 for serine and threonine. It is an enzyme that due to decreased production in the kidneys eliminates the phosphate groups binding the or increased resistance in the target organs calcium calcification 34

(decreased concentration of the receptors patients with nephrolithiasis and increased in the bowels due to ageing). absorption of calcium from the intestine. Hypocalcaemia results, followed by an in- Higher doses are usually unnecessary and creased level of PTH and the development of may have adverse effects (constipation, renal C senile osteoporosis. Treatment of the deficit stones). If the patient does not ingest enough depends on its cause. While type I may be calcium in the diet (intolerance of milk pro- treated by the inactive form of vitamin D, ducts, high content in the ingested pro- type II needs treatment with the active form ducts, etc.), then there are a number of calcium of calcitriol. Type I also responds to treat- preparations available. ment with calcitriol, while it is impossible to treat the type II with the inactive vitamin D. Calcium-Sensing Receptor (CaSR) A In practice the differentiation between these protein (MW 120 kDa) that can be found on two types is not simple and combinations of the surface of the cells of a number of organs both types are frequent (parathyroid gland, thyroid gland, renal tu- bules, bone, pancreas, keratinocytes, gastroin- Calcium oxalate calcification A calcifi- testinal mucous membrane, salivary glands cation process caused by calcium oxalate mi- and placenta). CaSR belongs to G-protein as- crocrystals. It is a sign of hyperoxalemia oc- sociated receptors. The gene coding for CaSR curring due to disturbance of the internal has been localized on the long arm of the 3rd environment, especially in dialysis patients. chromosome. A rise of extracellular Ca2+ con- centration leads to decreased secretion of PTH Calcium requirements in diet An ade- via the CaSR, and on the other hand, a drop of quate supply of calcium in the diet is essential Ca2+ causes an increase of PTH secretion and for the achievement of adequate bone stock increased proliferation of parathyroid gland in the premenopausal period. Calcium inhib- cells. CaSR also influences the secretion of cal- its the release of parathormone and increases citonin, but to a much smaller extent than the the levels of endogenous calcitonin, thereby PTH secretion. Inactivation mutations of suppressing osteoresorption. The calorific CaSR do not react to increased concentration value and fat content of recommended food of Ca2+, and therefore the secretion of PTH is should be taken into account when making not inhibited. Inactivation mutations in recommendations (cheese, milk, yoghurts, heterozygotes lead to the development of fa- fish and vegetables). milial hypocalcuric hypercalcaemia (FHH) A daily calcium intake of up to 2000–2500 and in homozygotes to severe neonatal hyper- mg is considered safe. It is hazardous only in parathyroidism. In activation mutations, the

Table 2. Optimal daily supply of calcium (mg)

Age Dose in mg Children 0 – 6 months 400 6 – 12 months 600 1 – 5 years 800 6 – 10 years 800 – 1200 Adolescents 11 – 24 years 1200 – 1500 Men 25 – 65 years 1000 over 65 years 1500 Women from 25 years to menopause 1000 postmenopausal, using HRT 1000 postmenopausal, without HRT 1200 – 1500 older than 65 years, pregnant, breast-feeding 1200 – 1500 35 CaSRcasr (calcium sensing receptor) modulators receptor reacts to physiological concentrations Caspases Cysteine aspartate-specific pro- of Ca2+ with a decrease in PTH secretion. Au- teases are enzymes cleaving the polypeptide tosomal dominant hypocalcaemia and idio- chain between the aspartic acid and any other pathic hypercalciuria with nephrolithiasis have amino acid using a cysteine residue. They been reported the clinical features of activa- have a fundamental role at the start of cellular C tion mutations of CaSR. Newly-developed apoptosis, in inflammatory reactions (mainly preparations affecting CaSR are divided into in the nervous tissue) and in the proteolytic calcimimetics and calcilytics. conversion of inactive precursors, such as pro-interleukin-1β, which is convert- Caplan’s syndrome → see Rheumatoid ed by caspase 1 (termed also ICE–IL-1β con- pneumoconiosis (Caplan’s syndrome) verting enzyme) to an active IL-1β. Currently, 10 different caspases are known, termed cas- Capsular pattern With certain joints pase 1 to 10. Caspases 1, 4 and 5 participate (shoulder, hip, etc.), involvement of the cap- mainly in inflammatory responses, while cas- sule in the course of a pathological process pases 2, 3 and 10 play an exclusive role in ini- such as osteoathrosis, always appears to limit tiating apoptosis. the range of passive movements within that “Knock-out” mice that lack the gene cod- joint in a specific pattern. Cyriax (Dr. James ing for caspase 1 are unable to produce IL-1, Cyriax, 1905–1985, Orthopaedic Surgeon in have significantly reduced levels of IFN-γ England) referred to this evolutional se- and are resistant to the endotoxin shock in- quence of movement pattern typical for the duced by lipopolysaccharide. Mice without given joint “capsular pattern”. In the shoulder the gene coding for caspase 3 lack the ability joint it begins with limitation of external ro- to eliminate impaired by apoptosis, tation, then abduction and ends with limita- which leads to a number of abnormalities es- tion of internal rotation. In the hip joint it pecially in brain tissue. The caspases are syn- begins with internal rotation, followed by ab- thesised in the form of enzymatically inactive duction, and ending with external rotation. precursor proteins. Their conversion to ac- tive forms is accomplished following contact Carpal tunnel syndrome (CTS) This is of the with Fas ligand, TNF-α the most frequently occurring peripheral with its receptor, via activity of granzyme B nerve compression syndrome. It accounts for (granzymes) and perforins released from cy- 20% of all compression syndromes and is the totoxic T-lymphocytes and NK-cells (which cause of 50% of all cases of brachyalgia. It is is the essence of their cytotoxic effect) or by twice as frequent in women than men and autoproteolysis. The proteolytic reactions usually occurs after the age of 50. The domi- made by caspases result in interruption of the nant hand is affected more frequently and in cell cycle, elimination of homeostatic and the case of bilateral impairment, more seri- reparation mechanisms, initiation of the sep- ous lesions affect the dominant site. aration of individual cells from its surround- Clinical symptoms: The most frequent ing tissue, disintegration of structural com- symptom of CTS is nocturnal paraesthetic ponents of the cell and the labelling of dying brachyalgia. Patients wake up in the night ex- cells for ingestion by macrophages. The activ- periencing paraesthesiae and a subjective ity of caspases is controlled by several natural feeling of finger oedema; however, there are or synthetic inhibitors. no objective signs of the oedema. The pain may radiate up to the elbow and shoulder. CaSR (Calcium sensing receptor) mod- Massage, change of the position of upper limb ulators Newly developed preparations in- or ‘shaking’ the hand may provide relief. The fluencing CaSR are divided into calcimimet- feeling of clumsy fingers and finger paraes- ics and calcilytics. The calcimimetics activate thesiae gradually subsides in the morning. CaSR thereby inhibiting the secretion of PTH. Currently, cinacalcet is the only avail- cauda equina syndrome (CES) 36

able calcimimetic drug used mainly in the CD2 (LFA-2) This transmembrane glyco- treatment of secondary hyperparathyroidism protein is localised especially on thymocytes in patients with chronic renal disease. The and adult T-lymphocytes. It is a receptor ad- calcilytics are CaSR antagonists inhibiting sorbing sheep erythrocytes, and so creates C CaSR thereby stimulating the secretion of the basis for various rosette tests for deter- PTH. At present, NPS 2143 is the only repre- mining T-cell counts. The adhesive molecule sentative of calcilytics. The calcilytics are re- LFA-3 is a natural ligand for CD2. garded as a possible future alternative for the treatment of postmenopausal osteoporosis, CD3 This is a complex molecule composed because of a presumed osteoformation effect of five polypeptide chains – members of the due to a regular, repeated and mild increase immunoglobulin superfamily – linked with of PTH secretion. Ca SR modulators are re- antigen receptors of T-cells (TCR). It is a typ- garded as prospective preparations for the ical marker for all adult T-lymphocytes. CD3 treatment of disturbances of phosphate-calci- transmits the signal from TCR into the cell. um metabolism. CD4 A glycoprotein belonging to the immu- Cauda Equina syndrome (CES) A poten- noglobulin superfamily is a typical surface

tially serious neurological disease causing marker for T-helper (TH) lymphocytes. In saddle anaesthesia, bilateral weakness of the much lower counts, it also appears on the calf muscles, Achilles tendon areflexia, dys- surface of macrophages, monocytes, dendrit- function of the ano-vesico-genital area with ic cells, cells of Langerhans and several oth- impairment of sphincters and impotence, as ers. It participates in the presentation of ex- well as polyradicular pain of lumbar and ogenous antigens by antigen-presenting cells sacral nerve roots. The syndrome is most fre- in the form of a complex with MHC class II of quently caused by herniation of an interver- HLA antigens. It serves as a receptor for HIV tebral disc into sacral roots of the spine, rare- infection, leading to AIDS. ly by malignancies or by a late form of anky- losing spondylitis. Chronic compression of CD5 A single-chain glycoprotein localised the cauda has an indistinct course, which can on B-lymphocytes, as well as on T-lympho- be manifested only by ano-vesicular sphinc- cytes. B-cells can be divided into the two sub- ters impairment and radicular pain in the sets CD5+ and CD5– depending on the pres- lower extremities. The diagnosis of CES in ence or absence of CD5. The CD5+-cells pro- patients suffering from lumbar pain requires duce natural antibodies, primarily of IgM urgent surgical intervention. isotype, enforcing the elimination of ill-con- ditioned or unnecessary inherent antigens Causalgia A burning pain sensation after a and cell structures. An increased CD5+-cell painful stimulus. It is elicited by damage to count has been found in certain autoimmune the sympathetic nervous system. The sensa- disorders (juvenile diabetes mellitus, Hashim- tion is localised to the area of innervation of oto’s thyroiditis, and systemic lupus erythe- the injured nerve or its surrounding environ- matosus). The cause for the increased au- ment. It is linked to autonomic changes toantibody formation can be due to the fact (trophic, vascular). that CD5+-cells produce IL-10, which inhib-

its the activity of TH1-cells, shifting the TH1/ CD (cluster of differentiation) The CD TH2 balance towards increased activity of

system is a group of surface attributes (anti- TH2-cells and thus increased autoantibody gens) on cells according to which it is possible formation. The CD72 is the ligand for CD5. to establish the type, the differentiation and developmental stage of the cell, or certain CD8 A transmembrane glycoprotein which other characteristics is a member of the immunoglobulin super- family and a typical surface sign of cytotoxic 37 CD40

(TC) T-lymphocytes. They participate in rec- imab) in the treatment of lymphoma, and B ognising antigens on the surface of the target cell mediated diseases such as systemic lupus cells, where they are present in the form of a erythematosus and rheumatoid arthritis. complex of immunogenic peptides with MHC class I HLA antigens. CD21 An antigen found on the surface of all C B-lymphocytes (characteristic feature of B- CD11 This is a family of three different gly- cells) and follicular dendritic cells. It func- coproteins forming α-chains (CD11a, CD11b tions as the receptor for the C3d fragment of and CD11c), which together with an identical the complement (CR2), as well as a receptor β-chain (characterised by differentiation anti- for the Epstein-Barr virus. gen CD18) create three heterodimeric mole- cules of leukoadhesive integrins: LFA-1 CD22 A typical surface antigen found on all (CD11a/CD18), Mac-1 or CR3 (CD11b/ B-lymphocytes (characteristic feature of B- CD18), and gp150,95 or CR4 (CD11c/CD18). cells). It is lost during transformation of a B- They participate mainly in adhesive interac- lymphocyte to a plasma cell (secreting anti- tions between leukocytes and endothelial cells bodies). during initiation of inflammatory reactions. Their ligands (anti-receptors) on the endothe- CD25 A single-chain glycoprotein creating lial cells are inter-cellular adhesive molecules the α-chain of the receptor for interleukin 2 ICAM-1 (CD54) and ICAM-2 (CD102). (IL-2R). It is localised on activated T- and B- lymphocytes and macrophages. CD15 An adhesive polysaccharide antigen referred to as Lewis’ antigen X. It is localised CD28 This glycoprotein homo-dimer can be on the surface of neutrophils and other leu- found on T-lymphocytes and serves as a co- kocytes. Via weak adhesive reactions with stimulatory molecule whose ligand is the selectins E and P (selectins) on the surface of CD80 (B7) antigen on antigen presenting endothelial cells, it creates a background for cells and B-lymphocytes. The CD28-CD80 the “rolling” of leukocytes over the endothe- interaction provides the lymphocytes with a lium (in inflammation). second co-stimulatory signal that is funda- mental for their activation. CD16 A differentiation antigen having the function of a low-affinity Fc-receptor for IgG CD31 This is an adhesive molecule referred (FcγRIII). It is localised on the surface of to also as PECAM-1 (platelet/endothelial cell neutrophils, macrophages, eosinophils and adhesion molecule). It is localised on the sur- NK-cells. It facilitates the phagocytosis of face of granulocytes, monocytes, macrophag- particles opsonised by IgG antibodies and es, B-lymphocytes, NK-cells and endothelial participates in ADCC (antibody-dependent cells. It is of cardinal importance in trans-en- cellular cytotoxicity) reactions. It is regarded dothelial migration of leukocytes to the focus a typical feature of NK-cells. of inflammation.

CD19 An antigen found on the surface of all CD35 An antigen representing CR1, the re- B-lymphocytes (characteristic feature of B- ceptor for C3b and C4b fragments of comple- cells). ment. It can be found on a number of cells including neutrophils, eosinophils, mono- CD20 A non-glycosylated phosphoprotein cytes, B-cells and erythrocytes. It plays an expressed on the surface of all mature B cells. important role in eliminating circulating im- Its function is unknown. It is a useful marker mune complexes. in B cell lymphomas, hairy cell leukaemia and B cell chronic lymphatic leukaemia. It is CD40 A co-stimulatory molecule localised the target for the monoclonal antibody (ritux- on the surface of B-lymphocytes. The CD40L CD44 38

molecule, found on the surface of T-helper CD50 The intercellular adhesive molecule lymphocytes, is the ligand of CD40. The ICAM-3, which is a ligand for LFA-1 (CD11), CD40-CD40L interaction provides the B-cell belongs to the immunoglobulin superfamily with a second signal necessary for its trans- and is found mainly on differentiated leuko- C formation to an antibody synthesising plasma cytes. cell. CD54 The intercellular adhesive molecule CD44 A transmembrane molecule found on ICAM-1, whose ligand is LFA-1 (CD11), is the surface of leukocytes, erythrocytes and localised mainly on endothelial cells and fol- thrombocytes. It functions as a receptor for licular dendritic cells. It is also a receptor for hyaluronic acid. Through the CD44 molecule rhinovirus. the cell can bind to the intercellular substance and accomplish other adhesive reactions, es- CD55 A single-chain glycoprotein bound to pecially those between leukocytes and en- phosphatidylinositol and found on the sur- dothelial cells, during initiation of the inflam- face of haematopoietic and other cells, where matory reaction, but also during nidation of it functions as a regulator of the complement cancer cells in the course of a metastatic pro- system (DAF, CD46). cess. In line with the above mentioned the increased expression of CD44 is found on CD56 This adhesive molecule is the basic metastasising cells or, for example, on epithe- differentiation antigen of NK-cells. It can be lial cells in patients with bronchial asthma. found also on neurons (N-CAM).

CD45 This membrane glycoprotein is found CD58 A single-chain adhesive glycoprotein in a great number of copies on all hae- mainly found on haematopoietic and other matopoietic cells except erythrocytes and cells. It is also referred to as LFA-3 (leukocyte thrombocytes. It exists in at least eight iso- function antigen 3) and is a ligand for the forms where the CD45RA molecule is typical CD2 antigen. for memory and activated T-cells. The indi- vidual isoforms differ in molecular weight, CD62 A family of adhesive molecules (selec- but they all possess a cytoplasmatic compo- tins) that includes three members: CD62E – nent with protein tyrosine phosphatase activ- E-selectin (found especially on endothelial ity. Through its effect, the tyrosine units of cells), CD62L – L-selectin (found on the sur- membrane glycoproteins can de-phosphory- face of granulocytes and lymphocytes) and late and so modulate the transmission of acti- CD62P – P-selectin (found on endothelial vating signals into the cell. cells and thrombocytes).

CD46 Regulatory factor of the complement CD64 A single-chain glycoprotein with a system MCP (membrane co-factor protein) function for the high-affinity Fc-receptor for found on the surface of haematopoietic and IgG (FcγRI). It is localized on macrophages other cells. It regulates the activation of com- and monocytes. plement via cleavage of the C3b component thereby preventing the activation of other CD66 A family of at least five antigens that complement components in its proximity. Its are found on neutrophils (CD66a), eventually presence on trophoblast cells contributes to on all granulocytes (CD66b), and certain mother’s tolerance to the foetus. This has cancer cells. For instance, CD66c is a typical been proven by clinical experience where antigen of neutrophils and colorectal carci- women lacking the CD46 molecule on their noma cells, and CD66e which is also referred trophoblast cells suffer miscarriages. Another to as a carcinoembryonic antigen (CEA). regulatory factor of complement, DAF (CD55) acts in a similar way. 39 centimorgan (cM)

CD72 A heterodimeric glycoprotein, which CD119 An antigen on the macrophages, is a typical feature of B-lymphocytes and is a monocytes, B-cells and epithelial cells. It is a ligand for CD5. receptor for interferon gamma (IFN-γR).

CD79 A group of two transmembrane glyco- CD120 It is found on a number of cells in C proteins that are components of the antigen two isoforms. Both isoforms, CD120a and receptor of B-lymphocytes (antigen recep- CD120b, are receptors for tumour necrotis- tors). The CD79a represents an Igα chain ing factors (TNFRI, TNFRII). Each of them (having been referred to as MB1), while the can bind TNF-α or TNF-β. CD79b represents Igβ chain (B29). They are localised on the surface of all adult B-lym- CD121 An antigen occurring in two iso- phocytes. forms. Both represent the receptors for IL-1. The CD121a represents IL-1RI and is loca- CD80 A co-stimulatory molecule found on lised on T-lymphocytes, thymocytes, en- the surface of antigen presenting cells, in- dothelial cells and fibroblasts. The CD121b cluding B-lymphocytes. Its ligand is CD28. represents IL-1RII and is localised on B-cells, macrophages and monocytes. CD88 An antigen on granulocytes, mast cells, macrophages and smooth muscle cells. CD122 This antigen on T- and B-lympho- It is a receptor for anaphylatoxin C5a. cytes, NK cells and monocytes possesses the function of β-chain of the receptor for IL-2. CD102 An adhesive molecule belonging to the immunoglobulin superfamily and is CD124 This antigen on B- and T-lympho- found on endothelial cells, lymphocytes and cytes and endothelial cells has receptor func- monocytes. It is also referred to as ICAM-2. tion for IL-4 (IL-4R). Its anti-receptor on the leukocytes is the inte- grin LFA-1 (CD11). CD125 An antigen mainly found on eosino- phils and basophils with the function of CD106 A vascular cell adhesive molecule α-chain of the receptor for IL-5. (VCAM-1) that is found on the cells of vascu- lar endothelium and during the transen- CD128 This antigen on neutrophils, baso- dothelial migration of leukocytes it reacts phils and certain subpopulations of T-lym- with VLA-4 (CD49d/CD29) molecules on phocytes has receptor function for IL-8 (IL- their surface (inflammation). 8R).

CD115 An antigen present on monocytes, CDR The hypervariable regions of immuno- macrophages and on the placenta. It acts as globulin chains. They are the integral compo- the receptor for macrophage colony stimulat- nents of binding sites for antibodies (immu- ing factor (M-CSFR). noglobulins, structure).

CD116 An antigen present on monocytes, CEA (carcinoembryonic antigen) It is macrophages, neutrophils, eosinophils, fibro- present in foetal endodermic tissue and can blasts and endothelial cells. It acts as a recep- be expressed on the surface of neoplastic tor for granulocyte and macrophage colony cells, especially in colorectal carcinoma (on- stimulating factor (GM-CSFR). cofoetal antigens).

CD117 An antigen present on the progeni- CentiMorgan (cM) A unit used in genetics tor cells of . It acts as the recep- for genome mapping. It represents the distance tor for stem cell growth factor (SCFR), also between two gene loci on the DNA molecule referred to as c-kit. that have a 1% recombinant frequency. certolizumab 40

Certolizumab Certolizumab (CDP-870; are needed (Emery et al. 2008, Landewé et al. Cimzia®) is a new agent that employs a novel 2008). strategy to neutralise TNF-α, namely the prokaryotic expression of TNF-α-specific Chaining of functional defects Config- C Fab antibody fragments, coupled to polyeth- uration of functional defects that develop as a ylene glycol. Certolizumab pegol is the first result of incorrect involvement of functional anti TNF treatment which has been coupled muscle chains in evolutionary kinesiology to polyethylene glycol (‘PEGylated’). This (mechanism of gait, breathing, swallowing process slows the body’s clearance of the ac- and grasp). tive compound from the blood, thereby pro- longing its active period and possibly also Charcot’s joint (neuropathic arthropa- resulting in differential accumulation in in- thy) The term Charcot’s joint refers to pro- flamed tissue over normal tissue. Certoli- gressive destructive changes in joints with a zumab pegol works by targeting TNF-α in typical clinical and radiological picture as a inflamed tissue, reducing symptoms and dis- consequence of sensory trophic neuropathy. ease progression in RA. The molecule is Fc- Clinical symptoms and signs: Charcot’s free, which means that the Fc region of the joint(s) is mainly a mono-articular or oligo- antibody, found in conventional anti-TNFs, articular arthropathy. The affected joint is has been removed. Although it has now been swollen and grossly deformed due to apposi- shown in RAPID 1 that the Fc region is not tion of the bone and soft-tissue swelling. required for efficacy in RA, it does have func- Later joint instability can occur. There is a tions which could potentially be detrimental, marked disparity between the prominent ob- including Fc-mediated cytotoxicity and jective signs and the minimal subjective com- transport across the placenta. Therefore, it is plaints of the patient (painless joint). X-rays hoped that pegylated certolizumab will last show a mixture of destruction and heterotro- longer and have fewer adverse effects. pic new bone formation. The severity of the Pegylated certolizumab adds significant articular changes and their distribution de- benefit in reducing the signs and symptoms pend on the underlying condition that pro- of RA in combination with methotrexate, duced the development of trophic neuropa- compared to using methotrexate alone. This thy and its duration. A variety of and represents a significant advance in the treat- diseases can damage the nerve supply to the ment of RA. joints. In tabes dorsalis and leprosy, the large In a phase III study, 59% of patients receiv- joints of the lower extremities are predomi- ing certolizumab pegol 200 mg plus metho- nantly affected, in diabetes mellitus the joints trexate, and 61% of patients receiving certoli- of the feet are more frequently involved and zumab pegol 400 mg plus methotrexate every in syringomyelia, the large joints of the upper two weeks achieved a 20% improvement in extremities (the shoulder in 80% of cases) are symptoms (ACR 20 response) after 24 weeks’ affected. Progression of the arthropathy can treatment. Only 14% of patients receiving be slow and may be associated with sub-acute methotrexate alone achieved an ACR 20 re- attacks of arthritis with significant swelling sponse over the same period, highlighting the and warming developing over several hours. superiority of the treatment combination at both doses of certolizumab pegol in patients Chemokines A superfamily of more than refractory to methotrexate. 40 small proteins (with molecular weights be- The majority of adverse events were mild tween 8 and 11 kDa) that belong to cytokines. to moderate and discontinuation due to AEs They act in concentrations of 1–100 pg/mL was low at 4.3%, 5.7% and 1.5% for certoli- via specific receptors mainly as chemotactic zumab pegol 200 mg, 400 mg and placebo re- factors for various leukocytes from where their spectively. Early studies in rheumatoid arthri- term arises (chemotactic cytokines). They are tis have shown promise, though more studies produced by practically all cells and the pro- 41 cholinergic crisis duction is induced by infectious agents, exoge- makines are termed as CXCL and similarly nous irritants and many cyto kines. They exert CCL, CX3CL and CL where the letter “L” means important inflammatory and regulatory activi- ligand to distinguish it from CXCR, CCR, ties especially on haematopoietic cells and the CX3CR and CR where “R” means receptor. exchange of lymphocytes between the circula- CXC chemokines act via 5 known recep- C tion and the lymphatic organs. The chemok- tors that are classified as CXCR1 to CXCR5. ines are regarded as second-degree proinflam- For CC chemokines there are 10 known re- matory cytokines because they are less pleio- ceptors (CCR1 to CCR10); for neurotactin tropic than first-degree cytokines (IL-1, IL-6, only one receptor has been identified to date

TNF-α, etc.). They are also referred to as inter- (CX3CR1). These receptors can be found on crines. This term was created in an effort to various cells and also participate in other ac- distinguish between these two groups of proin- tivities in addition to inflammation. For ex- flammatory cytokines that are structurally and ample, CXCR4 is a co-receptor for HIV-1 and genetically unrelated. Individual polypeptides plays an important role in the pathogenesis of of the chemokine superfamily can be divided AIDS. Experiments on mice have shown that into four subfamilies depending on the spacing CCR2, whose ligand is MIP-1, plays a crucial of their first two cysteine residues; juxta-posi- role in the initiation of . tioned (-C-C-), separated by one (-C-X-C-), three other intervening amino acids (-C-X-X- Chemotactic factors Substances regulat- X-C-), or one pair of cysteines (-C-). ing the directed movement of cells (chemo- The -C-X-C- subfamily is also termed taxy). They are abbreviated as chemotaxins. α-chemokines or CXC-chemokines and its Both endogenous and exogenous chemotax- genes are located on human chromosome 4; ins are recognised. The group of endogenous the -C-C- subfamily is also known as chemotaxins includes chemokines and sev- β-chemokines or CC-chemokines and its eral other cytokines, certain and genes are located on chromosome 17. The the fragments of certain proteins (for exam- α-chemokines include IL-8, neutrophil-acti- ple fibrin or fibronectin). Typical representa- vating protein-2 (NAP-2), and platelet fac- tives of exogenous chemotaxins are certain tor-4 (PF-4) that in particular are chemotac- bacterial oligopeptides containing N-formyl- tic and activating factors of neutrophils. The methionine (for example N-formyl-methion- β-chemokines exert chemotactic activity pre- yl-leucyl-phenylalanine). dominantly on monocytes and macrophages, but also on eosinophils, basophils, lympho- Chemotaxis The active movement of cytes and NK-cells. The CC chemokines in- phagocytes or cells in a general direction clude monocyte chemotactic protein (MCP-1 (positive chemotaxy) or opposite direction to MCP-5), macrophage inflammatory pro- (negative chemotaxy) related to the concen- tein (MIP-1 and MIP-3), CCL5 (previously tration gradient of the chemotactic factor. called Regulated upon Activation, Normal T- Chemotaxis is the stimulated and directed cell Expressed, and Activation; abbreviated migration of cells. RANTES), and eotaxin – a specifically effec- tive chemotaxin for eosinophils. The C- Chimeric antibodies These are antibodies chemokine subfamily has only one member in which one part of the molecule (variable to date – lymphotactin, which is a chemotac- domain) originates from one animal species tic factor for lymphocytes and NK-cells, but and the other part (constant domain) from not for neutrophils and macrophages. Also another animal species. Humanised antibod- the CXXXC-chemokines have only one ies are an example of such antibodies. member – neurotactin produced by micro- glial cells and belonging to neurokines (cy- Chloroquine → see Antimalarial drugs tokines acting primarily on brain tissue). Ac- cording to the newast nomenclature CXC che- Cholinergic crisis → see Myasthenia gravis chondrocalcinosis 42

Chondrocalcinosis (CCA; chondrocal- of treatment. It is used in the treatment of os- cinosis articularis) An induced distur- teoarthrosis bance (rarely genetic) of articular cartilage, presumably proteoglycans, with local over- Chondromatosis → see Synovial chondro- C production of inorganic pyrophosphate lead- matosis ing to its crystallisation. Microcrystals of cal- cium pyrophosphate dehydrate (CPPD) form Christmas disease → see Musculoskeletal a picture of pyrophosphate calcification of complication in rare inherited haemorrhagic the weakened of the joints that diatheses clinically manifests as episodes of crystalline induced arthritis, and leads to the develop- Chromatography A physiochemical sepa- ment of secondary osteoarthritis. It can be ration technique used for analytical and pre- associated with hypothyroidism, hyperpara- parative and for analytical purposed. The thyroidism, haemochromatosis and acro- principle exploits the differences in the affin- megaly. ity of different components (liquid or gas- Symptoms and signs: Recurrent attacks of eous) between two non-miscible phases, of acute or sub-acute arthritis (pseudogout) which one is mobile and the other stationary (mostly of large joints, especially the knees (immobilised). Depending on the nature of and shoulders) in the elderly with a non-spe- the mobile phase, liquid chromatography cific inflammatory response. Over time, it (LC) and gas chromatography (GC) are dis- can lead to secondary osteoarthritis and tinguished. There are different mechanisms of eventual destructive arthropathy. separation to include adsorption, distribution, Diagnosis The clinical picture may be typ- ion exchange, affinity (immunoaffinity), gel ical, especially with large shoulder joint ef- permeation (molecular screen), gas and high fusions. Radiographs show linear calcifica- performance liquid chromatography (HPLC; tion on the surface of articular cartilage or columns with small round particles and higher in the triangular ligament at the wrist. Joint mechanical endurance, high pressure). The aspiration may be inflammatory or haemor- method of washing out components of the rhagic, with polarised microscopy confirm- sample distinguishes between elution, frontal ing positively bifringent rhomboid shaped and size exclusion chromatographies; accord- crystals. ing to the geometrical organisation of the Treatment There is no curative treatment, chromatographic apparatus (bed shape). By but episodes of acute and subacute arthritis using chromatography techniques it is possible are treated by joint aspiration and steroid in- to determine or isolate various substances in- jection. Sometimes, NSAID’s or low dose ste- cluding antigens, haptens and antibodies. roids are required in patients with continuing symptoms of joint pain and stiffness. Chronic syndrome (CFS) A dis- order characterised by idiopathic (isolated) Chondroitin sulphate A macromolecular permanent fatigue that has a precisely de- substance which is a physiological compo- fined onset, does not subside after rest, great- nent of articular cartilage. The administra- ly limits the daily activities of the patient tion of chondroitin sulphate has a favourable compared to the status before the onset, and influence on the metabolism of chondrocytes. is inappropriate to the amount of exertion. Its It is administered in the form of granules or aetiology is unknown, but it is hypothesised capsules. The recommended dosage regimen that infections (especially viral), a primary is 2 capsules (1 capsule containing 400 mg) immune system defect, disturbance of hypo- twice a day or 1 sachet (800 mg) twice a day thalamic–pituitary–adrenal axis and neurop- for the first 14 days, then 1 capsule twice a sychiatric factors can play an aetiopathogenic day or 1 sachet daily for the next 3 months, role. Immunologically, there are abnormali- then a 3-month pause followed by 3 months ties in lymphocyte count and function, main- 43 club foot (pes equinovarus) ly NK-cells; elevated levels of certain cytok- Clinical symptoms: The chronic exanthe- ines and autoantibodies may be observed. ma is a maculopapular urticaria, rarely asso- There are no specific diagnostic laboratory ciated with pruritus. The trigger for urticaria tests for the diagnosis of CFS. A diagnosis is can be solar radiation. The arthritis is sym- often only made by exclusion of known ill- metrical and always affects knee joints. Ar- C nesses such as infections, neurological and thritis of hip joints, shoulders and the verte- psychiatric diseases. The diagnosis of prima- bral column has never been reported. Impor- ry CFS is often very difficult as it can be eas- tant symptoms of central nervous system dis- ily confused with a chronic state of fatigue ease are due to a chronic meningitis include secondary to various diseases. headaches, vomiting and convulsions; mental retardation development is very frequent. Chronic hepatitis → see Hepatitis Other organ impairments include oedema of optic nerve papilla, chorioretinitis, uveitis, op- Churg-Strauss syndrome (CSS) A syn- tic nerve atrophy, sight defects and even blind- drome characterised pathologically by a ne- ness. Serious growth retardation, which is not crotising vasculitis with extravascular necro- due to hormonal disturbance, is a generalised tising granulomas and eosinophilic infiltrates sign of CINCA. Mutations of the CIAS1 gene in the vessel walls and perivascular tissues. have recently been described. Clinical symptoms and signs: The most important manifestations are asthma (often CJD → see Creutzfeldt-Jakob disease (CJD) longstanding), allergic rhinitis, systemic symptoms and multisystem manifestations Clinical examination algorithm in like transient pulmonary infiltrates, mono- rheumatology neuritis multiplex, and rashes (often palpable 1. history A good history of onset, duration, purpura). The heart is often affected (with a localisation, character and subsequent higher mortality), but gastrointestinal and re- course of the rheumatic pain are particu- nal involvement are rare. There is a marked larly significant. peripheral blood eosinophilia that can reach 2. inspection Observation of changes in joint up to 50% of leukocytes; some patients have contour (flattening, coarsening, disfigura- high levels of serum IgE and up to 65% of pa- tion), swelling, oedema, colour of the skin, tients are p-ANCA (anti-MPO) positive. A joint deformities, muscle atrophy, rheu- biopsy of affected tissue shows necrotising matoid nodules, nodes, tophi, etc. extravascular granulomas with eosinophils 3. palpation The extent of palpable tender- and necrotising vasculitis. ness, skin temperature, joint effusion, are the treatment of choice (prednisone in crepitation (coarse, soft, snowy), bursal doses 40–60mg/day) with the addition of cy- swelling, painful insertions, zones and clophosphamide or azathioprine if there is an points of hyperalgesia as in fibromyalgia, incomplete response. The prognosis has im- trigger points, myogeloses etc. proved with 5 years survival at 70%. 4. examination of joint movement Both ac- tive and passive ranges of movement in CINCA syndrome CINCA is a rare, but se- affected joints are recorded, with restric- rious, rheumatic disease that affects new- tions in the movement pattern of individ- borns and children in early childhood char- ual joints caused by pain, inflammation, acterised by the appearance of chronic exan- or structural changes. Joint laxity/instabil- thema, recurrent joint inflammation and ity is also noted. Muscle strength/weak- central nervous system disease. The nomen- ness is assessed against gravity and resis- clature CINCA is derived from the English tance. names of its common features, taking the first letter of each: Chronic, Infantile, Neurologi- Club foot (pes equinovarus) This defor- cal, Cutaneous, Articular. mity is a birth defect characterised by a plan- cluster of differentiation 44

tar flexion of the foot, varus position of the endomysial antibodies and serum IgA anti- heel and adduction of the metatarsus. It is bodies against tissue transglutaminase. A de- corrected by wearing special orthopaedic finitive diagnosis is demonstrated by footwear in which pressure is applied to the histological and histochemical analysis of the C three fundamental points in the opposite di- biopsy specimen of the duodenum, usually rection to the described deformities. by gastroscopy. The only curative treatment is a life-long gluten-free diet Cluster of differentiation → see CD (clus- ter of differentiation) COL1A1 gene polymorphism A (G-T) polymorphism in the collagen gene COL1A1 Codmann’s exercises These are intended (located on the long arm of chromosome 17) to relieve the corrugated joint capsule in the coding for a binding site of the transcription affected shoulder joint. They consist of a factor Sp1 influences the transcription of swinging movement of the shoulder joint ei- COL1A1 gene for type I collagen and induces ther in a supine position with the upper ex- changes in the properties of the produced tremity loosely hanging over the edge of the collagen. The binding affinity of the poly- table, or in ante-flexion with both arms morphous allele “s” for the transcription fac- loosely hanging. The axial tension on the tor Sp1 increases which leads to the synthesis shoulder can be increased by gradually in- of larger amounts of the α (I) chain compared α 1 creasing weight. They are used as the first ac- to the 2(I) chain. A ratio of these two chains tive exercises in shoulder pain syndrome. in the collagen type I is 2,3 in “Ss” heterozy- gotes and 2 in “SS” homozygotes. This abnor- (Sprue) A genetically de- mal ratio of α chains in the collagen of “Ss” termined disorder characterised by an im- heterozygotes is associated with a predisposi- munopathological reaction against certain tion to osteoporotic fractures. A slight asso- prolamins (the proteinous fraction of grains; ciation between the “s” allele incidence and a gliadin in wheat, secalin in rye, hordein in lower BMD, and conversely an increased as- barley, avenin in oat; only rice and corn are sociation with fractures shows that this poly- considered safe) with consequent damage to morphism mainly affects the bone strength the intestinal mucosa. There is loss of villi, independent of the BMD. hyperplasia of the crypts and increased turn- over of enterocytes resulting in a reduced ab- Collagen type II defects Articular carti- sorption surface and increased mucosal per- lage collagens are types II, IX, X and XI. Type meability with the development of a malab- II collagen is the principal molecular compo- sorption syndrome. Typical gastrointestinal nent and consists of three identical polypep- symptoms and signs (profuse diarrhoea and tide chains. The gene for its production is lo- ) are found only in young calised on chromosome 12. Mutations of this children after weaning; later extra-intestinal gene lead to various diseases as achondrogen- symptoms and signs (growth disturbance, esis type II, , Kniest’s delayed puberty, arthralgia, dysthymia, dam- dysplasia, and most spondyloepiphyseal dys- aged tooth enamel, osteopenia or osteoporo- plasias. sis, anaemia, etc.) dominate or can be the only clinical symptomatology. Thus only a Colony-stimulating growth factors small number of patients are accurately and Glycoprotein cytokines regulating prolifera- timely diagnosed. A high prevalence (1:100 tion and maturation of haematopoietic pro- to 300 of a Caucasian population) occurs. genitor cells as well as the functional activity The most severe complication in untreated of mature cells. The best-characterised patients is an increased risk of intestinal tu- growth factors are CSF regulating the pro- mours (especially lymphomas) in late mid- duction of granulocytes and macrophages. dle-aged persons. There are serum IgA anti- There are four of them: macrophage M-CSF, 45 complement – biological activities granulocyte G-CSF, granulocyte-macrophage vated by four pathways – classical, alternative, GM-CSF and multi-CSF (IL-3). Some of lectin pathway, and by the production of the them are now available in a recombinant membrane attacking complex (MAC), which form, especially GM-CSF which has been ap- is a common continuation of all three afore- plied in the immunotherapy of tumours and mentioned activation pathways and is direct- C certain immunodeficiencies. ly responsible for the impairment and lysis of target cells (cells on whose surface the com- Combination Disease Modifying Anti- plement has been activated). Rheumatic Drug (DMARD) therapy Re- Constituents of complement reacting in cent clinical experience shows that joint in- the classical pathway are components termed flammation in rheumatoid arthritis (RA) can as C1, C2, C3 and C4, whereby the C1 com- be better suppressed by a combination of ponent has three subunits C1, C1r and C1s. DMARDs, if one alone fails. At present, how- These components, except for C1q, also par- ever, it is impossible to explicitly state wheth- ticipate in the lectin complement activation er combination DMARD therapy should be pathway, while the components C5b, C6, C7, given as initial therapy in RA. C8 and C9 together form the membrane at- Combination of DMARDs tacking complex. Factors B and D and the C3 • with documented efficacy: component are constituents of the alternative methotrexate + antimalarials, pathway, which is also controlled by factors P methotrexate + antimalarials + sulfasala- (properdine), H and I. The other regulatory zine, glycoproteins are named according to their methotrexate + cyclosporin, function, for example C1-INH (C1-inhibi- sulfasalazine + methotrexate, tor), C4-bp (C4b-binding protein) and MCP sulfasalazine + cyclosporin, (membrane co-factor protein); or they methotrexate + etanercept, among receptors specifically binding only methotrexate + infliximab, fragments of certain components, for exam- • with probable efficacy: ple, C3b and iC3b fragments bind to recep- methotrexate + injectible gold, tors CR1 to CR4, the C5a fragment binds to sulfasalazine + antimalarials, C5aR, and so on. The individual components • with unconfirmed efficacy: are gradually activated by a cascade mecha- injectible gold + antimalarials, nism. The activation of one component is fol- antimalarials + cyclosporin, lowed by the occurrence of usually an active methotrexate + azathioprine, proteolytic enzyme, which cleaves the next penicillamine + antimalarials. component into two fragments, one of which is a protease cleaving the next one, etc. Cer- Combined B- and T-cell deficiency De- tain fragments are not proteolytic enzymes, fects in the function of B- and T-cells appear but possess the function of cofactors or vari- with subsequent insufficiency of humoral ous bioregulatory substances. and specific cellular immunity, and some- times phagocytosis. Typical examples are se- Complement – biological activities vere combined immunodeficiency (SCID), The complement system has executive and ataxia-telangiectasia and Wiskott-Aldrich regulatory functions involving the complex syndrome. of its terminal components (MAC), individu- al fragments of the first components and of Complement (C) A set of over 30 different certain factors, as well as a number of recep- executive and regulatory glycoproteins, some tors on the surface of diverse cells and hu- of which can be found in the blood serum moral regulators. In a view of the macroor- and others on the cell surface, where they ganism, the activity can be either beneficial form various receptors. Complement exists or harmful. The basis of beneficial activity is in serum in an inactive state and may be acti- mainly protection against pathogenic micro- complement – genetics 46

organisms and heterogeneous cells, then par- nuclear animal cells and gramnegative bacte- ticipation in inflammatory reactions and ria can be accomplished only by the complex

regulation of the immune response. Harmful C5b678(9)n. The C9 component, being a typ- activity (impairment of one’s own cells and ical perforin, plays a decisive role and the C tissues) is expressed in certain immuno- MAC contains 6 to 18 of C9 monomers. The pathological reactions, especially in those in- whole complex forms hollow tubules that are duced by circulating immune complexes and built into the cytoplasmic membrane of the cytotoxic autoantibodies (immunopatholo- target cells, thereby producing holes through gy). The main biological activities of comple- which ions, water and other low-molecular ment include cytotoxic and cytolytic reactions weight substances may flow uncontrolled, as (MAC being responsible for them), the pro- the osmotic pressure inside the cell is higher duction of anaphylatoxins, C5a, C3a and C4a, than in its environment. This leads to cell opsonins (C3b, iC3b and C4b fragments) and oedema, splitting of its cytoplasmic mem-

chemotactic factors (C5a, C5adeArg, and Ba brane and then to cell lysis. fragments). Complement receptors These are pres- Complement – genetics Immunogenet- ent on the surface of various cells and specifi- ics relating to the localisation, structure and cally recognise and bind fragments of certain regulation of genes coding for individual components and fragments of the comple- components of the complement system. The ment system. They can be divided into two genes for the majority of glycoproteins of the groups: complement system demonstrate two main 1. CR1 to CR4 whose ligands are C3b and forms of genetic variability: fragments derived from C3b • absence of a proper gene or existence of zero 2. Receptors for other components of com- alleles in the corresponding locus in certain plement, such as receptor for C1q (C1R), individuals in the population The zero allele anaphylatoxins (C5aR) of factor H (HR). is coding for a non-functional protein or does not transcribe into a protein product Complex BT → see Balneotherapy (BT) at all. Thus a certain deficiency develops that may manifest in various autoimmune Complex regional pain syndrome of or infectious disorders (complement defi- the shoulder (CRPS; humeroscapular ciency). periarthropathy; painful shoulder) A • existence of a complement protein polymor- common term for various lesions of the peri- phism To date, the incidence of polymor- articular structures of the shoulder joint. phic forms has been found not only in the Most frequently, they are tendinopathies of majority of components and factors of the rotator cuff tendons, or together with cal- complement, but also in certain comple- cium accumulation (calcific tendinitis), then ment regulators such as C4-bp (C4-binding bursitis (most frequently subacromial bursi- protein) and CR1 (C3b receptor). The de- tis), rotator cuff rupture and lesions of the termination of these polymorphic forms tendon of the long head of biceps. Differen- (allotypic variants) has a significant mean- tiation of the pain aetiology and localisation ing in the genetic characterisation of the of the lesion are essential for effective therapy. individual and in population studies See algodystrophy syndrome (ADS). (Moreland et al. 2004). Complotypes Polymorphic genes coding Complement (MAC) An abbreviation for for C2 and C4 components of the comple- membrane attacking complex. Penetration of ment and factor B which are inherited as a the cytoplasmic membrane and lysis of heter- single unit, thus as one haplotype. They are ologous erythrocytes can be undertaken by located in the HLA complex region on the the complex C5b678 alone, whilst lysis of short arm of the sixth chromosome. There is 47 conventional antibodies a close relationship between complotypes evance of cervical spine changes in rheuma- and HLA haplotypes, indicating that certain toid arthritis – spondylodiscitis, atlanto-axial HLA haplotypes are always related to certain subluxation, erosion of the dens; enables dis- complotypes. tinction between inflammatory and degen- erative processes of the spine, disc protrusion C Computed Axial Tomography → see and herniation. CT is helpful in the diagnosis Computed Tomography (CT; Computed Ax- of joint complications, e.g. osteomyelitis, sep- ial Tomography, CAT scan) tic arthritis, complications after intra-articu- lar aspiration and injection or after surgical Computed Tomography (CT; Comput- intervention. ed Axial Tomography, CAT scan) A di- Arthro-CT agnostic method using ionizing radiation for A CT scan is performed after intra-articu- imaging. The imaging of tissues is based on a lar administration of contrast. Compared to densitometric principle; detectors scan the conventional arthrography, CT is better in amount of radiation, which after emission the evaluation of joint cartilage and subchon- from the source of X-ray go through the dral bone. Arthro-CT enables high quality scanned area of the human body. Absorption two-dimensional reconstructions in different of radiation after transition through body planes, which provides more transparent im- structures is measured. CT enables imaging aging. of a particular locality in the transverse plane. As CT is based on ionizing radiation with a The computer converts the values of radia- low sensitivity to soft tissue imaging, ultra- tion absorption from digital form into a par- sound and MRI are currently preferred in ticular degree of grey and thereby forms the certain rheumatological diagnostic tests. final image of organs and tissues. Based on this data, modern CT scans can also produce Conglutinin A lectin that can be found in subsequent two- and three-dimensional re- the serum and on the surface of various hu- constructions. Administration of contrasts man and other mammalian cells. It specifi- (orally, intravenously, intracavity, intrathe- cally recognises and binds to the monosac- cally) is used to improve imaging (emphasis- charides N-acetyl , L-fructose, ing density differences) of human tissues. L-glucose or mannose. Lectin interaction CT is not used in the diagnosis of rheu- with saccharides induces cell aggregation or matic inflammatory diseases as a basic evalu- activation of the lectin complement pathway ation method of the extent and distribution (complement). of bone change, and is not helpful in evaluat- ing early changes. Compared to conventional Conventional antibodies These are pro- , CT, by tomographic visualisa- duced in individual organisms after acciden- tion, enables better imaging of articular le- tal, targeted or experimental immunisation sions, erosions, destructions and positional by complete antigen (immunogen). They are changes, which are only partially visible on characterised by heterogeneity. Conventional plain X-ray. antibodies do not consist of one population CT plays an important role in the imaging of immunoglobulin molecules whose poly- of acetabular protrusion, precise visualisation peptide chains have an identical sequence of of a reduction in acetabular cavity and the ex- amino acids, but consist of a mixture of tent of proximal femur displacement, which a number of molecule types whose binding is essential for orthopaedic interventions. It is sites (immunoglobulin binding site) have a also useful for imaging areas with difficult ac- different affinity, and thereby also different cessibility by conventional radiography – specificity to particular epitopes of the com- sacroiliac joints, sternoclavicular, sternocostal, plete antigen that induced their production. costotransverse joints and temporomandibu- Each epitope in an antigen molecule stimu- lar joints. CT supplements the diagnostic rel- lates one particular clone of B lymphocytes to convertases 48

produce antibodies. As complete antigens corticosteroid treatment), and deficiency of have a number of epitopes, they activate sev- these anabolic hormones may contribute to eral clones of B lymphocytes and therefore the development of osteoporosis. produce polyclonal antibodies. Conventional C antibodies are basically a mixture of mono- → see Tietze’s syndrome clonal antibodies against a complex antigen and costochondritis containing several epitopes. COX-1 inhibitors → see Non-steroidal anti- Convertases Proteolytic enzymes develop- inflammatory drugs (NSAIDs) ing during activation of components and fac- tors of the complement to cleave the C3 or C5 COX-2 inhibitors → see Non-steroidal anti- components to C3a and C3b, or C5a and C5b inflammatory drugs (NSAIDs) fragments, respectively. Thus, there are two convertases, C3-convertases and C5-con- Coxa saltans (snapping hip syndrome) vertases. These differ in whether they form A voluntary or involuntary movement of the during the classical or alternative comple- iliotibial tract over the greater trochanter ment activation pathways. The C3-convertase causing an audible click. It can be caused by of the classical pathway consists of C4b2b an uneven length of the lower limbs or some fragments and the C3-convertase of the alter- other anatomic anomaly. The irritation of the native pathway consists of C3bBb fragments. greater trochanteric bursa can be manifested The C5-convertase of the classical pathway by tenderness or pain. consists of C4b2b3b fragments and the C5- convertase of the alternative pathway consists C-reactive protein (CRP) An acute phase of C3bBb3b fragments. reactant produced by the liver and acting mainly as an opsonin for bacteria, fungi, par- Corticosteroid-induced Osteoporosis asites and immune complexes. In the pres- The pathogenesis of osteoporosis in patients ence of calcium it binds to phosphorylcholine with endogenously or exogenously mediated which is a regularly occurring component of excess of glucocorticoids is complex. The di- phospholipids and complex polysaccharides rect influence of glucocorticoids on bone re- richly present in the cellular wall of a number modelling may be regarded as the most im- of bacteria and in the membranes of eukary- portant. Glucocorticoids act via specific glu- otic cells. It activates the classical pathway of cocorticoid receptors on osteoblasts. Activa- the complement system and is regarded as a tion of these receptors leads to an inhibition primitive antibody protecting the organism of replication and differentiation of osteo- until specific antibodies develop. It also binds blasts. Glucocorticoids reduce the duodenal to certain components of the nucleus of the absorption and the renal tubular resorption cell – chromatin, histones and small nuclear of calcium causing the development of sec- nucleoproteins – with reports also of binding ondary hyperparathyroidism. The other ef- to adhesive molecules of fibronectin and fect of glucocorticoids is their negative influ- laminin types, and certain biological polyca- ence on the skeletal muscles (protein catabo- tions. CRP is the most evaluated acute phase lism), which causes decreased stimulation of reactant in rheumatology. It has a very low new bone formation through relative inactiv- basal serum concentration with rapid and ity. Glucocorticoids also exert a negative in- prominent increase within a few hours after fluence on the hypothalamic-pituitary axis inflammatory or infective stimulation and with a consequent deficiency of sex hormones. short half-life of less than 24 hours. The adrenal production of oestrone, dihydroe- piandrosterone (DHEA) and androstenedione An audible phenomenon created decreases due to ACTH suppression (in pri- during movement of joints or tendons. A mary hypercorticism and during long-term coarse crepitus is present in degenerative dis- 49 cryoglobulins ease involving a major joint, a fine crepitus is One C-terminal propeptide is released from present in patello-femoral arthritis; a subcu- each collagen molecule built into the collagen taneous crepitus is present on the chest and fibril. It is released as an intact subunit with a neck, for example, in a superficial emphyse- molecular weight of l00 kDa. ma following a traumatic pneumothorax. The N-terminal (NTX) connection of the C N-terminal telopeptide with the helical area CREST (Calcinosis, Raynaud Esoph- of another collagen molecule is another site agus, Sclerodactyly, Telangiectasiae) of deoxypyridinoline and pyridinoline pro- syndrome → see Systemic sclerosis (SSc) duction in the bone collagen. These N-telo- peptides contain more deoxypyridinoline Creutzfeldt-Jakob disease (CJD) A dis- compared to the C-telopeptides. A substan- order elicited by prions, belonging to the pri- tial advantage of methods assessing the pyri- onoses. In the past, there was an erroneous dinoline crosslinks is that these fragments assumption that it was caused by unconven- carry information of the collagen from which tional (“slow”) viruses. The disease occurs in they are cleaved. Using this method to mea- three forms: hereditary, spontaneous (spo- sure urinary pyridinolines, the peptides de- radic) and the new variant CJD. The heredi- rived from the type II collagen (for example tary form is transmitted from the parent to in the rheumatoid arthritis and osteoarthro- their child and represents approximately 15% sis) should not cross-react. Currently, mea- of all CJD cases. It is caused by point muta- surement of serum NTX is preferred in order tion in the gene for the prion protein. The to eliminate the biovariability of urinary as- sporadic form of CJD occurs in mid and late says. Furthermore, other factors including an life (50 to 70 years), and has a rapid progres- incomplete urine collection is excluded. sion. Dementia and myoclonus (brief muscle The degradation products of collagen – spasms) are typical symptoms and signs. The NTX and CTX – significantly increase in new variant CJD has only recently been rec- conditions with accelerated bone turnover, ognised. It has been demonstrated that it is especially in prevailing osteoresorption. They caused by the same prion that had caused the are utilised mainly in the follow-up of effica- epidemic of bovine spongiform encephalopa- cy of the antiresorptive treatment. thy (BSE) in Great Britain (first recognized in November 1986). The disease affects younger Crow-Fukase-Takatsuki syndrome → age categories (18 to 38 years) and ends in see POEMS syndrome death usually within one year. It has devel- oped by the breakthrough of the interspecies Cryoglobulins They can be classified into barrier most probably by consuming food three groups: prepared from inoculated cows. In the years Type I – consists of cryoglobulins formed 1996 up to 2004, some 120 young people died by a single cryoprecipitable immunoglobulin from the new variant CJD in Great Britain of IgG, IgA or IgM class without known anti- alone. body-mediated immunity; rarely this can in- volve monoclonal light chains (Bence-Jones Crosslinked telopeptides of type I col- protein), lagen The C-terminal (CTX) fragment of type Type II – mixed cryoglobulins consisting of I collagen stems from cross-linked C-terminal a monoclonal immunoglobulin, most fre- telopeptides of two α1 chains of type I collagen quently IgM (but sometimes IgG or IgA), with the helical area of either the α1 or α2 chain with antiglobulin activity against the poly- from another collagen molecule and is released clonal IgG, during bone resorption. This fragment is prob- Type III – mixed cryoglobulins consisting ably bone-specific because it contains trans- of polyclonal immunoglobulins of one class verse bonds of a mature collagen that cannot be or sometimes with non-immunoglobulin found in type I collagen from other sources. molecules, for example C3 or lipoproteins. crystalline-induced arthropathy 50

The mixed cryoglobulins form the circu- CTX → see Crosslinked telopeptides of type I lating immune complexes and often induce collagen, Markers of osteoresorption, Peptide symptoms of . They occur fragments of collagen type I (NTX, CTX) in systemic lupus erythematosus, Sjögren’s C syndrome, and other au- Cyclooxygenase The cyclooxygenase en- toimmune, infectious and lymphoprolifera- zyme consists of two related isoforms that are tive disorders. Mixed cryoglobulinaemia was about 60% homologous (Figure 1). Both iso- usually linked with the hepatitis B virus in- forms convert arachidonic acid to endoper- fection. More recent studies have demon- oxides (PGH), thereby creating prostaglan- strated a strong association with chronic dins (PG), and prostacyclin. hepatitis C virus infection (30–98%) (Della The first isoenzyme (COX-1) was identified a Rossa et al. 2008). The absolute IgG concen- long time ago, when it was found to be the tration in the cryoglobulin may be a useful target site of the effect of non-steroidal anti- indicator in the diagnosing and monitoring inflammatory drugs (NSAIDs). The second of the disease, unlike the qualitative cryocrit isoenzyme COX-2 is also sensitive to NSAIDs. test, which only gives limited information. Recently a third isoform COX-3 has been de- tected that is derived from a gene for COX-1. Crystalline-induced arthropathy A The COX-3 differs from COX-1 and COX-2 group of inflammatory arthritides caused by in that it is more sensitive to the inhibitory intra-articular crystals, such as urate (gout), action of . calcium pyrophosphate (chondrocalcinosis The constitutive isoform of cyclooxygenase or pseudo-gout), and sometimes other crys- (COX-1) is found in almost all cells and ful- tals such as calcium hydroxyapatite and cal- fils the role of an enzyme responsible for cium oxalate. Diagnosis may be suspected maintenance of homeostasis at the cellular clinically by the history and distribution of level. It facilitates the mechanisms for protec- joint involvement, but can only be confirmed tion of gastrointestinal mucosa, perfusion of by joint aspiration and a combination of light renal parenchyma, homeostasis on the level and polarised microscopy of the synovial of vascular endothelium and platelet func- fluid. tion. The inducible isoform COX-2 is present exclusively at the site of inflammation or

Figure 1. Cyclooxygenase isoenzymes 51 cyclosporin damaged tissue. It is released after stimula- tween three and six months after oral admin- tion of the cell by different factors, cytokines istration; earlier with parenteral administra- and other mediators of the inflammation. tion. The disadvantage of pulse treatment is a The COX-2-dependent prostaglandins can higher number of infectious complications also have physiological roles in certain tis- and increased incidence of malignant diseas- C sues, especially in the brain, in renal perfu- es. A full blood count should be assessed con- sion and glomerular hemodynamics, func- tinuously – every 14 days for the first two tions of the uterus, responses to stressful months, and then every 6 to 8 weeks. When stimuli and in the physiology of embryonic thrombocytopenia or leukopenia occurs, the membranes. NSAIDs have been shown to dose should be reduced, and treatment dis- suppress both COX isoforms, i.e. COX-2 and continued if no improvement. It is advisable COX-1. They differ, however, in terms of to monitor the hepatic transaminases every their COX-2/COX-1 inhibition ratio, and so eight weeks and perform regular urinalysis, have been labelled as COX-1-specific inhibi- especially looking for haematuria (a sign of tors, non-specific COX-2/COX-1 inhibitors, haemorrhagic cystitis). selective COX-2 inhibitors and specific COX-2 The most frequent adverse events of cyclo- inhibitors, the so-called coxibs. COX-1 does phosphamide treatment are nausea and vom- not participate in the pathogenesis of inflam- iting. Their incidence rises in proportion to mation and the onset of pain. the dose, but can be effectively suppressed by ondansetron – a serotonin antagonist. A mild Cyclophosphamide N,N-bis(2-chloro- elevation of hepatic transaminases and leu- ethyl)-tetrahydro-2H-1,3,2-oxazaphospho- kopenia often occur due to bone marrow rin-2-amino-2-oxide, an alkylating agent that suppression. In long-term daily use of cyclo- after binding to DNA changes its structure, phosphamide, hemorrhagic cystitis can de- and consequently its properties. In addition velop. The acrolein toxicity can be decreased to anti-neoplastic action, it possesses signifi- by a high fluid intake and concomitant ad- cant immunosuppressive effects, predomi- ministration of compounds containing sulf- nantly against B-lymphocytes and antibody hydryl groups such as sodium 2-mercapto- production. ethansulfonate (MESNA). Dosage and clinical efficacy: It is an alky- lating agent that has the ability to interfere Cyclosporin (Ciclosporin) (CyA) A fun- with the nucleic acid molecules. Due to its gal cyclic peptide consisting of 11 amino acid rather high toxicity, it is not a first line treat- units. The first cyclosporins were derived ment, and the risk-to-benefit ratio should be from the fungal strain Tolypocladium infla- very carefully assessed before proposing it for tum isolated at the turn of 1969 and 1970. treatment. It is used most frequently in the Nowadays, however, cyclosporins represent treatment of severe forms of systemic vasculi- relatively common secondary metabolites of tis such as microscopic polyarteritis, Wegen- the soil fibrous fungi Acremonium, Aphano- er’s granulomatosis, and severe systemic lu- cladium, Beauveria, Fusarium, Verticillium, pus erythematosus and now less frequently in Tolypocladium and Trichoderma. It has been . The usual initial oral the most important immunosuppressive agent daily low dose regime lies between 1–2.5 mg/ used as a treatment in clinical medicine, espe- kg/day. Once a clinical effect has been cially transplantology, but also in the treat- achieved (usually after 6 months) the dose is ment of various autoimmune disorders. Its reduced to a maintenance dose of 0.5 mg/kg/ primary mode of action is to bind to cyclo- day or changed to an alternative less toxic im- philin causing blockade of IL-2 production munosuppressive agent, such as Azothi- and IL-2R expression by T-lymphocytes. aprine. Intermittent pulse intravenous treat- Clinical efficacy: Cyclosporin (A) is used ment is given at doses of 500–1500 mg/m2/ in the treatment of rheumatoid arthritis (RA), month. The treatment often takes effect be- either as monotherapy or as part of combina- cyriaxCyriax method 52

tion treatment. It is not considered a first-line body as signalling compounds. They affect treatment of RA. Its efficacy in monotherapy the direction, intensity and duration of im- is comparable to the other disease modifying mune and inflammatory reactions, as well as anti-rheumatiс drugs (DMARDs) such as oral other physiological and pathophysiological C and parenteral gold compounds, antimalari- manifestations of the cells in a paracrine, au- als and sulfasalazine, though it is limited by a tocrine or endocrine way. When they act narrow therapeutic versus toxicity ratio. The preferentially within the immune system, slowing down of the radiological progression they are referred to as immunokines; if their of bone erosions has so far not been conclu- primary target is the central nervous system, sively confirmed, though there are several they are referred to as neurokines. Cytokines studies showing positive evidence of this ef- are interconnected in the network responsi- fect (Zeidler et al. 1998, Forre et al. 1994, Fer- ble for intercellular communication within raccioli et al. 1997). the nervous system, as well as for information Dosage: In the treatment of RA the dosage exchange between the immune system and of CyA is in the range of 2.5–4.0 mg/kg/day, other systems in the body. Cytokines include with initiation at the lower dose. CyA is ad- lymphokines, interleukins, interferons, tu- ministered in divided dose twice a day, usu- mour necrosis factors, colony stimulating ally with a meal. When necessary, the dose is factors, transforming growth factors, poly- gradually increased by 0.5 mg/kg/day up to a peptide growth factors, chemokines (interk- maximum dose of 4 mg/kg/day. If there is no ines), stress proteins and others. benefit after using the maximum dose for six months, treatment should be discontinued. Cytophilic antibodies Antibodies that In the course of treatment blood pressure bind to the surface of cells through Fc-recep- and the serum creatinine level are monitored. tors and not through their own binding sites. If blood pressure rises or the serum creatinine Similarly IgE can bind IgE antibodies to the level becomes increased by 30% compared surface of mast cells and basophils through with the pre-treatment value, the dose should high affinity receptors for the Fc fragment. Af- be decreased or treatment discontinued. ter such binding, they still have a free binding Adverse effects of CyA treatment: site available for the specific antigen epitope. renal complications: increase in serum creati- nine, tubular atrophy, interstitial fibrosis, Cytotaxins Chemotactic factors (chemot- arterial hypertension, axins) are compounds inducing the chemo- consequences of : recur- tactic movement of cells (chemotaxy). This rent infection, risk of malignancy, movement can be positive (cells moving to- other: hepatotoxicity, gastrointestinal distur- wards the source of cytotaxins, i.e. in the di- bances, hypertrichosis, gingival hyperpla- rection of rising cytotaxin concentrations), or sia, hyperkalaemia. negative (cells moving in the direction of fall- ing cytotaxin concentrations). Cyriax method An exercise of applied and functional anatomy in which assessment of Cytotoxic antibodies Antibodies that body movements indicates where lesions lie. specifically react to superficial epitopes of First described by James Cyriax (1905–1985, target cells and thereby activate complement. Orthopaedic Surgeon in England) as “the Subsequently, the activated complement method of systematic examination of the damages or even lyses the cell marked in this moving parts by selective tension”. manner. Cytotoxic antibodies (particularly IgG) may be involved in cell impairment by Cytokines An extremely large group of gly- the ADCC (Antibody dependent cell-medi- coproteins or proteins that are used in the ated cytotoxicity) mechanism. D

Dactylitis → see (PsA) such a situation. Apart from the typical skel- etal X-ray changes, other findings include a DAS 28 (disease activity score based on a 28 high serum PTH level, hypophosphataemia joint assessment) and increased serum alkaline phosphatase. The disease activity of rheumatoid arthritis The 25-OH vitamin D level is very low. Defi- can be quantified by official criteria of the ciency of the active metabolite of vitamin D European League Against may also occur in severe chronic liver disease, (EULAR), being referred to as DAS (disease chronic renal impairment or with certain an- activity score). After assessment of 28 tender ticonvulsant drugs. Hereditary defects of vi- joints (0–28), 28 swollen joints (0–28), the tamin D metabolism include vitamin D-de- erythrocyte sedimentation rate, and a patient pendent type I with 25-OH vitamin global assessment (GA) by a Visual Analogue D-1 alpha hydroxylase deficiency or heredi- Scale (0–100), the DAS 28 is calculated is as tary resistance to calcitriol (previously re- follows: DAS 28 = 0.56√t28 + 0.28√sw28 + ferred to as vitamin D-dependent rickets type 0.7ln(ESR) + 0.014GA (t – tender joints, sw II), which represents the group of rare dis- – swollen joints). The DAS 28 activity evalua- eases with a functional defect of vitamin D tion: remission DAS 28 < 2.6, low activity receptors. DAS > 2.6 < 3.2, medium activity DAS > 3.2 < 5.1, high activity DAS 28 ≥ 5.1. Deficiency of C1-inhibitor This is ex- DAS calculation: pressed as hereditary angioedema. This defi- Automatic at http://www.das-score.nl/www. ciency is inherited as an autosomal dominant das-score-nl/DAS28calc.htm trait and there are three mechanisms induc- In Excel format at http://www.das-score.nl/ ing it: decreased level of C1-INH (partial de- www.das-score-nl/DAS28ne.xls ficiency), malfunction of its molecule (a mu- tation in the relevant gene) or the presence of de Quervain’s stenosing tenosynovi- autoantibodies against C1-INH. tis Roughening of the tendon sheaths of the extensor pollicis longus and brevis muscles Deficiency of complement The defi- and abductor pollicis longus muscle, which ciency can involve individual components, evoke pain radiating to the thumb and fore- factors or regulatory glycoproteins of the arm. The pain worsens when grasping or complement system (C). The vast majority of squeezing the hand. Operative solution – re- primary deficiencies are inherited as an auto- moval of the roughened tendon sheath. somal recessive trait. The absence of the first components participating in the classical ac- Defect of vitamin D metabolism Hy- tivation pathway (C1q, C1r, C4 and C2) is pocalcaemia is not frequent in vitamin D de- expressed as a systemic lupus erythematosus- ficiency as a secondary increase in parathor- like syndrome. The deficiency of C3, leading mone (PTH) usually retains the serum calci- to chronic pyogenic infections, belongs to the um level within the normal range. However, most severe deficiencies. The deficiency of it is possible in long-term the terminal components (C5 to C9) is mani- and can lead to clinical rickets in children. fested by increased susceptibility to infections Failure to supplement vitamin D in a breast- induced predominantly by Neisseria gonor- fed child along with other risk factors (insuf- rhoeae and Neisseria meningitidis. The most ficient calcium intake in food) may lead to severe deficiency of regulatory glycoproteins deficiency of iga,IgA, selectiveselective 54

is the deficiency of C1-inhibitor with angioe- Deformities These are often the result of dema as a consequence, and also DAF or rheumatic inflammatory and degenerative MACIF deficiencies, which cause the devel- disorders. In rheumatoid arthritis there may opment of paroxysmal nocturnal haemoglo- be deformities of the hand and fingers (swan- binuria. neck deformity, boutonniere deformity, mal- let-finger deformity, Z deformation of the Deficiency of IgA, selective D This is one thumb, flexion and subluxation deformities of the most frequent selective immunoglobu- or ulnar deviation in the metacarpophalan- lin deficiencies (involving individual immu- geal (MCP) joints, bayonet position in the noglobulin classes or subclasses). Approxi- wrist, volar subluxation or luxation of the ra- mately 0.2% of clinically healthy blood do- diocarpal joint (drop hand). nors have a significantly decreased level of A flexion and supination position of the IgA in the serum and mucosal secretion. The forearm with limited movement in the proxi- situation becomes critical when the concen- mal radio-ulnar joint. tration of serum IgA drops below 1 mg/L. An adduction deformity of the shoulder These patients suffer from recurrent respira- together with a cranial shift of the scapula. tory, gastrointestinal and genitourinary tract An adduction, flexion and internal rota- infections. In addition they are prone to - tion deformity in the hip, Knee deformities ly-type allergic reactions, such as food aller- such as genu varum or valgum, longitudinal gies or atopic bronchial asthma. Treatment and transverse flat-foot, hallux valgus, ham- with an intravenous immunoglobulin prepa- mer toes, crossing toes. ration containing IgA is contraindicated due to the possibility of developing an anaphylac- Dendrites Thin branched projections aris- tic shock. In some patients with IgA deficien- ing from the body of the nerve cell. They cy, it is possible to choose a cautious treat- serve as an input region for stimuli and trans- ment approach by influencing mucosal im- mission of electrical impulses to the cell munity, where IgA plays an important role body (autovaccination, or the administration of bacterial lysates). Depo-medrone (Methylprednisolone) → see Glucocorticoids, Intraarticular gluco- Deficiency of phagocytosis Inefficient corticoid treatment function of professional phagocytes expressed predominantly as an increased susceptibility Dermatomyositis → see Idiopathic inflam- to infectious diseases. It is divided into a pri- matory myopathies (IIM), Non-inflammato- mary deficiency that is caused by abnormal ry myopathies, Juvenile dermatomyositis or missing relevant genes, and secondary de- (JDM) ficiency that can be induced physiologically (infants and elderly) through poor nutrition, DEXA → see DXA harmful factors of the external environment, various disorders or the toxic effect of xeno- Diabetes mellitus A metabolic disorder of biotics, including drugs. The most important glucose, lipids and proteins that occurs as a of the primary defects of phagocytosis in- consequence of a relative or absolute lack of clude: chronic granulomatous disease, leuko- insulin, or its insufficient effect. In 1990 the cyte adhesion deficiency (LAD syndrome), WHO accepted a new classification, according Job’s syndrome, Chédiak-Higashi syndrome, to which diabetes has two basic types. Type I the deficiency of specific granules, myeloper- has two subtypes either immunologically con- oxidase deficiency, glucose-6-phosphate de- ditioned or idiopathic. Insulin resistance or hydrogenase deficiency and tuftsin deficien- deficit prevails in type II. The other specific cy. types of diabetes are genetic disturbance of β-cell function, genetic disturbances of the ef- 55 diathermy fect of insulin, disorders of the endocrine pan- capsule of 50 mg each. It is administered creas, endocrinopathies, diabetes induced by twice a day after food for at least 6 months. drugs and chemical agents and rare forms of immunologically conditioned diabetes. Diadynamic currents (Bernard) Single- Immunopathological mechanisms play an or double-phase, one-way connection, modi- important role especially in type I diabetes. fied low-frequency (50–100 Hz) sinus currents The immunogenetic predisposition is provid- applied in various modalities. They have anal- D ed by an association with major histocompat- gesic and hyperaemic effects. A simple impulse ibility leucocyte antigens HLA-DR3, HLA- current (MF-monophase) has analgesic and DR4, HLA-DQ2 and HLA-DQ8. vasodilatatory effects. Currents shifting in Bone and joint manifestations of diabetes short periods (CP) have a spasmolytic effect. mellitus include specific arthropathy of the Currents shifting in long periods (LP) have hands and feet, shoulder joints, spine, and os- mainly an analgesic effect. Diadynamic cur- teopenia. rents are used for acute rather than chronic Arthropathy in the hands is characterised pain. by: • limitation of joint movement (LJM) – Dialysis associated osteoarthropathy cheiroarthropathy, A group of musculoskeletal diseases develop- • Dupuytren’s , ing in relation to chronic renal failure and • tenosynovitis of the peritendons of I, III chronic dialysis treatment. and IV fingers, • diabetic sclerodactyly or scleroderma dia- Diathermy A treatment with high-frequen- beticorum, cy currents where the electrical energy is con- • carpal tunnel syndrome. verted in the body to heat (CAVE: pace- Affection of the foot: maker and metallic implants). • Charcot’s osteoarthropathy, Types of diathermy: • limited movement of the joint, 1. short-wave: a wavelength of 22.1 metres Affection of the shoulder: (deep heating in the condenser or induced • adhesive capsulitis, frozen shoulder syn- field), drome, 2. microwave: a wavelength of 12.5 centi- • calcified periarthropathy, metres (relatively better heating of the • limited movement of the joint, muscles; not used in children due to the • generally, the joints are affected by limited possibility of damage to the growth carti- movement, osteoarthrosis and chondro- lage and the lens), calcinosis. 3. ultra short-wave: a wavelength of 69 centi- Changes to the spine: metres (focusable electromagnetic wave). • Increased susceptibility to DISH (diffuse It has the same indication as for short- idiopathic skeletal hyperostosis). wave diathermy, in terms of effects it be- • neuropathic osteoarthropathy of Charcot’s longs to thermotherapy. joint type. The shorter the wavelength, the more uni- Changes in bone mass: form the heating of the tissue. The applica- • diabetic osteopathy. tion of diathermy induces deep production of heat in a circumscribed region that is ex- An acetylated (4,5-diacetyloxy-9, pressed by deep leading to in- 10-dioxo-anthracene-2-carboxylic acid) form creased tissue metabolism and relaxation of of , an extract of rhubarb, is a drug used striated and smooth muscle spasm. In patients in osteoarthritis. Inhibition of the effect of in- with rheumatoid arthritis, caution needs to be terleukin-1 and other proinflammatory cy- taken due to the possibility of inflammation tokines is its most important action. The outbreak (overheating). The main fields of preparation is encapsulated in a gelatinous indication for diathermy are osteoarthrosis diffuse diffuse cutaneous cutaneous ssc SSc (dcssc) (dcSSc) 56

(except for activated osteoarthrosis), fibrosi- paired relative to the usual standard of an in- tis, enthesiopathy and chronic periarthritis. dividual of their group. It may be reversible. Refer to “ICF classification” for newer infor- Diffuse cutaneous SSc (dcSSc) → see mation. Systemic sclerosis (SSc) Disease-Modifying Anti Rheumatic D Diffuse Idiopathic Skeletal Hyperos- Drugs (DMARDs) Disease-modifying anti- tosis (DISH; ankylosing hyperostosis; rheumatic drugs (DMARDs) or slow-acting Forestier’s disease) A chronic skeletal dis- antirheumatic drugs (SAARDs) are a group order of unknown aetiology occurring in of drugs with the potential to suppress dis- middle and later years. The characteristic fea- ease activity and thus reduce or prevent joint ture is massive new bone formation in the damage and preserve joint function. They shape of calcification and ossification of the were first used in rheumatoid arthritis, but spinal ligaments, predominantly in the region are now indicated in most immunologically- of the anterior longitudinal ligament causing mediated chronic joint inflammatory diseas- bony ankylosis of the anterolateral horns of es (psoriatic arthritis, juvenile idiopathic ar- the spine, more frequently on the right and thritis, etc.). They were initially only used in anterior aspects, with significant ossification. well established disease, but modern practice Involvement of the peripheral skeleton is is to introduce them very early (3–6 months) generally expressed by extensive enthesopa- to gain the most benefit. DMARDs include thies. Its aetiology is unknown; several au- methotrexate, sulphasalazine, leflunomide, thors classify it amongst the degenerative azathioprine, myocrisin and hydroxychloro- disorders of the skeleton, whilst others assign quine (see in relevant sections of the text). it to a metabolic or endocrine disorder. The They require careful monitoring under the American College of Rheumatology put it supervision of a rheumatology unit to ensure amongst the disorders of bone and cartilage. that the effective dosage regime is reached As a distinct disease, it has only appeared in and proper monitoring for toxicity. literature in recent years; previously it was usually mentioned in relation to the differen- Diseases causing diffuse oedema Dif- tial diagnosis of ankylosing spondylitis and fuse lower extremity oedema may be due to osteoarthrosis. arthritis such as traumatic arthritis, infec- Clinical symptoms and signs: tious arthritis, gout, seronegative spondy- • onset of clinical symptoms usually after the loarthritis and rheumatoid arthritis. Other 40th birthday, causes include Sudeck’s syndrome, diabetic • centripetal type of obesity, arthropathy – occurs in poorly controlled • insidious, often asymptomatic limitation diabetics in which leg or foot ulcerations and of spinal movements, osteolytic changes on the bones can be ob- • enthesopathic pain in the periphery (heels, served. Oedema can be caused by lymphoe- knees, elbows and shoulders), dema or cardiac, renal, hypoalbuminaemia • neurological signs of compression, or other aetiology. Among endocrinological • radiographic evidence of extensive hyper- disorders, it may be present in myxoedema. ostotic ossifications. Diseases causing foot oedema: conditions with foot deformity – pes equinus, pes equi- Digitus rigidus → see Toe swelling/defor- novarus, congenital pes varus, pes valgus, pes mity and associated diseases calcaneovalgus, pes excavatus, pes paralyti- cus, pes planovalgus. DIL → see Drug-induced Lupus Also tarsal tunnel syndrome may be in- volved (see below) in conditions mentioned Disability A condition or function judged above. to be significantly physically or mentally im- 57 Dougados’dougados’ system system of of assessment assessment of of spondyloarthritis spondyloarthritis (SpA) (spa)

DISH → see Diffuse Idiopathic Skeletal Hy- acid. In addition to these main bases, it can perostosis (DISH; ankylosing hyperostosis; also contain the so-called minority bases as Forestier’s disease) base modifications with low or no gene ex- pression. The adenine is always linked by the DMARDs → see Disease-Modifying Anti hydrogen bond to the thymine, cytosine to Rheumatic Drugs (DMARDs) guanine. The presence of complementary pairs of bases in the DNA double-helix en- D DNA antibodies Antibodies directed against ables the existence of a regular structure, be- DNA form a heterogeneous group of antibod- cause all pairs of bases have the same size. ies directed against various antigenic determi- The DNA molecule does not contain all four nants on the DNA molecule. Antibodies bases in the same molar proportions. Their against double-stranded DNA (dsDNA) are contents can be expressed by the following diagnostically specific (97%) for systemic lu- relation A/T = G/C ≈ 1. The sequence of the pus erythematosus (SLE), while antibodies bases in the chain is not random, as it is de- against single-stranded DNA (ssDNA) are fined and creates the genetic information present in the course of various diseases, such whose carrier is the DNA. More than 90% of as rheumatoid arthritis, Sjögren’s syndrome, DNA is located in the nucleus of the cell, as a progressive systemic sclerosis, drug induced component of chromosomes, while part of it lupus, chronic active hepatitis or infection. lies in the structure of the cell and mitochon- Anti-dsDNA was first described by a number dria. The mutation of individual genes (sec- of authors in 1957. A positive correlation be- tions) of DNA can lead to the development of tween these antibodies and the presence of genetically determined diseases. In 1953 nephritis in the course of SLE was observed. James Watson, Francis Crick and Maurice Circulating anti-dsDNA belongs to IgM, IgG Wilkins received the Nobel Prize for the dis- and rarely IgA classes; IgG antibodies are covery of DNA. An understanding of its more significant than IgM as their presence structure enabled other discoveries, leading correlates with the activity of the disease and to the development of genetic engineering, with the severity of nephritis. Such a correla- reliable identification of an individual on the tion can be found also among antibodies basis of DNA, but also to the successful map- which fix and activate the complement, par- ping the whole human DNA (genome). ticularly IgG anti-dsDNA. The pathogenicity of anti-dsDNA depends on their various Dougados functional index A function- physical properties. Although single assess- al index completed by the patient of 20 ques- ment of anti-dsDNA is highly diagnostic, tions using activities of daily living (e.g. put long-term monitoring of these antibody lev- on your shoes, breathe deeply), most com- els is recommended for prognostic purposes, monly in patients with . as increasing titres of anti-dsDNA indicate Each question is answered by either yes, yes increasing disease activity and may predict but with difficulty, or no. It has largely been disease flare. superseded by the Bath AS functional index (BASFI). DNA (Deoxyribonucleic Acid) The ge- netic material of all cells and many viruses. Dougados’ system of assessment of The DNA molecule is a dextrorotatory dou- SpondyloArthritis (SpA) The system con- ble-helix polymere consisting of two polynu- sists of two parts: cleotide chains interconnected between the 1. articular index Examined by a physician purine and pyrimidine bases by a hydrogen (pressure on the thorax from the front and bond. DNA contains the two purine bases ad- from the side, maximum flexion in the hip enine (A) and guanine (G) and the two py- joint, a pressure on the middle part of glu- rimidine bases cytosine (C) and thymine (T); teus maximus muscles, spine rotation furthermore, 2-deoxyribose and phosphoric while sitting with the upper limbs crossed down’sDown’s syndrome 58

– pressure pain is evaluated in four de- and systemic sclerosis, but is now recognised grees). as only a very mild disease modifying anti- 2. functional index Evaluation of the ability rheumatic drug, and has a high incidence of to perform certain daily activities (Douga- side effects. Its onset of action takes many dos functional index, DFI). months as the dosage regime is start low and increase slowly. It is initiated at 125–250 mg D Down’s syndrome Caused by duplication daily in the morning on a empty stomach of part of the entire 21st chromosome (tri- with increases of 125 mg daily every 4 to 6 somy), which manifests in mental retardation, weeks to a dose of 500–750mg daily. In sys- disturbances of immunity and congenital heart temic sclerosis, it has mild effects in retarding disease. The genes for certain proteins impor- the progress of skin thickening and survival, tant for the immune and nervous systems but usually at a dose of 750–1,500 mg daily. (CuZn-, β-chain of the Full blood count and urinalysis are necessary leukoadhesive integrins, interferon receptors, every 1–2 weeks for the first 2 months, then etc.) are located in the chromosomal region every 4–6 weeks thereafter. 21q22. The increased expression of these pro- Adverse events: teins participate in the underdevelopment of Mucocutaneous: the thymus and abnormal maturation of T- • mouth ulcers, stomatitis, lymphocytes that results in their defective • pruritus, rashes, function leading to an increased risk of infec- • hair loss, dermatitis, pemphigus, tions, an increased incidence of malignancies • cutis laxa (elastolysis),* and autoimmune disorders (especially hypo- • elastosis perforans serpiginosa.* thyroidism). Patients can also suffer from hy- Pulmonary: permobility of the joints and atlanto-axial in- • acute pneumonitis, stability with spinal cord compression. • acute alveolar haemorrhage, • bronchiolitis obliterans. D-penicillamine A chelating agent which Autoimmune disorders: binds copper and other metals. This ability is • myasthenia gravis, utilised in the treatment of Wilson’s disease, • polymyositis/dermatomyositis, where copper accumulates in tissues. Based • drug-induced lupus erythematosus, on the assumption that it could dissociate im- • pemphigoid, pemphigus, mune complexes by disrupting the disulphide • Goodpasture’s syndrome. bonds between the chains of the immuno- Renal: globulin molecule, it was introduced in the • proteinuria, haematuria, treatment of rheumatoid arthritis (RA) many • glomerulonephritis. years ago, but is now rarely used. It has also Haematological: been used in the treatment of systemic sclero- • thrombocytopenia, leukopenia, sis, though clinical efficacy now appears poor. • aplastic anaemia. Pharmacokinetics: After oral administra- Gastrointestinal: tion, it is detected in the plasma as early as 20 • nausea, loss of taste, minutes. The maximum plasma concentra- • hepatitis, tion is reached in 1.5 to 4 hours. After oral • cholestasis. administration 40–70% of the drug is ab- Gynaecomastia sorbed. Its bioavailability can be significantly * detected in patients with Wilson’s disease decreased by concomitant food intake, antac- and cystinuria treated with high doses of D- ids and iron preparations. It binds to albumin Penicillamine in the circulation and is largely excreted in the urine within 12 hours. Drug-induced Lupus Many drugs, par- Efficacy: D-Penicillamine is used in the ticularly those from the groups of cardiac an- treatment of RA, juvenile idiopathic arthritis tiarrhythmics, antihypertensive agents and 59 dystrophia musculorum progressiva anticonvulsive drugs may evoke a clinical the height of the vertebral body without a his- condition similar to lupus in some patients. tory of major trauma belongs to the most im- More recently, it has been caused by the ad- portant risk factors of development of another ministration of biologic therapy. Such a clini- fracture and independently of the measured cal condition is called drug-induced lupus BMD. With the combination of BMD and as- (DIL, sometimes also drug-related lupus) and sessment of vertebral morphometry, we may usually recovers after discontinuation of the achieve better selection of the patients with a D inducing drug. DIL constitutes less than 10% higher risk of fracture. The relatively short du- of diagnosed lupus. Compared to systemic ration of the scan and low radiation dose and lupus erythematosus, DIL is more frequent in BMD measurement at the same time are the males than in females. advantages of this method. The capital cost of Clinical symptoms: the newer densitometers with the necessary • most frequent: arthralgia, myalgia, weak- software, the not infrequently worse projec- ness, fever, pleuropericarditis tion of the vertebrae, especially in the upper • less frequent: skin and mucosal symptoms, thoracic part of the spine compared to a classi- haematological abnormalities (anaemia, cal X-ray, are its disadvantages. leukopenia, thrombocytopenia), • rare: central nervous system impairment, Dynamic aerobic exercise Greatly in- nephritis. creases muscle strength and stamina, as well aerobic capacity compared with a static exer- Drug induced muscular diseases → see cise. In rheumatoid arthritis, muscle strength Non-inflammatory myopathies and stamina are affected by age, concomitant diseases and functional disability. Drug-induced Osteoporosis Several drugs may influence adversely bone turnover Dysesthesia Unpleasant, abnormal sensa- and bone mineral density thereby increasing tions occurring spontaneously or after a the risk of fracture, when taken in the long stimulus. term. Most frequently, they are glucocorti- coids, heparin, anticonvulsants, high doses of Dystrophia musculorum progressiva medrooxyprogesterone acetate, and high One form of hereditary non-inflammatory doses of thyroid hormones. disease of the muscles. Onset can occur in childhood or adulthood. It predominantly af- DXA – Morphometric lateral scans The fects proximal muscles (shoulder and hip newer DEXA devices can perform rapid lateral girdles) in a symmetrical fashion which as scans of the thoracic and lumbar spines. This they weaken, lead to a “duck” gait and climb- allows evaluation of changes in height and ing the thighs on straightening from a knees- shape of individual vertebrae. These scans are bend. There is a detectable myogenic lesion evaluated by special software for measurement on EMG (electromyography). The serum cre- of vertebral body height. The differences in the atine kinase and aldolase levels are increased measured height of vertebra in the dorsal, me- and creatinuria is present. Biopsy confirms a dial and anterior part of its body can indicate non-inflammatory myogenic atrophy of the wedging, and thus a fracture. Thus the scan muscles with fibre degeneration. enables an evaluation of vertebral fractures at Treatment: There is no effective treatment, the same time as BMD measurement without but careful physiotherapy. Anabolic hormones the conventional lateral X-ray. Reduction of and vitamin E are sometimes given. E

Early T lymphocyte activator 1 → see Eiselsberg’s phenomenon → see Acute Osteopontin (OPN) shoulder pain

Ehlers-Danlos’ Syndrome (EDS) A group Electromyography (EMG) A recording of of hereditary connective tissue disorders, char- the electric potentials from striated muscles. acterised by hyperelasticity and fragility of the The potentials are recorded with surface elec- skin and hypermobility of the joints. Various trodes, or more accurately by direct needling. forms differ by their clinical picture and ge- The potentials are amplified by the EMG de- netic background. In individual patients, EDS vice and displayed on a screen. EMG is used has a very diverse and variable disease sever- in the diagnosis of peripheral motor neurone ity leading to a highly variable clinical pic- lesions. In rheumatology, it is used in the di- ture. The frequency of EDS is 1:5000 live- agnosis of tunnel syndromes and myopathies, born in both genders and all ethnic groups. such as myositis, where the potentials are Clinical symptoms and signs: The hyper- narrower, have smaller amplitude and are elasticity skin can be folded and distended up polyphasic. In myopathic syndromes, the po- to several centimetres. After release, it returns tentials are narrower and smaller, but the ve- to its original state. Even mild trauma of the locity is normal. In myasthenia gravis, the skin usually leads to superficial lacerations. amplitude and frequency of the potentials de- Metacarpophalangeal joints and other parts crease with repeated voluntary contractions. of the body where the bones protrude clearly under the skin are often covered by . Electrotherapy The use of various forms of There is a tendency towards the development electrical energy in the treatment of diseases, of haematomas and pigmentation of the scars. mainly by physiotherapists. A direct current, Grape-like swellings, referred to as mollus- variously shaped alternating current impulses coid pseudotumors, may occur in these re- of low and middle frequencies, high-frequen- gions. On the calves and forearms small, hard cy field and high-frequency ultrasound, laser mobile subcutaneous nodules may be detect- and transcutaneous nerve stimulation can all ed on palpation. To a varying degree there is be used. Electrotherapy has analgesic, myo- joint laxity, excessive movements of the joints relaxing and vasodilatatory effects, as well as and orthopaedic complications are common stimulating local and general metabolism. especially in people with extreme hypermo- Electrical energy is also used in electrodiag- bility. Dermatological, cardiovascular, gastro- nostics. intestinal, neurological, ophthalmological, urological, respiratory and dental abnormali- ELISA (Enzyme-Linked ImmunoSor- ties may also occur. of the aorta, bent Assay) ELISA is a two step biochemi- rupturing of major arteries, gastrointestinal cal technique used mainly in immunology to bleeding and perforations (see below) have quantify the level of an antibody or an anti- all been documented as complications of vas- gen in a sample. The antigen is immobilized cular EDS. on a solid support (usually a polystyrene mi- The fragility of tissues and the tendency crotitre plate) either non-specifically (via ad- towards bleeding can complicate surgical sorption to the surface) or specifically (via procedures and labour. These problems can capture by another antibody specific to the be minimised by accurate diagnosis of EDS same antigen, in a “sandwich” ELISA). The forms. sample (usually serum) is added and incu- 61 ergometry (bicycle, winch, treadmill) bated allowing the formation of antibody- ta of the subcutaneous adipose tissue lobules, antigen immune complexes. A secondary or the deep dermis. The clinical picture is ex- antibody, which is linked to an enzyme pressed by an orange peel appearance and through bioconjugation, is then added to link rough surface to the affected skin. The un- onto the primary antibody or to the antigen- even surface is caused by retraction of the antibody complex (sandwich principle) to adipose tissue septa. There may also be sub- determine its level. Between each step the cutaneous induration fixed to the deep tis- plate is typically washed with a mild deter- sues. In addition, there may be arthralgias, gent solution to remove any proteins or anti- arthritis, joint , tunnel compres- E bodies that are not specifically bound. After sion syndromes, involvement of striated the final wash step the plate is developed by muscles, and occasionally interstitial pulmo- adding an enzymatic substrate to produce a nary fibrosis and dysmotility of the oesopha- visible signal, which indicates the quantity of gus. bound secondary antibody and indirectly the In laboratory tests, there is eosinophilia amount of antigen in the sample. Older ELI- (more than 10% of the whole leukocyte SAs utilize chromogenic substrates, though count), especially at the onset of the disease. newer assays employ fluorogenic substrates Generally, there is hypergammaglobulinae- with much higher sensitivity. This is now a mia and increased erythrocyte sedimentation universal, efficient and automated technique rate. Histological examination shows a pic- employed in modern laboratories for detect- ture of inflammatory changes in the cutane- ing serum antibody levels. ous fascia. The disease generally has a benign course. Treatment usually only requires small Enteropathic arthritis (EA) Defined as doses of glucocorticosteroids and antimalari- arthritis induced by an intestinal disorder als, but with a severe disease, pulse corticos- (ulcerative colitis, Crohn’s disease), or as ar- teroid treatment with cyclophosphamide may thritis occurring concomitantly with the in- be necessary. testinal disorder. These are acute, recurrent oligo- or polyarthritis often following the in- Epicondylitis humeri Painful insertions flammatory activity of the enteric disorder. on the lateral (tennis elbow), or less frequent- Clinical symptoms and signs: ly the medial (golfer’s elbow), epicondyle of • peripheral arthritis, usually oligoarticular, the humerus. Causes include posttraumatic asymmetric, with predilection the lower and degenerative changes or splitting of the limb joints, tendon; more rarely there are painful tendon • frequent involvement of the axial skeleton insertions as part of a generalised rheumatic in terms of sacroileitis and/or spondylitis, condition (fibrositis syndrome). • dactylitis (in post-enteric reactive arthri- tis), Epitheses Prostheses that cosmetically help • enthesitis, to cover up a physical imperfection. They are • involvement of the skin and mucous mem- mainly dental and ocular prostheses and branes: iritis, erythema nodosum, pyoder- breast implants. Their importance is to help ma gangrenosum and other ocular involve- eliminate any secondary mental consequenc- ment. es arising from aesthetically prominent dam- age. Eosinophilic fasciitis (Shulman’s Syn- drome) A disorder characterised by the sud- Ergometry (bicycle, winch, treadmill) den onset of painful swelling replaced later by Exercise functional diagnostics dealing with a stiffness of the skin and dermis of the trunk the examination and assessment of the fitness and limbs. This condition is caused by in- and adaptation of the cardiorespiratory, meta- flammatory, fibrotic and sclerotic changes in bolic and other physiological or pathophysi- the fascia of the adjacent muscle, fibrous sep- ological function to various forms of exer- ergotherapy 62

tion. The exercise treadmill test is used in the A disorder characterised diagnosis of the severity of heart disease and by reddening of the skin on the limbs associ- allows modification of the treatment and re- ated with burning pain and swelling. It can habilitation regime. The most frequently used occur at any age, but most frequently in mid- measure is cycle ergometry which allows dle age; men are more often affected than graduated increase in the load, ECG record- women. The disease is either primary or sec- ing and the measuring of blood pressure. In ondary to disorders such as hypertension, patients with rheumatic disorders, a regime polycythaemia vera, essential thrombo- E of gradual and fixed aerobic training is util- cythaemia, angiitis obliterans or other vascu- ised. lar, haematological or neurological diseases. Certain drugs ( or bromocryptine) Ergotherapy Utilised with different specif- can also induce this disease. The aetiology of ic activities for improving the functional con- skin involvement is acute arterial hyperae- dition of the patient. Working therapy is in- mia. cluded. Clinical symptoms and signs: A redden- ing in the region of the limbs dominates the Erosive osteoarthritis This primarily af- clinical picture, with lower limbs being more fects middle aged and older females and par- frequently affected than upper limbs. The ticularly affects the small joints of the hand. reddening is associated with a burning pain Initially, it manifests itself by DIP (distal in- and swelling, and worsens when the limbs are terphalangeal) and PIP (proximal interpha- exposed to heat or hang below the level of the langeal) joints inflammation and inflamma- body. On the other hand, exposing the limb tion of the wrist; with subsequent deformities to cold air or immersion into cold water, or of these joints. The ESR or CRP may be limb elevation brings relief. The skin is sensi- slightly raised, and the latex fixation test may tive to touch and hyperhidrosis is present. be weakly positive. The radiological picture Erythromelalgia should be distinguished shows arthritic changes of affected joints and from ischaemia in occlusive arterial disorders the development of marginal erosions. and from . In contrast Treatment: Non-steroidal anti-inflamma- to these conditions, the peripheral pulses are tory drugs; physiotherapy to help maintain easily felt, and neurological examination is the joint function and provide an analgesic normal. effect. ESR → see Erythrocyte Sedimentation Rate Erythema nodosum (EN) → see Arthritis (ESR) associated with erythema nodosum in the course of infection Essential mixed cryoglobulinemia (EMC) This is characterised by the presence Erythrocyte Sedimentation Rate (ESR) of immunoglobulins that precipitate revers- The simplest and commonest parameter of ibly in the cold. These are cryoglobulins of inflammation. It is best at assessing disease types II and III (a mixture of at least two types activity in certain diseases (polymyalgia of antibodies against a polyclonal IgG). The rheumatica) and in systemic diseases of the onset of the disease is in the 4th and 5th de- connective tissue (systemic lupus erythema- cade, more frequently in women. tosus, systemic sclerosis, Sjögren‘s syndrome) Clinical symptoms and signs: Character- in which C-reactive protein (CRP) is often istic signs include purpura and ulcerations on not significantly increased. The combination the lower limbs, , protein- of ESR and CRP is often very useful in assess- uria, microscopic haematuria, arthralgias or ing the disease activity of rheumatoid arthri- arthritis, and detection of the cryoglobulin tis, ankylosing spondylitis and other diseas- on blood tests. es. 63 exercise techniques

Etanercept A recombinant-DNA drug Exercising Classification according to tar- made by combining two proteins to a fusion get and effect protein which combines with the Fc fragment • training strength This constitutes short- of human IgG on the soluble TNF receptor term exercise with maximum exertion on (sTNF-R) to block the effect of TNF. The ma- the muscles, where mostly tonic fibres are jority of cells have two kinds of receptors for being stretched. Includes resistance exer- TNF, transmitting different signals: TNF-RI cises – movements with a short trajectory, (55 kDa) and TNF-RII (75 kDa). The soluble but a lot of strength. forms of TNF-R are important inhibitors of • training speed Mainly phasic muscle fibres E TNF. In active rheumatoid arthritis (RA), are activated here. A lot of output is soluble TNF-R is present in an increased con- achieved through a relatively small amount centration in the serum and synovial fluid, of work. With this exercise, the connective however, not even this increased concentra- tissue accumulates and fat is not deposited tion is able to neutralise the overproduction in the muscle. of TNF in high inflammatory activity. Etan- • training endurance This incorporates long- ercept is licensed for patients with severely term exercises (work therapy) that do not active rheumatoid arthritis and psoriatic ar- require maximum muscle strength. They thritis who have failed treatment with at least are frequently repeated and long-term. two disease-modifying antirheumatic drugs, • training dexterity This is also referred to as including methotrexate. More recently, it has training neuromuscular coordination and received a license for severe ankylosing spon- is based on the principle that repetition dylitis. Studies have demonstrated the in- leads to stabilisation of the dynamic stereo- creased efficacy when combined with metho- type. This includes the training of balance, trexate (MTX) (Weinblatt et al. 1999, Klareskog as well as the training of all new and so- et al. 2004). The preparation is given subcuta- phisticated movements. neously at a dose of 25 mg twice or 50 mg once a week. It has a rapid onset of action Exercise techniques Alexander technique with some patients reporting an improve- A technique that endeavours to produce nor- ment within two weeks of treatment. Recent mal body posture and movement habits in studies have shown very good responses our everyday life and activities. It is a method when etanercept is administered in early RA of posture control that releases the increased with severe disease activity inducing remis- tone of postural muscles and leads to easy sion and preventing progression of radiologi- natural body-control. It is targeted at people cal changes (Bathon et al. 2000, Emery et al. with bad body posture, back pain, migraine 2008). and living in stressful situations. Adverse events: Local skin reaction in the Feldenkrais technique An exercise tech- region of administration, increased suscepti- nique that tries to uncover and prevent faulty bility to infection of the upper respiratory movement patterns and substitute them tract, pneumonia, pyelonephritis, generalised gradually with a targeted mental activity, sepsis, and reactivation of tuberculosis, leu- which is also accompanied by improvement kocytoclastic vasculitis, positive anti ds-DNA of the psyche, positive thinking and mental antibodies, discoid lupus, hypertension, heart health. The essence of the Feldenkrais meth- failure and demyelinating diseases. od is to relearn the movements that we were able to perform in childhood (exercises in Euro Quol questionnaire → see Instru- prone and supine position, crawling, walk- ments of assessing (health status measure- ing on all fours). Regained mobility of the ments, outcome measurement) body also manifests in greater mental flexi- bility. Eutony method → see Exercise techniques Rolf technique – rolfing By returning to a normal body posture and anatomically nor- extra-articular rheumatism (extra- articular rheumatism; rheumatism of soft tissues) 64

mal movement habits, this decreases or elim- has six basic pillars: breathing, concentration, inates pain in the locomotor organs. It uses control, powerhouse, accuracy and fluency. certain elements of yoga as well as techniques of deep massage of the connective tissues. Extra-articular rheumatism (extra- Eutony method It places the main emphasis articular rheumatism; rheumatism of on balanced muscle and mental tone (eutony), soft tissues) Diseases affecting extra- which stabilises itself by perception of the articular soft tissues of the musculoskeletal whole environment (smell, sound, touch, system such as muscles, tendons, periten- E gravitation) and also by conscious perception dons, tendinous insertions, fascia and bursae. of the movement of one’s own body. The causes vary, but most frequently are due Pilates technique – The Pilates techniques to local overuse, acute or repeated trauma place emphasis on proper performance of and microtrauma during sporting activity or movement patterns together with quality work, impaired movement coordination, in- breathing and principles of biofeedback. It is correct gait, inflammation etc. the training of deep-seated muscles creating a Extra-articular rheumatism has three stabilisation system, the so called powerhouse forms: – central muscle girdle. The aim is to acquire generalised – fibromyalgia, chronic fatigue a synergy of transversus abdominis, multifidi, syndrome, myofascial syndrome, longissimus, iliocostalis and pelvic girdle regional – complex shoulder pain syndrome muscles, posterior fibres of the obliquus in- (humeroscapular periarthropathy) and hip ternus muscle and diaphragm. Pilates called (hip periarthropathy), his system “The art of control”. The system localised – bursitis, tendinitis etc. F

Fab fragment A fragment (part) of the im- ent fluorescence labelling of cells simultane- munoglobulin molecule (usually IgG) able to ously, thereby giving the whole device a high- bind to an antigen. It is formed by its proteo- er sorting ability. Using fluorescence labelled lytic degradation and contains one binding monoclonal antibodies against the differen- site between the variable domains of the light tiation antigen CD4, it is possible to deter- and heavy chains. mine, for example, the T-lymphocyte count in the peripheral blood; using the antibody

F(ab)2 fragment A double Fab fragment. It against CD8, the cytotoxic T-lymphocyte contains both binding sites of the original count; using the antibody against CD3, the molecule. It is practically an immunoglobu- total T-lymphocyte count, etc. lin molecule without the C-terminal halves of the heavy chains that form the Fc-fragment. Factor P → see Properdin

Fabry’s disease Belongs to the group of Familial hypocalciuric hypercalcae- sphingolipidoses. It is an inherited X-linked mia A condition characterised by mild hy- recessive inborn error of the glycosphingo- percalcaemia with relative hypocalciuria (i.e. lipid metabolism. It occurs due to a deficien- normal value of calcium excretion in the cy of the enzyme α-galactosidase A which is urine with serum hypercalcaemia). It is in- coded by a gene localised on the long arm of herited as an autosomal dominant trait and is the X-chromosome (Xq22). As a consequence caused by mutation of the gene for CaSR (cal- of this enzyme defect, a glycolipid known as cium-sensing receptor). Patients are usually globotriaosylceramide accumulates in blood asymptomatic, only rarely do they feel mild vessels, other tissues and organs. tiredness, weakness, lack of concentration or Clinical symptoms and signs: polydipsia. Recurrent pancreatitis, cholelithia- • episodes of painful acroparaesthesia, sis, diabetes mellitus and myocardial infarc- • a significant reduction or absence of per- tion occur more frequently in the families. spiration (anhidrosis), Bone turnover assessed by biochemical pa- • characteristic skin lesions (angiokerato- rameters can be slightly increased but bone mas), mineral density is normal and patients are • ocular changes, not more susceptible to fractures. The serum • decreased activity of α-galactosidase A. calcium level (total and ionised) is elevated throughout life with a tendency to fall with FACS (Fluorescence Activated Cell age. The serum can also be Sorter) A separator of fluorescence activated slightly elevated; conversely serum phosphate cells (flow cytometer). This device allows the is slightly decreased. Renal function remains analyses and division of a mixture of cells normal. Parathormone and calcitriol levels based on their diverse ability to bind a certain are within the physiological range, except in a antibody labelled by a fluorescence dye. It is a minority of patients when it can be mildly technique referred to as flow cytometry (cyto- ele vated. fluorography). The device has two detectors, one of which separates the cells according to Familial Mediterranean fever (FMF) A the intensity of their fluorescence, and the genetically determined autosomal recessive other one according to their size. Newer cell disorder occurring only in certain ethnic analysers make it possible to use three differ- groups such as Sephardi Jews, Anatolia Turks farber’s disease 66

and Arabs. The gene, called MEFV, has been Fc-receptors The binding sites for the Fc localised on chromosome 16. Typically the domains of the immunoglobulin molecules onset is in adolescence, usually before the age localised on surface of leukocytes and other of 20. cells. Every class of immunoglobulins has its Clinical symptoms and signs: own type of FcR. There are specific Fc-recep- • recurrent attacks of fever, peritonitis, uni- tors for IgG, IgE, IgM and IgA. The FcR for lateral pleuritis and arthritis, IgG and IgE can be found in multiple iso- • periods of remission are usually asymp- forms, usually as high-affinity and low-affini- tomatic, ty receptors. They are important in the pro- • in untreated patients type AA amyloidosis cesses of phagocytosis and antibody-depen- may develop, dent cellular cytotoxicity (ADCC). F • regular treatment with prevents attacks and prevents the development of Feldenkrais technique → see Exercise amyloidosis. techniques

Farber’s disease A disease belonging to the Felty’s syndrome The combination of sphingolipidoses, with musculoskeletal mani- rheumatoid arthritis with splenomegaly and festation, characterised by an accumulation leukopenia. The syndrome mainly affects pa- of lipids in tissues due to an enzyme deficien- tients with long-term seropositive, nodular cy. Farber’s lipogranulomatosis is an auto- and deforming rheumatoid arthritis. Some somal recessive defect caused by a deficiency patients have low articular activity at the time of ceramidase, an enzyme which cleaves fatty of Felty’s syndrome manifestation. Many of acids from ceramide producing sphingosine. these patients test positive for antinuclear an- It appears in the neonatal period. tibodies, have leg ulcers and hyperpigmenta- Clinical symptoms and signs: Red painful tion. xanthomas form around joints and the peri- tendons, which lead to the development of Fever Fever or pyrexia is a transient increase joint and tendon contractures. Motor devel- in body temperature above the normal value opment retardation, macular degeneration of 37.5°C, when taken orally. It can be graded and mental retardation are present. Patients as low (<39°C), moderate (39–40°C) or high die early. The primary cause of death is oe- (>40°C). It is one of the systemic changes ac- dema in the laryngeal region and epiglottis companying a protective or impairing in- leading to recurrent pulmonary infections. A flammation. It is part of the physiological mild form of this disease allows longer sur- protective reaction of the organism. It occurs vival, and these children may present to a due to an upregulation of the thermoregula- rheumatologist with their joint problems and tion centre in the hypothalamus by endoge- mental retardation. There is no curative treat- nous pyrogens (especially IL-1, IL-6 and ment. TNF-α) from a normal value to a higher one. This stimulation is indirect, mediated by Farnesyl diphosphate synthetase PGE as the second messenger. The cellular (FPPS) → see Bisphosphonates metabolism2 and many immune processes are activated in fever leading to more rapid elim- Fc fragment A crystallisable fragment of ination of the infectious agent or other fac- the immunoglobulin molecule formed by its tors inducing the inflammatory reaction. The proteolytic fragmentation. It represents the pattern of fever can help to clinically diag- C-terminal end of both heavy chains con- nose diseases (e.g. malaria, Still’s disease). nected by a disulphide bond. It is unable to bind antigen, but has other important bio- Fibroblast growth factors (FGF) Belong logical effects, the most important of which is to a family of 23 members in humans, which its ability to bind to Fc-receptors. are structurally-related signalling molecules. 67 fibromyalgia (FM)

Initially, two isoforms were recognised – an Clinical picture: Suspicion of this disorder acidic aFGF (FGF-1) and basic bFGF (FGF-2) should be considered in the newborn, before factor. Both of these are members of the cy- the occurrence of calcifications, due to the tokine family and belong to the oldest known characteristic finding of shortening and mal- growth factors. They act on mesenchymal formation of the big toes. Some patients have and endothelial cells, provide important sig- shortened and malformed thumbs. Synosto- nals during the body’s development and have sis and phalangeal hypoplasia is common. angiogenic activity (angiogenesis). Moreover, Other malformations of the fingers, however, FGF directly stimulates the migration and are not typical for this disease. Later, swelling proliferation of cultured endothelial cells and of the soft tissues with subsequent extra-skel- induces the production of differentiated etal calcification confirms the diagnosis. F blood , so are important in wound Some patients are wheelchair-dependent in healing. adulthood. The painful swelling of the soft tissues occurs more frequently in the first de- Fibrodysplasia ossificans progressiva cade of life, either spontaneously or after a A very rare but interesting connective tissue minor trauma (for example an intramuscular disorder sometimes referred to as myositis injection). These lesions swell over several ossificans progressiva. Patients are born with days, become indurated and their formation short big toes and usually develop recurrent is accompanied by fever. Some of them re- episodes of painful swelling of the soft tissue semble an infectious process. Typical locali- leading to heterotropic ossifications in child- sation is in the paravertebral and limb girdle hood. The disease affects all ethnic groups muscles. After varying periods (weeks to with a frequency of approximately 1:1,000,000 months), some regress spontaneously, but births. It is inherited as an autosomal domi- most pass through enchondral ossification nant allele on chromosome 2q23-24 with with subsequent development of bone tissue. variable expressivity, but most cases are spo- Once ossification occurs, it is permanent. radic due to a new mutation. Gonadal mosa- The bone matrix gradually ankyloses certain icism is possible. A very similar disorder in joints and contractures or deformities occur, cats has become the animal model for study- initially around the neck and shoulders. ing this disease. When the muscles of mastication are affected Pathogenesis and histological picture: following local anaesthetic injection for den- Initially, there is an accumulation of B- and T- tal surgery, the limitation of movement of jaw lymphocytes in the perivascular spaces of can significantly limit food intake and chew- muscle that otherwise appear normal. Among ing. Ankylosis of the spine and thorax conse- the oedematous muscle fibres there is a visi- quently reduces lung and cardiovascular ble T-lymphocytic infiltrate followed by an- function, leading to frequent chest infections. giogenic proliferation of the fibres. The lym- The disease does not affect the vocal cords, phocytes present in the muscle synthesise diaphragm, oculomotor muscles and smooth excess bone morphogenetic protein-4 BMP4, muscle. Hearing impairment and alopecia is a product that contributes to the develop- observed more frequently than in the healthy ment of the skeleton in the normal embryo. population. Enchondral ossification takes place with the subsequent formation of healthy bone tissue Fibromyalgia (FM) A chronic, non-in- with a normal haverian system. The trabecu- flammatory myofascial (musculoskeletal) lar bone contains haematopoietic bone mar- syndrome characterised by widespread pain row. The diagnostic difficulty and concerns and points of increased tenderness to pres- over aggressive juvenile fibromatosis or sar- sure and typically accompanied by profound coma often result in a biopsy of the acute le- fatigue. It may be primary and secondary; the sion if the clinician doesn’t recognise the latter is usually associated with a rheumatic clinical picture. disorder. Some patients fulfil the diagnostic fibromyalgia impact questionnaire (FIQ) 68

criteria of chronic fatigue syndrome (CFS). shortened, which causes abduction and supi- Although the long term course of the disease nation of the anterior part of the foot. In such a causes much hardship, it does not reduce life case of impaired mechanics, the transverse expectancy, nor lead to deformities, cosmetic arch of the foot extends and the heads of the changes or locomotor disability. medial metatarsal bones descend in a plantar Clinical symptoms and signs: direction. This leads to callosities under the • widespread musculoskeletal pain, feet. Medial incurvation and typical three- • multiple tender points, point load are missing on the plantogram. • painful spasms, Treatment is based on prevention with • fatigue, sleep and mood disturbance, post- foot exercises, arch supports or orthotics. exercise pain, F • headache, paraesthesia and functional or- Fluorides Belong to the stimulators of os- ganic syndromes. teoformation with a consequent increase of bone density in the region of trabecular bone Fibromyalgia impact questionnaire (spine). Their influence on the density of (FIQ) → see Instruments of assessing (health cortical bone and decrease of incidence of status measurements, outcome measure- fractures has not been unambiguously docu- ment) mented with some studies showing an in- creased risk of non vertebral fractures. They Fibrous dysplasia A skeletal disorder with are therefore no longer advocated in treatment sporadic incidence. of osteoporosis. (Lane and Leboff 2005). Pathogenesis: All types of the disease orig- inate in the activating mutation of the gene FMF → see Familial Mediterranean fever coding for the Gs-alfa subunit of the G-pro- (FMF) tein that stimulates the production of cyclic adenosine monophosphate. Insufficient dif- Foreign-body induced arthritis This ar- ferentiation of mesenchymal cells to osteo- thritis develops post-traumatically by the pene- blasts leads to the skeletal lesions. The nas- tration of a foreign body into the articular cav- cent cells form imperfect bone tissue. The ity and after intra-articular implants. Chronic overproduction of interleukin 6 seems to be inflammatory of non-infec- an important pathogenic factor. tious origin can develop. Sometimes an infec- Clinical symptoms and signs: The onset tion is spread along with the foreign body. of the disease occurs in the first decade of life The foreign body can be of plant origin affecting both genders equally. Foci of ex- (thorns, hawthorn, rose, cactus and others), panding fibrous tissue appear in one or more mixed kind (splinters of wood, fish bone, bones. They are most frequently visible on stone debris, rubble, glass, rubber, plastic) or the long bones and the skull. Patients suffer could be fragments of joint prostheses (ce- from pain in the bones; deformities and frac- ment, silicone, metal, methyl metacrylate). tures may occur. However, in many cases the Clinical picture: Pain, swelling and oede- foci are asymptomatic and found incidentally ma of the joint immediately after trauma, or on radiographs performed for some other in- sometimes after a delayed period of time. dication. Suspicion of this diagnosis relies on a good history (contiguous trauma) and the exclu- Flat foot (pes planus) The commonest stat- sion of other causes of monoarthritis. Some- ic defect of the civilized population. It is char- times it is difficult to confirm the diagnosis, acterised by gradual retrogression of the physi- especially in children and the elderly, who of- ological longitudinal arch of the foot. In a typi- ten do not remember, e.g. a thorn prick. To cal case, the longitudinal arch flattens or disap- demonstrate the foreign body we use an ultra- pears, the posterior part of foot is in the valgus sound arthroscopy, but mainly joint sonogra- position, and fibularis (peroneal) muscles are phy or magnetic resonance imaging. 69 functional muscle chains

Therapy lies in the surgical removal of the Frozen shoulder → see Adhesive capsulitis foreign body. Functional muscle chains This refers to a Forestier’s Disease → see Diffuse Idio- sequence of integrated muscle groups neces- pathic Skeletal Hyperostosis (DISH; ankylos- sary for performing a certain activity (creep- ing hyperostosis; Forestier’s disease) ing, crawling, bipedal gait, and breathing). They are programmed in the central nervous system.

F G

Galvanisation A treatment which uses geneous immunoglobulin or its components. low-frequency direct current. Included are: Gammopathies may be monoclonal or poly- • downstream galvanic current (anode proxi- clonal. mally, cathode distally) – having analgesic In monoclonal G, only one clone of cells and spasmolytic effects, (plasma cells or their precursors belonging to • upstream galvanic current (anode distally, B cells) reproduces beyond control and re- cathode proximally) – stimulating the leases identical immunoglobulin molecules nerves and muscles, of a certain class or parts of the immunoglob- • Kowarschik’s galvanic current (two elec- ulin molecule (light or heavy chains). With trodes placed lengthwise, the direction of polyclonal G, two or rarely more cell clones the current is transversal) – having an an- reproduce, each of which produces an anti- algesic effect, body with different specificity. The undesir- • four-chamber hydro galvanic bath – the able Ig (s) are released into the blood in great limbs are put into special baths with water abundance and can be determined in the se- (the direction in the current is from top to rum by protein electrophoresis or immuno- bottom or vice versa); it has an analgesic fixation technique. Monoclonal gammopathy effect and causes hyperaemia. It is used of undetermined significance (MGUS) is with benefit in patients with involvement asymptomatic and can have a benign course of the peripheral joints (rheumatoid arthri- with a low rate of conversion to malignancy. tis, ankylosing spondylitis, Sjögren’s syn- However, most monoclonal gammopathies drome). are a malignant growth of antibody-producing cells including multiple myeloma, Walden- Gamma/delta T-lymphocytes These are ström’s macroglobulinaemia and heavy chain T-lymphocytes which have a T-cell receptor disease. In multiple myeloma, malignantly consisting of gamma and delta polypeptide growing plasma cells can be found in the chains on their surface. They make up about bone marrow and produce monoclonal mye- 5% of the T-lymphocyte population loma IgG, IgA, IgD, or IgE often together with Bence-Jones proteins, whose molecule Gammaglobulins These are fractions of consists of one of the two light chains. In blood serum glycoproteins that have the low- Waldenström’s macroglobulinaemia, there is est mobility in alkaline pH during electro- a malignant growth of atypical lymphocytes phoresis and migrate in the direction of the secreting an excessive amount of monoclonal anode. The majority of immunoglobulins IgM. In heavy chain disease, there are incom- and antibodies belong to this fraction. plete heavy chains of γ (characteristically of the IgG class), α (IgA) or μ (IgM) found in Gammopathy A disorder characterised by the serum of patients. the overproduction of undesirable immuno- globulins (Ig). Unlike normal Ig, these mole- Gate control theory of pain Pain is not cules represent a structurally and functionally simply perceived but is modulated by inter- homogeneous population. The term is derived acting neurons, according to Melzack and from a serum protein fraction in which Ig’s Wall. Based on this theory, the nociceptive are found (gammaglobulins). Gammopathies signal is conducted by thin nerve fibres to the (G) develop when a clone of plasma cells or spine where the existence of neurons (in the lymphocytes uncontrollably secrete a homo- dorsal horn of the spinal canal) with gate 71 genu varum (bowleggedness) function is suggested. These neurons trans- 3. as a section of the DNA (or RNA in the case mit less or more signals to the brain depend- of RNA viruses) with a regulatory func- ing on how wide the ‘gate’ is open. The ‘gate’ tion (regulatory gene). is opened by afferentation from thin fibres and closed by afferentation from coarse Generalised nodal osteoarthritis nerve fibres. The existence of an ‘interpreta- (GNOA) → see Osteoarthritis – primary gen- tion centre’ in the subcortical region is sug- eralised nodal osteoarthritis (GNOA) gested. The centre modulates when and un- der what circumstances these signals are Genome All of the genes in a cell (cell ge- conducted into consciousness as pain. It has nome) or a virus (viral genome) containing been found that nociceptive afferentation the whole hereditary information. Not all can be blocked by ‘closure’ of synapses con- these genes must be functionally expressed in ducting nociceptive afferentation by the use the given environment and stage of develop- of substances similar to . These are ment. The genome of a prokaryotic cell con- G referred to as endorphins, which are synthe- sists of genes situated in the nuclear DNA and sised by the brain (psychological modula- plasmids; the genome of a eukaryotic cell tion of pain). comprises a gene situated in the nucleus and mitochondria, and chloroplasts in herbal Gaucher’s disease A disorder inherited by cells. autosomal recessive trait. Due to a deficiency of the lysosomal enzyme glucocerebrosidase Genu recurvatum (backward curva- (also known as β-glucosidase) the membrane ture of the knee) glycolipid glucocerebroside accumulates in 1. unilateral – hyperextension of the knee as- body organs and tissues forming the so-called sociated with instability; most frequently Gaucher cells. post-traumatically (meniscus, cruciate Clinical symptoms and signs: Often he- ligaments), patosplenomegaly, bone pain and osteopenia, 2. bilateral – as the manifestation of local disturbances of the bone marrow (anaemia, joint laxity or generalised hypermobility thrombocytopenia) are present caused by an (hypermobility syndrome). infiltration by Gaucher cells. Aside from clin- ical signs, the disorder can be suspected by Genu valgum (knock kneed) A knee high activity of alkaline phosphatase in the with an increased internal angle. It occurs as serum. a consequence of tibial overload after rickets, in renal in children and cer- Gene The basic unit of inheritance localised tain metabolic disorders. Women may have a on a certain position of the chromosome (lo- physiological valgosity of 8°. In adults, it can cus). The gene can be defined functionally occur in rheumatoid arthritis and osteoar- (its product underlying a certain trait in the thritis as a consequence of the compensatory phenotype) or structurally (a particular sec- mechanism of the adduction contracture in tion of the DNA molecule or RNA molecule the hip, advanced destruction of the knee when RNA viruses are implicated). The gene joint and damaged medial collateral liga- can manifest phenotypically (phenotype) in ment. three cardinal functional forms: 1. as a section of the DNA chain coding for Genu varum (bowleggedness) A knee the primary structure of a polypeptide with a reduced internal angle. It occurs in the (structural gene), proximal part of the tibia or distal part of the 2. as a section of the DNA chain transcribing femur in metabolic or systemic disorders. A itself into the primary structure of tRNA, mild physiological varosity is seen in 2 to 3 rRNA or other types of RNA that are not year old children, but it is necessary to ex- subject to translation, clude rickets, or of the medial gestagens 72

part of the proximal tibia (Blount’s disease). corticoids do not cure, and likely do not More severe forms occur in adults secondary change the prognosis of rheumatoid arthritis to osteomalacia and Paget’s disease. In mid- (RA), they are amongst the most effective dle-age, it causes rapid development of go- symptomatic anti-inflammatory drugs. There narthrosis (more frequently in women). It is is increasing evidence that they slow the pro- accompanied by instability of the knee. gression of erosive changes in early RA. Their use in rheumatology is frequent, and indis- Gestagens Their androgenic activities have pensable in many cases. The effect of glucocor- a beneficial influence on bone production ticoids is determined by the concentration and and mineralisation. They also compete with density of their peripheral cellular receptors. cortisol for the binding site on osteocyte re- Due to the extensive physiological influence ceptors. (anti-inflammatory, immunological, metabol- ic, mineralocorticoid effects, and the feedback G → see Temporal Arteri- inhibition of the function of hypothalamic-pi- tis (TA) tuitary-adrenal axis), it is advisable in the in- terest of the patient to follow the guideline of Glandular fever → see Infectious mononu- giving the minimally effective dose for the cleosis shortest period to minimize adverse toxicity and minimise suppression of the hypothalam- Glomerulonephritis (GN) A group of dis- ic-pituitary-adrenal axis on withdrawal. It is orders characterised by inflammation and le- one of the major disadvantages of glucocorti- sions of the renal glomeruli. Immune mecha- coids that withdrawal after long-term systemic nisms participate in the pathogenesis of the (mainly oral) administration is possible only in majority of primary and secondary glomeru- a limited number of RA patients. lonephritis. More than 70% of patients with Adverse effects: GN have deposits of immunoglobulins in the Preventive measures against suppression of glomeruli, frequently in association with the hypothalamic-pituitary-adrenal axis func- complement deposition. Damage to the tion during long-term treatment: glomeruli is induced by an inflammatory re- • do not use corticosteroids with extended action initiated by either deposits of circulat- biological activity – corticosteroids with a ing immune complexes (as for example in medium biological half-life are recom- systemic lupus erythematosus) or by cyto- mended (prednisolone, methylprednisolo- toxic antibodies against glomerular antigens. ne), Goodpasture’s syndrome is one example of a • always give the lowest possible, effective cytotoxic antibody reacting with the basal dose, membrane of the glomerulus. The so formed • consider administering the dose on an al- immune complexes (similar to deposits of cir- ternate day regime, though may not be culating immune complexes) activate comple- possible as it may be ineffective in control- ment which leads to damage of the basement ling the disease membrane either directly or its chemotactic • when decreasing the dose: fragments attract neutrophils which cause – if the period of administration is two damaging inflammation. weeks or less, it is usually possible to de- crease the dose by 1 tablet daily (5 mg of Glucocorticoids A group of steroid hor- prednisone/prednisolone) every week, mones with the ability to bind to the gluco- – if the administration is longer than two corticoid receptor and secreted by the supra- weeks and especially longer than six renal (adrenal) cortex. They have been used months, then decrease very slowly by 1 for many years as antiinflammatory drugs, tablet daily every 15–30 days. immunosuppressants and replacement treat- Indications for the systemic administration of ment in endocrinology. Even though gluco- glucocorticoids: 73 gold salts

• persisting synovitis in several joints in spite ing 250 mg of GS; 3 tablets are given twice a of regular administration of non-steroidal day or 1 sachet (1500 mg) of GS once daily. anti-inflammatory drugs (NSAIDs) and a The treatment lasts usually 2 to 3 months. DMARD (disease-modifying antirheu- The treatment course is repeated twice a year. matic drug), GS is also given intramuscularly twice a week. • severe systemic signs (for example fever A possible structure-modifying effect of glu- and loss of weight) or extraarticular in- cosamine sulphate is hypothesised, though volvement (vasculitis, or pleuri- the results of good evidence based studies are tis), awaited • occasionally glucocorticoids are prescribed early in disease for a limited period to sup- Glucose-6-phosphate dehydrogenase press the signs of inflammation, until the This enzyme participates in the metabolism expected effect of DMARDs occurs. of glucose (its oxidation in the hexose mono- Systemic administration of glucocorticoids: phosphate shunt). In professional phagocytes, G glucocorticoids are given usually in a daily it ensures the production of nucleotide re- dose below or up to 7.5 mg of prednisone. ductase (NADPH), which is essential for the The following are treatment regimens in respiratory burst and the formation of neces- RA: sary antimicrobial substances. In glucose-6- • continuous: administration of the daily phosphate dehydrogenase deficiency, there is dose several times a day – in the morning, a decrease of its activity in neutrophils to less at noon and in the evening, where the eve- than 1% of the average normal value. ning dose is the lowest, • daily: administration of a single daily dose, Glycoproteins Biomolecules composed of usually in the morning, both amino acid units and saccharides. • alternating: twofold dose every other day, • intermittent: administration over 2 to 3 Glycosylation The process whereby glyco- days, then 2 to 3 days drug free, proteins are formed. The addition of sugar • intramuscularly: administration of 120 mg chains (saccharides) to these compound pro- methylprednisolone (Depo-medrone), teins occurs in a posttranslational modifica- • pulse: intravenous administration of high tion by virtue of glycosyl transferase en- doses of methylprednisolone (250–1000 zymes. mg) daily for 3 to 5 days. The therapeutic plan should take into ac- Gm allotypes An allotypic determinant lo- count the length of the overall activity of glu- calised to the constant region of the heavy cocorticoids: hydrocortisone, prednisone, chains of human IgG1, IgG2 and IgG3. The prednisolone and methylprednisolone act for allotypes are products of individual alleles of a short term (24 to 36 hours), triamcinolone the same structural gene. To date there are 25 for a middle term (up to 48 hours) and dex- different known Gm allotypes in the human amethasone and betamethasone for a long population. term (more than 48 hours). Gold salts They started to be used in the Glucosamine sulphate (GS) The basic treatment of tuberculosis and other infec- substrate for synthesis. It tious diseases at the end of the last century. It is used in the treatment of osteoarthritis was accidentally discovered that during treat- (Rovati 1997, Reginster et al. 2001, Pavelka et ment of tuberculosis with gold salts, patients al. 2002). Glucosamine sulphate is well ab- with co-existent rheumatoid arthritis noticed sorbed from the . Stimu- an improvement in their arthritis. lating effects on the biological function of Myocrisin chondrocytes are attributed to glucosamine Gold has a number of oxidative forms. The in vitro. Dosage: tablets and capsules contain- gold agents used in the treatment of RA con- gold salts 74

sist exclusively of monovalent Au+, which and inhibits the release of lysosomal en- binds to the organic molecule through a sul- zymes from phagocytosing cells, phur atom. From three gold compounds, which • Influence on monocytes: salts of gold in- contain sulphur (sodium aurothiomalate, so- hibit the production of IL-1, chemotaxis, dium salt of aurothiomalic acid, aurothioglu- chemiluminescence and the production of cose and aurothiosulphate), sodium auro- reactive oxygen forms, thiomalate is now used by intra-muscular in- • Influence on lymphocytes: gold binds to jection. HLA-DR antigens of lymphocytes, modi- Auranofin fies their structure and therefore inhibits This triethylphosphine compound of gold antigen presentation with subsequent acti- differs from other compounds by its better vation of specific T-cells; in vivo particular solubility in lipids. Compared to other gold subpopulations of T-cells do not change; in agents, auranofin is well absorbed after oral vitro salts of gold inhibit mitogen induced G administration. The reactivity of auranofin proliferation of lymphocytes. with sulphydryl groups is less than in other • Cytokines: gold inhibits the production of gold compounds. As such reactivity deter- IFN-γ, IL-1, IL-2 and IL-2 receptor, IL-6, mines the biological activity of gold agents, IL-8, compared to sodium aurothiomalate and au- • Influence on B lymphocytes: in vivo the rothioglucose, the efficacy of auranofin is salts of gold reduce the increased number lower. of circulating CD5+ B-lymphocytes, de- Pharmacokinetics: Sodium aurothiomalate crease the level of immunoglobulins, rheu- (25 to 50 mg every 1 to 4 weeks) and auranofin matoid factor and immune complexes. (6 to 9 mg daily) bind to plasma proteins, es- Adverse effects: pecially albumin. The maximum plasma con- • Skin and mucosa – dermatitis, mouth ul- centration of gold (4 to 7 mg/L) is achieved ceration, pruritus, erythema, eczema, urti- within 2 to 3 hours of intramuscular adminis- caria, erythroderma, morbilliform or - tration. Initially, it is excreted from the blood latiniform exanthema, nail changes, chry- with a plasma half life of approximately 6 siasis greyish pigmentation, gingivitis, days, but an equilibrium between absorption vesicular, bullous and ulcerative stomatitis, and excretion is achieved after 5 to 7 weeks hypersalivation, alopecia, photosensitivity, and deposits of gold form in the body. The metallic taste, gold bound to albumin is transported into • Vasomotoric (nitroid) reactions – facial synovial fluid where it reaches 50% of its rash, hot flushes, nausea, , fa- plasma concentration. Gold has an affinity tigue, towards inflamed synovial tissue. • Renal – proteinuria, haematuria, membra- Mechanism of action nous glomerulonephritis, nephrotic syn- Properties of salts of gold: drome, renal impairment – associated with • Inhibitory effect on expression of the en- HLA-DR3 and HLA-B8, dothelial adhesion molecule for leukocytes • Haematopoietic system – eosinophilia, (ELAM 1) on synovial cells thrombocytopenia, neutropenia, aplastic and therefore they reduce the transfer of anaemia, inflammatory cells into synovial tissue, • Pulmonary system – hypersensitivity pneu- • In vitro inhibition of proliferation of syn- monitis with pulmonary infiltrations, ovial fibroblasts, synovial cells and colla- obliterating bronchiolitis, gen, • Liver – cholestatic jaundice, hepatocellular • Gold influences polymorphonuclear leu- damage, occasionally acute liver dystro- kocytes (PMN): gold inhibits phagocytosis, phy, chemiluminescence, chemotaxis of PMN • Pancreas – pancreatitis, and the release of reactive oxygen forms; in • Gastrointestinal system – enterocolitis, nau- vitro it stabilises the cellular membranes sea, vomiting, diarrhoea, 75 growth factors

• Nervous system – peripheral and cranial cohol intake, obesity, hypertension, hyperlip- neuropathy, encephalopathy, Guillain- idaemia, glucose intolerance and kidney dis- Barre syndrome, ease. • Eyes – chrysiasis (pigmentation) of cornea or lens, , corneal ulceration Granulocytopenia Abnormally low granu- • Miscellaneous – metallic taste, headache. locyte count in the peripheral blood.

Goniometry A method used for measuring Granulocytes Leukocytes with a nucleus the range of movement within individual usually lobed into three segments and a cyto- joints. In physiotherapy it is important to de- plasma containing characteristic granules termine the range of motion of the joints and (mostly typically lysosomes). According to spine. Passive movements are measured (ar- the pigment type where the granules can be throtest). It is universally accepted that the histologically stained, they are divided into method “neutral-0” depending on the planes, neutrophilic (neutrophils), eosinophilic (eo- G referred to as SFTR (sagittal, frontal, trans- sinophils) and basophilic (basophils) granu- verse, and rotatory), be measured. Every locytes depending on the pigment type deter- movement is recorded using three values: mined by histological staining. An alternative outer limit value (e.g. extension), zero posi- term for granulocytes is polymorphonuclear tion and outer limit value (e.g. flexion). For leukocytes (PMN), but this is not exactly true example, the limitation of flexion in the knee as the term polymorphonuclear leukocyte is is expressed as 0–0–45°. synonymous with neutrophils. Granulocytes represent 40–70% of all leukocytes in the pe- Goodpasture’s syndrome An autoim- ripheral blood. mune disorder induced by antibodies against the basement membrane of the glomeruli Granuloma An organised structure of and/or alveoli, or against the non-collagen mononuclear cells that is a typical feature of domain type IV collagen molecule. As a re- cell-mediated immunity. The immunological sult, a highly progressive vasculitis develops, granuloma is characterised by a central core especially of small vessels in the lungs and consisting of epithelioid cells and macrophag- kidney, leading to pulmonary haemorrhage es, occasionally with multinucleated giant and acute membranous-proliferative glom- cells (hypothesised to be the final develop- erulonephritis with the potential to rapid mental stage of the monocyte-macrophage death of the patient if not treated. cell-line). Sometimes (for example in tuber- culosis) this central part contains a necrotic Gottron’s sign → see Idiopathic inflamma- zone of destroyed cells. The macrophage-epi- tory myopathies (IIM), Juvenile dermatomy- thelioid part of the granuloma is surrounded ositis (JDM) with lymphocytes.

Gout (gouty arthritis) A clinical disease Granzymes The serine proteases found in developing in people with hyperuricaemia the granules of cytotoxic T-lymphocytes and due to an inflammatory reaction of the body NK-cells. They participate in cytotoxic reac- to the presence of sodium urate crystals. It tions performed by these cells. They are also can be classified as primary or secondary. referred to as fragmentins. Clinical symptoms and signs: It most fre- quently affects middle-aged men. Acute epi- Growth factors These belong to cytokines. sodic severe arthritis is typical. In its chronic They regulate the growth and metabolic ac- form, tophi often occur. The most frequently tivity of various cell populations and are affected joints include the first MTP (meta- termed accordingly. When they influence the tarsophalangeal) joint, the ankles and knees. proliferation of colony-forming haematopoi- Gout may be associated with an increased al- etic cells, they are referred to as colony- growth hormone 76

stimulating factors; when they influence leu- tion and differentiation of osteoblasts. Its ef- kocytes, they are called interleukins; and fects are mediated directly (interaction with when they influence other cells, they have specific growth ) or indi- different terms such as nerve growth factor rectly (via growth factors – insulin like growth (NGF), epidermal growth factor (EGF), fi- factors – IGF-1 and IGF-2). Growth hormone broblast growth factor (FGF), platelet-derived and growth factors also possess other impor- growth factor (PDGF), etc. tant effects influencing bone metabolism. Stimulation of 1-alpha-hydroxylase increases Growth hormone Affects bone by several the concentration of 1,25-dihydroxy vitamin mechanisms. It increases metabolic turnover D, thereby increasing absorption of calcium with a presumed influence on osteoforma- and phosphate in the small intestine. Other ef- tion and influences calcium resorption. It fects include influencing gonadal steroids, plays an important role in achieving peak modulation of the immune system as well as G bone mineral density. It stimulates prolifera- an anabolic effect on skeletal muscle. H

Haemochromatosis (HMCH) A heredi- kinds of disturbance have been identified: de- tary (autosomal recessive) disorder in which ficient production of the globin chains (so- mutations of the HFE gene (a MHC class called thalassaemias), or a mismatch of the 1-type gene) causes increased intestinal iron sequence of amino acid (so-called true hae- absorption. This diagnosis should be consid- moglobinopathies). ered in patients with early onset osteoarthri- Clinical symptoms and signs: tis (especially involving the metacarpopha- • painful crises in the juxta-articular regions langeal joints) in association with liver or of the long bones, spine and ribs other endocrine diseases. The diagnosis can • dactylitis now be made by genotyping for the HFE mu- • osteonecrosis tation in patients with very high serum iron • osteomyelitis studies (Olsson 2008). Involvement of joints • gout. is characterised by the accumulation of iron pigment causing the degeneration of articular Haemophilia → see Musculoskeletal com- cartilages. The disorder can be associated with plication in rare inherited haemorrhagic the occurrence of chondrocalcinosis (CCA). diatheses The radiographic appearance can be divided into two categories: Haemophilic arthropathy This can oc- 1. Articular calcification develops in approx- cur following repeated bleeding into the joint imately 30% of patients. The hyaline carti- after microtrauma or spontaneously in pa- lage in HMCH heavily protrudes into the tients with haemophilia, a group of related joint. The fibrous cartilage in the symphy- inherited bleeding disorders. Recurrent pro- sis is affected in HMCH more frequently tracted bleeding can result in synovitis, hae- than in CCA. mosiderosis and functional disturbance of 2. Structural damage of the joints develops the joint, eventually leading to joint destruc- in almost 50% of cases. These are similar tion. Bleeding into muscles can also occur to those seen in CCA except on the radial and can create a so-called haemophilic side of the metacarpophalangeal joints pseudotumour. The radiographic findings where hooky osteophytes are formed in are characterised initially by the formation of patients with HMCH. In CCA, the 2nd and cysts and erosions, but later the articular sur- 3rd MCP joint are affected, in HMCH the faces flatten and sclerosis occurs at the edges, 4th MCP joints is also involved. eventually leading to severe osteoarthritis. Treatment of the underlying disease involves Prophylactic use of Factor VIII or intensive regular venesection to normalise the serum on-demand Factor VIII replacement therapy iron studies, though this has little effect on to reduce the frequency or severity of joint the joint symptoms. Consideration should be bleeds delays the progress of joint disease. given to screening 1st degree relatives of the patient for the disease (Olsson 2008). Hallux rigidus (Stiff big toe) The big toe is stiff with marked limitation in the move- Haemoglobinopathies and involve- ment of the first metatarsophalangeal joint ment of the locomotor organs Haemo- making the normal push off of the foot when globinopathies are inherited disturbances of walking difficult. There may be a pain in the the production and function of haemoglobin. big toe. As a consequence of the gene mutation, two hallux valgus 78

Hallux valgus → see Toe swelling/deformity Health assessment questionnaire and associated diseases (HAQ) → see Instruments of assessing (health status measurements, outcome measure- Hammer toe → see Toe swelling/deformity ment) and associated diseases Health status measurements → see In- Hand silhouette Similar to a palmogram, struments of assessing (health status mea- the contour of the hand with all fingers ad- surements, outcome measurement) ducted and then with all fingers maximally abducted is traced; the lateral shape of the Heat shock proteins (HSP) They are syn- hand is also traced (the 5th finger lies on the thesised in two ways: paper). The method can be utilised for moni- 1. after induction by increased temperature toring treatment targeted at the hand. For or by other stress factors. These are induc- example, it is used in systemic sclerosis, but able HSPs, also in other disorders of hand function. 2. constantly synthesised without the effect H of any stress factor called constitutive or Handicap A category expressing an irre- cognitive HSPs, which are more common- versible loss of a certain physical or mental ly referred to as HSCs. function that decreases the ability of the indi- The production of HSPs can also be induced vidual to assert oneself in occupation, family by pathophysiological conditions (infections, or other sphere of his/her social life. The IDH inflammation, malignancies etc.), immuno- (impairment–disability–handicap) classifica- logical factors (e.g. phagocytosis, certain cy- tion is now expanded and modified in the tokines, free radicals, organ transplants) as new “ICF classification”. well as normal physiological conditions (cell cycle, embryonic development, cell differen- Hauffe’s bath A branch of hydrotherapy tiation etc.). HSPs have a similar amino acid characterised by a gradual increase in the structure in the cells of different organisms, temperature of a bath, for example, for the from single celled organisms to humans. feet of patients with a disturbance of macro- They act as chaperone proteins (attendant or microcirculation (in diabetes or systemic proteins) to protect the structure (biologically sclerosis), in which the sudden immersion in active form) of other proteins, play an impor- a hyperthermic bath would produce an unde- tant role in the protection of cells against pro- sirable initial vasoconstriction. teotoxic agents and are involved in various immune mechanisms. HBeAg Hepatitis B virus nucleocapsid anti- gen. Its presence in the serum is a feature of Heberden’s nodes → see Osteoarthritis – the contagious stage of the disease. hands (Heberden and Bouchard type)

HBsAg Hepatitis B virus surface antigen. Henoch-Schönlein purpura A leukocy- toclastic vasculitis involving small vessels Head’s zones In diseases of certain internal with deposits of immune complexes contain- organs, regions of altered sensation appear on ing predominantly IgA. The disorder typi- the skin at relevant spinal cord segments, cally affects the skin, bowels, and kidneys named Head’s zones after their discoverer (Sir (glomeruli) and is associated with arthritis. It Henry Head, neurologist in England, 1861– occurs predominantly in childhood, more 1940). They can be used diagnostically and frequently in boys. The inciting agent can be therapeutically to influence the affected or- an infection, allergic reactions to medica- gans. tions, food, insect bite or exposition to cold. A purpuric rash on the lower extremities and/ or buttocks together with swelling of the large 79 HIV (human immunodeficiency virus) joints is a typical presentation. Some patients months after the fadeout of HBsAg and are a suffer from abdominal pain and may have sign of acquired immunity. The most at-risk blood in the stools and micro- or macroscop- groups for contracting hepatitis B are health ic haematuria. More severe manifestations in professionals, haemodialysis patients, hae- the gastrointestinal tract (changes to the mes- mophiliacs, drug addicts and homosexuals. enteric vessels, diarrhoea) and the involve- Hepatitis C is caused by an RNA virus that is ment of the central nervous system (CNS) or often transmitted parenterally mainly by testicles are indications for treatment with blood transfusions, less frequently via infect- glucocorticoids. ed needles in drug addicts or via sexual inter- In tests, rheumatoid factors of IgA class are course. The disease has a milder course than often present. A recurrent purpuric rash ap- hepatitis A or hepatitis B. pears in 1/3 to 1/2 of patients, mostly within 6 Chronic hepatitis weeks, rarely after several years. Antibiotics are The inflammation of the liver lasts longer usually given when concomitant infection is than six months and includes a heteroge- suspected. The prognosis depends on the ex- neous group of liver diseases with typical in- tent of renal and CNS involvement. In severe flammatory infiltrations, necrosis of hepato- H forms the administration of glucocorticoids in cytes and signs of regeneration processes as various forms is necessary combined with im- well as fibrosis, but without the signs of a cir- munosuppressant treatment or plasmapheresis. rhotic transformation. They include viral hepatitides such us hepatitis B, C and D, auto- Hepatitis An inflammation of the liver that immune hepatitis, primary biliary cirrhosis, can present as jaundice. It appears in multiple primary sclerosing cholangitis and some forms that can be infectious or chronic. Infec- overlapping syndromes whose diagnostic, tious hepatitis is induced by viruses and can be histological, or clinical signs are typical for of several types – A, B, C (formerly nonA, different nosological diseases classified under nonB), D or E. The type A hepatitis (infectious chronic hepatitis. jaundice) is caused by type A virus from the Picornaviridae family. It is manifested by tired- Heterobispecific antibodies These are ness, malaise, anorexia, disturbance of liver monoclonal antibodies that are not produced functions, and eventually jaundice. The dis- during normal immune responses. They can ease is transmitted through food and water be prepared by hybridoma technology or by though the source of the infection is always a gene engineering methods. They possess two human. The virus causing type B hepatitis binding sites with different specificity (each belongs to a group of “hepdna” viruses (hep- binds a different epitope). atitis-DNA virus). It contains the following diagnostically significant antigens: surface Heterocytotropic antibodies These are HBsAg, the nuclear HBcAg and HBeAg. In- antibodies of a particular animal species, fection is transmitted exclusively parenterally which also have a high affinity for the Fc-re- (via blood). The incubation period is 2 to 7 ceptors of cells of another animal species. weeks. HBsAg is positive as early as two weeks before the onset of clinical symptoms Hippotherapy A complex physiotherapeu- and signs that are similar to those seen in tic method based on neurophysiological hepatitis A. It vanishes within 6 weeks after principles that uses a living instrument – a the infection unless the disease becomes horse – for treatment purposes. Hippothera- chronic. The occurrence of antibodies against py is classified as a proprioceptive neuromus- HBeAg is a sign of immunity and the begin- cular facilitatory method. It is closest to the ning of subsidence of the infection. Increased Bobath and Kabat methods. levels of antiHBc antibodies of the IgM class indicates a new acute infection. AntiHBs an- HIV (human immunodeficiency virus) tibodies appear in the course of several The abbreviation for the human immunode- HLA 80

ficiency virus that causes the acquired immu- I and II, we can also find genes for certain nodeficiency syndrome (AIDS). It is a retro- components of complement, cytokines and virus (a virus family whose genome is com- other proteins (more than 40 in total) that are posed of RNA that after penetration into a usually termed HLA antigens of class III, susceptible cell transcribes its information even though they do not participate directly into the cellular DNA), which has a typical in the major histocompatibility system. envelope glycoprotein gp120 on its surface. This glycoprotein can specifically bind to the Homocystinuria Homocystinuria is an au- CD4 molecule, which allows it to enter and tosomal recessive inherited enzymatic defect infect cells having this feature on their sur- of methionine metabolism that is character- face (T-helper lymphocytes, macrophages, ised by cystathionine β-synthetase deficien- follicular dendritic cells, microglia). After the cy. HIV particle has penetrated T-helper lym- Clinical symptoms and signs: The disease phocytes, it can start reproducing, thereby manifests in mental retardation, often ac- causing cell death with a serious disturbance companied by ectopy of the lens, glaucoma, H of immune homeostasis leading to clinical arachnodactyly and other signs of Marfan signs related to AIDS. To date, two types of syndrome, such as osteoporosis, muscle these viruses are well-characterised – HIV-1 weakness, connective tissue dysplasia and and HIV-2. In the diagnosis and prognosis of kyphoscoliosis. Also coxa valgum, genu val- AIDS, an essential role is played by the dem- gum, deformities of the feet (pes cavus), laxity onstration of viral antigens p24 and gp120, as of joints and signs of hypermobility can well as the antibodies against them in the se- be present. Hepatomegaly often occurs in rum of the infected individual. homocystinuria; epileptic seizures can occur. There is often hyperreflexia and mild spastic- HLA The commonly used abbreviation for ity of the limb muscles. In tests, hypermethi- human leukocyte antigens which belong to oninemia, hypergammaglobulinaemia and the histocompatibility antigens. They are hyperhomocysteinemia can be found. Exam- products of the human major histocompati- ination of the urine shows homocystinuria. bility complex (HLA complex) and according to their structure and function are divided Homocytotropic antibodies These are into HLA antigens of class I and class II. The antibodies which have a higher affinity to Fc- molecules of HLA class I consist of two poly- receptors of the cells of the animal species in

peptide chains (α- and β2-microglobulins, which they are produced than to Fc-receptors while only the α-chain is coded from the HLA of the cells of other animal species. In hu- complex) and are localised on the surface of mans, IgE antibodies belong to this group. all nucleated cells. The molecules of HLA class II also consist of two polypeptide chains Hormonal effects The sexual hormones, (α and β), forming a heterodimer and are rou- growth hormone, calciotropic hormones, cor- tinely found on the surface of immune system tisol, insulin, local factors and thyroid hor- cells, as well as on other activated cells. mones all have important effects on the regu- lation of bone remodelling. HLA complex A complex of genes located on the short arm of the 6th chromosome and Hormonal Replacement Therapy (HRT) codes the human major histocompatibility From a pathophysiological point of view, it system. These genes comprise several regions was the treatment of choice in patients with and sub-regions and their products represent the postmenopausal osteoporosis. Oestro- the HLA antigens of class I (HLA-A, HLA-B, gens prevent osteoresorption (a vicarious ef- HLA-C, HLA-E, HLA-F and HLA-G) or class fect on the osteoclasts and reduction of osteo- II (HLA-D, HLA-DP, HLA-DQ and HLA- blast apoptosis). Oestrogens with or without DR). Among the loci coding for HLA classes progesterone significantly reduce the risk of 81 Hunter’s disease osteoporotic fractures (femoral neck, spine, other molecules participating in the immune forearm). The optimal duration of adminis- responses. tration is more than 5 years. After termina- tion of treatment, osteoresorption dominates Hubbard’s tank A special bath shaped like again over osteoformation. Due to an in- a butterfly which allows the physiotherapist creased risk of invasive breast cancer, thromb- to access the patient from either side. There embolic events, cardiovascular and cerebro- are different jets in the basin and an under- vascular complications, HRT is no longer the water massage is also possible using a water treatment of choice in postmenopausal os- hose. A suspension mechanism enables the teoporosis. However, some postmenopausal immersion of a patient with polyarticular im- ladies, after counselling on the risks and ben- pairment in the water for the subsequent ap- efits of HRT, still decide that HRT is their plication of physiotherapeutic procedures. treatment of choice to improve their quality of life. Hughes syndrome → see Antiphospholip- id syndrome (APS) Hormones of the thymus The hormones H produced by the thymus. There are more than Human leukocyte antigens → see HLA 40 peptides and polypeptides whose main function is the regulation of T-lymphocyte Humanised antibodies Monoclonal anti- development and maintenance of the delicate bodies prepared by recombinant DNA tech- balance between various subgroups. Thymo- nology. Their molecules possess binding sites poetins, thymosins and thymulin belong to or whole variable domains originating from the most studied hormones. mice or rats, while the rest of the molecule (constant domains) is encoded by human 5-HPETE 5-hydroperoxyeicosatetraenoic genes. The humanised molecule, after ad- acid is an intermediate product formed in the ministration to humans for diagnostic or metabolic cascade of arachidonic acid. By therapeutic purposes, significantly decreases virtue of the lipooxygenase enzymes, it is the immune response to foreign antigen converted to leukotrienes and lipoxins. Simi- which would have occurred if the entire mol- lar to LTB4, it is an effective chemotactic fac- ecule had been encoded by mouse or rat ge- tor for the neutrophils, monocytes and mac- nome alone. rophages. It also causes the release of hista- mine and other mediators by degranulation Hungry bone syndrome Occurs in the of mast cells. presence of rapid termination of resorption and/or increased activity of osteoblasts. The HSP Abbreviation for heat shock proteins, causes include the early phase of treatment of which belong to stress proteins. Their pro- with rapid mineralisa- duction within the cell is increased by a ele- tion of excessive amounts of osteoid without vated temperature, ionised radiation, heavy adequate calcium supplementation, after sur- metals, anoxia, glucose deficiency and other gery for hyperparathyroidism or hyperthy- stressful conditions. The HSP form a super- roidism; or rarely in children due to the activ- family of several tens of molecules differing ity of osteoblastic metastasis. Biochemical in their molecular weight and cellular func- results include hypocalcaemia, and possibly tion. Their best known function includes the hypophosphataemia and hypomagnesaemia chaperone function (i.e. the ability to protect with corresponding clinical manifestations, the molecules of other proteins against dena- such as tetany. turation and diverse proteotoxic agents that could induce the loss of their biological activ- Hunter’s disease → see Mucopolysacchari- ity). They regulate the production of immu- dosis (MPS) noglobulins, expression of HLA antigens and Hurler’s disease 82

Hurler’s disease → see Mucopolysacchari- ferred to as chondrocytes. The components dosis (MPS) of the cartilaginous matrix are self-synthe- sised and self-produced. Chondrocytes can Hyaline cartilage A non-vascular, non- be found in the tiny spaces of the matrix neural and non-lymphatic type of dense con- called lacunae. The primary lacuna is one con- nective tissue. It is a hard translucent smooth taining a chondrocyte that stopped secretion of tissue covering the ends of bones to form a the intercellular substance into its surrounding smooth articular surface to joints. In a young environment. However, such a chondrocyte is body it has a blue-white colour and is slightly able to reproduce, which is demonstrated by transparent, in an older body it becomes yel- mitosis and is called the interstitial growth of low-white and opaque. It is composed of the cartilage. The daughter cell is located in chondrocytes (derived from mesochymal the same lacuna and a tiny barrier of intercel- cells) which secrete a matrix composed main- lular matrix is formed between the cells. ly of type II collagen fibres and proteoglycans, Sometimes the daughter cells undergo fur- though also has a high water content (65– ther mitotic reproduction so that up to four H 80%). Nutrition of chondrocytes is provided cells are located in one lacuna. Such an aggre- by the diffusion of compounds through the gate is called a chondrocyte nest. The chon- synovial membrane. The intensity of nutri- drocytes situated in one nest represent a clone tion of the tissue is low, but the metabolic (that is descent from the original cell of the turnover of chondrocytes is high. As chon- primary lacuna). The size and shape of chon- drocytes are bound in lacunae and cartilage drocytes are very variable; the young ones are has no blood supply, cartilage has a poor re- usually flattened; the adult ones are big and pair mechanism. oval. The chondrocytes of articular cartilage During embryonic development, mesen- retain their ability to produce components of chymal cells condense in regions where carti- the intercellular cartilaginous matrix during lage normally develops, and differentiate into their life, however, under normal conditions chondroblasts which then produce the mac- they do not reproduce. The production of romolecular components of the cartilaginous new matrix is the only mechanism by which matrix. In the circumference of these cells a articular cartilage can compensate for the loss fibrous envelope called perichondrium be- caused by everyday use. This limitation has gins to form. Chondroblasts stem from the been recognised by estimations of chondro- cells of the inner perichondrium layer. This cyte proportions in the matrix showing that layer is referred to as the chondrogenic layer the relative cell count in articular cartilage of the perichondrium. The chondroblasts de- decreases with age. Chondrocytes in adult posit new cartilaginous matrix on the surface cartilage are longliving cells that rarely repro- of previously formed cartilage, leading to ap- duce. However, their reproductive ability re- position growth of the cartilage. The cells of mains preserved and can be regenerated the outer perichondrium layer differentiate when the matrix collagen network in their into fibroblasts producing collagen and creat- proximity is impaired, such as in osteoarthri- ing the fibrous layer of the perichondrium tis. that persists on certain cartilages up to adult- hood (e.g. the cartilaginous rings of the tra- Hyaluronic acid The sodium salt of hy- chea and the cartilages attaching the anterior aluronic acid is the main component of ends of the ribs to the sternum). Both layers synovial fluid and the intercellular matrix of of the perichondrium vanish from the articu- hyaline cartilage and can be administered in lar cartilage leaving the articular cartilage in the treatment of osteoarthrosis. The prepara- the synovial joint no longer covered by the tion Hyalgan (500–730 kDa) is administered perichondrium. intraarticularly at weekly intervals up to a to- After the intercellular matrix of the carti- tal of five times. The treatment cycle can be lage covers the chondroblasts they are re- repeated twice yearly. The preparation Syn- 83 hypermobility syndrome (HMS) visc (Hylan G-F 20) is a high molecular poly- a marker of bone resorption, it also produced saccharide (6000 kDa) that has a viscosupple- from degradation of the C1q component of mental effect and regulates synovial fluid ho- complement and in the rheumatoid arthritis meostasis. Synvisc is administered intra-ar- and other inflammatory disorders can be re- ticularly in three weekly doses. Both sponsible for up to 40% of hydroxyproline in preparations are administered strictly intra- the urine. Moreover, this method demands a articularly, especially in osteoarthrosis. diet lasting at least 24 hours because the col- lagen content in food may influence its con- Hydrocortisone → see Glucocorticoids centration in the urine. Therefore, more spe- cific markers of bone breakdown of the pyri- Hydrops articulorum intermittens (in- dinoline type are now used. termittent hydrops of the joint) A re- current joint effusion occurring without de- Hyperaesthesia Increased sensitivity to monstrable cause, mainly affecting the knee various stimuli (increased sensation). joint. There is no synovitis, with the joint usually being cool and non-tender. The swell- Hyperalgesia An increased response to H ing usually lasts 2 to 6 days and recurs at stimulus that normally elicits pain: various time intervals (for example over 7, 14 • primary – in the area of damage, or 21 days). • secondary – a pain felt in the undamaged Treatment: Joint aspiration, intraarticular area surrounding the damaged area. injection of glucocorticoids, or rarely syno- vectomy may be necessary. Nonsteroidal Hyperalgesic zones (HAZ) Areas in the antiinflammatory drugs or mild disease skin, subcutaneous tissues, muscles, fascias modifying antirheumatic drugs may be ad- or periosteum with altered sensitivity that de- ministered. The disease is often referred to as velop as a manifestation of reflex events in a prerheumatoid as approximately half of cases segment elicited by nociceptive irritation. By go onto develop rheumatoid arthritis. eliminating HAZ (using reflex massage or by injecting the site with Bupivacaine (Marcaine, Hydrotherapy The use of water of various etc.) it is possible to interrupt the reflex events temperatures for therapeutic and prophylac- in, for example, vertebrogenic pain syn- tic purposes. The procedure can involve sim- dromes. ple methods such as applying thermal stimuli (hot and/or cold), or mechanical stimuli such Hypergammaglobulinemia An in- as bead bath, whirlpool bath, various show- creased concentration of serum immuno- ers, and chemical stimuli applied through globulins. baths with ingredients. Hydrotherapy can be combined with kinesiotherapy, so-called hy- Hyperkinesis A pathological involuntary drokinesiotherapy. movement caused by a disturbance of the central motor . Hyperkinesis includes Hydroxychloroquine → see Antimalarial tics, tremors, spasms, manifestations of spi- drugs nal cord automatisms, choreaform and athe- toid movements. Hydroxyproline It represents approxi- mately 13% of the total aminoacid composi- Hyperlipidaemias → see Musculoskeletal tion of collagen. It is formed by posttransla- symptoms in primary hyperlipidaemias tional hydroxylation of proline in the collagen chain. Approximately 10% of the total hy- Hypermobility syndrome (HMS) It is droxyproline produced during degradation characterised by the occurrence of musculo- of collagen is excreted in the urine. Even skeletal symptoms in individuals with joint though hydroxyproline is regarded mainly as hypermobility who do not suffer from any hypermobility test 2 (according to janda) 84

other rheumatic disease. When the syndrome overlapping contralateral acromion, even was first described in 1967, many rheuma- reaching the scapula, tologists were very sceptical – such a syn- • Extended elbows test – elbows can touch drome was considered more as a clinical curi- during gradual extension, even above the osity than a rheumatic disease. The set of five angle of 110°, manoeuvres referred to as Beighton criteria • clasped hands test – palms remain in con- with nine grades are characteristic for the di- tact during elevation of elbows, even in a agnosis of HMS: wrist angle of 90°, 1. Dorsal flexion in the 5th MCP (metacar- • Forward bend test – the whole palms can pophalangeal joint) by 90°, touch the floor in the fingers-floor test, 2. Apposition of the thumb to the volar as- • Bend to side test – vertical line arising from pect of forearm, axilla reaches the contralateral side during 3. Hyperextension of the elbow by 10°, lateral flexion of the lumbar segment of the 4. Hyperextension of the knee by 10°, spine, 5. Place the palms on the floor without bend- • Behind the heel sit down test – gluteal H ing the knees. muscles reach the floor between the heels One point is awarded to each manoeuvre, when the patient is sitting between the with two points for bilateral involvement, heels, giving a maximum score of nine. A score >3 • Forward bend in sitting position test – is considered indicative of generalised hyper- trunk rests completely on the thighs, mobility. • Bend to side in kneeling position test (in- Clinical symptoms: Are characterised by a formative) – the extent of the side bend is wide range of easily detectable traumatic le- increased. sions and lesions due to overloading, e.g. traction traumas of tendons and ligaments, Hyperostosis A common term for multiple synovitis of joints and bursae, chondromala- disorders having an increased bone density. cia patellae, rotator cuff lesions of the shoul- These disorders may be detected radiograph- der, or back pain. Some patients suffer from ically as an increase in bone density. However, joint instability and recurrent dislocations. In without a histomorphological examination, it others, chronic arthritis develops either low is impossible to differentiate an increase of grade synovitis of traumatic origin or osteoar- new bone formation from a decrease of its throsis, which many authors consider to be destruction. The aetiology of these disorders a complication of HMS. Inflammation mark- is currently unknown. It is a complex of fac- ers are negative in laboratory tests. Therapeu- tors decreasing the resorptive activity of the tic techniques consist of establishing the cor- osteoclasts. A disturbance in the lysosomes, rect diagnosis, proper therapeutic rehabilita- viral inclusions, abnormal PTH synthesis and tion and elimination of provoking factors. disturbance of interleukin-2 production have all been implicated. Carboanhydrase II defi- Hypermobility test 2 (according to ciency in erythrocytes causes a specific form Janda) of hyperostosis (, renal tubular • Head rotation – greater than 80°, acidosis and cerebral calcification). Usually, • Scarf test – elbow is placed behind the ver- the disorders are not accompanied by an ex- tical axis of the body; fingers are placed cess of minerals when compared to bone ma- behind spinous processes of the cervical trix substance, but osteopetrosis is an excep- vertebrae, tion. Hyperostosis may also be encountered • Arms swinging downward/backward test in hyperparathyroidism. If successfully treat- – fingers and palms are interlocked to a ed, the degree of bone resorption reduces certain extent, very rapidly and sites with increased new • Arms swinging behind head test – fingers bone formation followed by increased densi- from one arm are crossed behind the head ty, mainly in areas of healing brown tumours 85 hypomagnesaemia may occur. In hypothyroidism and acromeg- berty, they rise sharply in boys to an average aly, an increase in bone density with pre- value of 0.36 mmols/l and remain around served architecture may occur. Skeletal hy- this level throughout life. In girls, the levels perostosis can be found after a long-term of serum uric acid rise very little at puberty treatment with synthetic . but rise to levels similar to men after the menopause (pre-menopausal average value Hyperpathy Exaggerated response to pain- of 0.24 mmols/l). Using the oxidation-reduc- ful stimulus. tion method with phosphotungstic acid for determining the level of serum uric acid, lev- Hyperphosphatasia This syndrome is els greater than 0.42 mmols/l and 0.36 mmols/l characterised by high serum activity of alka- are regarded as hyperuricaemia in men and line phosphatase. At present there is no con- women, respectively. Using the uricase meth- sensus regarding the use of these terms (hy- od, serum urate levels are 0.04 mmols/l lower. perphosphatasaemia and hyperphosphatasia). The occurrence of hyperuricaemia in the pop- Hyperphosphatasaemia represents a heteroge- ulation varies in different studies between 4 neous group of conditions characterised pre- to 40% (Pavelka 2000). It seems that the H dominantly by high alkaline phosphatase lev- worldwide incidence of hyperuricaemia is els in serum (S-ALP). The hyperphosphata- rising. In the Central-European region, the saemia (hyperphosphatasia) group includes estimated incidence of hyperuricaemia is 10 completely benign conditions that are bio- to 20% (Pavelka 2000). chemical abnormalities accompanied by a significant increase in S-ALP, but also clinical Hypoalgesia Decreased or impaired sensa- conditions associated with severe bone defor- tion of painful stimulus. mities that are a form of bone dysplasias. → see Achondropla- Hyperphosphataemia Occurring when sia and hypochondroplasia the ability of the kidneys to eliminate phos- phate in the urine is decreased (renal insuffi- Hypoesthesia A decreased sense of touch ciency, hypo- and pseudohypoparathyroid- or sensation. ism) or in excessive delivery of phosphate to extracellular fluid during enhanced catabo- Hypogonadism This is characterised by lism or tissue destruction (long-lasting exces- sex hormone deficiency. This may be primary sive intake of beverages with a high phos- due to testicular and ovarian failure, or sec- phoric acid content or recurrent rectal ene- ondary due to hypothalamus – pituitary dys- mas of , acute leukaemias, haemo- function. Hypogonadism can lead to osteo- lytic anaemias, cytotoxic treatment, injuries porosis. or non-traumatic rhabdomyolysis). Clinical manifestations include tetany and other man- Hypomagnesaemia Magnesium (Mg) ifestations of hypocalcaemia, eventually lead- depletion is substantially more frequent than ing to hyperparathyroidism and soft tissue its accumulation. Hypomagnesaemia occurs calcifications. with the serum concentration of magnesium below 0.7 mmol/L. Hypersensitive reactions → see Immu- Pathogenesis: can nopathology occur due to a lack of intake, malabsorption in the gastrointestinal tract or increased renal Hyperuricaemia The presence of an ele- loss. vated serum uric acid level. Levels of serum Causes of magnesium deficiency (according uric acid depend on gender and age. In the to Rude 1993, Whang 1994): pre-pubertal period, the concentration of se- • decreased intake of Mg in food: malnutri- rum uric acid is low in both genders. At pu- tion, 86

• gastrointestinal causes: vomiting, malab- suppresses the growth of hydroxyapatite crys- sorption syndrome, resection of the bowel, tals and impairs mineralisation of the skele- acute and chronic diarrhoea, intestinal fis- ton. The zones of insufficient mineralisation tula, acute pancreatitis (saponification of are expanded and osteoid accumulates. Mg in the fat necrosis), primary infantile Clinical symptoms and signs: The bone hypomagnesaemia, has a primitive structure and remodelling • renal losses: long-term parenteral nutrition, does not occur, leading to a picture resem- osmotic diuresis (glucose, mannitol, urea), bling rickets. Ossification of the flat bones is metabolic acidosis, hypercalciuria, hyper- substantially limited. aldosteronism, Bartter’s syndrome, chronic The congenital form is inherited by an au- pyelonephritis, interstitial nephritis, chron- tosomal recessive trait. The skeleton of af- ic glomerulonephritis, polyuric phase of fected individuals is demineralised and in- the acute tubular necrosis, renal tubular volvement of the skull is called “caput mem- acidosis, renal transplantation, isolated fa- branaceum” (soft calvarium). Intracranial milial hypomagnesaemia, bleeding can occur. The extremities are de- H • treatments: diuretics (furosemide, bu- formed by multiple fractures. The condition metanide), aminoglycosides, cisplatin, cy- is usually fatal. The infantile form manifests closporin, amphotericin B, glycosides, itself within the first six months of life. The • other mechanisms: hungry bone syndrome, child fails to thrive, is hypotonic and has burn injuries, excessive perspiration, ex- wide opened fontanelles and the skull is hy- change transfusion. pomineralised. The condition resembles se- Long term (>3-weeks) magnesium deficiency vere rickets, though the hypocalcaemia is leads to depletion of the intracellular Mg re- associated with hypercalciuria leading to sulting in a decrease in parathormone (PTH) vomiting and renal impairment. Functional secretion along with resistance of end organs craniostenosis and skull deformation may (bone and kidneys) to the biological effects of occur. Respiratory difficulties, due to a de- PTH and disturbed production of cAMP (cy- mineralisation of the thorax, leads to death in clic adenosine monophosphate). As a conse- up to a half of patients. A juvenile form leads quence, hypocalcaemia develops with all its to premature loss of milk teeth before the 5th associated symptoms. year. Afflicted persons have weak growth and dolichocephalia (a long narrow head). Be- Hypoparathyroidism This disorder is sides retarded growth, there is also bone pain characterised by parathormone deficiency or and deformities develop (coxa vara, genu its insufficient action on target tissues. There varum, kyphoscoliosis, etc.), which are the is an increased neuromuscular irritability, most frequent symptoms and signs of hypo- psychosis and trophic changes in the lens, phosphatasia. Individual limbs are strikingly nails and teeth. Blood tests reveal hypocal- short, while the head, neck and trunk are caemia and hyperphosphataemia. The treat- normally developed. The gait is often wad- ment of choice involves the administration of dling due to marked muscle weakness. In calcium and active forms of vitamin D. adults the disease manifests in middle age by fractures and pseudofractures. Characterised by low The signs of hypophosphatasia first mani- serum activity of alkaline phosphatase. fest after reaching the first year of life. Chil- Pathogenesis: There are approximately 50 dren lag behind in growth and do not thrive described mutations of the gene that codes in weight. The fontanelles close prematurely tissue non-specific alkaline phosphatase and development of craniostenosis with sub- which is localised on chromosome 1, with sequent changes to the shape of the skull. further mutations being recognised. Osteo- During growth, the clinical signs may improve blasts lack alkaline phosphatase activity. The in early childhood. In addition to the above accumulation of inorganic pyrophosphate mentioned symptoms, tetany and spontane- 87 hypoxaemic reperfusion (hypoxic reperfusion oxidative injury) inducing joint damage ous fractures rarely occur in familial hypo- sion of the vasculature of the synovial phosphatasia. X-rays show changes similar to membrane with subsequent hypoxia. This in- those seen in rickets or osteomalacia. duces the production of hypoxanthine or xan- thine, which in a healthy synovial membrane in Hypoxaemic reperfusion (hypoxic rep- the presence of xanthine dehydrogenase can be erfusion oxidative injury) inducing joint degraded, in an inflamed synovial membrane damage This is the method by which hypox- the hypoxanthine is converted to xanthine by aemic reperfusion of reactive oxygen species the enzyme xanthine oxidase, thereby enabling complexes in the joint cause joint damage. The the production of reactive oxygen species. Once intra-articular pressure in a healthy joint is low- joint activity ceases, the complex of reactive er than atmospheric pressure and after activity oxygen species penetrates the joint cavity where does not increase. An inflamed joint has in- it participates in the degradation processes of creased intra-articular pressure at rest which proteins, lipids and proteoglycans, and so per- increases following activity causing compres- petuates inflammation and joint destruction. H I

Ibandronate A bisphosphonate licensed for rheumatic disorders (such as scleroderma, the treatment of postmenopausal osteoporo- systemic lupus erythematosus, Sjögren’s syn- sis. The drug can be administered orally or by drome or rheumatoid arthritis). Certain other slow intravenous injection. Orally, it is given disorders are included such as inclusion-body before meals and washed down with a cup of myositis (IBM), granulomatous myositis, and water; afterwards, the patient must sit and not eosinophilic myositis or focal and nodular lie down for 30 minutes. The oral dose of 150 myositis. mg is given once a month, a regimen thought Clinical symptoms and signs: Idiopathic to improve compliance. It can also be adminis- inflammatory myopathies are characterised by tered by slow intravenous injection at a dose of the presence of symmetrical, predominantly 3mg in 3mls every 3 months. This is particu- proximal muscle weakness, biopsy evidence of larly useful in patients with gastrointestinal muscle fibre impairment, elevated serum levels intolerance of bisphosphonates. of muscle enzymes or myoglobin and the pres- ence of multifocal myopathic signs on electro- ICAM → see Intercellular adhesion molecule myography. In DM characteristic changes of (ICAM) the skin appear. Impairment of other systems such as joints, lungs, heart and gastrointestinal ICF → see International classification of func- tract occur with variable frequency. There may tioning (ICF) be an association with malignancy, especially in the older population. Idiopathic infantile hypercalcaemia Criteria of classification Minimally modi- Patients resemble children with Williams- fied criteria of Bohan and Peter are used and Beuren-syndrome; some of them can have include the following manifestations: heart disease, facial dysmorphism, hyperten- • predominant or strictly proximal, usually sion and radio-ulnar synostosis. Further symmetrical muscle weakness, progressive there can be strabismus (squint), inguinal over weeks or months, with or without my- hernia and hyperacusis, which are persistent. algias, Polyuria and polydipsia are frequent. In some • biopsy evidence of muscle fibre necrosis patients, an elevated PTHrP (parathyroid and regeneration with a mononuclear in- hormone-related protein) level can be detect- flammatory infiltrate (perivascular or in- ed. The hypercalcaemia persists much longer travascular) with or without perifascicular than in Williams-Beuren-syndrome and atrophy, sometimes requires limitation of the calcium • elevated serum creatine kinase (MM- intake, exclusion of vitamin D and adminis- isoenzyme), aldolase and myoglobin lev- tration of glucocorticoids. els, • multifocal myopathic changes on electro- Idiopathic inflammatory myopathies myography (small, short and polyphasic (IIM) Acquired inflammatory disorders of potentials) with increased insertion activi- the striated muscles of unknown aetiology. ty, with or without spontaneous potentials, They can be sub-divided into primary idio- • a rash typical for DM, especially heliotro- pathic polymyositis (PM), primary idiopathic pic exanthema and Gottron’s signs. dermatomyositis (DM), PM–DM in child- A diagnosis of IIM is definite when 4 or more hood, myositis associated with malignancy, criteria are present, it is probable when three and myositis combined with other systemic criteria are present. 89 idiotype

A diagnosis of DM is definite in the pres- the pathogenic process, and often associate ence of a rash and three other criteria; it is with other clinical signs (table 3). probable in the presence of a rash and two other criteria. Idiotope An idiotope is a unique set of anti- Laboratory tests: Serum levels of creatine gen determinants found in variable domains kinase (CK), lactate dehydrogenase, serum of immunoglobulin polypeptide chains. glutamic oxaloacetic (SGOT) or aspartate transaminase (AST), aldolase and myoglobin Idiotype It is a shared characteristic be- are raised. The rise occurs in the course of ac- tween a group of immunoglobulin or T cell tive disease and often normalises during re- receptor (TCR) molecules based upon the mission. The level of MM-CK isoenzyme is antigen binding specificity and therefore especially elevated but also the MB-CK frac- structure of their variable region. Also it is a tion which comes from a repeatedly damaged set of idiotopes at the binding site for a cer- regenerating muscle. Occasionally the level of tain antibody. Antiidiotypic antibodies that CK is normal due to the presence of inhibi- are one’s own anti-antibodies can develop tors or in association with malignancy. Au- against the idiotypes. Their binding site is toantibodies are present in the serum of 70– complementary to the binding site of the first 80% of patients. The erythrocyte sedimenta- antibodies and so it has a spatial structure I tion rate (ESR) and acute phase proteins are identical to the antigen determinant that is often normal. Mild anaemia can be present. specific for this first antibody. These antiidio- The autoantibodies probably play a role in typic antibodies are therefore referred to as

Table 3. Associations for myositis-specific autoantibodies (modified according to: Miller, F.W., JAMA, 270, 1993) (Miller 1993)

Myositis- Clinical Onset of myositis Response Prog- HLA Frequen- specific picture to treat- nosis associa- cy of inci- autoanti- rate seve- season ment tion* dence in body rity myositis Antisyn- Arthritis, Acute Severe Spring Moderate, Poor, DR3 20–40% thetases interstitial outbreak 5-year DRw52 (anti-Jo-1) pulmonary at dose survival DQA1*0501 fibrosis, decrement in 70% fever, “hand of cases mechanics”, Raynaud phenom- enon Anti-SRP Cardiac Very Very Autumn Poor, Very DR5 5% involve- acute severe aggressive poor, DRw52 ment, chemo- 5-year DQA1*0301 myalgia therapy survival needed in 25% of cases Anti-Mi-2 DM Acute Mild Anytime Good, but Good, DR7 15–20% classifica- the rash 5-year DRw53 tion with a persists survival DQA1*0201 distribution long in of rash in almost the V and 100% of shawl cases shape type DM – dermatomyositis, SRP – signal recognition particle IgA 90

the inner antigen picture of homoantibodies. the placenta. They activate complement after It is assumed that the idiotypes and antiidio- binding with the antigen (immune complex- types form a regulatory network in the body. es) or in the form of self aggregates (clusters of one’s own molecules). IgA A class of immunoglobulins whose mol- ecules can exist in two forms, either serum IgM They have the biggest relative molecular IgA (a monomer) or secretory IgA (a dimer weight (900,000 Da) and sedimentation coef- whose molecule also contains a J-chain and a ficient (19S). Their molecule consists of five secretory component SC). Secretory IgA (S- identical subunits (each with 180 kDa and IgA) can be found in mucosal secretions 8S), thus forming a pentamere that aside where it participates in local immune reac- from 10 light chains and 10 heavy chains con- tions. Penetration of epithelial cells onto the tains also one J-chain. A small amount of cir- surface of the mucous membrane is facilitat- culating IgM (up to 5%) forms a hexamere. ed by the secretory component. There are The basic subunit 8S of IgM is not circulat-

two known isotypes of heavy chains α – α1 ing, but remains in membrane form as a com-

and α2 – which produce antibodies of IgA1 ponent of the antigen receptor on the surface and IgA2 subclasses. of B-lymphocytes. Antibodies belonging to I the IgM class are produced mainly upon first IgD Immunoglobulins with a less well un- contact of the organism with a corpuscular derstood biological function. IgD molecules antigen. They have the greatest additive effect are, together with IgM monomers, most fre- of multivalency, which makes them particu- quently incorporated in the cytoplasmic larly effective in the agglutination of bacteria membrane of B-lymphocytes, having a dis- and in activating complement via the classi- criminative function of the antigen receptor cal pathway (after formation of immune component. complexes or aggregates).

IgE In physiological circumstances, their se- IL-1 to 18 → see Interleukin 1 to 18 rum concentration is the lowest of all immu- noglobulins. These antibodies participate in IL-1R The IL-1 receptor occurs in two iso- the protection of the body against parasitic types – I and II. The type II has a shorter cy- infections and, just like reagins, are responsi- toplasmic part compared to the type I which ble for early hypersensitive reactions (aller- consequently causes insufficient intracellular gies, anaphylaxis). Serum IgE levels are raised transmission of the signal after binding IL-1. in parasitic infections and are especially high in allergic reactions. IL-1RA An antagonist of the IL-1 receptor. IL-1 is a cytokine participating in normal IGF → see Insulin-like growth factor (IGF) physiological processes as well as regulation of the inflammatory responses. IL-1RA oc- IgG This class of immunoglobulins is the curs in three isoforms: one secretory (sIL-1- most widespread in extracellular fluids. Their RA) and two intracellular (icIL-1RAI and molecules consist of two identical light and icIL-1RAII). The function of secretory IL- two identical heavy chains that are spatially 1RA consists in local inhibition of IL-1 and organised into domains. There are four blockade of acute phase proteins, while the known heavy chains γ distinct in antigen function of the intracellular IL-1RA is un- structure, which form the four subclasses known. IgG1, IgG2, IgG3, and IgG4. The antibodies of IgG class are formed mainly during the re- Immune complexes Complexes arising sponse to the repeated administration of sol- from the reaction between an antigen and an uble antigens. They are the only antibodies to antibody. They can occur either in vitro cross the human foetal-maternal barrier in (where they are the essence of immunochem- 91 immunity ical assays and diagnostic methods) or in vivo that is a prerequisite for the existence of all (in which case they facilitate phagocytosis of superior animals. The most important prop- bacteria or other particles opsonised by the erty of the IS is its ability to differentiate its antibodies, or can induce immune complex own molecular structures from foreign ones disorders if the immune complexes are solu- (antigen). Proper and fully-functioning anti- ble, or autoimmune disorders when the reac- gens are normally tolerated; heterogeneous tion between an autoantibody and autoanti- (on the surface of microorganisms or trans- gen occurs in an organ). With in vivo condi- planted cells) or proper but functionally al- tions or in the presence of blood serum, the tered (estranged as for example on tumour- immune complexes can also bind to certain transformed or virus infected cells) are inac- components of complement. tivated and destroyed in the course of an im- mune response. Immune system (IS) This is a diffuse (not strictly delineated) organ that weighs around Immunity The capability of an organism to 1,000 grams in an adult and consists of mul- withstand infectious germs (viruses, bacteria, tiple tissues, cells and molecules. It is a com- fungi, cytozoon), foreign and estranged cells ponent of the neuro-endocrine-immune su- (cells transplanted from a genetically differ- persystem, ensuring the input and processing ent individual and one’s own altered cells I of all information necessary for the survival (cancerous) or cells invaded by viruses) and of humans and other superior organisms. their products, producing the ability to react The fundament component of the IS is lym- against the antigen by the immune response phatic tissue either condensed in lymphoid to the benefit of the body. This immunity can organs or existing in the form of free cells be either non-specific (natural, innate) or (lymphocytes, leukocytes). The lymphoid or- specific (acquired, adaptive). Both are deter- gans are divided into central (primary) or pe- mined by an individual’s genetic makeup (ge- ripheral (secondary). As well as lymphocytes, nome). the other important cells include antigen pre- Numerous anatomical structures (for ex- senting cells and phagocytes (especially mac- ample the skin and mucous membranes) and rophages and neutrophils). Essential mole- physiological systems (for example haemoco- cules involved in the reactions of the IS include agulation) that are not directly part of the im- antibodies (immunoglobulins), components mune system (they represent a natural resis- and factors of the complement system (com- tance), as well as specialised molecules (the plement), various immunohormones, cyto- complement system, many cytokines) and kines and other immunoregulatory substances, cellular mechanisms (phagocytosis) partici- and numerous receptors on the surface of im- pate in non-specific immunity. The activity munologically active cells, such as antigen of innate immune mechanisms is not condi- and immunoadherence receptors, Fc-recep- tioned to prior sensitisation with a certain tors etc. The basic function of the IS is to ob- antigen, and so they are effective against vari- tain information from the internal and exter- ous antigens and do not possess an immuno- nal environment, their logical processing and logical memory. response (immune response), the result of Contrary to these, the mechanisms of spe- which is usually a defence-adaptation reac- cific immunity are activated only after con- tion (induction of immunity), but can also tact with a certain antigen and referred to as sometimes cause damage to one’s own tissues, acquired or adaptive immunity. They are spe- cells and their structure in the autoimmune cific in acting only against the antigen that or other immunopathological responses (im- has activated it, possess immunological munopathology). In this respect the immune memory and are evolutionary younger than system is similar to the neuroendocrine sys- components of the natural immunity. Cells tem, with which it is closely linked, thus and molecules can participate in both non- forming a single superinformation system specific and specific immunity. Phagocytosis immunity – cellular immunity 92

and NK-cells are basic mechanisms of non- liferate and differentiate and the production specific cellular immunity, while the execu- of antibodies is induced. tive (cytotoxic) and regulatory (helper and suppressive) T-lymphocytes are responsible Immunity – transplantation immunity for specific cellular immunity. The comple- An acquired immunity against the cells, tis- ment system (complement) is the most im- sues and their antigens (major histocompati- portant component of non-specific humoral bility antigens) induced following their trans- (molecular) immunity, while acquired hu- fer from a genetically non-identical donor. moral immunity is executed by antibodies There can be two responses to heterogeneous (immunoglobulins). histocompatibility antigens: host versus graft rejection (HvG) or graft versus host reaction Immunity – cellular immunity Immu- (GvHR). The host versus graft rejection can nity executed by cells belonging to the im- be hyperacute (executed by the antibodies, mune system (lymphocytes and professional for example, in blood group differences or xe- phagocytes for specific and natural or non- notransplantations), acute (reaction of cyto- specific cellular immunity, respectively) toxic T-lymphocytes against heterogeneous HLA antigens) or chronic (participation of I Immunity – humoral immunity The im- antibodies against weak histocompatibility munity mediated by executive molecules be- antigens). longing to the immune system and often found in body fluids (= humors). These mol- Immunoadherence This is the ability of ecules are mostly antibodies. This type of im- professional phagocytes to adhere to their munity is also called antibody-mediated im- immunoadherent receptors (FcR or CR) of munity. bacteria or other particles opsonised by anti- bodies or the C3b fragment of complement. Immunity – non-specific immunity This is a set of reactions at the tissue, cellular Immunoadherent receptors These are and molecular level that are congenitally present particularly on the surface of profes- present in the body and whose activity is in- sional phagocytes where they are involved in dependent of prior contact with the antigen. phagocytosis with the binding and ingestion This allows them to respond immediately af- of bacteria, immune complexes and other ter contact of the body with an infectious particles covered by antibodies or C3b, iC3b, agent. Non-specific immunity is activated or possibly C4b fragments of complement. predominantly in the elimination of hetero- The particles covered by antibodies are rec- geneous substances from tissues and in anti- ognised by Fc-receptors while particles op- infectious and anti-neoplastic defence. sonised by C3b or C4b fragments are bound to CR1 and CR3. In primates, CR1 is present Immunity – specific immunity It is also on erythrocytes and is involved in the clear- referred to as acquired immunity. It is the ance of immune complexes from the circula- ability of the body to react against a heteroge- tion. neous antigen with a specific immunological response. Specific antibodies, effector lym- Immunoadsorbent An insoluble sub- phocytes and lymphocytes with an immuno- stance (carrier) with a bound antigen or anti- logical memory able to react solely with the body used as a functional ligand. If the anti- antigen that has induced their production oc- body is bound to the carrier, a simple separa- cur in specific immunity. They do not exert tion of a specific antigen is possible or vice action immediately after contact of the im- versa (immunoadsorbent chromatography). mune system with a specific antigen, but in- stead require a latent period of several days Immunoassay, chemiluminescence An during which the relevant clones of cells pro- immunochemical method used to measure 93 immunodiffusion the concentration of antigen (hapten) or anti- Immunocompetence A genetically deter- body, in which one of these reactants is la- mined ability of certain lymphocytes to react belled by a chemiluminophore (chemilumi- against an antigen with a specific immune re- nescence). sponse in a quantitative and qualitative sense. This is the ability of the body to produce a Immunoassay, enzymatic An immuno- normal immune response following exposure chemical method used for determining the to an antigen. When applied to lymphocytes, concentration of a certain antigen (hapten) or it means that a B or T lymphocyte is mature antibody in which one of these reacting com- and can recognise antigens and is capable of ponents is labelled with an enzyme. After in- mounting an immune response. teraction, the resultant immune complex is also labelled with this enzyme and the precise Immunodeficiency A deficiency of im- level of immune complexes can be quantified munity caused by disturbances in the mecha- by an enzymatic reaction with a suitable, usu- nisms of specific and/or non-specific immu- ally coloured substrate. nity in which T-cells, B-cells or both types of lymphocytes, antigen-presenting cells, pro- Immunoassay, fluorescence Fluoroim- fessional phagocytes, other accessory cells, munoanalysis is an immunochemical method antibodies, cytokines, complement system, I for determining the concentration of antigen or other components of the immune system (hapten) or antibody in a compound mixture participate. The aetiology can be due to re- of different substances in which the antigen duced numbers or abnormal activity of these or antibody is labelled by a fluorescent agent cells, the absence, malfunction or decreased (a fluorophore). The level of analysed sub- synthesis of executive and regulatory mole- stance is then measured by fluorimetry or cules of the immune system. These distur- photon absorptiometry. bances can involve immune system cells at different stages of development. This produc- Immunoassay, particle-enhanced An es a broad range of clinical symptoms and immunochemical method for determining signs, the most common of which are distur- the concentration of antigen (hapten) or anti- bances of anti-infectious and anti-neoplastic body in which one of these reactants is ad- immunity. Depending on their origin, the sorbed or chemically linked to the surface or immunodeficiency can be divided into pri- a particle (erythrocyte, latex particles, colloid mary (hereditary, innate), whose aetiology is gold, etc.). Following interaction with the a missing or defective gene or even a group of other reactant, agglutination or particle lysis genes, or secondary (acquired during devel- occurs, which can be measured by various opment of the individual). Secondary immu- techniques. nodeficiency can be induced by various unfa- vourable physical, chemical, biological and Immunoassay, radioisotope An immu- psychosocial factors, or by insufficient or im- nochemical method used to determine the proper nutrition. If the activity of the unfa- concentration of an antigen or hapten, in vourable factor wears off, secondary immu- which added external antigen is labelled by a nodeficiency usually normalises, in contrast radioactive isotope giving rise to the term, to primary immunodeficiencies. A list of the radioimmunoassay (RIA). Conversely, if the most important primary immunodeficien- antibody is labelled with the radioactive iso- cies is given in table 4. tope, the method is called an immunoradio- metric assay (IRMA). Immunodiffusion A diffuse movement of the antigen and antibody molecule, usually in Immunoblotting A method used to detect agar or agarose gel. The movement velocity a specific protein in a given sample of tissue depends on the concentration of both com- homogenate or extract. ponents and diffusion constants. A gel pre- immunodiffusion 94

Table 4. Human primary immunodeficiencies

Primary specific immunodeficiencies Antibody – mediated X-linked agammaglobulinemia immunodeficiency selective deficiency of immunoglobulin classes (mostly IgA) selective deficiency of IgG subclass selective deficiency of specific antibodies transient infantile hypogammaglobulinaemia common variable immunodeficiency (CVID) Specific cell-mediated immunodeficiencies • severe combined adenosine deaminase deficiency (ADA) immunodeficiency (SCID) SCID T––B– (absence of T- and B-lymphocytes) SCID T––B+ (absence of T-lymphocytes and NK-cells) Protein kinase Jak-3 deficiency Protein kinase ZAP-70 deficiency • disturbance of phagocyto- DiGeorge’s syndrome sis function of T-lympho- Nude lymphocyte syndrome (absence of HLA class II molecules) I cytes Failure of HLA class I molecules expression hyper-IgM syndrome Chédiak-Higashi syndrome (CHS) Omenn’s syndrome familial haemophagocytosing lymphohistiocytosis lymphoproliferative X-linked syndrome familial lymphoproliferative hyper-IgE autoimmunity syndrome (Job syndrome) • other antibody- and hyper-IgD syndrome cell-mediated immunodefi- mucocutaneous candidiasis ciencies ataxia-telangiectasia Primary non-specific immunodeficiencies Phagocytosis deficiency • disturbance of neutrophil Kostmann syndrome count cyclic neutropenia reticular dysgenesis glycogenosis of IIb type • disturbances of phagocyte chronic granulomatous disease (CGD) function LAD-syndrome I LAD-syndrome II Deficiency of certain lysosomal enzymes (thesaurismosis, storage diseases) α-chain of IFN-α receptor deficiency deficiency of specific granules Complement deficiency defects in individual components C1-inhibitor deficiency Disturbance of iC3b receptors (LAD-syndrome I) Mannose binding protein (MBP) deficiency

cipitate can be seen in the presence of the evaluated component, in a similar fashion to sought antigen or antibody at the point where simple radial immunodiffusion. Immunodif- they meet and their concentration is approxi- fusion methods are used for confirmation of mately equal. Under the correct conditions, it diagnostically significant antigens (where a is also possible from the surface of the pre- specific antibody is available) or antibodies cipitate to determine the concentration of the (where a specific antigen is available). 95 immunoglobulin superfamily

Immunoelectrophoresis This laboratory munoglobulins (), technique is a combination of electrophoresis abnormal function of immunoglobulins and immunodiffusion in agar or agarose gel. (gammopathy), hypercatabolism (excessively Using immunoelectrophoresis techniques, it is rapid degradation of the immunoglobulin possible to determine the presence and amount molecules), excessive loss (upon heavy haem- (concentration) of antigens substantially faster orrhage) or damage to lymphocytes (for ex- than by a simple immunodiffusion method. ample by drugs or lymphocytotrophic virus- Depending on technique, immunoelectropho- es). These can all lead to diseases in which the resis can be subdivided into 5 groups: classical pathogenesis is a decreased immunity against immunoelectrophoresis according to Grabar most infectious agents. Subsequent severe re- and Williams (used especially for confirming current infections are usually resistant to multiple myeloma immunoglobulins), rocket conventional antibiotic treatment. Primary immunoelectrophoresis, counterimmunoelec- immunoglobulin deficiencies include agam- trophoresis, two-dimensional immunoelec- maglobulinaemia and selective deficiency of trophoresis and immunofixation. IgA, or also other immunoglobulin classes and subclasses, severe combined immunode- Immunofixation An immunoelectropho- ficiency and hereditary ataxia-telangiectasia. resis method in which the separated antigens I are detected directly in the gel on the basis of Immunoglobulin, normal human In- their precipitation with a specific antibody. travenously applicable immunoglobulin prep- aration made from the blood plasma of at Immunofluorescence A property of cer- least 1,000 healthy donors. It contains pre- tain molecules to absorb light or other form dominantly IgG and is used for substitution of energy and show it in the form of a photon treatment (in deficiencies of antibody pro- (light with longer wave-length than that of duction), for prophylaxis and the treatment absorbed light). It is used in immunohis- of certain infectious and auto-immune disor- tochemistry and immunoassay techniques. ders (immunoglobulins, therapeutic prepara- Using the antibodies labelled by an immuno- tions). fluorescent stain it is possible to localise the applicable antigens in histological slides, or Immunoglobulin superfamily A com- study the fluorescent immune complexes plex of glycoprotein molecules coded for by through a fluorescent microscope. The same genes with an evolutional homology, i.e. a principle is also applied in sensitive fluores- common predecessor. The members of the cent immunoassays (immunoassay, fluores- immunoglobulin superfamily have several cent). common sections of polypeptide chains in their molecules, with the same stereometric Immunogenetics A branch of science rep- structure as the immunoglobulin chains (im- resenting the boundary between immunolo- munoglobulin domains). There are three gy and genetics and dealing with the genetic types of stereometrically homologous do- analysis of executive and regulatory mole- mains identified among the members of the cules of the immune system (especially anti- Ig superfamily: the variable (V), the constant gens of the major histocompatibility complex, (C) and the H domain. Currently, there are immunoglobulins, cytokines and compo- more than 40 known members of this super- nents and factors of complement), as well as family whose basic functions are discrimina- the genetic regulation of immune responses. tive (immunoglobulins, antigenic receptors on T-cells, antigens of class I and II of the ma- Immunoglobulin deficiency This can be jor histocompatibility complex, differentia- induced by abnormal function of B-lympho- tion antigens CD2, CD3, CD4, CD8 and re- cytes or both B- and T-lymphocytes. Affected ceptors for Fc domain of immunoglobulins – individuals manifest with a low level of im- FcR), adhesive (connecting) or regulatory immunoglobulins (ig)(Ig) 96

interactions between cells. The group of ad- two types of chains, the molecule of polymer- hesive molecules include for example ICAM-1 ic immunoglobulins (IgM and secretory IgA) (CD54 – intercellular adhesion molecule-1), also contains one joining (J) chain and the ICAM-2 (CD102), VCAM-1 (CD106 – vas- secretory IgA molecule a secretory compo- cular cell adhesion molecule) and PECAM-1 nent (SC). (CD31 – platelet-endothelial cell adhesion molecule). Besides the discriminative mole- Immunoglobulins – classes Isotypic cules, the receptor for polymeric immuno- variants that differ from one another by the globulins (p-IgR) and platelet-derived growth antigenic structure of constant domains of factor receptor also possess a regulatory func- the heavy chains of their molecules (immu- tion. noglobulins, chains). There are five known classes of immunoglobulins: IgG (having the Immunoglobulins (Ig) These are glyco- heavy chain (γ), IgM (μ), IgA (α), IgD (δ) and proteins of animal origin and include all anti- IgE (ε)). bodies. Their molecules consist of two identi- cal light chains and two identical heavy poly- Immunoglobulins – effector functions peptide chains interconnected by disulphide All functions except those serving at the I bonds. The chains are spatially organised into binding site. These include the ability to acti- domains (immunoglobulin domains) and vate the complement, bind to the cellular Fc- modules. The first domains of the light and receptors, pass through the placenta, etc. heavy chains are variable, while the others are constant. In the variable domains, the se- Immunoglobulins – genetics → see Ge- quence of amino acids of the polypeptide netics of immunoglobulins. chains changes amongst the antibody mole- cules with diverse specificity, while in the Immunoglobulins – hypervariable re- constant domains remains unchanged. The gions This is the section of polypeptide sections of variable domains with particularly chains in the variable domains where indi- intensive changes of amino acids in individu- vidual amino acids are able to a greater extent al positions are called hypervariable sections. to change positions, and thus allow immense The hypervariable sections of light and heavy diversity to generate millions of antigen-spe- chains are positioned in the Ig molecule side cific antibodies. There are six such sections in by side and form the antibody binding site, general – three on the light chain and three accounting for antibody-mediated specificity. on the heavy chain. During the final stereo- There are two types of light chains (Kappa metric arrangement of the immunoglobulin and Lambda). Heavy chain immunoglobulins molecule, they become mutually close and are classified into five classes (IgA, IgD, IgE, form an antibody binding site. The hyper- IgG and IgM). variable sections are also called complemen- tary determining regions (CDR). Immunoglobulins – chains Polypeptide chains constituting the immunoglobulin Immunoglobulins – idiotypes Immu- molecule. Each of the molecules contains at noglobulin variants determined by a set of least two identical light (L) chains and two antigenic determinants, mainly in the hyper- identical heavy (H) chains: There are two variable sections of both light and heavy types of light chain: kappa (κ) or lambda (λ); chains. Such an idiotype represents the anti- they determine the type of immunoglobulin genicity of the antibody binding site. Some molecule (K or L). The heavy chains belong idiotypes can be found only in the organism to five different isotypes: gamma (γ), mu (μ), of a certain individual (private idiotypes), alpha (α), delta (δ) and epsilon (ε); each of while other can be confirmed in multiple in- them determines membership to a specific dividuals (common or cross-reacting idio- immunoglobulin class. In addition to these types). 97 immunoglobulins – therapeutic preparations

Immunoglobulins – isotypes These rep- Immunoglobulins – secretory compo- resent individual classes (sub-classes) and nent (SC) A polypeptide chain synthesized types of immunoglobulins. They identify by epithelial cells to be a component of their their antigenic determinants localised in the receptor for polymeric immunoglobulins. It constant domains of heavy and light chains is a component part of the secretory IgA mol- and are identical in all individuals of the giv- ecule. In IgA deficiencies, the SC binds to a en animal species. They are products of dif- secretory IgM molecule. The poly-Ig-recep- ferent structural genes and can be identified tor and from it the resulting SC regulate the using xenogenic antisera (for example, rabbit transport of these polymeric immunoglobu- antiserum against human IgG will react with lins to the surface of mucous membranes, the IgG of all individuals of the human popu- where they participate in the mechanisms of lation, but not with the IgG of other biologi- local immunity. cal species). Immunoglobulins – subclasses Immu- Immunoglobulins – J chain A additional noglobulin variants determined by the char- glycopeptide chain that is a component part acteristic antigenic determinants on the con- of all polymeric immunoglobulin molecules stant domains of heavy chains. There are four (secretory IgA and IgM). The J (= joining) known subclasses of human immunoglobu- I chain is linked by disulfide bridges to the Fc lins of the IgG class (IgG1, IgG2, IgG3, and region of immunoglobulin molecules. IgG4) and two subclasses of the IgA class (IgA1 and IgA2). Immunoglobulins – modules The high- est form of stereometric arrangement of the Immunoglobulins – therapeutic prep- immunoglobulin molecule. It is an aggregate arations These are pure immunoglobulin arising from the mutual stereometric ar- preparations suitable for clinical use. They rangement of the polypeptide chains of two are made from plasma collected from at least adjacent variable or constant domains. 1,000 healthy donors. First generation prepa- rations (immune serum gamma globulin) Immunoglobulins – molecule frag- can be administered only subcutaneously or ments They develop as a result of enzymatic intramuscularly (Subcuvia and Subgam), or chemical fragmentation (cleavage) of Ig while second and third generation prepara- molecules. For example, the papain enzyme tions (normal human immunoglobulin) can splits the molecule into the fragment antigen also be administered intravenously. However, binding (Fab) and fragment crystallisable they have to match safety and efficacy re- , (Fc) regions, while pepsin creates the F(ab )2 quirements, such as the requirement to con- and pFc, fragments. Fab contains one binding tain pure IgG, which must not be in the form , site of the original IgG molecule and F(ab )2 of aggregates that could induce adverse ana- two of them. Chemical degradation causes phylactoid reactions. The presence of IgA in the cleavage of interchain disulphide or cer- intravenous preparations can induce the pro- tain peptide bonds. duction of anti-IgA autoantibodies in IgA- deficient individuals and in the event of sub- Immunoglobulins, monoclonal → see sequent administration, cause the reoccur- Monoclonal antibodies rence of anaphylactoid, or the occurrence of anaphylactic adverse reactions. Normal hu- Immunoglobulins, myeloma Whole im- man immunoglobulin preparations such as munoglobulin molecules or their parts pro- Sandoglobulin, Flebogamma, Gammagard, duced by malignant plasma cells or their pre- Octagam and Vigam are used as substitution cursors. They can be found in the serum of treatment for primary and secondary anti- patients with multiple myeloma (monoclonal body-mediated immunodeficiency, or can gammapathy). even be effective in several other disorders immunohormones 98

Table 5. Overview of disorders that can be tional activity of other cells by acting on spe- effectively treated using intravenous prepara- cific receptors. Some of them have a typical tions of normal human immunoglobulin hormonal character (hormones of the thy- mus – thymosins), whereas others act mainly Very likely effective as local hormones (cytokines). The hormones Primary immuno- X-linked agammaglobuli- are secreted in an endocrine manner and deficiencies naemia their target cells, to which a specific signal is common variable immunodeficiency transmitted, can be localised anywhere in the selective IgG deficiency body. The secretion of local hormones is done severe combined in a paracrine or autocrine manner and their immunodeficiency (SCID) principal effect is usually limited to the neigh- Secondary transplant acceptors bouring cells. Lymphocytes, however, have immunodeficien- chronic lymphocytic the ability to move around in the whole body, cies leukaemia and so their immunoregulatory products (in- high-risk newborns AIDS in children terleukins, lymphokines) can also have a sys- Kawasaki’s disease temic effect, despite having the character of local hormones. I Other disorders idiopathic thrombocy- topenic purpura (acute) haemophilia, autoanti- Immunological tolerance A state of spe- bodies against the factor cific unresponsiveness (inhibition) of the im- VIII mune system to a specific antigen that under Possibly effective normal circumstances would induce an im- Burns mune response. In these circumstances, the Multiple myeloma reactivity of the lymphocyte clone capable of Autoimmune disorders (SLE, APS) responding to this antigen is decreased or Juvenile rheumatoid arthritis completely suppressed, or this clone has been Myasthenia gravis eliminated from the body. The ability to re- Rheumatoid arthritis spond to other antigens is preserved in an in- AIDS dividual tolerant to a certain antigen (known as a tolerogen). Immunological tolerance has (table 5). They can be administered as a pro- therefore the same specificity as the immunity phylaxis to persons whose antibody-mediat- itself. It can be either natural (spontaneous ed immunity has not adequately developed at non-response to one’s own antigens emerging the time of definite or probable exposition to during the individual’s ontogenetic develop- a certain contagion. These preparations con- ment also called “autotolerance”) or second- tain an increased volume of antibodies, for ary (non-responsiveness to extrinsic anti- example, against the diphtheria toxin, hepati- gens). Under experimental conditions, toler- tis B virus or rabies virus. When using im- ance to a specific antigen can be induced arti- munoglobulin preparations one has to con- ficially. sider not only their substituting effects, but also their regulatory influence, which is why Immunomodulation The therapeutic in- they can influence the immune homeostasis fluence on the immune response performed of the individual in both a positive, but also a for the purpose of stimulation (immunos- negative way. timulation), suppression (immunosuppres- sion) or normalisation of the immune re- Immunohormones Immunoregulatory sponse. Drugs normalising the immune re- active substances possessing the nature of sponse are those modulating a decrease or hormones. They are synthesised in certain increase in the immune system activity to- immunologically active cells and influence wards normal function. the development, differentiation and func- 99 immunoprophylaxis

Immunomodulation therapy Treatment ma (TSH-receptor blockade) or myasthenia aimed at modulating the immune system ac- gravis (acetylcholine receptor blockade), the tivity of an individual. It is done either to in- autoantibodies inhibit function. The majority crease the actual activity of the immune sys- of autoimmune reactions belong to the sec- tem (immunostimulation) or to suppress its ond type of hypersensitivity according to this activity (immunosuppression). The objective manner of classification. is immune normalisation, when activity of the immune system is restored to normal lev- Immunophilins Intracellular proteins with els. peptidyl-prolyl-cis-trans-isomerase activity specifically bind immunosuppressive drugs Immunopathology This is a sub-speciali- such as cyclosporine (CyA), FK506 and ra- sation with the application of immunological pamycin. There is a specific cytosolic immu- techniques in the field to the practice of pa- nophilin for each of them (cyclophilin for thology. It studies the pathological changes CyA), which after binding to the relevant im- occurring as a consequence of abnormal, in- munosuppressant loses its enzymatic activity creased (hypersensitive) or defective (immu- and thereby the ability to transmit the activa- nodeficiencies) immune responses, their tion signal from the T-lymphocyte receptor aetiology and diagnosis. Immunopathologi- to the nucleus. This is the principle of their I cal (hypersensitive) reactions are nowadays immunosuppressant activity. classified according to Coombs and Gell into four types: Immunopotency The ability of a certain 1. immediate or anaphylactic reactions (ana- antigen molecule to serve as an antigenic de- phylaxis) mediated in humans by the IgE terminant, thereby inducing the production class of antibodies, of a specific antibody. 2. cytotoxic type mediated by IgG or IgM an- tibodies against one’s own cellular or tis- Immunopotentiation An increase in im- sue antigens; the tissue damage is caused mune system efficacy (stimulation). primarily by activated complement, 3. immune complex reactions where soluble Immunoprecipitation This is the produc- immune complexes are formed and are tion of a precipitate upon the reaction be- deposited in various tissues and organs, tween a soluble antigen and its specific anti- such as the vascular system, the kidneys, body. It can occur in a solution or a semisolid the connective tissue or skin. Subsequent- (gel) environment (usually in agarose gel). ly, reactive oxygen species and lysosomal The technique is carried out in a qualitative enzymes are released from neutrophils or quantitative manner. Using qualitative im- leading to tissue damage mediated by the munoprecipitation, it is possible to determine immune complex deposition, the relationship between the amount of pre- 4. delayed type hypersensitivity where T- cipitate and the antigen-antibody concentra- lymphocytes, macrophages and certain tion ratio. Huge excess of one of the two reac- cytokines are involved. tants can redissolve the immunoprecipitation Recently, a fifth type of immunopathological (according to the precipitation curve or response has been proposed with involve- Heidelberger curve) ment of autoantibodies against the cellular receptors. These autoantibodies can influ- Immunoprophylaxis Prevention of a dis- ence organ function via pathological stimula- ease by either vaccination that induces active tion (as agonists) or inhibition (as antago- immunisation, or by administering an im- nists). Thyrotoxicosis is an example of stimu- mune serum (containing specific antibodies), latory hypersensitivity in which the autoanti- or by administering specific active lympho- bodies can falsely stimulate the TSH-receptors cytes, which induce passive immunity. in the thyroid, whereas in primary myxoede- immunoradiometry 100

Immunoradiometry Immunoradiometric the occurrence of allergic and autoimmune analysis (IRMA) by which the antibody, not disorders is observed. the antigen, is labelled by an active radioiso- tope. Immunotoxins Conjugates (complexes) of monoclonal antibodies and cytotoxic com- Immunostimulation A non-specific in- pounds can bind through a binding site of the crease in the level of natural (innate) or spe- antibody to a specific antigen of the target cific immunity of an individual, manifested cell, most frequently a neoplastic cell, and so by increased rapidity and intensity of the im- by the action of the toxic agent can kill the mune response against various antigens, es- cell without causing injury to other cells in pecially bacteria, viruses and neoplastic cells. the body. Various vegetable or animal toxins, Various immunostimulatory drugs which act cytostatic agents and radionuclides can be on the immune system can elicit this. used as the toxic component of immunotox- ins. Currently, immunotoxins have only been Immunosuppression The suppression of experimentally tested in the treatment of cer- the body’s immune responses by external in- tain tumours. tervention either intentionally during immu- I nosuppressive treatment, or incidentally as Impairment A term which describes a tran- an adverse event (for example by the influ- sient or permanent decrease in the function ence of ionizing radiation or certain drugs – of an organ or body when compared with the especially cytostatic agents, xenobiotics and norm in the anatomical, physiological or bacterial toxins). Immunosuppressive treat- mental sphere. These are, for example, im- ment is used in organ (especially kidney), tis- pairments of speech and sensory organs, joint sue and bone marrow transplants to prevent function, etc. For newer approaches see “ICF rejection, and in the treatment of certain au- classification”. toimmune disorders and other diseases with an immunopathogenesis. Impingement syndrome of the shoul- der Narrowing of the subacromial space Immunotherapy The treatment of abnor- leads to painful friction of the affected struc- mal immune responses by an immunostimu- tures as a consequence of various influences, lating or immunosuppressive agent, or by bio- such as trauma, microtrauma or inflamma- logical products of either natural or recombi- tion. Typical is the so-called painful arc, i.e. nant origin (for example certain cytokines), pain during abduction of the shoulder from vaccines and immune sera. It also includes 60° to 120° when the head of the humerus has desensitisation in allergic disorders. a pathologically altered subacromial space.

Immunotoxicology The investigation of Impulse waves These are pneumatically the toxic and adverse effects of various natu- generated ballistic waves with optional im- ral and industrial toxins, harmful substances pulse frequency varying from 5 to 10 Hz, ad- and toxic agrochemicals (xenobiotics) in the justable level of energy 1 to 4 bars and a pow- living and working environment, as well as er density on the impulse transmitter of the adverse effects of drugs on the immune 0.01–0.23 mJ/mm. It is used in the manage- system. The immunotoxic effects of these ment of painful body areas. The impulse gen- agents can manifest itself through suppres- erated in the device is accelerated, thus creat- sion of the immune system (immunosup- ing the impulse wave, which penetrates the pression), which leads to reduced immunity area of the body exposed to the wave. Indica- in the affected individuals against infectious tions of impulse waves include area applica- and neoplastic disorders, or on the contrary, tion in the soft tissues, e.g. treatment of en- through immunopathological stimulation thesopathy and ; spatially re- (immunostimulation) when an increase in stricted application used to influence trigger 101 infliximab (remicade) points and tender points; and point applica- (particularly neutrophils, macrophages, T lym- tion for acupuncture points. phocytes, endothelial cells, eosinophils, mast Indications: cells, thrombocytes), multi-enzymatic systems • Tendon injury, of blood plasma (complement, haemocoagu- • Calcar calcanei (painful heel), lation system, fibrinolytic and kinin system), • Dupuytren’s contracture, pro-inflammatory and anti-inflammatory • Trigger points. cytokines, acute phase proteins, prostaglan- dins and other metabolites of arachidonic Incisura scapulae syndrome The su- acid, as well as certain other mediators of in- prascapular nerve is compressed in the su- flammation, are involved in an inflammatory prascapular notch. Dull pain and tenderness reaction. to palpation is present in supraspinatous fos- A fundamental cell of acute inflammation, sa. The abduction test is positive. The patient which reacts to its development, and which as places the hand of the affected site on the the first cell translocated into the locus of in- contralateral shoulder, so that the elbow is in flammation, is the neutrophil. Macrophages a horizontal line at the level of both shoul- and T lymphocytes are particularly involved in ders. Then the patient makes a movement of chronic inflammation. At the required time, the elbow towards the healthy shoulder. these cells produce the required amount of I When the suprascapular nerve is compressed, mediators, enzymes and cytotoxins, which the patient experiences a sharp pain. No kill and decompose invading pathogens or changes are visible on X-ray. damaged tissue in the course of protective in- Treatment: Injections are administered lo- flammation. If the inflammatory stimulus cally (mesocaine + glucocorticoid) in the still persists or if the above mentioned prod- proximity of suprascapular notch. ucts are synthesised in an excessive amount, harming inflammation develops, the result of Infectious mononucleosis Also com- which is damage to its own cells and tissues, monly known as glandular fever or Pfeiffer’s leading to impairment of function of various disease. It is caused by the Epstein-Barr virus organs and systems, and possibly death. In- (EBV), which infects B lymphocytes. It is flammatory cells can put their activities into most prevalent in adolescents and causes fe- effect only if they translocate from the circu- ver, lymphadenopathy, sore throat and fa- lation into the tissue where the inflammatory tigue, though can cause arthralgias. The Paul- reaction develops. This transendothelial mi- Bunnell test is positive, though the monospot gration (diapedesis) of leukocytes takes place test looking for heterphile antibodies is now in postcapillary venules by a number of adhe- more commonly used. sive interactions between adhesive molecules on the surfaces of leukocytes and endotheli- Inflammation The body’s complex biologi- um. It is a multi-step process, in which selec- cal response of vascular tissues to harmful tins, integrins and immunoglobulin super- stimuli, such as pathogens, damaged cells, or families, such as ICAM-1, ICAM-2, VCAM-1 irritants. The aim of inflammation is liquida- and others, are involved. tion, dilution or elimination of the injurious stimuli and damaged tissue, or at least its de- Inflammatory bowel diseases → see Ar- marcation and reparation. Based on various thropathy in the course of inflammatory criteria, the inflammation can be split into bowel diseases, Enteropathic arthritis (EA) protective or harming, acute or chronic, su- perficial or deep etc. Four phases can be ob- Infliximab (Remicade) A chimeric mono- served during the inflammatory response: vas- clonal antibody (consisting of murine and cular response, acute cellular response, chronic human components) of the IgG1 class, which cellular response and healing. A number of binds specifically to human TNFα. It is ad- cells that are a part of the immune system ministered by intravenous infusions at regu- infrared radiation 102

lar intervals in doses of 3 mg/kg (rheumatoid 2. middle-wave band IR-B (1400–3000 nm), arthritis), 5 mg/kg (ankylosing spondylitis, 3. long-wave band IR-C (over 3000 nm). psoriatic arthritis or psoriasis, and Crohn’s dis- IR-A has a superficial thermal effect and pen- ease) over 2 hours. After the initial infusion, etrates to a depth of up to 1 cm; it is used for subsequent infusions are administered after diathermy of tissue. IR-B and IR-C are used two weeks, six weeks after the first dose, and for warming-up of tissue. then all subsequent doses are administered ev- ery eight weeks. The serum concentrations of Inherited complete heart block → see infliximab are more sustained with concomi- Neonatal Lupus tantly administered methotrexate (MTX; a fixed oral dose of 15–25 mg/week). The co- Instruments of assessing (health sta- administration of infliximab and MTX (or an tus measurements, outcome mea- alternative immunosuppressant drug if MTX surement) Questionnaires that are either is not tolerated) not only significantly sup- completed in a controlled patient/physician presses the inflammatory activity of rheuma- interview or are self administered by the pa- toid arthritis, but also seems to improve the tient. The questions are directed to obtain immunological tolerance of infliximab. The relevant answers as to the quality of life of the I onset of action of infliximab is relatively rapid, patient in relation to his/her health status. usually seen soon after the first doses of the They contain items (dimensions, domains) drug, and usually persists during the whole that focus on the patient’s physical, mental treatment period. However, relapse of the dis- and social status. Individual items or domains ease occurs in the majority of patients on with- are scored separately. Some systems express drawal of treatment, which can be suppressed the result as a score. by restarting anti-TNF treatment. There are two main groups of instruments: Treatment: It should only be indicated in generic, used in different diseases to assess severely active RA with unfavourable prog- the overall state of health of the patient, and nostic factors, which is refractory to treat- condition-specific, for the given disease. ment with at least two disease-modifying an- Generic instruments ti-rheumatic drugs (DMARDs), one of which MOS-SF – medical outcome study – short should be MTX. Infliximab is sometimes ad- form 36 ministered in early RA with significant activ- MOS-SF-36 8-item questionnaire with 36 ity and progression. Treatment with inflix- questions was designed specifically for global imab has very favourable results in the treat- assessment of the population health status. ment of severe ankylosing spondylitis unre- The questionnaire investigates the limitations sponsive to conventional high dose NSAIDs, in physical functions, limitations of normal and also in active and resistant forms of pso- daily activities caused by decreased function, riatic arthritis. limitations in social activities, body pain, and Adverse effects: Headache, nausea, upper mental health, limitations in normal role ac- respiratory airways infections, urinary infec- tivities because of emotional problems, vital- tions, tuberculosis, leukoclastic vasculitis, ity, and general health perceptions. The ques- exanthema, allergies, pruritus, anti-dsDNA tionnaire is filled in by the patient/proband. antibody positivity, and rarely drug induced Nottingham health profile (Hunt et al. systemic lupus erythematosus. 1985). There are 38 questions answered simply Infrared radiation The invisible part of the with yes/no. The patient/proband fills in the optic spectrum, with a wavelength longer questionnaire alone, usually over 5 to 10 min- than that of visible light. It is divided into utes. Each question is assigned a weighted three bands according to wavelength: value. The best score is 0, the worst is 100. 1. short-wave band IR-A (wave-length of Sickness impact profile – SIP (Bergner et al. 760–1400 nm), the initial radiation band, 1985). 103 instruments of assessing (health status measurements, outcome measurement)

It has 6 main items containing 136 ques- Nine simple tasks (for the hand, the whole tions. It monitors the level of self-attendance, upper and lower extremity) performed by the mobility, ambulation, sleep, eating, work, patient and assessed by a physician revealing home management, social interactions, rec- any functional limitations. They can be easily reation, communication, alertness and emo- used in daily rheumatological and rehabilita- tional behaviour. Individual items are scored tion practice. and the profile is formed by summation of Rapid assessment of disease activity in rheu- similar items. matology (RADAR; Mason et al. 1992 a, b). Condition-specific The patient self assesses the course of the For rheumatoid arthritis: disease over the last 6 months. Morning stiff- Health assessment questionnaire (HAQ Fries ness is assessed in 6 time intervals using the et al. 1980). VAS. According to the ARA criteria, the pa- Originally developed for RA it has also tient is classified to the relevant class of func- proved useful in osteoarthritis. It is also com- tional disability; and assesses pain and ten- monly used in many other chronic diseases. derness at 10 chosen joints. There are national versions of the question- Rheumatoid arthritis disease activity index naire. It contains 20 items for the assessment (RADAI; Stucki et al. 1995). of activities such as dressing, cleaning, rising Besides being a model for indicating pain- I from a chair, eating, walking, doing body ful joints, the system contains the Likert’s care, arising and reaching for various remote scale for assessing , and also items and activities outside the house. The psychometric data. visual analogue scale (VAS) for pain assess- Overall status in rheumatoid arthritis ment is also part of it. The score from these (OSRA; Symmons et al. 1995). items is averaged out and the disability index Using a 3-degree scale (0, 1, 2) it assesses obtained. The questionnaire takes about 5 questions in 4 divisions (demographic data, minutes to complete. disease activity index, impairment in the Arthritis impact measurement scale (AIMS; functional and social sphere and treatment in Meenan et al. 1980). AIMS has 9 items con- the given time). The system is valid and rapid taining a total of 46 questions. Mobility, physi- and is undertaken by directed interview. cal activity, dexterity, social sphere, household Rheumatoid arthritis pain scale (RASP; An- activities, activities of daily living (ADL), pain, derson et al. 1987). depression and are all assessed. Subse- This is a valid and reliable system for as- quently other questions were added relating to sessing pain in patients with RA. It contains the function of the upper and lower limbs and 24 items, each of which is evaluated on a scale activities needed for working, leisure time from 0 to 7. utilisation and the independence of the pa- Piper fatigue scale (PFS; Piper et al. 1990). tient. Similarly to HAQ, it is often used in RA It contains 41 questions (the revised ver- but in contrast to HAQ is time-consuming. sion 22 items) divided into 4 sections. All McMaster Toronto arthritis patient prefer- questions are answered using the VAS. Some ence disability index (MACTAR; Tugwell et al. of them contradict each another. The total 1987). score is evaluated. Beside demographic questions are 25 ques- For ankylosing spondylitis: tions related to the possibility of performing Bath ankylosing spondylitis indices (BAS- certain activities, which are assessed by three indices; Calin 1995). possible answers rating between no problem BASG is a global assessment tool to assess performing the activity, performing the ac- the total impact of the disease on the patient tivity with a little difficulty and performing over a time interval. The patient’s assessments the activity is impossible. are made using the VAS. Signals of functional impairment (SOFI; BASDAI (BAS disease activity index) con- Eberhardt et al. 1988). sists of 6 questions, 5 of which are related to 5 insulin 104

main symptoms: tiredness, pain in the spine, tains a vertical visual analogue score. It is the pain and swelling of the joints, localised re- most widespread questionnaire for assess- gions of increased sensitivity and morning ment of patient’s quality of life. stiffness; the question assesses both the de- Oswestry low back pain disability question- gree and duration of stiffness. All questions naire (Haas and Nyiendo 1992). are measured using the VAS. It contains 10 items (pain intensity, per- BASFI (BAS functional index) assesses re- sonal care, lifting, walking, sitting, standing, sponses to 10 questions affecting activities of sleeping, social life, travelling and changing daily living using the VAS. degree of pain). Each item has a choice of 6 BASRI (BAS radiological index) has 4 de- answers. grees of radiographic assessment of sacroile- For osteoarthrosis: itis. Lequesne’s algofunctional test and assess- BASMI (BAS metrology index) rates mea- ment of the severity of hip joint impairment surements of rotation in the cervical spine, (Lequesne et al. 1987). the distance between the tragus of the ear and Contains the 3 items pain, walking and the wall (Forestier fleche), both lateral devia- daily activities. The assessment of each item tions, Schober’s distance in a modified ver- uses a severity scale from 1 to 6. The activities I sion and intermalleolar distance. are rated with 3 points. One number express- Dougados’ functional index (DFI) – (Dou- es the function. A score of 1 to 4 indicates gados et al. 1988). normal hip joint function; a score of 4 to 8 It has 20 items focusing on activities of indicates moderate impairment; a score of 8 daily living and evaluated by three possible to 10 indicates significant impairment; and a answers. The testimony of this questionnaire score over 11 represents an indication for to- is more valid than metric measurement. The tal joint replacement. results are similar to those obtained by Western Ontario and McMaster universities BASFI. osteoarthritis index (WOMAC; Bellamy et al., For systemic lupus erythematosus: 1988). Systemic lupus erythematosus disease activ- This specific questionnaire is designed for ity index (SLEDAI; Bombardier et al. 1992). assessing the function in patients with hip- or The assessment of clinical symptoms by knee-OA. The patient him/herself answers 24 the severity level of the symptoms. 8 symp- questions divided into 3 sections. Five ques- toms are rated with 8 points, 6 with 3 points, tions deal with pain, 2 with stiffness and 17 7 with 2 points and 3 with 1 point. with the activities of daily living. It is evalu- For fibromyalgia: ated on a 5-point scale. Fibromyalgia impact questionnaire (FIG; Burckhardt et al. 1991). Insulin As well as its most important role on This assessment consists of 4 items. The glucose metabolism, insulin has effects on first item contains 10 questions focusing on the normal development of the skeleton. It daily and social activities; the second one fo- stimulates the synthesis of bone matrix and cuses on the overall well-being in the past has an influence on its mineralisation. The week; the third one focuses on the possibility effect on the osseous bone tissue is direct as of work; and the fourth one focuses on how well as mediated by IGF-1. fibromyalgia problems influence the patient’s work capacity. It is evaluated using the VAS Insulin-like growth factor (IGF) IGF-1 and individual items are scored. and IGF-2 increase the production of the col- Euro Quol questionnaire (Hurst et al. 1994). lagens of bone, the synthesis of matrix and This contains 5 items, each of which con- stimulate replication of the osteoblasts. In ad- tains 3 questions. For each question there are dition, IGF-1 inhibits the degradation of the 3 possible answers. The best score is 5, the bone collagen. worst is 15. In addition to questions it con- 105 intercellular substance of cartilage matrix

INT Test An analytical method using iodon- belonging structurally to the immunoglobulin itrotetrazolium (INT) solution, which chang- superfamily. ICAM-1 (CD54) is a membrane es colour when incubated with leukocytes in glycoprotein found on various cells, including the presence of phagocytosable particles, endothelial and dendritic cells. ICAM-1 binds which is evidence of the ability to produce specifically to the β2- receptor LFA-1, superoxide and other reactive oxygen inter- thereby helping to perform various interac- mediates (ROI). The intensity of the red tions between T-lymphocytes and antigen- colour is measured photometrically (485nm) presenting cells (immune response initiation), and is proportional to the ability of the leuko- between neutrophils and cells of the vascular cytes to kill bacteria after phagocytosis. endothelium (initiation of the inflammatory reaction), or between other pairs of cells. Integrins A family of heterodimeric glyco- IFN-γ, TNF-α and IL-1 stimulate its produc- proteins whose molecules contain two types tion. ICAM-2 (CD102) and ICAM-3 (CD50) of polypeptide chain – α and β. They are di- have similar properties to ICAM-1. Apart vided into subfamilies whose members have from LFA-1, they can also bind to the comple- a common β chain but different α chains. In ment receptors CR3 and CR4. humans, 19 α and 8 β subunits have been Intercellular substance of cartilage I characterised. The subfamily of β1-integrins is referred to as very late antigens (VLA-1 to matrix Basically an amorphous gel consist-

VLA-6); the subfamily of β2-integrins is com- ing mostly of proteoglycans, but also contain- posed of leukocyte adhesins and has three ing proteins and glycoproteins. This gel is re- very well characterised members: LFA-1 inforced by a fine, strong network of type II (CD11a/CD18), CR3 (CD11b/CD18) and collagen with small amounts of type VI, IX CR4 (CD11c/CD18), while the cytoadhesins and XI collagens. Among glycoproteins, the of the β3-integrin subfamily represent the re- matrix contains chondronectin and chondro- ceptors for vitronectin. Integrins are surface calcin. adhesion molecules responsible for tissue co- Approximately half of the organic matter herence, cellular interactions during embry- of the matrix consists of viscous hydrophilic onic development and for immune responses, proteoglycans. The presence of large macro- including the binding of cells to molecules of molecular arrangements of glycoproteins, the extracellular matrix, including collagens which provide a molecular substrate for the and fibronectin. They play a major role in the considerable elasticity (resilience) of the car- colonisation of lymphoid tissues and organs tilage, is a typical attribute of the matrix. Mol- by lymphocytes and other immune system ecules of proteoglycans form the skeleton in cells, in the migration of leukocytes from the which molecules of interstitial fluid and ions microcirculation to the tissues during inflam- are present. Certain molecules of interstitial mation (diapedesis) and in the interaction of fluid even bind through hydrogen bridges to lymphocytes with antigen presenting cells. negatively charged units in the glycosamino- The dominant osteoclastic integrin αvβ3 is glycan chains of proteoglycans. Enormous, a member of αv family of integrins. It is ex- for cartilage specific, proteoglycan is denoted pressed on osteoclasts following activation as aggrecan. Its molecules are immobilized in with RANKL and is an essential part of phys- the skeleton of collagen fibrils. Approximate- iological bone resorption. The competitive ly 100 chains of chondroitin sulphate and 30 ligands for αvβ3 are able to slow down the chains of keratan sulphate are bound to the osteoresorption and are candidates for anti- protein nucleus of aggrecan. Aggrecan be- resorptive treatment of bones longs to the group of hyaluronan binding proteins. The bond between aggrecan and Intercellular adhesion molecule (ICAM) hyaluronan is stabilised by a protein called At present, there are four types known – link protein. Negative charge and high os- ICAM-1, ICAM-2, ICAM-3 and ICAM-4 – all motic pressure are formed in the skeleton of intergrins 106

proteoglycans as each molecule of aggrecan Interferon beta (IFN-β) It is produced contains amounts of sulfone groups. It is the mainly by fibroblasts with nucleic acids of vi- reason that the cartilage tends to seal up. The ral or other origins serving as its inductors. sealing up is controlled by the skeleton of col- Its gene is also localised on chromosome 9. lagen fibrils, which are permanently stretched, Recombinant IFN-β (Betaferon) is used in even in uncharged cartilage. Charged cartilage the treatment of relapsing multiple sclerosis. reacts by a change of osmotic and hydrostatic IFN-α and IFN-β have antiviral and antipro- pressure and interstitial fluid moves from liferative effects, and to a lesser extent immu- charged to uncharged areas of the cartilage, noregulatory effects. while aggrecan remains bound to hyaluronan and immobilised in the collagen skeleton. Interferon gamma (IFN-γ) A product of

activated T-helper (TH1) and T-cytotoxic (TC) Intergrins A family of small cytokines more lymphocytes or NK-cells synthesized by them commonly referred to as chemokines. in response to a specific antigen or mitogens. It is therefore considered a typical lym- Interferential currents (IC) The applica- phokine whose gene is localised on chromo- tion of two medium-frequency currents that some 12. Its main function is immunoregula- I easily overcome skin resistance. An effective tory, but it does have antiviral and antiprolif- low frequency current develops in the depth erative effects as well. It is able to activate of the affected tissue after their interference many different genes allowing activation of and its size is determined by the difference macrophages, giving them the ability to kill between the frequencies of both alternate intracellular bacteria, to lyse neoplastic cells currents. and exprime HLA class II antigens on their Modulations used: surface. It also stimulates the expression of • constant 0–10 Hz: used for muscle gym- HLA class I antigens on different cells, there- nastics, by making them more sensitive to the activity • constant 90–100 Hz: has a sedative and of cytotoxic T-lymphocytes. It facilitates the spasmolytic effect, differentiation of B- and T-lymphocytes. Re- • constant 100 Hz: spasmolytic effect, combinant IFN-γ (Actimmun) is used for the • rhythmic 0–10 Hz: for muscle gymnastics, prevention and treatment of the chronic • rhythmic 50–100 Hz: has an analgesic and granulomatous disease and certain viral dis- spasmolytic effect and causes hyperaemia, orders. IFN-α and IFN-β exert their activity • rhythmic 90–100 Hz: has an analgesic and via the same receptor, while IFN-γ has a spasmolytic effect, unique receptor. • rhythmic 0–100 Hz: has an alternating suppressive and irritating effect; used in Interferon omega (IFN-ω) Originally re-

pathologically altered cellular functions ferred to as IFN-α2. It has similar properties (oedema). to IFN-α.

Interferon alpha (IFN-α) The main type Interferons Classed amongst the cytokines. of interferon produced by leukocytes. It is in- In mammals, there are five known types of duced by foreign cells, cells infected by a vi- interferons (IFN) which are divided into two rus, neoplastic cells and bacteria. It has about classes. IFN-α, IFN-β, IFN-ω and IFN-τ be- 15 isotypes whose genes are localised on long to the first class, while the second class is chromosome 9 in man. Recombinant IFN-α represented by IFN-γ. (Intron A, Roferon A) is used in the treat- ment of hairy-cell leukaemia, chronic myelo- Interleukin 1 (IL-1) A glycoprotein with MW id leukaemia, Kaposi sarcoma, malignant 17 kDa. It exists in two forms – IL-1α and IL- melanoma, multiple myeloma, chronic hepa- 1β – which are coded for by separate genes on titis B and C and several other disorders. chromosome 2. They act via a common re- 107 interleukin 6 (IL-6) ceptor (IL-1R), which is found on different Interleukin 3 (IL-3) A glycoprotein with types of cells. The biological effects of IL-1 MW 20 kDa secreted mainly by TH1- and are therefore pleiotropic. IL-1α and IL-1β are TH2-lymphocytes, NK-cells and mast cells. Its typical pro-inflammatory cytokines synthe- gene is localised on chromosome 5 in the sised by macrophages, monocytes and den- proximity of the gene for GM-CSF. In the dritic cells involved in the immune responses, past it was referred to as a multipotent colo- inflammatory processes and haematopoiesis. ny-stimulating factor (multi-CSF, colony- They stimulate the proliferation of B- and T- stimulating growth factors). It acts via a com- lymphocytes, cause the expression of recep- mon receptor for IL-3 and GM-CSF. It is a tors for IL-2, leukoadhesive molecules on growth factor of haematopoietic stem cells, neutrophils and endothelial cells, the chemo- megakaryocytes, erythrocytes, granulocytes, taxy of neutrophils, macrophages and lym- mast cells and macrophages. phocytes, and the cytotoxic activity of NK- cells. Further actions include the proliferation Interleukin 4 (IL-4) It is produced mainly and synthesis of collagen by epithelial cells by TH2-lymphocytes, but also by mast cells and fibroblasts, the synthesis of prostaglan- and basophils. It is coded for by a gene loca- dins in macrophages and the hypothalamus, lised on human chromosome 5. It stimulates and the synthesis of acute phase proteins in the proliferation of early B-cells inducing I hepatocytes. It participates in the majority of their differentiation and production of IgM, overreactive and pathological immune reac- IgG1 and IgE. Furthermore, IL-4 stimulates tions. It exerts a damaging effect in rheuma- the proliferation of T-lymphocytes, the pro- toid arthritis and chronic inflammatory bow- duction of antigen-specific cytotoxic T-cells, el diseases (ulcerative colitis, Crohn’s disease). the expression of HLA antigens and is an ac- This harmful effect can be therapeutically tivating factor of macrophages and a growth blocked by monoclonal antibodies against factor of mast cells. With its capability to IL-1 or by the natural antagonist of its recep- switch antibody production from IgM to IgE, tor (IL-1RA). it can greatly influence the development of the immediate type of allergic reactions which are Interleukin 2 (IL-2) A glycoprotein mediated by IgE antibodies. It has an antiin- with MW 15.5 kDa coded for by a gene loca- flammatory effect. lised on human chromosome 4. It acts via its receptor IL-2R, which can have low-affinity, Interleukin 5 (IL-5) Secreted mainly by medium-affinity or high-affinity forms. It is TH2-lymphocytes and activated mast cells. Its produced by TH1-lymphocytes after their ac- gene is localised on chromosome 5. It’s most tivation with an antigen and IL-1. IL-2 is a important pleiotropic effects include the acti- growth factor for T- and B-lymphocytes and vation and stimulation of B-cell and eosino- an activating factor of TC-lymphocytes and phil proliferation, stimulation of cytotoxic T-

NK-cells. In TH-lymphocytes, it stimulates lymphocytes and the capability of switching the production of other cytokines such as between the production of IgM antibody iso- IL-4 and IFN-γ, as well as the antineoplastic type to IgA antibody isotype, and the ability activity of LAK-cells. Sufficient production of to increase the expression of receptors for IL-2 and expression of IL-2R is of crucial im- IL-2. During these activities it has a synergic portance for adequate T-cell immunity. A de- action, especially with IL-2 and IL-4. Togeth- creased production of IL-2 is observed in pa- er with IL-3 and GM-CSF it controls the de- tients with severe combined immunodeficien- velopment of eosinophils. cy, Nezelof’s syndrome, AIDS, type I diabetes mellitus and systemic lupus erythematosus. Interleukin 6 (IL-6) A glycoprotein whose The stimulation of LAK-cells has gained gene is localised on chromosome 7. Origi- ground in the treatment of certain neo- nally it was termed IFN-β2. It is synthesised plasms. by various cells including TH2- and B-lym- interleukin 7 (IL-7) 108

phocytes, macrophages, endothelial cells, fi- Interleukin 9 (IL-9) It acts predominantly broblasts, mast cells and a number of neo- as a helping, co-stimulatory factor of other plastic cell lines. It is considered a typical cytokines during the development of hae- proinflammatory cytokine. Its production is matopoietic cells. It thus potentiates the pro- also induced by a number of other cytokines liferation of certain clones of T-helper cells, (IL-1, IL-2, TNF-α, IFN-γ, etc.). It acts as an foetal thymocytes in the presence of IL-2, endogenous pyrogen and an activator of syn- mast cells after their induction by IL-3 and thesis of acute phase proteins in hepatocytes, erythrocytes in co-operation with erythro-

as well as a final growth factor for the differ- poietin. It is produced mainly by TH2-lym- entiation of the B-cell to plasma cells, and as phocytes under the influence of IL-1. Its gene growth factors of plasmocytomas and myelo- is localised on chromosome 5 together with mas. Increased IL-6 synthesis is observed in a the genes coding for IL-3, IL-4, IL-5 and GM- number of disorders, such as rheumatoid ar- CSF. The deletion of this chromosomal sec- thritis, systemic lupus erythematosus, AIDS, tion is linked to the occurrence of malignan- other infections, a number of neoplasms, and cies (, acute non- in acute transplant rejection. lymphocytic leukaemia).

I Interleukin 7 (IL-7) It facilitates the differ- Interleukin 10 (IL-10) It is produced

entiation of lymphoid stem cells into early mainly by TH2-lymphocytes and to a lesser

precursor B- and T-cells, and acts as a growth extent by TH0-lymphocytes, monocytes, mac- factor of T-lymphocytes. It is synthesised by rophages and activated B-lymphocytes. It is a stromal cells of the bone marrow and thymus. pure protein (contains no saccharides) with a It activates macrophages and stimulates the MW 18KDa. It inhibits the production of proliferation of thymocytes. It acts via high- other cytokines (IFN-γ, TNF-β, IL-2 and

affinity receptors belonging to the hae- IL-3) by TH1-lymphocytes, cytotoxic T-lym- matopoietin receptor superfamily. phocytes and NK-cells. It inhibits the synthe- sis of pro-inflammatory cytokines IL-1, IL-6, Interleukin 8 (IL-8) It belongs to chemo- IL-8, GM-CSF and TNF-α in macrophages. It kines and was originally called neutrophil- blocks the presentation of proteinous anti- activating peptide-1 (NAP-1). Its gene is loc- gens. It acts as a natural immunosuppressive alised on human chromosome 4 and codes and anti-inflammatory agent. Therefore, it is for a small protein containing only 79 amino- of possible clinical use in chronic inflamma- acid units (MW 8.4 kDa). It is produced tory conditions and autoimmune disorders. mainly by monocytes, macrophages and en- dothelial cells during a response to various Interleukin 11 (IL-11) It has multiple bio- factors inducing an inflammatory reaction. It logical properties similar to IL-6. Both these acts via a specific receptor that can be found cytokines, however, have separate receptors. only on neutrophils, and so IL-8 is their cru- IL-11 particularly controls the lymphopoietic cial chemotactic and activating cytokine. In and haematopoietic systems, hepatic cells

addition, it also induces the expression of β2- and adipogenesis. It is a growth factor of integrins on neutrophils, which is of crucial megakaryocytes and, together with IL-3, par- importance for their transendothelial migra- ticipates in the development of thrombocytes. tion to the focus of inflammation. Its effect is It stimulates B-lymphocytes during the anti- hypothesised in pathological reactions in- body-mediated response to T-independent volving the neutrophils, such as in adult re- antigens. It is produced by the supporting fi- spiratory distress syndrome (ARDS), idio- brous tissue in bone marrow and by fibro- pathic pulmonary fibrosis or the late phase of blasts. Its gene is localised on chromosome 5. bronchial asthma. It facilitates the development of plasmocyto- ma, which indicates its role in tumour pro- duction. 109 interleukin 16 (IL-16)

Interleukin 12 (IL-12) Its molecule con- and differentiation of B-lymphocytes, similar sists of a heterodimer of two glycoprotein to IL-4. chains linked together by disulphide bonds. The genes for both chains in a human are lo- Interleukin 14 (IL-14) A glycoprotein with calised on different chromosomes. The gene MW 55 kDa which previously was termed a coding for the polypeptide chain p35 is loca- high-molecular B-cell growth factor. It is se- lised on chromosome 3 and a gene coding for creted mainly by follicular dendritic cells, T- p40 is localised on chromosome 5. The prin- cells of the germinal centres and certain neo- cipal producers of IL-12 are monocytes and plastic cells. Its main function is to increase macrophages. It is an activation factor of NK- B-cell proliferation and to induce and main- cells, stimulating their cytotoxicity in the tain the production of memory B-cells. The ADCC reaction (antibody-dependent cell cy- receptor for IL-14 can be found only on acti- totoxicity), and increasing the expression of vated B-lymphocytes, not on resting ones. the CD56 molecule which is their typical sur- The IL-14 molecule has a similar amino-acid face marker. By its activity, NK-cells develop sequence as the Bb factor, present in the alter- into the more effective LAK-cells. In this ac- native pathway of complement activation. tivity it resembles IL-2, but with a lower effect (about 50%). In addition, IL-12 facilitates the Interleukin 15 (IL-15) A glycoprotein with I occurrence of specific human cytotoxic T- MW 15 kDa and the function of a pro-in- lymphocytes against certain neoplasms, stim- flammatory cytokine. It is produced by mul- ulates the proliferation of TH- and TC-cells tiple cells and tissues, including activated and inhibits the secretion of IgE stimulated macrophages, fibroblasts, skeletal muscles by IL-4. It is considered to be the principal and the kidneys. It increases the cytotoxicity stimulator of IFN-γ production by TH1-lym- of CTL (cytotoxic T-lymphocytes) and NK- phocytes. In this sense, it acts in synergy with cells. In this way, it is similar to IL-2 and IL- IL-18. With respect to these immunoregula- 12. It binds to a receptor consisting of three tory influences, IL-12 has been studied in the polypeptide chains, two of which are identi- treatment of parasitic and neoplastic disor- cal to the receptor for IL-2. IL-15 induces ders with the advantage of low toxicity and proliferation on mast cells, helper and cyto- minimal adverse events. toxic lymphocytes, including those having the antigen receptor gamma/delta. It stimu- Interleukin 13 (IL-13) An anti-inflamma- lates the production of IL-5 by allergen-spe- tory cytokine whose gene is localised on cific T-cell clones, thereby moving the TH1/ chromosome 5 in close proximity to the gene TH2 balance to favour TH2-cells, with associ- coding for IL-4. It has similar biological ef- ated participation in allergic responses medi- fects as IL-4. It is produced predominantly ated by this T-lymphocyte subpopulation. by activated TH2-lymphocytes. It exerts a IL-15 is an effective chemotaxin of T-lym- regulatory activity on various immune sys- phocytes; it suppresses their apoptosis and tem cells, especially monocytes, macrophag- induces the expression of ligands for leu- es, B-lymphocytes and NK-cells. It is a koadhesive β-integrins. It is hypothesised chemotactic factor for monocytes and mac- that it plays a key role in the upkeep of chron- rophages, but inhibits the production of pro- ic inflammation in diseases such as rheuma- inflammatory cytokines in them. It therefore toid arthritis, pulmonary sarcoidosis, bron- can be regarded as a significant endogenous chial asthma and ulcerative colitis. anti-inflammatory regulator, similar to IL-10. It inhibits the replication of HIV-1 in mac- Interleukin 16 (IL-16) An immunomodu- rophages and monocytes, so differs from IL-3 latory and pro-inflammatory cytokine whose and GM-CSF, which, on the contrary, stimu- structure is much conserved among individ- late the replication of this aetiological agent ual animal species. It is synthesized by cyto- of AIDS. It also stimulates the proliferation toxic (CD8+) lymphocytes in the form of a interleukin 17 (IL-17) 110

high-molecular precursor (MW 80 kDa), tive precursor that is cleaved by caspase 1 whereby polypeptide chains with a MW (formerly this protease was referred to as IL- 14 kDa emerge in the producing cells. These 1β converting enzyme – ICE) to the active chains polymerise to tetrameres which are cytokine. IL-18 is structurally similar to IL- the only biologically effective form of IL-16. 1β and is coded for by a gene localised on They are secreted by CD8+ lymphocytes in chromosome 9. It acts mainly via a specific response to an antigen, mitogen, histamine receptor, IL-18R, whose soluble form (sIL- or serotonin. IL-16 uses the CD4 molecule as 18R) is able to neutralise the effects of IL-18. a receptor, which is why it exerts its action The most significant pro-inflammatory ac- not only on helper T-lymphocytes, but also tivity of IL-18 is its capability to induce the on macrophages and eosinophils which also production of TNF-α, IL-1β, GM-CSF, have this differentiation antigen on their sur- chemokines CXC and CC, Fas ligands and face. IL-16 is a chemotactic factor for these the nuclear factor κB (NF-κB). The stimula- cells and it induces in them the synthesis of tion of Fas ligand expression on NK-cells and other cytokines and also the expression of T-lymphocytes then leads to an increase in HLA-DR histocompatibility antigens. On the their cytotoxic activity. On the other hand, other hand, after binding to CD4+ lympho- IL-18 is a very effective activator of HIV-1 I cytes, IL-16 inhibits the ensuing immune re- (aetiological agent of AIDS) replication in sponse as well as the infectiousness and intra- human macrophages. The normal concentra- cellular replication of HIV-1, the aetiological tion of IL-18 in the blood is 50 to 150 pg/mL, agent of AIDS. The epithelial cells of the air- whereas in patients with acute lymphoblastic ways of patients with asthma can also release leukaemia, chronic lymphocytic leukaemia a biologically effective IL-16, while the epi- and acute and chronic myeloid leukaemias, it thelial cells of healthy individuals can’t. This rises to 200 to 1200 pg/mL. The overproduc- suggests a potential therapeutic effect for IL- tion of IL-18 leads to an increased produc- 16 inhibitors. tion of nitric oxide (NO), which then partici- pates instantly in various pathological reac- Interleukin 17 (IL-17) A glycoprotein con- tions. taining 155 amino acid units that has been described as recently as 1995. Its amino acid Interleukins Cytokines participating in the sequence shows a considerable homology regulatory interactions between leukocytes. with one of the proteins of herpetic lympho- There are currently 33 known interleukins, tropic virus (HVS13). It is produced as a di- which are termed by abbreviations IL-1 to IL- mer by activated T-lymphocytes. It stimulates 33. fibroblasts, endothelial and epithelial cells to synthesise IL-6, IL-8 and GM-CSF, which in- Intermittent hydrarthrosis of the dicates that it could contribute to inflamma- joints (hydrops articulorum intermit- tory processes involving T-lymphocytes. tens) Characterised by recurrent attacks of a predominantly unilateral and relatively pain- Interleukin 18 (IL-18) A pro-inflammato- less, non-inflammatory joint effusion. It is a ry cytokine which was originally described in long-lasting disorder often with life-long per- 1989 as an inducing factor of IFN-γ (IGIF). sistence. The knee joint is the most frequently However, this activity is performed in con- affected joint, though rarely it can affect the junction with a secondary stimulus such as elbow, hip or shoulder joints. IL-12, mitogens or a microbial agent. Both Clinical symptoms and signs: cytokines (IL-18 and IL-12) act in synergy periodic recurrent joint effusion, and have a critical role in inducing the pro- no apparent radiologic joint damage,

duction of IFN-γ especially by TH1-lympho- very rarely progresses to rheumatoid arthri- cytes. IL-18 is produced predominantly by tis. activated macrophages in the form of an ac- 111 isolated vasculitis of the central nervous system (CNS)

International classification of func- • radiological deterioration of the joints – tioning (ICF) This has replaced the previous steroid arthropathy (Charcot-like arthrop- IDH classification (impairment–disability– athy, osteonecrosis – low incidence), handicap). In 2001, the ICF (international • iatrogenic infection – very rare complica- classification of functioning) was issued by tion, the World Health Organisation as an interna- • rupture of the tendons, tional framework for measuring health and • tissue atrophy, adipose necrosis, calcifica- disability at both individual and population tions, levels. It was endorsed by all 191 Member • nerve damage (most frequent after carpal States of the World Health Organisation. The tunnel injection), ICF classification replaced the term “disabili- • post-injection flare, ty” by “activity”, while a number designate • uterine bleeding, “diminished activity”. In place of “handicap” • pancreatitis – rarely, it uses the term “participation” (in social life). • erythema and sensation of warmth on the A number also designate “restricted partici- face and body, pation”. In the ICF classification “environ- • posterior subcapsular (only after ment” is a new dimension, where facilitating many injections). “F” and barrier “B” factors are also included. I Iontophoresis This is a non-invasive meth- Intraarticular glucocorticoid treatment od of inserting treatments into the body using The intraarticular injection of glucocorticoids a galvanic current. Histamine (muscle relaxant is a useful method for suppressing active syno- effect), novocaine, , dionine (analge- vitis within a joint. Intraarticular injections sic effect), hyaluronidase (fibrolytic effect) and should not be used too frequently or to joints hydrocortisone (anti-inflammatory effect) are without signs of actual inflammation. One inserted from the anode. Salicylates (anti-in- joint should not be treated more than 3–4 flammatory and fibrolytic effect) and iodine times in a year. Most frequently triamcinolone (fibrolytic effect) are inserted from the cath- acetonide (Kenalog) and methylprednisolone ode. When using non-steroidal anti-inflam- (Depomedrone) are used, though hydrocorti- matory drugs, the active electrode can vary. sone can be used if only a short term effect is required. Ir genes (immune response genes) An obsolete term for genes regulating the immune Intraarticular treatment Rheumatoid ar- response of an individual to specific antigens, thritis in adults and adolescents is probably both in a quantitative and qualitative sense the disorder in which most intraarticular in- (immune response genes). The current view is jections are given by rheumatologists. They that these genes are now the class II MHC are particularly useful when exceptional in- (major histocompatibility complex) genes. flammatory activity is present in one or more joints. They are also used following disease Isolated vasculitis of the central ner- flare to cover the delayed effect of an increase vous system (CNS) A rare disorder occur- in general systemic treatment (DMARDs). In ring in middle age. Headache, nausea and children with juvenile idiopathic arthritis, the vomiting are the most prominent clinical fea- choice of preparations is limited (methyl- tures. Confusion, dementia and loss of con- prednisolone is more appropriate) due to po- sciousness together with signs of focal isch- tential growth disturbance of the affected aemic cerebral event (stroke) can also be joint. The dosing interval between intraar- seen. The diagnosis is confirmed using cere- ticular injections into the same joint should bral angiography, or a targeted biopsy of the generally not be less than 3 months. CNS. Aggressive treatment with corticosteroids Potential hazards of intraarticular and in- and cyclophosphamide can reduce the mor- tralesional injections of glucocorticoids: tality of this, often fatal, disorder. J

Janda hypermobility test → see Hyper- gomphosis – dental alveoli connection mobility test 2 (according to Janda) with the help of collagen fibres (teeth in bony sockets), Jansen type metaphyseal chon- • cartilaginous articulations: drodysplasia An autosomal dominant he- synchondrosis – the bones are connected reditary metaphyseal chondrodysplasia with by hyaline cartilage (synchondrosis dysproportional nanism () and sphenopetrosa, synchondrosis manu- short and deformed limbs. The metaphyses briosternalis and xiphosternalis), have a shape resembling rickets. It may be symphysis – the bones are connected pre- confused with rickets in the neonate and in- dominantly by a fibrous cartilage and a fant. However, X-rays show visible prominent very small amount of hyaline cartilage separation between the and the (symphysis pubis, symphysis interverte- , especially at the distal end of the bral). In the course of life a cleft often femur and proximal end of the tibia. During appears in the fibrous cartilage of the toddler age, spotty calcifications appear in symphysis. This articulation is called the metaphysis, formed by a partially calcified hemiarthrosis and is considered to be a cartilage protruding into the . Be- transition form of a joint towards diar- sides long bone involvement, the skull and throsis (for example the vertical cleft spine can also be affected. There is usually filled with synovial fluid – cavum sym- generalised demineralisation of the skeleton. physis in the fibrous cartilage of symph- Laboratory tests show the same as in primary ysis pubis – pubic symphysis, the clefts hyperparathyroidism, with increased serum in the intervertebral discs of the cervical calcium and alkaline phosphatase levels and a spine – uncovertebral clefts). Rigid con- low serum phosphate, but the serum concen- nection of the bones by bone tissue is trations of the parathormone (PTH) or PTHrP called synostosis. (PTH-related protein) are very low. Hypercal- Diarthroses – Joints with a cavity (cavum ar- ciuria and elevated hydroxyprolinuria are ticulare) containing synovial fluid. The bones present. The aetiology is a mutation of the touch one another with the contact surfaces gene coding for the PTH/PTHrP receptor, covered by a hyaline cartilage, except for the which is then capable of self-activation with- perimeter of contact surfaces where they are out the presence of bound hormone. connected by fibrous tissue forming a joint capsule composed of dense collagen tissue Joint A point of inter-connection of two or lined by synovial membrane on the inside more bones that enables movement between and strengthened by ligaments externally. them. The degree of movement depends on Such joints are called synovial joints. The the type of joint. range of movement in them is substantially The following types of joints are recognised: greater than with synarthroses. Synarthroses – Joints without a cavity. Diarthroses whose mobility is substantially Movement is very limited. The bones are in- limited due to the shape of articular surfaces ter-connected by fibrous tissue or cartilage. and strong ligaments are referred to as am- • fibrous articulations: phiarthroses (for example, the proximal tibio- syndesmosis – the bones are connected by fibular joint and the sacroiliac joint). dense fibrous tissue (sutures, distal tibio- fibular articulation), 113 juvenile ankylosing spondylitis

Joint and Periarticular structures A pending on the fixation method, they can be complex functional unit consisting of articu- subdivided into cemented prostheses – the lating bones, intra-articular structures (me- components are fixed to the bone by bony nisci), articular capsule, solidifying ligaments, cement, uncemented – the components are adjacent muscles, tendons, peritendon and fixed to bone without a cement interlayer, bursae. Neuro-regulatory mechanisms from and hybrid – each component is fixed in a peripheral nerves to central nervous system, different manner. In terms of construction, and arterial, venous and lymphatic systems, there are prostheses shaped as a monoblock belong to this unit. The basic physical exami- – the prosthesis is made from one piece of nation consists of five tests: material, or as modular – the prosthesis is 1. inspection, made up of multiple components. 2. palpation, Indication for the use of joint prostheses: 3. active and passive movements examina- • primary – primary treatment of the joint tion, by prosthesis, 4. examination of physiological movements • revision – the prosthesis is used after pri- in the joint, mary implantation failed, 5. muscle strength testing (ability of muscu- • tumorous (individual) – replacement of a lar resistance). joint and other articular structures affected by a neoplastic disease. Joint involvement in syphilis Syphilitic J arthropathies are arthritides occurring in Joint protection The main principles: syphilis. • To control and save overall energy output Clinical symptoms and signs: Changes in • Large joints and muscle groups must be in- the joints occur at any stage of syphilis, but is volved in each activity commoner in early syphilis. Typically the • Limit the influence of gravity during each joints are painless or only mildly painful at activity (shuffle objects, do not elevate night, which is in contrast to the large swell- them) ing of the joints. A beneficial response from • Use joints and muscles on those functional antiluetic treatment is also typical. levels in which their performance is most effective Joint play This is the paraphysiological • All activities during which the joints are in movement in a joint that can only be elicited one particular position for a long time are passively as a ventro-dorsal or medio-lateral contraindicated shift, or, for example, a dorsal shift of the tibia • Do not attempt any difficult muscle exer- and internal rotation of the knee. These are cise that cannot be immediately terminated the mutual shifts of articular surfaces, rota- if necessary tion and distractions. Juvenile ankylosing spondylitis The Joint Prosthesis An artificial joint de- rare onset of ankylosing spondylitis in child- signed from special material (metal, ceram- hood (mainly in pre-pubertal boys) gives a ics, polyethylene, etc.) for replacing a joint clinical picture in which affection of peri- damaged by trauma, osteoarthrosis, arthritis, pheral joints precedes that of the axial skele- tumour, etc. The most frequently used have ton. The presence of the HLA-B27 antigen in been hip and knee joint prostheses, but in- blood tests helps to confirm the diagnosis. creasingly shoulder, ankle and elbow joints, Patients usually develop typical features of small joints of the hands and feet and the ankylosing spondylitis after puberty. spine are being used. Prostheses are divided Clinical symptoms and signs: into total joint prostheses – replacement of enthesitis of the Achilles tendon insertion on the whole joint – and hemiprostheses – re- the calcaneus and other enthesopathies, placement of a certain part of the joint. De- arthritis of the lower limbs. juvenile chronic arthritis (JCA) 114

Juvenile chronic arthritis (JCA) → see the day and last longer than three months); Juvenile idiopathic arthritis (JIA) maculopapular, sometimes confluent non- itching rash that comes and goes; generalised Juvenile dermatomyositis (JDM) A rare lymphadenopathy (capable of causing abdom- multisystem disorder of autoimmune aetiol- inal pain); hepatosplenomegaly, serositis, ogy manifested by an aseptic inflammation of myocarditis; arthralgia – polyarthritis (espe- the skin and striated muscles. cially the knees, wrists and ankles are affect- Clinical symptoms and signs: ed); growth disturbances. The mortality rate • acute type: is 4% (infections and amyloidosis). fever, Polyarticular form malaise, Affects mostly girls between 8 and 14 years characteristic heliotrope rash on the upper old. eyelids, an erythematous rash over the Clinical symptoms and signs: Systemic dorsal aspects of the MCP joints (Got- symptoms and signs are mild or absent. A tron’s sign) and an erythematous rash on symmetrical polyarthritis develops acutely or the chest. subacutely. It affects especially hands, knees, symmetrically painful/tender muscles with ankles, cervical spine and temporomandibu- weakness, most marked proximally. lar joints, potentially leading to severe con- difficulty swallowing solid food (dys- tractures if untreated. Local changes of bone J phagia). growth (micrognathia) are frequent features. • chronic type: Not infrequently accompanied by fever and arthralgia, possibly arthritis, lymphadenopathy. Acute phase reactants (ESR, weakness, falls, stumbling, CRP) are often markedly elevated. Rheumatoid inability to climb stairs and do press-ups nodules may be present, especially in patients soft tissue calcification in the limbs. with positive rheumatoid factor. Radiological The diagnosis is suspected from the clini- changes show periarticular osteoporosis and cal picture associated with elevated muscle erosions. In severe cases, severe deformities enzymes, and confirmed by electromyog- and ankylosis can develop. The prognosis can raphy and muscle biopsy. Treatment usu- be poor. ally involves corticosteroids with or with- Therapy: Initially, NSAIDs drugs are ad- out immunosuppressive agents. The prog- ministered. In actively progressing cases, nosis is very variable. DMARDs are given, followed by biological treatment (anti-TNF therapy) in unrespon- Juvenile idiopathic arthritis (JIA) Previ- sive cases. Continuous exercise (prevention ously referred to as juvenile rheumatoid ar- of contractures) and physiotherapy are im- thritis (JRA) or juvenile chronic arthritis portant; in severe disturbances of function, (JCA). It is a chronic inflammatory disorder surgical reconstruction is applicable. with onset before 16 years of age which has a Systematic exercise, positioning and wear- prominent manifestation involving the mus- ing orthoses is important. A multi-disciplin- culoskeletal system, but can also affect vari- ary approach with nurses, physiotherapists, ous organs and tissues. It is a heterogeneous occupational therapists and school tutors is disease containing several forms (pauciartic- important to ensure a good quality of life. ular, polyarticular, systemic). Pauciarticular form Forms of JIA It occurs in girls before the age of 5. Systemic form (Still’s disease) Clinical symptoms and signs: Four or Affects both genders, more frequently fewer joints are involved. It usually affects boys, with onset usually between 1 and 4 major joints, especially the knees, ankles, years of age, rarely between 6 and 7. wrists or elbows. Fever and other systemic Clinical symptoms and signs: High tem- symptoms rarely occur. Typically there is perature (intermittent, can subside during chronic iridocyclitis. The disease goes into re- 115 juvenile systemic lupus erythematosus mission after 5 years in 30–40% of cases, with Juvenile sclerosis A heterogeneous group the prognosis for joints being very good. of disorders characterised in localised form Therapy: NSAIDs are used. DMARDs and by induration of the skin and dermis, in the glucocorticoids are not indicated in most systemic form other organs are also affected cases. The intraarticular injection of gluco- due to vasculitis of the capillaries and small corticoids is the most appropriate way of sup- vessels. pressing the arthritis. Regular eye review by Clinical symptoms and signs: an ophthalmologist is recommended to de- • localised form: tect and treat (topical hydrocortisone) any morphea, chronic iridocyclitis to prevent blindness. linear scleroderma, Still’s disease in adults • systemic form: The disease resembles the systemic form of sclerodactyly or scleroderma, JIA but has its onset in adulthood. Raynaud’s phenomenon, Clinical symptoms and signs: Rash, fever, arthritis. leukocytosis and marked increase in serum calcinosis ferritin level. Therapy: Salicylates and NSAIDs are given Juvenile systemic lupus erythemato- to reduce fever. In severe disease, glucocorti- sus A multisystem chronic disorder charac- coids and DMARDs are given. The treatment terised by inflammation of the connective of choice in adults now is Anakinra 100 mg sc tissue, immune complex vasculitis and pro- J daily. duction of antinuclear antibodies. Clinical symptoms and signs: A very rare disor- • fever, der (several reported cases). The onset is usu- • weight loss, ally between the 8th and 12th year of age and is • skin signs, especially photosensitive rash manifested by bone pain, kyphosis and frac- • arthritis/arthralgia, tures. Initially, it is important to exclude os- • butterfly rash, teogenesis imperfecta in the patient or family. • anaemia, leukopenia, Its pathogenesis is unclear and therefore no • lymphadenopathy, known treatment modality is recommended. • pericarditis, • hepatitis, Juvenile rheumatoid arthritis (JRA) → • neuropsychiatric disturbances, see Juvenile idiopathic arthritis (JIA) • growth retardation, • pulmonary fibrosis. K

Kallikrein A proteolytic enzyme that is a comprise a fever lasting longer than 5 days component of the kinin and haemocoagula- plus 4 of the following: conjunctivitis and ocu- tion systems. It participates in the production lar erythema, dry red lips and tongue, gingivi- of bradykinin, activates Hageman’s factor and tis, cervical lymphadenopathy (the size of one is able to directly cleave the C5 component of node at least 1.5 cm), oedema and erythema the complement. on the palms and soles, polymorphous rash on the trunk. Kaltenborn method A set of three exer- cises mainly used in vertebrogenic syndromes Kegel exercise An exercise developed by for relaxing the rigidity of the spine at blocked American gynaecologist Arnold H. Kegel points. The movements can be targeted seg- (1894–1981). The exercises are aimed at mentally at a given section of the spine and strengthening the pelvic floor and should with their help release the whole of the spine. help to prevent stress incontinence (involun- In rheumatology, the Kaltenborn method can tary urine leakage). The exercise system con- be utilised in vertebrogenic disorders and the tains 4 phases: visualisation (to perceive with early stages of ankylosing spondylitis. inner vision the region controlled by the muscles), relaxation (to learn how to breath Kawasaki disease (KD) It is also known as in a comfortable supine position with pillow mucocutaneous lymph node syndrome. It is under the knees), isolation (controlling the an infantile systemic inflammatory disease vaginal and anal sphincters) and strengthen- with polyarteritis, aseptic lymphadenopathy, ing (isometric contraction of vaginal sphinc- and inflammation of the skin and mucous ters). membranes. It is an acute febrile disease of children younger than five years of age that Kenalog (Triamcinalone) → see Gluco- occurs mainly in Japan, but sporadically in corticoids, Intraarticular glucocorticoid other countries. It mainly has a mild course treatment but in approximately 2% of patients, it is fatal due to a necrotising vasculitis or multiple an- Kibler’s fold A fold of the skin is moved be- eurysms of the coronary arteries (detectable tween the thumb and the index finger, for by Echocardiography). Laboratory findings example, on the back. Increased skin resis- include raised acute phase reactants, leucocy- tance (inability to move the fold further) in- tosis and often a marked thrombocytosis. Its dicates a hyperalgesic cutaneous zone related aetiology is unknown. An infection or a cer- to a certain section of the spine eliciting a tain toxin produced by infecting microorgan- burning pain sensation in the examined pa- isms at the onset is hypothesised, followed by tient. a number of immunological abnormalities such as increased production of IL-1 and Kienbock’s disease Avascular necrosis of TNF-α, as well as immune complexes. These the lunate bone in the wrist named after the cause damage to the vascular endothelium radiologist Robert Kienböck (Vienna, 1871– during the acute stage of the disease. Treat- 1953). The disorder predominantly affects ment includes intravenous immunoglobulin men between 20 and 30 years of age and can (2 g/Kg) and high dose . develop after strenuous work, for example Clinical symptoms and signs: Diagnostic with a pneumatic hammer. An innate predis- criteria (American Heart Association 2004) position is also reported. 117 krause-weber’s test

Kinesiology The scientific study of human Köhler (1874–1947), is an aseptic necrosis of movement. It encompasses an understanding the navicular bone, often in both feet, espe- of the interaction of anatomy, physiology, cially in 3 to 8 years old boys. There is a pres- biomechanics and psychology in movement. sure and after load pain in the anterior part of A full understanding of kinesiology is impor- the foot causing a thickening of the metatar- tant in the field of physiotherapy, but also in sal part of the foot, gait disturbance and occupational therapy, osteopathy and chiro- alimp. Radiological findings include widen- practic practice. ing of the articular cavity between the navic- ular and surrounding bones with increased Kinesiotherapy The main, active compo- density (sclerosis) of the body of the navicu- nent of physiotherapy and a means of restor- lar bone. ing the range of movement, improving mus- cle strength and endurance, improving move- Köhler’s disease II Spontaneous osteone- ment coordination, increasing the aerobic crosis predominantly in 12 to 18 years old capacity and inducing a global sensation of girls. It affects the capitulum of the 2nd or 3rd wellness. In rheumatic disorders, especially metatarsals. in inflammatory forms, therapeutic exercise is governed by the activity of the disease and König’s disease Osteochondritis dissecans by the degree of functional impairment, age (first described 1887 by Franz König, Ger- and endurance of the patient. The passive, ac- man surgeon, 1832–1910), predominantly af- tive, assisted or anti-gravitational exercises fecting elbow or knee, and rarely ankle or hip. can help to restore the range of movement. It is more frequent in men. In contrast to the K Endurance is improved by frequent repeating Perthe’s disease, the necrosis affects the sur- of exercise with a low load; muscle strength is face of the bone around the joint. Loose bod- restored by a small number of exercises with ies may form within the joint on separation of a higher load. It has been demonstrated that the bone fragments. this therapeutic exercise has a positive influ- ence on the increase in aerobic capacity, im- Krause-Weber’s test Used in the assess- provement in the rheological properties of ment of mobility and especially to monitor synovial fluid and improvement of the overall changes in mobility following treatment. It mobility and skills of the patient. Kinesiother- consists of five elements, each of which is apy may also have negative effects (theory of rated on a scale from 0 to 10, with a maxi- hypoxemic reperfusion of reactive oxygen spe- mum score of 50 points. cies complexes into the joint cavity during 1. exercise: the patient lies in a supine posi- movement; inactivation of α1-antitrypsin in tion with his/her hands behind the head the synovial fluid; increased degradation of and should sit up without raising the low- hyaluronic acid due to exercise). er limbs from the floor, 2. exercise: the patient lies on the floor with Kininases Enzymes inactivating the kinins. their hands behind the head and should In human plasma, there are two of them, ki- elevate the lower limbs by 25–30° for 10 ninase I or carboxy peptidase N, which seconds, cleaves the C-terminal arginine from kinins 3. exercise: the patient lies in a prone posi- and anaphylatoxins and kininase II which is a tion with their hands behind the head and peptidyl dipeptidase cleaving the C-terminal should elevate the head and the upper part dipeptide Phe-Arg from the kinin molecules. of the thorax off the floor for 10 seconds, In this way angiotensin I is converted to an- 4. exercise: the patient lies prone with hands giotensin II. behind their head and extend the lower limbs off the floor for 10 seconds, Köhler’s disease Köhler’s disease, first de- 5. exercise: the patient is in a standing posi- scribed by the German radiologist Alban tion with feet together and should bend ku antigen 118

forward so that he/she touches the ground Ku antigen → see Antibodies against Ku an- with tips of the fingers without bending tigen the knees.

K L

Laboratory indicators of the bone growth and reproduction of micro-organ- turnover In the process of bone remodel- isms. ling, the crosslink fragments of collagen enter the blood, and then may be detected in the LAK cells These are lymphokine (mainly serum or urine. IL-2) activated killer cells. NK cells are most At the present time their assessment is uti- frequently subject to activation, less frequent- lised for: ly cytotoxic T-lymphocytes. LAK cells are • monitoring the effect of treatment (a sig- also able to lyse those target cells that cannot nificant change can be seen in 3 to 6 be lysed by less active NK cells. This has re- months), cently led to their use in the treatment of cer- • prediction of bone loss, especially for the tain tumours. identification of so-called fast-losers, i.e. persons with increased bone turnover, Lambert-Eaton Syndrome A complica- • prediction of fracture risk independently tion of intrathoracic tumours, especially of the bone mineral density scan. small cell lung cancer. Muscle weakness is the The individual markers differ by their speci- primary manifestation but myalgias and ficity, sensitivity and severity of assessment, paraesthesiae can occur. and their availability in the routine clinical Aetiology – decreased release of acetylcho- practice. The significance of individual mark- line in the nerve terminals; ers and their combination is still the subject EMG – has differential diagnostic value. of clinical monitoring. Treatment: Includes tumour excision, glu- We subdivide the markers of osteoforma- cocorticoids and guanetidine administra- tion from the markers of osteoresorption. tion. Markers of osteoresorption: • crosslink compounds of collagen – deoxy- Laminin Glycoprotein of high molecular pyridinoline (DPD), weight (MW 900 kDa) comprising three (al- • C-terminal telopeptide fragment of type I pha, beta and gamma) polypeptide chains. collagen (CTX), Fifteen different forms of laminin have been • N-terminal telopeptide fragment of type I identified. Laminin belongs to adhesive mol- collagen (NTX), ecules and is part of the intercellular matrix, • C-telopeptide crosslink domain of type I where it is bound to collagen type IV, heparan collagen (ICTP). and participating in the Markers of osteoformation: formation of the basement membrane of • Bone specific isoenzyme of alkaline phos- many tissues, including vessels. It is involved phatase (bALP), in the adhesion and chemotaxis of neutro- • osteocalcin, phils. Laminin is the morphogenic factor of • propeptides of type I procollagen (PICP, epithelial cells and hepatocytes, and by bind- PINP). ing to receptors on the surface of nerve cells it enables mutual aggregation of these cells and Lactoferrin Protein that contains iron, the production of dendrites. It is produced by found in milk and in secondary granules of macrophages. The importance of laminins is neutrophils in which it is involved in anti- illustrated by the fact that the dysfunctional microbial pathways by absorbing iron from structure of laminin-2 is the cause of some the environment. Iron is crucial for the types of muscular dystrophy. large granular lymphocytes 120

Large granular lymphocytes → see LGL phagocytosed nucleus surrounded by small (large granular lymphocytes) amounts of cytoplasm. The original nucleus of a phagocytosing leukocyte is compressed Laser (Light Amplification by Stimu- to the cell membrane. LE cells are typical for lated Emission of Radiation) therapy systemic lupus erythematosus, although they (LT) Utilisation of monochromatic (only one may occasionally be present in rheumatoid wavelength) polarised (undulation only on arthritis and systemic sclerosis. At present one plane) coherent (vibration in one phase) the detection of LE cells has been superseded light for medical treatment. Only so-called and more sensitive techniques, such as im- “low level lasers” with power of 40–200 mW munofluorescent ANA detection, are used. are used in physiotherapy. Depending on the radiation technique, devices are divided into: Lectins Proteins and glycoproteins which 1. spot radiation, are able to specifically recognise and bind to 2. scanners, different mono-, di- and trisaccharides. They 3. clusters; shower of lasers with several in- activate the agglutination of erythrocytes and frared diodes in one probe. other cells, and are polyclonal (non-specific) Indications in rheumatology are painful dam- mitogens of lymphocytes (e.g. phytohaema- age of soft tissues such as tendinitis, bursitis, glutinin, concanavalin A). This property is epicondylitis, myositis, periarthritis, and os- enabled by the presence of glycocalyx, which teoarthritic pain. Lasers can also be used for is located on the surface of most of the cells irradiation of acupuncture points referred to and which contains different oligosaccharide as “laser acupuncture”. In laser therapy, safety chains. Lectins were originally isolated from procedures and contraindications (eyes and plants, but now are also known to be present L thyroid gland irradiation in particular) must in animals (so called collectins in human and be respected. other mammals) and micro-organisms.

Lazy leukocyte syndrome An older term Leflunomide A dihydroorotate dehydroge- for unidentified conditions associated with nase inhibitor which selectively blocks de deficient chemotaxis of leukocytes leading to novo synthesis of pyrimidines in rapidly pro- increased risk of pyogenic infections. Nowa- liferating activated lymphocytes. This sus- days, specific causes of deficient chemotaxis pends activated autoimmune lymphocytes in have been identified, so the nomenclature has the G1/S phase of cell cycle, whilst not affect- been modified, e.g. leukocyte adhesion defi- ing other lymphocytes in G0 phase, as long as ciency (LAD) syndrome. they are not needed in the immune response. Though primarily acting as an immunomod- LcSSc → see Systemic sclerosis (SSc) ulating agent with anti-inflammatory activity, leflunomide does not have the property of a LE cells The history of antinuclear antibod- non-selective immunosuppressant. It inhibits ies (ANA) began in 1948 when Hargreaves IL-2 synthesis and the expression of adhesive described the phenomenon of LE cells. An LE molecules, decreasing the number of neutro- cell is a polymorphonuclear (PMN) leuko- phils that infiltrate the joint cavity. cyte, which has phagocytosed the released Leflunomide belongs to the group of disease nuclear material of another leukocyte. Anti- modifying antirheumatic drugs that have bodies against nucleosomes, which in vitro been registered for the treatment of rheuma- bind to a released nucleus, are responsible for toid arthritis (RA). Chemically, it is N-(4’- the LE phenomenon. As a consequence of the trifluoromethylphenyl)-5-methylisoxazole-4 binding, complement is activated, with op- -carboxamide. It is administered orally with a sonisation of nuclear material, and finally bioavailability of about 80%. An effective thera- phagocytosis by a PMN leukocyte occurs. peutic level is reached approximately 6 to 10 This results in the formation of a large lucid hours after administration. Leflunomide is 121 lesion of the axillary nerve metabolised in the liver and one of the active Legg-Calve-Perthes Disease Bone ne- metabolites has a very long biological halftime crosis and necrosis of the bone marrow of the up to 14 days. A higher dose is often adminis- femoral head caused by blood supply impair- tered initially (100 mg a day during the first ment. Its aetiology is unknown, but may in- three days) to ensure more rapid achievement volve inherited vascularisation impairment. of equilibrium, otherwise it can take up to two Onset at the age of 2–8 years old, and is more months if the maintenance dose (10 to 20 mg frequent in males (4:1). It lasts for 4 to 4.5 daily) is administered initially. Approximately years. 40% of its metabolites are eliminated via the Clinical symptoms: Hip pain, pain could urine and 50% via the stool. eventually be located in the perineum and Clinical efficacy: The efficiency of lefluno- thigh or in the limb. Necrosis with fractured mide against placebo and other commonly and compressed trabeculae leads to deforma- used DMARDs in the treatment of RA has tion of the femoral head and thereby to in- been tested. Clinical studies have proven congruence of the head and articular cavity comparable efficiency of leflunomide to (development of coxarthrosis). methotrexate (MTX) and sulfasalazine (SSZ) Radiologically the disease progresses in three (Strand et al. 1999, Smolen et al. 1999). It was stages: shown that leflunomide improved inflamma- 1. initial stage, tory parameters such as the ACR 20 index in 2. stage of fragmentation, patients with RA, improves the quality of the 3. stage of re-ossification. patient’s life and delays radiological erosive Differential diagnosis: specific and non-spe- progress in joints over 6 and 12 months of cific coxitis. treatment. Leflunomide is also licensed for Treatment: Conservative, avoidance of ex- treatment of psoriatic arthritis. cessive physical activity, plasters (splints), L Dosage: Leflunomide can be administered avoidance of muscle atrophy by active exer- at a dose of 100 mg per day for three days cise. In mid-life may require hip joint replace- (though this is associated with a higher inci- ment. dence of diarrhoea and so is now often avoid- ed), followed by 10 mg or 20 mg over the long Lequesne’s algofunctional test and term. Its clinical effect is apparent at the end assessment of the severity of hip joint of the first month. Blood count and liver en- impairment → see Instruments of assessing zymes should be checked on a monthly basis. (health status measurements, outcome meas- After discontinuation of leflunomide treat- urement) ment due to severe toxicity, switching to an- other DMARD, e.g. MTX, or before concep- Lesion of the accessory nerve The cause tion, the patient must undergo a washout phase is most often iatrogenic. As an example, based on administration of 8g of cholestyramine lymph node biopsy in the neck area can lead 3 times a day or administration of 50 g of acti- to atrophy of the trapezius muscle and de- vated charcoal 4 times a day for a period of 11 pression of the shoulder. Electromyographic days. examination reveals a neurogenic lesion. Adverse effects: Blood cell count distur- Treatment: Exercise, impulse therapy. bances, diarrhoea, increased liver enzymes, leukopenia, anaemia, thrombocytopenia, hair Lesion of the axillary nerve This can be loss, skin rashes. The agent is contraindicated caused by trauma, haemorrhage, or pressure in pregnancy and during breast feeding. in the axilla. Abduction and elevation of the Women of a fertile age should be informed shoulder can be weakened and there is hy- that in the case of planned pregnancy, a two poaesthesia in the shoulder area and on the year period must elapse between termination lateral side above the elbow. Electromyograph- of treatment and conception, or confirmation ic examination confirms a neurogenic lesion. of zero serum levels following washout. Treatment: Physiotherapy. lesion of the long thoracic nerve 122

Lesion of the long thoracic nerve The drome, Gaucher’s disease), impaired hae- lesion is most frequently caused by nerve matopoiesis (aplastic anaemia, , compression (e.g. when carrying heavy carcinoma metastasis, malignant lympho- loads). Hypoaesthesia is not a typical symp- mas) or it can be a side effect of certain drugs tom. The serratus muscle becomes atrophic, like analgesics. In rheumatology, it may be which results in difficulty or inability to ele- disease associated mainly in systemic lupus vate the shoulder above the horizontal line. erythematosus and Felty’s syndrome. Treatment: Physiotherapy. Leukocytosis An increased number of leu- Lesions and ruptures of the humerus kocytes in peripheral blood. It is physiologi- rotator These are frequent after traumas cally present in newborns, during pregnancy, and micro-traumas, mainly in sportsmen but and after excessive physical activity. With also as a consequence of trophic changes to pathological conditions, it most frequently tendons, especially in the elderly. Painful arc accompanies infectious diseases, malignan- according to lesion localisation is typical. cies, certain intoxications, metabolic imbal- Subsequent atrophy of affected muscles is fre- ance (diabetes, uraemia, hepatic coma), or quent. traumas (burns, fractures, crush syndrome, surgical interventions). Leukocytosis can be Leukocytes Cells derived from mesenchy- present in polyarteritis nodosa, acute exacer- mal tissue. They are involved in the body’s bation of systemic lupus erythematosus, der- defensive mechanism. They are divided into matomyositis and in Still’s disease. lymphocytes (B-lymphocytes, T-lymphocytes and natural killer cells, NK cells, also called Leukopenia → see Leukocytopenia (leuko- L large granular lymphocytes, LGL), granulo- penia) cytes (neutrophils, eosinophils, basophils) and mononuclear phagocytes (blood mono- Leukotrienes (LT) Metabolites of arachi- cytes and tissue macrophages), which repre- donic acid formed by the action of the 5-li- sent the mononuclear phagocytic system. poxygenase enzyme. The most important

are LTB4, chemotactic factor for neutrophils,

Leukocyte granules The membrane-lim- monocytes, macrophages and LTC4, LTD4,

ited cell organelles found in the cytoplasm of LTE4 (previously called slow reacting sub- granulocytes, certain lymphocytes (LGL) and stance of anaphylaxis, SRS-A), which evoke mast cells. Some of them are typical lyso- increased vascular permeability and long somes. The granules contain hydrolytic en- term contraction of smooth muscles, mainly zymes, cytotoxic substances, certain recep- in the bronchus. They participate in the de- tors, diverse mediators and other substances. struction of joint cartilage. There are three types of granules in the neu- trophilic granulocytes – azurophilic, specific LFA-1 (lymphocyte function-associat- and small – that differ in their electron mi- ed antigen-1) Belongs to leukocyte integ- croscopic structure and biochemical compo- rins (CD11a/CD18). It is particularly impor- sition. tant during adhesive interactions of leukocytes with endothelial cells during inflammation Leukocytopenia (leukopenia) A re- and adhesive interactions of T-lymphocytes duced number of leukocytes in peripheral with antigen presenting cells during immune blood. May be inherited, may be present in and inflammatory responses. certain infectious diseases (influenza, atypi- cal pneumonia, infectious mononucleosis, LFA-3 LFA-3 or CD58 is the ligand for CD2, sepsis, miliary tuberculosis, toxoplasmosis, which is also known as LFA-2. It is a differen- malaria, typhoid fever) may be a symptom of tial mark of T-lymphocytes. LFA-3 is a mem- hypersplenism (liver cirrhosis, Felty’s syn- ber of the immunoglobulin superfamily. 123 looser zones

LGL (large granular lymphocytes) Large clasts. They modulate the activity of other granular lymphocytes are a subpopulation of systemic regulators. They are produced by peripheral lymphocytes with typical granules osteocytes, endothelial cells, blood cells, fi- within the cytoplasm. The granules contain broblasts and chondrocytes. They are repre- perforins and other cytotoxic substances. sented by growth factors, cytokines and pros- LGL possess NK-activity (also called NK taglandins. cells) and by induction of apoptosis are able Currently, very many local factors have to kill malignant cells and cells infected by been recognised. viruses. Localised Osteoporosis Besides genera- Licofelone (LCF) is the first lised osteoporosis, there are conditions asso- member of a new group of anti-inflamma- ciated with local bone mineral density loss. tory drugs. The drug inhibits three major en- Normally referred to as regional or localised zymes of the cascade of arachidonic acid – osteoporosis, it can be found after a fixation cyclooxygenase 1, cyclooxygenase 2 and li- and immobilisation of a limb, after poliomy- poxygenase. By inhibiting these three en- elitis, at insertions of tendon lesions, and in zymes, licofelone decreases the synthesis of the area surrounding inflamed joints in ac- prostaglandins and leukotrienes. LCF has got tive RA. The cause of localised osteoporosis a good safety profile in terms of gastrointesti- in an immobilised site is mainly due to a de- nal (GIT) side effects. In clinical trials involv- crease of afferent signalling from various re- ing 36 patients with osteoarthritis of the hip ceptors, the so-called decrease of a trophic or knee, LCF had better GIT tolerance when influence of the nervous system. The aetio- compared with (500 mg/day) even pathogenesis of periarticular osteoporosis in when a double dose of Licofelone (400 mg) rheumatoid arthritis is multifactorial and local L was administered. Symptom relief in patients factors play the key role. They directly regulate with knee osteoarthrosis, evaluated using the bone remodelling at the cellular level. They af- WOMAC system, was better with LCF than fect the differentiation of precursor cells, the the selective COX-2 inhibitor . Fur- activity of osteoblasts and osteoclasts and their ther work on the clinical role and licensing of numbers. They modulate the activity of other this drug is awaited. systemic regulators. They are represented by growth factors, cytokines and prostaglandins. Likert 5-degree scale → see Algometry Regional osteoporosis may develop due to (evaluation of pain threshold) inadequate osteoblast and num- bers in a certain region. The complete re- Limited cutaneous SSc (lcSSc) → see modelling cycle requires a sufficient and con- Systemic sclerosis (SSc) stant supply of precursor cells from the bone marrow. Limiting factors of rehabilitation • pain, Looser zones Poorly defined transparent • muscle contractures, zones on bone X-rays. They run vertically to • signs of inflammation, the bone surface and are caused by the aggre- • swelling, gation of non-mineralized osteoid. They occur • joint effusion, symmetrically or asymmetrically in stressed • psychological barrier (anxiety, depres- areas of the skeleton, most frequently in the sion). shoulders, tibia, fibula, metatarsal bones and ribs, less frequently in the radius and ulna. Local factors Bone remodelling is regulated They are not considered a fracture but may at a cellular level by local factors. They affect fracture at any moment. Looser zones are the differentiation of precursor cells, the ac- typical of osteomalacia and are its frequent tivity and numbers of osteoblasts and osteo- symptom. lower limb length 124

Lower limb length An important mea- scribed in Europe: B. valaisiana and B. lusita- surement in prosthetics and physiotherapy niae from which B. valaisiana is associated for measuring leg length discrepancy. Ana- with the development of erythema migrans. tomical – the distance between the greater Clinical picture: With LB this can be ex- trochanter and lower margin of the lateral tremely varied and multisystemic and the malleolus; functional – the distance from an- overlapping of symptoms are typical. It can terior iliac crest to the lower margin of the be differentiated into: medial malleolus; umbilico-malleolar – from • stage of early localised infection: with typi- the umbilicus to lower margin of the medial cal symptom of erythema migrans (as soli- malleolus. tary lesions, but multiple lesions may oc- cur) and systemic symptoms like fatigue, Lupus These are antibod- subfebrile body temperatures, headache, ies directed against β2-glycoprotein-1, pro- myalgia and arthralgia, thrombin, or annexin V and others. They are • stage of early disseminated infection: devel- detected by a prolongation of in vitro clotting ops 1 to 9 months after infection and may assays, usually the activated partial thrombo- be characterised by cardiac symptoms (ar- plastin time (APTT) is not corrected by 1:1 rhythmias, pericarditis, myocarditis), neu- dilution of patient’s plasma with normal plas- rological symptoms (meningitis, cranial ma. In vivo, however, there is a paradoxical neuritis, radiculoneuritis, possibly neuro- increase in arterial and venous thromboses. pathy), These IgG or IgM antibodies occur in pa- • stage of late infection or chronic stage: is tients with primary antiphospholipid anti- characterised by arthritis, neurological de- body syndrome, but also in SLE with an- fects (encephalopathy, axonal polyneuro- L tiphospholipid syndrome, in some patients pathy and leukoencephalitis), ophthalmic, with neoplasms or in patients with drug sen- muscle (myositis, myopathy), lympho-re- sitivity and occasionally in healthy individu- ticular and skin (acrodermatitis chronica als and patients with AIDS and active oppor- atrophicans) symptoms. tunistic infections. Lyme disease → see Lyme borreliosis (Lyme Lupus – drug induced → see Drug-In- disease) duced Lupus Lymphocytes Basic cells of lymphatic tis- Lyme borreliosis (LB, Lyme disease) A sue, lymph and blood. They are spheroidal multisystemic inflammatory disease caused with a diameter of 7–12 μm with a large cen- by spirochetes belonging to the Borrelia stem tral nucleus, surrounded by a narrow rim of (B. burgdoferi sensu stricto, B. garinii, B. af- cytoplasm. Larger lymphocytes possess more zelii). It is transmitted to humans after a bite cytoplasm, which does not usually contain from the Ixodes tick. Skin, neurological and any granules. However, large granular lym- joint symptoms are the most typical clinical phocytes (LGL) do have granules in their cy- symptoms. Clinical symptoms correlate with toplasm. According to their function, surface the occurrence of a particular genospecies antigens and ultrastructure, lymphocytes are and globally it is applicable that B. burgdoferi divided into three main population groups: B sensu stricto invokes joint defects, whereas B. lymphocytes (B cells), T lymphocytes (T garinii invokes neurological impairment and cells) and NK cells. The NK cells are usually B. afzelii skin diseases (particularly chronic identical with LGL. B lymphocytes are re- skin diseases). A disease similar to LB associ- sponsible for specific antibody immunity, T ated especially with skin symptoms and lymphocytes are responsible for specific cel- caused by a new borrelia species, B. lonestarii lular immunity and NK cells for non-specific species nova, has recently been described in cellular immunity (particularly against ma- the US. Two more genotypes have been de- lignant cells and cells infected by viruses). 125 lysozyme

Particular populations of lymphocytes can be where, during the initiation of immune re- distinguished according to their CD antigens. sponses, B and T lymphocytes react with an- A calm (metabolically “sleeping”) lympho- tigen presenting cells. cyte is activated by an antigen or mitogen and becomes a metabolically activated lympho- Lymphomatoid granulomatosis (LG) blast, which in association with cytokines is A rare multi-systemic disease from the group then subject to division and differentiation, of vasculitides which is characterised by focal whereby memory and efficient lymphocytes, and transmural infiltration of the vascular which are involved in immune responses, de- wall by lymphocytes, plasma cells and histio- velop. cytes. Clinical symptoms: Dependent on the se- Lymphocytes – circulation The move- verity of organ impairment. Most frequent ment of lymphocytes in the body takes place are pulmonary symptoms (cough, dyspnoea, between the blood and lymphatic system, ) and skin rashes (erythema, indu- lymph nodes, spleen and tissues. Less than ration). Fever, malaise and weight loss are 10% of the total volume of lymphocytes is non-specific symptoms. constantly circulating, while the rest are de- posited in tissues and organs. Approximately Lymphotoxin (LT) One of the tumour ne- 70% of circulating lymphocytes have the ca- crotizing factors (TNF-β). It is produced pability to re-circulate, i.e. they move in a cer- mainly by TH1 lymphocytes after antigen or tain cycle during which they leave the sys- mitogen stimulation. LT inhibits the growth temic circulation and return back to lymph of tumours both in vivo and in vitro and nodes, lymphoid follicles and the spleen, blocks tumour transformation of cells in- from where the cycle may recommence. voked by carcinogens. LT is also involved in L These cells are mostly long-life mature T lym- protection against viral and saprophytic in- phocytes, but also memory B lymphocytes. fections. It was one of the first lymphokines Approximately 30% of lymphocytes in the to be detected and currently is considered to vascular space are not subject to re-circula- be a member of the cytotoxin group. tion. These are mostly short-lived immature T and B cells that terminate their life in ves- Lysosomes They are organelles localised in sels, or can be activated and then leave the the cytoplasm of all cells that contain a nucle- vascular space. The re-circulation enables us. They are notably abundant in the cyto- lymphocytes to perform immune surveil- plasm of professional phagocytes (phagolyso- lance throughout all of the body, mobilise some). Typically they contain hydrolytic themselves to localities where immune pro- (lysosomal) enzymes. Lysosomes of phago- tection is needed and also reactivate non- cytes contain different antimicrobial sub- functional cells. stances, typical neutral proteases and compo- nents of certain receptors (granules of leuko- Lymphoid organs Organs in which lym- cytes). Antibodies against lysosomal enzymes phocytes prevail but other cells are also pres- of leukocytes may be produced (ANCA). ent. They are divided into primary and sec- These antibodies are associated with certain ondary lymphoid organs. The thymus and vasculitides and other autoimmune diseases. bone marrow, which is considered to be the equivalent of the bursa of Fabricius in birds, Lysozyme An enzyme that lyses the β-1,4- are amongst the primary lymphoid organs. B glycosidic linkage of polysaccharides. The lymphocytes (bone marrow) or T lympho- older name of this enzyme was muramidase. cytes (thymus) mature in primary lymphoid It occurs in egg white, tears, saliva, nasal se- organs. Secondary lymphoid organs comprise cretions, skin, specific granules of leukocytes lymph nodes, the spleen, lymphoid tissue in and in serum. Lysozyme is able to lyse cell mucosa, and tonsils. These are the places membrane glycoproteins of certain gram- lysozyme 126

positive (mostly non-pathogenic) bacteria interaction of other antimicrobial factors and thereby cause their osmotic lysis. It can (complement, secretory IgA, leukocyte’s pro- only destroy other micro-organisms with the teases etc.).

L M

Mab → see Monoclonal antibodies (Mab) the presence of antibodies they can kill cells that have their specific antigens on their sur- Macrophages Large, mostly single nucleus face. This is possible due to the presence of Fc- cells of 16–22 μm in diameter. They are usu- receptors (FcR). The antibody binds through ally formed from blood monocytes after their the Fc-component of its molecule to FcR on deposition in different tissues. Some of the the surface of the macrophage and to the normal macrophages deposited in certain or- binding site on the antigen determinant on gans, such as the lungs, can also directly un- the surface of the target cell. Such contact of dergo division. They are a component part of two cells leads to the killing of the target cell the mononuclear phagocytic system (MPS) by the mechanism of antibody-dependant and belong to the group of professional cellular cytotoxicity (ADCC). phagocytes constituting the basic component Apart from immune system functions, of natural (non-specific) immunity against macrophages are involved in certain meta- pathogenic microorganisms (phagocytosis). bolic reactions, e.g. cholesterol metabolism, They represent a heterogeneous population metabolism of vitamin D and arachidonic of cells in the human body and differ from acid. They are also important secretory cells. each other in terms of development, func- They release various antimicrobial and cyto- tional activity, anatomical localisation and toxic substances, bioactive lipids, complement biological function. They can be divided into components, certain factors of haemocoagula- normal and inflammatory cells. Macrophages tion, cytokines, proteolytic and other enzymes, of tissue (histiocytes), the liver (Kupffer’s as well as inhibitors of enzymes, stress proteins cells), lungs (alveolar macrophages), serum and factors involved in tissue reorganisation. fluid (pleural and peritoneal macrophages), They thereby significantly interfere with vari- skin (histiocytes, Langerhans’ cells) and other ous physiological and pathophysiological tissues belong to the group of normal mac- processes in the body. rophages. Inflammatory macrophages occur in inflammatory exudates where they have Magnesium (Mg) The fourth commonest important effector (cell-killing, matrix de- cation in the human body and the second stroying) and regulatory (matrix regenerat- commonest intracellular cation. Magnesium ing) functions. They originate almost exclu- is essential for the function of approximately sively from blood monocytes. 300 enzyme systems, transcription of deoxy- From a functional aspect, macrophages oc- ribonucleic acid and proteosynthesis, and is a cur in the three stages: silent (non-reactive), natural antagonist of the calcium channels as pre-activated and activated. Activation is due well as being essential for bone mineralisa- to cytokines (MAF, MIF, interferon-gamma) tion. or due to some components of micro-organ- isms. In terms of function, only activated Magnetic Resonance Imaging MRI is a macrophages are fully competent, these being medical imaging technique based on the ef- of principal importance in natural immunity fect that hydrogen protons in tissues exposed against intracellular parasites and malignant to an external magnetic field produce a rotat- cells. Apart from antimicrobial and tumoro- ing magnetic field (so called spin) detectable cidal effect, macrophages act in the early by the scanner. Externally, tissues show differ- phase of the specific immune response as an- ent sizes of magnetic torque, the vector of tigen presenting cells and as K cells, where in which is oriented identically with the vector magnetic therapy 128

of the magnetic field. To measure this mag- the contrast. Saturation of synovial fluid is netic torque, it must be diverted by magnetic slower. In clinical practice, Gd-DTPA (gado- impulse, the energy of which is absorbed by linium chelate with diethylenetriaminepen- protons and a resonance can be detected. taacetic acid also called gadopentate dime- Thereby the longitudinal tissue resonance de- glumine) is used as the contrast substance. It creases and transverse tissue resonance in- is a paramagnetic substance which by short- creases. When the electrical impulse is dis- ening the T1 in T1 measured images gives a continued, relaxation occurs (T1 longitudinal stronger signal from the tissues to which it relaxation time, T2 transverse relaxation penetrates. time). Imaging of tissues is based on the dif- MRI is of major importance in the diag- ference of these times in tissues and assigned nostics of impairment as- intensity of grey (black/white scale). It does sociated with rheumatic diseases, particularly not use a noxious ionizing radiation for im- cervical spine impairment in rheumatoid ar- aging. thritis. In atlantoaxial subluxation, not only is Magnetic resonance imaging in rheuma- pannus invading the ligamentous apparatus tology enables excellent imaging of soft tis- of this segment captured, but possible ero- sues like cartilage, synovial tissue, ligaments, sions of the dens of the axis, compression of and tendons along with bone structure imag- spinal canal and the level of myelopathy can ing. The picture can be obtained in different be identified. planes and sections. This is the advantage of MRI over standard X-ray and CT (computed Magnetic therapy Utilisation of magnetic tomography). MRI compared to X-ray is fields for therapeutic purposes. There are more sensitive in terms of capturing early three types of magnetic field: changes in the inflammatory arthropathies; it 1. static magnetic field Occurs around per- is also able to capture defects of the cartilage manent magnets or conductors and coils M and bone that are not visible on X-ray pic- through which direct current flows. The tures. MRI enables better monitoring of tis- magnetic field is constant. sue response to treatment than standard radio- 2. alternating magnetic field Occurs around graphy and is free of radiation. conductors and coils supplied by alternat- For musculoskeletal system imaging by ing electrical current. Its parameters MRI, the T-1 spin echo (SE) sequences are change smoothly in form of a curve from usually used due to their relatively short im- a zero value to a maximum value, back to aging time and the well detailed anatomic zero and onwards to minimum value etc. picture they provide. T2 SE sequences make 3. pulsatile magnetic field Occurs around it possible to view processes with higher wa- conductors and coils supplied by pulsatile ter content but their disadvantage is the lon- electrical current. It is similar to alternat- ger imaging time. Newer modern sequences ing magnetic field, forming a curve from that shorten the imaging time are now em- zero to maximum, back to zero and to ployed like gradient echo sequence and turbo minimum, but in jumps. spin (fat suppression); they provide more sig- The intensity of the magnetic field is directly nificant contrast between synovia and the proportionate to the flowing electrical cur- surrounding tissues on post-contrast scans. rent and indirectly proportionate to the dis- It is important to image synovial prolifera- tance from the conductor (in metres). The tion and fluid that occur long before destruc- intensity of the magnetic field is measured in tive bone changes and develop in the early ampere/metre (A/m). The unit is defined as stage of rheumatoid arthritis. Inflamed syn- the intensity of the magnetic field at a dis- ovia and pannus absorb the contrast after IV tance of r’ = 1/2 π (m) from the conductor injection. Enhancement of proliferated syn- through which electrical current of 1 ampere ovia is rapid, with the maximum reached flows. The unit of magnetic field induction is within 0.5 to 1.5 minutes after IV injection of 1 T (tesla). 129 markers of osteoresorption

Therapeutic utilisation of magnetic fields defect is localised on chromosome 15 result- results from its physiological effect on the ing in impairment of collagen and glycopro- body. It particularly possesses analgesic, anti- tein synthesis. In the clinical picture, affected inflammatory and anti-oedematous proper- individuals are tall and very slim with thin ties and also induces myorelaxation and va- extremities (dolichostenomely) and typical sodilatation. The least efficient is a static prolonged lower part of the body and fingers magnetic field, with a stronger effect pro- (arachnodactyly). Hyperextensibility of the duced by an alternating magnetic field and fingers and high arched palate are typical. the strongest effect by a pulsatile magnetic Pectus excavatum or pectus carinatum may field. A static magnetic field activates exclu- be present. Component parts of the clinical sively the vagus nerve, while alternating and picture include ophthalmic and cardiovascu- pulsatile magnetic fields also partially activate lar complications. Ophthalmic complications the sympathetic nervous system. Importantly, include lens ectopy, myopia and iris vibra- metal implants are not a contraindication for tion. Cardiovascular complications include this treatment. Recently the TAMMEF system dilatation of the aorta and aortal valve insuf- (therapeutic application of a musically modu- ficiency, as well as mitral valve prolapse, dis- lated electromagnetic field) has been em- section of the aorta, pulmonary artery dilata- ployed. The electromagnetic field reacts to tion, arrhythmias and even heart failure. Ge- musical impulses in a pulsatile way. netic counselling is important as there is a 50% risk of inheritance of the disease to any Major histocompatibility complex offspring and pregnancy in patients with (MHC) One of many histocompatibility sys- Marfan’s syndrome is a high risk due to car- tems, it holds a dominant position among the diac complications. given animal species. It is a system of genes whose products are strong transplant anti- Markers of osteoformation Biosynthesis gens. Typical features of MHC are its com- of bone takes place in two steps. The first is M plexity and polymorphism, the ability of its mediated by osteoblasts and consists of the molecules to regulate the immune response intracellular synthesis of precursors of the and induce a reaction in mixed lymphocyte bone matrix components (type I collagen, os- cultures (MLC), with membership of the im- teocalcin, sialoproteins, proteoglycans, and al- munoglobulin superfamily and responsibility kaline phosphatase). These are secreted into for the immunochemical uniqueness of every the extracellular space where composition of individual in the population. The human collagen fibrils and organisation of collagen MHC is referred to as the HLA complex. and associated molecules into a lamellar os- teoid occurs. In this phase, mature interfibril- Mantoux test (Charles Mantoux, French lar bonds (crosslinks) are then formed extra- physician, 1877–1947) cellularly. This so-called maturation phase of A test in which 0.1 ml of tuberculin (1 in bone matrix formation will have been con- 1,000 strength) is injected intradermally and cluded in the course of 5–10 days before the the reaction is read at 72 hours. A positive re- course of the second phase (mineralisation) action (induration >10 mm in diameter) in- of bone growth. Some of them, especially dicates delayed sensitivity (immunopatholo- serum osteocalcin and alkaline phosphatase, gy) to Mycobacterium tuberculosis, indicating are used practically for the evaluation of os- that an individual has previously been ex- teoformation following treatment of osteopo- posed to this microbe or is now infected. rosis or Paget’s disease.

Marfan’s syndrome (Antoine Marfan, Markers of osteoresorption The process French paediatrician, 1858–1942) of bone resorption is mediated by osteoclasts An autosomal dominant disorder affecting that dissolve the mineral component and the bones and connective tissue. The genetic break down the bone matrix. This leads to the Maroteaux-Lamy disease 130

release of calcium, phosphate, a number of gen, binds to these receptors. During the sec- enzymes and degradation products of the ond or subsequent contact, the allergen can matrix, which can then be measured in the bypass the IgE molecules and directly bind to blood or urine with variable bone specificity. mast cells, causing degranulation with release However, the most popularly used are several of histamine and other mediators of anaphy- degradation products of collagen such as se- laxis. These mediators can also be released by rum or urinary excretion of N-telopeptide anti-IgE antibodies, and anaphylatoxins C3 (NTX) or carboxy-terminal collagen cross- and C5a for which there are specific receptors links (CTX). These are helpful in monitoring on the surface of mast cells. the effectiveness of anti-resorptive treatment in osteoporosis, where a fall of greater than M-cells (microfold cells) Specialised cells of 40% in urinary NTX excretion or serum CTX the intestinal epithelium. They transport mi- at six months of treatment compared to base- croorganisms and macromolecular compo- line correlates with subsequent improvement nents of food from the intestinal lumen to in measured BMD. Peyer’s patches (aggregations of lymphoid tis- sue) where they present these components to Maroteaux-Lamy disease → see Muco- antigen-presenting cells found on the baso- polysaccharidosis (MPS) lateral side. M-cells have a filtering function for the presentation of intra-intestinal anti- Massage We distinguish the following types gens and thereby are involved in the regula- of massage: tion of immune response induction at the • hand massage (standard massage, reflex level of mucosal immunity. massage, sports massage, cosmetic mas- sage), McCune-Albright syndrome (polyostot- • apparatus-assisted massage (massage un- ic fibrous dysplasia) A complex of polyostotic M der water, vibratory massage, vacuum mas- (rarely also monoostotic) fibrous dysplasia, sage, syncardial massage). Massage of the pigmented skin macules of “café au lait” type internal organs (vagina, prostate, soft pal- and overactivity of one or more endocrine ate and cardiac massage) also belongs to glands constitute the McCune-Albright syn- this type of massage. drome (Donovan James McCune, American The aim of the massage is to positively influ- paediatrician, 1902–1976, and Fuller Al- ence the general condition, problems and bright, American physician, 1900–1969). In a changes due to disease, trauma or excessive typical case, the endocrinopathy is represent- physical effort. The general effect of massage ed by precocious puberty but can also include is in the influence on the autonomic nervous acromegaly, thyrotoxicosis, Cushing syn- system, circulation, local influence on the drome, hyperprolactinaemia, or hyperpara- skin, muscles, extra-articular structures, thyroidism. The loss of phosphate may then blood and lymphatic system. result in hypophosphataemic disease remi- niscent of oncologic rickets, but unlike it, the Mast Cells A heterogeneous population of disease is caused by inhibition of phosphate cells varying in shape and size (diameter 10– transport by intestinal mucosa cells, not by 30 μm) and containing numerous character- the renal tubules. Endocrine hyperfunction is istic electron-microscopic dense granules in basically caused by overactivity of the target their cytoplasm. They occur predominantly organ. An aromatase inhibitor and testoster- in connective tissue, mucosa, skin and around one were used to suppress early puberty in vessels. They have high affinity receptors for females; treatment with medroxyprogester- the Fc domains of IgE that result in their in- one has also been reported. Calcitriol and volvement in early type allergic reactions (IgE phosphate supplementation in associated hy- mediated). Specific IgE, arising after the first pophosphataemic bone disease may eventu- contact of the individual with a certain aller- ally improve the X-ray picture of rickets, but 131 methotrexate it is not routine practice. Administration of inhibitor of the enzyme dihydrofolate re- pamidronate in McCune-Albright syndrome ductase (DHFR) leading to reduced produc- improved clinical symptoms, particularly tion of tetrahydrofolate. Its mode of action in pain and associated gait disturbance. rheumatoid arthritis and other autoimmune diseases remains unclear. McMaster Toronto arthritis patient Pharmacokinetics: Methotrexate is usual- preference disability index (MACTAR) ly well absorbed after oral administration. → see Instruments of assessing (health status Major differences have been found with re- measurements, outcome measurement) gard to biological availability after oral ad- ministration, 33% (range 13–76%) of MTX in MCTD → see Mixed connective tissue disease particular patients when compared with in- (MCTD) travenous administration. Differences in an individual patient on repeated testing were Mechanical therapy Utilisation of me- considerably smaller. The biological avail- chanical instruments and appliances for ability after intramuscular injection is better medical treatment. These include certain ac- (76%) and more consistent. Therefore, better tive and passive body movements or parts of long-term clinical results are achieved by par- the body with traction, extension, massage, enteral administration, though disadvantages stationary bicycle, walking machine etc. include higher costs and inconvenience to the patient. Nowadays subcutaneous is the Melsack’s questionnaire → see Algome- application of choice. In active cases with an try (evaluation of pain threshold) induction phase, intravenous administration may also be preferable. Absorption is rapid, Membrane immunoglobulin The mole- with maximum concentration achieved in an cule of immunoglobulin whose C-ends of average of 83 minutes, serum elimination heavy chains are prolonged by a hydrophobic half-life is 6 to 7 hours. MTX is metabolized M tail consisting of 20 amino-acid units. There- predominantly in the liver, 30 to 80% is elim- by the molecule is embodied in the cytoplas- inated via the kidney and 3 to 23% via bile. mic membrane of B lymphocytes, where it Administration becomes a component of the B cell antigen The initial oral dose varies between 10– receptor complex (Ig-α/Ig-β antigen recep- 15 mg weekly, often given at once or spread tor). Particularly IgD and IgM monomers over 24 hours in divided doses. Folic acid possess this attribute. (5 mg daily) is given on the other days to re- duce toxicity either 5 mg once weekly or 1 mg Mesna → see Cyclophosphamide daily. Dosage escalation of MTX can occur at 2 to 6 weekly intervals to a maximum of 25 to Methotrexate As a medical agent, metho- 30 mg weekly. Subcutaneous MTX is often trexate was first described in 1946 and then given in a similar regime. Blood count and administered in children with leukaemia in liver function should be monitored one 1948. It was first successfully used in rheuma- month after initiation, but then every three toid arthritis (RA) and psoriatic arthritis months when on a stable regime. (PsA) in 1951, but the FDA only approved Clinical efficacy: A large number of clini- MTX for PsA treatment in 1971 and for RA cal trials over the last 15 years have confirmed treatment even later in 1988. However, the methotrexate as one of the most effective eighties was a period of increased concerns DMARDs for RA. Considering efficiency over MTX, which resulted in a large number versus toxicity, methotrexate is now preferred of publications. to oral or parenteral gold, sulfasalazine, aza- Mechanisms of action Methotrexate is a thioprine and cyclosporin. It has been shown typical antimetabolite. After entry into target to retard the radiological progression of bone cells, it acts as a competitive and reversible erosions. methotrexate as a component of dmardsDMARDs combination treatment (disease-modifying anti-rheumatic13232 drugs)1

Adverse effects of methotrexate treatment combined with anti TNF therapy (infliximab, in autoimmune disease: entanercept or adalimumab), rituximab and • gastrointestinal: nausea, dyspepsia, stoma- abatacept. titis, mouth ulceration Clinical efficacy: A large number of clini- • bone marrow depression: leukopenia, cal trials over the last 15 years have confirmed thrombocytopenia, aplastic anaemia, pan- methotrexate as one of the most effective cytopenia, DMARDs for RA. It has been shown to re- • liver impairment: hepatosplenomegaly, tard the radiological progression of bone ero- liver fibrosis, liver cirrhosis, sions. • lung impairment: acute interstitial pneu- Contra-indication: monitis, interstitial lung fibrosis, dry/exu- • pregnancy: methotrexate is highly terato- dative pleuritis, lung oedema, pulmonary genic so should not be administered for at nodules, least three months before conceiving and • infections and malignancies: cell immunity during pregnancy. defects, non-specific and specific infec- • interactions: avoid trimethoprim and tions. trimethoprim including antibiotics as in- creased risk of severe toxicity (bone mar- Methotrexate as a component of row aplasia, desquamation of oesophagus) DMARDs combination treatment (dis- ease-modifying anti-rheumatic drugs) Methylprednisolone → see Glucocorti- Methotrexate (MTX) theoretically has good coids, Intraarticular glucocorticoid treat- eligibility to become a suitable component of ment combination treatment of rheumatoid arthritis (RA). It has rapid onset of action, acceptable Metric measurement of vertebral col- long-term toxicity and presumably a different umn in spondyloarthritis (SpA) M mechanism of action than other immunomod- Schober’s test: From the junction of both ulating drugs. The treatment combination of posterior superior iliac spines, measure 10 MTX, sulfasalazine and hydroxychloroquine cm cranially and mark both points. During (O’Dell regime) is more effective than a combi- the maximum forward flexion to touch the nation of only sulfasalazine + hydroxychloro- toes, both points move more than 13 cm apart quine or MTX monotherapy. Other combina- (3 to 5 cm movement). This distance is re- tions include MTX and cyclosporin. The trial duced in patients with limited flexion of the showed that, compared to a control group of lumbar spine (Paul Schober, German physi- MTX monotherapy (32% of patients), better cian, 1865–1943). disease control occurred in patients receiving Schober’s test modified: From the anal cleft, combination treatment. Another study com- measure 15 cm up the spine and mark each pared combination treatment with MTX, sul- point. During the maximum forward flexion fasalazine and a high dose of prednisolone to touch the toes, both points move more (60 mg a day) with sequential reduction, than 20 cm apart (>5 cm movement). against classic sulfasalazine monotherapy. Ott’s sign: Mark the spinal process of C7 Again, this combination treatment produced and then another point 30 cm caudally. The better disease control than monotherapy. A distance between both points increases at lower radiological disease progression was least by 3 to 4 cm during maximum forward achieved and this effect persisted even one flexion (Viktor Rudolf Ott, German physi- year after termination of treatment. However, cian, 1914–1986). sulfasalazine monotherapy did not retain a Rotation of cervical spine: Using a tape beneficial clinical effect after withdrawal of measure note the distance from the spinal MTX and prednisolone. Recently, in order to process of C7 to the centre of the jaw. Then suppress very severe RA activity (clinical and ask the examined individual to rotate the radiological), MTX has been successfully head towards the measured side. The differ- 133 mixed connective tissue disease (MCTD) ence between the central position and maxi- regular (annual) monitoring of their immu- mum rotation should be 8 to 10 cms. This is noglobulins as a small number will progress markedly reduced in the elderly. Measure the to myeloma with time. opposite side in the same way. Rotation of thorax and lumbar spine: With MHC → see Major histocompatibility com- the individual in the standing position, mark plex (MHC) the spinal process of L5 and the point on the jugular notch. Ask the patient to rotate to- Microfold cells → see M-cells (microfold wards the opposite side. The range of move- cells) ment should be 8 cm. Measure the opposite side in the same way. Microscopic polyangiitis Necrotising Rotation of lumbar area: Marks are made at vasculitis that affects small vessels in the kid- the level of L5 and the xiphoid process. The neys, skin and lungs. p-ANCA (MPO-AN- examined individual rotates maximally and CA) is present in 70% on laboratory testing. the distance between both marks is measured. The most severe organ involvement is kidney, The distance during rotation to the opposite leading to impairment with microscopic hae- side is measured in the same way. maturia and mild proteinuria. Lung involve- Finger floor distance: The distance between ment is less common than in Wegener’s the fingers and the floor during maximum granulomatosis. High dose glucocorticoids forward bend is measured with the knees (up to 60 mg per day) and cyclophosphamide straight. This is a good measure of overall are used in treatment, often in pulse intrave- progress of ankylosing spondylitis. nous form. Measurement of bend to side (lateral devia- tion): The examined individual stands with Microscopic polyarteritis → see Micro- their legs together, arms by their sides, and scopic polyangiitis, Polyarteritis nodosa slides their hands along the lateral side of the (PAN) M thigh. Normally the movement on the thigh is 20 cm. Care must be taken in performing Migration Tight adhesion of leukocytes to the test that subjects don’t leave the frontal vascular endothelium (inflammation). plane by bending forward or backward. Chest expansion: Measurement of the dis- Mixed connective tissue disease tance between complete exhalation and com- (MCTD) An overlap syndrome characterised plete inspiration. The normal range in healthy by the presence of symptoms of systemic lu- individuals is >5 cm. pus erythematosus (SLE), systemic sclerosis Special tests of Bath Ankylosing Spondyli- (SSc) and polymyositis (PM). It was first de- tis and Dougados functional index provide a scribed by Sharp in 1972. The presence of complex functional evaluation. Raynaud’s phenomenon, diffuse ‘sausage-like’ swelling of the fingers and high titre autoan- MGUS (monoclonal gammopathy of tibodies against small nuclear ribonucleopro- unknown significance) Monoclonal gam- tein, which is sensitive to ribonuclease, re- mopathies often do not manifest themselves ferred to as U1RNP, are typical for the syn- clinically (often discovered incidentally on drome. U1RNP is a polypeptide complex with blood tests including serum protein electro- molecular weight of 68 kDa. High titre of an- phoresis). MGUS does not have direct ag- ti-U1RNP autoantibodies is a permanent gressive potential, does not require treatment finding in certain patients; sometimes these but is supposed potentially to progress to antibodies disappear with time. multiple myeloma or other blood malignan- Clinical symptoms: Various clinical symp- cies. The portion of actively proliferating toms are present in MCTD. Scleroderma, dif- plasma cells can be determined by analysing fuse swelling of the fingers, arthritis, myosi- bone marrow. Patients with MGUS will need tis, leukopenia, serositis, interstitial pneumo- MLC (mixed-lymphocyte culture) 134

nia, are among the most frequent symptoms. with in vivo diagnosis of malignancies (ra- Clinically MCTD suggests PM, SLE, rheuma- dioimmunoscintigraphy) and treatment us- toid arthritis and SSc in the early oedematous ing immunotoxins are being carried out. phase. Humanised monoclonal antibodies are now most commonly used. Biologic agents based MLC (mixed-lymphocyte culture) A on Mabs include these three letters mab in test prepared by mixing lymphocytes isolated their generic name like infliximab, adali- from two different individuals whereby one mumab, certolizumab, golilumab or ritux- of them is usually the potential donor and the imab. other one is the potential recipient of a trans- plant. As the two individuals (except mono- Monoclonal gammopathy of un- zygotic twins) are not genetically identical, known significance → see MGUS (mono- different histocompatibility antigens on the clonal gammopathy of unknown signifi- surface of donor lymphocytes will activate cance) the recipient lymphocytes and vice versa. The result is activation of DNA synthesis (the Monocyte Large cell (diameter 16 to 22 measurement is based on incorporation of μm) with kidney-shaped nucleus and an tritium labelled thymidine) and the prolifera- abundance of organelles in their cytoplasm tion of lymphocytes. This is called mixed- (lysosomes, mitochondria and pinocyte vac- lymphocyte reaction (MLR). The test is im- uoles). Monocytes are present in peripheral portant for determining histocompatibility blood (2 to 10% of leukocytes in humans). between donor and recipient in the trans- After migration into tissues, they transform plantation of bone marrow and organs. into tissue macrophages. Macrophages are part of the mononuclear phagocyte system MLC Test Mixed-lymphocyte culture test. (MPS) and belong to professional phago- M cytes. Monoclonal antibodies (Mab) Identical copies of immunoglobulin molecules that are Monokines Cytokines that are produced of the same primary structure, identical spec- mainly by mononuclear phagocytes – mac- ificity of binding sites and identical functions rophages and monocytes. Typical representa- as they are products of one particular clone of tives are IL-1 and TNF-α. plasma cells. Monoclonal antibody concen- trations rise spontaneously during malignant Mononuclear phagocyte system Con- growth of plasma cells, or of their precursors sists of blood monocytes, tissue macrophages (gammopathy) or artificially in laboratory and their precursor cells in bone marrow. conditions by hybridoma technology. Mono- Their common property is active phagocyto- clonal antibodies are specific against a par- sis, pinocytosis and the ability to adhere to ticular determinant (epitope) of a certain an- various surfaces. On their surface, monocytes tigen. The properties of monoclonal antibod- and macrophages possess receptors for the Fc ies do not essentially differ from conventional domains of immunoglobulins and for the antibodies. However, they possess certain im- C3b fragment of complement. This enables portant advantages. Mabs are chemically them to perform very effective phagocytosis. identical which is why they are monospecific They express class II MHC (major histocom- and effective. It is possible to produce Mabs patibility complex) antigens on their surface, in unlimited quantities, even when using im- enabling them to perform the function of an- pure antigens. They are used predominantly tigen presenting cells. The term MPS (mono- in analytic and isolating immunochemical nuclear phagocyte system) has recently been laboratory methods, and in the differential substituted by the previously used term “re- diagnosis of viral, bacterial and parasitic in- ticuloendothelial system” (RES). fectious diseases. Trials of their utilisation 135 mucopolysaccharidosismucopolysaccharidosis type type IS is (Scheie’s(scheie’s disease)

Morquio-Brailsford’s disease → see Mu- polysaccharides) leading to lysosomal storage copolysaccharidosis (MPS) diseases. MPS typically leads to multiple or- gan impairment with a variable clinical pic- Morton’s metatarsalgia → see Tunnel ture. Most are inherited as autosomal reces- syndromes of foot sive, except Hunter’s disease which is an X- linked recessive. MOS-SF – medical outcome study – short form 36 → see Instruments of assess- Mucopolysaccharidosis Type IH (Hurl- ing (health status measurements, outcome er’s disease) This is the most typical and measurement) most frequent form of MPS. The incidence of the syndrome is estimated at 1:100,000 new- Movement Passive movement is a move- borns. The lysosomal enzyme deficiency is l- ment in which the patient does not actively iduronidase. The disease can manifest itself participate. However, even passive movement biochemically as early as at birth, with clini- is basically active muscle exercise as the cal symptoms developing in the second year change of muscle length and the realisation of of life. Typical features are growth retarda- the motion activates a sensitive component of tion, facial dysmorphism with wide flat nose, motion regulation. It is used for maintaining , thick lips, macroglossia and the range of motion (ROM), stimulating pro- macrocephaly. Gradually, articular contrac- prioceptive signalisation from propriorecep- tures of fingers cause claw hands. The clinical tors (muscle spindle, muscle and ligament picture also includes corneal opacities, skin proprioreceptors), improving the circulation. defects (dry skin, acanthosis, and hirsutism) It helps to prevent muscle atrophy and the de- and cardiovascular symptoms. A protuberant velopment of contractures. abdomen due to hepatosplenomegaly is often Active movement is performed by a patient a significant sign. Although early mental de- using his own strength. If the physiotherapist velopment can be normal, later signs of men- M assists or the movement is performed with- tal retardation appear. The prognosis is ex- out gravity, it is referred to as active assisted tremely severe, as the disease leads in most movement. If resistance is applied to the cases to death in childhood. The disease has a movement, it is referred to as resisted move- typical X-ray picture with progressive chang- ment; if maximal resistance is applied, it is es of bone structures such as multiple dysos- referred to as absolute resisted movement. tosis imaging as skull coarsening, extended Isokinetic (machine) movement is performed ribs and clavicles, coarser shoulder blades, at a constant speed and resistance in the ovoid and partly hook-shaped vertebral bod- whole range. ies, dysplasia of bones. Phalangeal and metacarpal bones are widened and short- M-protein Can have two meanings: ened, the pointed proximal ends of the meta- • complete or incomplete molecule of mono- carpal bones have a characteristic ‘sugar loaf’ clonal immunoglobulin which is produced appearance (Gertrud Hurler, German paedi- in multiple myeloma, atrician, 1889–1965). • type specific surface antigens of group A beta-hemolytic streptococci. Mucopolysaccharidosis Type IS (Scheie’s disease) This disease has a slow- Mucocutaneous lymph node syn- er progression though the clinical symptoms drome → see Kawasaki disease (KD) develop in childhood. Articular stiffness, claw hands and corneal opacities are the prin- Mucopolysaccharidosis (MPS) A com- cipal symptoms of the disease. The lysosomal plex of diseases whose common attribute is enzyme deficiency is the same as Hurler’s dis- an inherited lysosomal defect for deficient ease (Harold Glendon Scheie, American oph- degradation of glycosaminoglycans (muco- thalmologist, 1909–1990). mucopolysaccharidosis type iiII (hunter’s(Hunter’s disease) 136

Mucopolysaccharidosis Type II (Hunt- whose manifestation includes skin, mucosal er’s disease) Hunter’s disease only affects and synovial nodular lesions, potentially de- males, as it is X-linked recessive. Clinical and structive symmetric polyarthritis, with a ten- radiological symptoms are similar to type IH dency towards multiple organ impairment. but the disease has a milder course and slow- Histopathologically, it is characterised by typi- er progression. Corneal opacity is not pres- cal infiltrations of large multinucleated giant ent. The lysosomal enzyme deficiency is cells and lipid-laden histiocytes in skin and iduronate-2-sulphatase (Charles A. Hunter, synovia. Large cells may be of asymmetric Scottish-Canadian physician, 1873–1955). shape and 50 to 100 μm in size on average and may contain up to 20 nuclei. Mucopolysaccharidosis Type III (San- Clinical symptoms: Arthritic changes are filippo’s disease) The facial and skeletal the initial features of the disease in 2/3 of symptoms are less distinct, but the mental cases. Eruption of skin nodules occurs within and motor deterioration are particularly se- several months to years (3 years on average). vere. Several lysosomal enzyme deficiencies They can occur as the first sign in 18 to 20% have been described (Sylvester Sanfilippo, of cases. In other cases, skin nodules may de- American pediatrician). velop simultaneously with arthritis. Systemic symptoms such as intermittent fever, fatigue, Mucopolysaccharidosis Type IV tiredness, nausea, or weight loss may occur in (Morquio-Brailsford’s disease syn- the course of the disease. In some patients, drome) Characterised by severe dwarfism the disease has a tendency towards spontane- with short trunk, pectus carinatum, kyphosco- ous remission of active inflammation after liosis (gibbus) and coxa valga, but with normal several years. However, the disease leads to a mental function. Radiological changes are mutilating form of arthritis in 12 to 45% of similar to type I with changes in the areas of cases. Treatment can vary from NSAIDs, ste- M the epiphyses and universal platyspondyly roids, and alkylating agents. are more distinct. Compression of the spinal cord due to atlantoaxial dislocation can occur Multiple myeloma → see Plasmocytoma (needs surgical intervention). Progression of and its musculoskeletal symptoms (MM; hearing impairment may lead to complete multiple myeloma) deafness. Aortal valve insufficiency is a fre- quent finding. At least two lysosomal enzyme Muscle activation The property of muscle deficiencies have been described. fibres – shortening of the fibres during mus- cle contraction. Muscle activation can be di- Mucopolysaccharidosis Type VI (Mar- vided into following types: oteaux-Lamy disease) Characterised by • Isotonic – muscle contraction leading to normal intellect and skeletal symptoms which movement are the same as in type IH, but progression is • Isometric – muscle contraction without slower. Growth retardation develops at the movement age of 2 to 3 years old. The disease is often • Isokinetic – the muscle performs a move- accompanied by corneal opacity. The lyso- ment of a certain force balanced with equal somal enzyme deficiency is arylsulphatase B. resistance.

Mucopolysaccharidosis Type VII (Sly’s Muscle atrophy A decrease in the volume disease) Very rare, the picture is similar to of muscles due to various reasons (denerva- Hurler’s disease. The lysosomal enzyme defi- tion, inactivity). This results in the muscle ciency is β-glucuronidase. becoming weaker, as strength is related to muscle mass. Multicentric reticulohistiocytosis A rare systemic disease of unknown aetiology 137 muscles

Muscle contracture A pathological condi- Grade 4: the active movement is performed tion characterised by muscle shortening in to the full range and is able to overcome me- the absence of the activated contractile mech- dium resistance; it correlates to 70% of nor- anism, with standstill action potential. The mal muscle strength, causes can be neurogenic, myogenic, reflex, Grade 5: normal power within the full functional or fibrous. range when the muscle is able to overcome intensive external resistance; it correlates to Muscle disequilibrium A condition in 100% of normal muscle strength. which one group of muscles predominates over another group, e.g. flexors over extensors Muscle tone (tonus) Residual muscle ten- (iliopsoas muscle versus gluteus maximus sion is reflectively maintained muscle tone, muscle, hip flexors over hip extensors etc.). which depends on impulses from peripheral receptors and is also subject to supraspinal Muscle hypertonia Increased muscle tone. regulation. The loss of tonus (hypotonia) de- velops in peripheral motor nerve palsy or Muscle hypotonia Decreased muscle central nervous system (CNS) malfunction. tone. Generally reduced tonus is usually associated with laxity. Increased tonus (hypertonia) oc- Muscle spindle A sensory organ present curs in CNS dysfunction (e.g. hypertonus in within skeletal muscles, which acts as a perma- patients with spastic ). A general nent detector (proprioception) of inner mus- decrease or increase in muscle tone originates cle tone. from subcortical structures (reticular forma- tion, basal ganglions, and cerebellum). Relax- Muscle strength The ability of muscle fibre ing techniques are used in the treatment of to respond to a stimulus by contraction. It is hypertonic syndrome. proportional to the number of muscle fibres. M Muscle weakness A decrease in muscle Muscle synkinesis Involuntary muscle ac- strength less than would be expected given tivity accompanying voluntary muscle move- the person’s general physical fitness. It de- ments of other muscles, usually due to miswir- pends on energy source depletion, lack of ing of nerves following injury (e.g. neck tight- oxygen and inhibition of the area of the cere- ness on smiling after facial nerve (Bell’s palsy). bral cortex, from which the impulses that promote muscle function originate. Muscle testing Muscle strength is assessed by muscle testing. The results are divided into Muscles Muscle tissue consists of muscle six grades: cells and muscle fibres (fibrils) and is derived Grade 0: no signs of contraction, despite from mesenchyme. There are three types of maximum attempt to make the movement muscles: skeletal (striated muscle – free), car- Grade 1: flicker of contraction, the muscle diac muscle (striated muscle – involuntary) is able to perform a contraction but the and smooth muscles (visceral – involuntary). strength is insufficient to activate much Skeletal muscle is further divided into type I movement; it correlates to 10% of normal fibres (slow twitch) and type II fibres (fast muscle strength, twitch). The human body possesses more Grade 2: the active movement is only pos- than 600 muscles (40% of body mass). Muscle sible when gravity is eliminated; it correlates function: kinetic, thermogenic, postural. to 20% of normal muscle strength, Muscle impairment in rheumatoid arthritis Grade 3: the active movement is performed (RA) – causes: to the full range against gravity (the limb • Myositis – non-specific myositis associated weight) alone; it correlates to approximately with RA; plasma cell and lymphocytic in- 50% of normal muscle strength, filtration and atrophy of type IIa myofibrils musculoskeletal complication in rare inherited haemorrhagic diatheses 138

occur in muscles surrounding the affected basis of an immune defect or by infiltration of joint, as well as in remote muscles, a parasite into musculoskeletal system struc- • Arthritis – nociceptive irritation with in- tures. flammation of affected joint reflexively in- Clinical symptoms: Arthralgia, myalgia, hibits active muscle contraction, arthritis, myositis and vasculitis occur in para- • Inactivity – many muscles become func- sitic diseases. The condition improves fol- tionless due to long-term reduction in joint lowing eradication of the parasite. mobility, • Vasculopathy – narrowing of and Musculoskeletal symptoms in prima- venules due to inflammation causes de- ry hyperlipidaemias Diseases character- creased blood perfusion to the muscles ised by a defect of the lipoprotein metabolism with reduced metabolism leading to mus- due to increased synthesis or impaired degra- cle weakness and atrophy, dation of lipoproteins, which are involved in • Iatrogenic – drug induced myopathy (peni- transporting cholesterol and triglycerides in cillamine, chloroquine, glucocorticoids), plasma. Pathologically, elevated concentra- • Sensory neuropathy – infiltrates in peri- tions of lipoprotein particles play a causal role pheral nerves secondary to rheumatoid in the development of atherosclerosis and arthritis, pancreatitis. Joint symptoms may be the clue • Changes of muscle spindles – degeneration to the diagnosis long before xanthomas and of extrafusal muscle fibres. ischemic heart disease (IHD) develop. Clinical symptoms: Ophthalmic, derma- Musculoskeletal complication in rare tologic, musculoskeletal, cardiovascular and inherited haemorrhagic diatheses abdominal symptoms indicate the possibility Haemophilia is defined as a qualitative or of lipid metabolism defect: quantitative defect of factor VIII (haemophil- • ophthalmic: corneal arcus lipidis, retinal M ia A), factor IX (haemophilia B or Christmas lipidaemia, disease) or factor XI (haemophilia C). • dermatologic: xanthomas, can be clinically Clinical symptoms devided into xanthelasma palpebrarum, repeated intra-articular haemorrhage, tuberous, tuberoeruptive and eruptive xan- haemophilic arthropathy, secondary destruc- thomas, xanthoma striatum palmare, tive arthropathy due to repeated intra-articular • musculoskeletal: xanthomas on tendons bleeding. and in periosteal areas (Achilles tendon, tendons of extensors of fingers to hand and Musculoskeletal manifestations of foot), arthralgia, arthritis, tendinitis, less sarcoidosis Sarcoidosis is a multisystem often myalgia, granulomatous disease of unknown aetiology • cardiovascular: ischaemic heart disease, characterised by the presence of non-caseat- myocardial infarction, hypertension, aortal ing granulomas in various organs. stenosis (xanthoma of aortal valve), arte- Clinical symptoms: Depend on severity of riosclerosis of lower extremities – claudica- organ involvement. Typical features of the tion, disease are musculoskeletal symptoms in- • abdominal: pancreatitis, cholelithiasis he- volving the joints, bones and skeletal mus- patosplenomegaly, liver steatosis, abdomi- cles. nal pain.

Musculoskeletal symptoms in para- Musculoskeletal symptoms in sitic diseases The manifestation of para- Scurvy is a disease caused by deficiency of sitic diseases rarely involves the musculoskel- vitamin C, characterised by purpura, gingival etal system. These are acute, sub-acute and bleeding, tooth loss and pallor. chronic diseases occurring mainly in tropical Clinical symptoms: Vitamin C deficiency and subtropical areas. They originate on the manifests in skin and mucosal affections with 139 mycotic arthritis folliculitis, skin haemorrhages ranging from Cholinergic crisis purpura to ecchymoses, mucosal fragility, hy- Develops due to an overdose of cholinest- pertrophic gingivitis, septic complications and erase inhibitors. Symptoms include vomiting, thrombophlebitis. In terms of musculoskeletal abdominal cramps, increased salivation, system impairment, haemarthrosis into major muscle cramps and mental symptoms (dis- joints and osteoporosis may occur in adults, orientation). whereas in children growth impairment due to Swallowing and respiratory muscles im- metaphyseal defects of long bones develops. pairment may be present during both a myas- thenic and cholinergic crisis. Mutation Changes of the nucleotide se- Diagnostic test Edrophonium chloride quence of the DNA molecule in an organism (Tensilon®) is used by slow IV administration during cell division, either spontaneously or (edrophonium chloride 10 mg/mL), with im- due to effects of chemical mutagens or ioniz- mediate relief of the symptoms. Atropine is ing radiation. They can be divided into point administered in cholinergic crisis. mutations (change, exchange, deletion or in- Treatment: Cholinesterase can be blocked sertion of only one nucleotide) and group by the following drugs: neostigmine, prostig- mutations (several are affected). mine, pyridostigmine bromide (Mestinon®), They do not have to be functionally mani- edrophonium chloride. Other options are fested and may cause one or possibly more thymectomy, or irradiation of the thymus. gene defect. Myasthenia can be induced by D-peni- cillamine and chloroquine; aminoglycoside Myasthenia gravis A neuromuscular dis- antibiotics can induce myasthenia by block- ease leading to fluctuating weakness of mus- ing the neuromuscular transfer. Miosis (small cles and fatiguability. Muscle weakness in- pupils) is the major sign in cholinesterase in- creases during the day and after repeated hibitors overdose. nerve stimulation of muscles. M Aetiology Autoimmune blockade of the Myasthenic crisis → see Myasthenia gravis neuromuscular junction is caused by anti- bodies against acetylcholine receptors. Hy- Mycobacterial, mycotic and parasitic perplasia of the thymus is frequent. The dis- infections of musculoskeletal system ease moderates or remits after thymectomy. Most frequently these are infections caused Typical symptoms Initially, after prolonged by the direct presence of infectious agents in activity, weakness of the proximal muscles the articular cavity or tissue; agents can reach occurs. Weakness of the upper eyelid elevator these structures by various routes (via blood, leads to ptosis, which is a common sign and lymph or direct entry following injury etc.). may be accompanied by diplopia. The patient can experience difficulties with mastication, Mycotic arthritis Granulomatous arthritis swallowing (dysphagia) and speech (dysar- caused by certain fungal species. They occur thria). Eventually, symptoms are present in patients who suffer from serious diseases without any physical activity. In severe long- such as malignancy or haematological disor- term cases, progressive muscle atrophy may ders or in patients taking glucocorticoids or develop. Clinically it is literally life saving to immunosuppressants. recognize impairment of the respiratory Clinical picture: An inflammatory arthri- muscles (especially the diaphragm). tis can occur in the course of mycotic diseases following haematogenous spread of infection Myasthenic crisis Significant worsening of from its primary focus, or after trauma, skin muscle weakness, and paresis of respiratory and mucosal defects. A regional lymph node muscles is characteristic (check peak expira- reaction occurs and in more severe cases all tory flow rate!). It may be caused by intercur- internal organs can be involved, including the rent diseases, pregnancy and mental stress. central nervous system. myeloperoxidase (MPO) 140

Myeloperoxidase (MPO) An enzyme of • type III intermediate – intermediate, un- peroxidases located in azurophilic granules differentiated, potential source of three of neutrophils. Together with hydrogen per- previous types. oxide and an oxidative cofactor (CI– or I–) they form the myeloperoxidase system, the Myoglobin A single chain globular protein most effective antimicrobial and cytotoxic containing haeme which is the primary oxy- mechanism of human and other mammalian gen binding protein of skeletal and cardiac leukocytes. Patients with MPO deficiency are muscle. Unlike haemoglobin, myoglobin particularly liable to infectious diseases caused binds only one molecule of oxygen. The se- by Candida albicans. rum concentration of myoglobin is an index of damage to the myocardium and striated Myeloperoxidase system The most ef- muscles. Myoglobin is not present in smooth fective antimicrobial and cytotoxic system of muscle. Raised levels of serum myoglobin are leukocytes. It consists of myeloperoxidase found in the active phase of polymyositis and (MPO), hydrogen peroxide and an oxidative dermatomyositis, as well as following myo- cofactor. It acts in two forms: cardial infarction, crush syndrome, blast syn- – – drome and in thermal damage. Moreover, 1. MPO + H2O2 + Cl → H2O + OCl – – increased myoglobin levels are present in 2. MPO + H2O2 + I → H2O + OI The products of the first form are hypochlo- muscular dystrophy, skeletal muscle ischemia rites, even free chlorine, which are direct (cardioversion, post-infectious myoglobinu- toxic agents. Hypochlorites are a thousand ria), in rhabdomyolysis (Conn syndrome, times more toxic for target cells than hydrogen crush syndrome, tetanus, typhoid fever, trau- peroxide. A product of the second form is free ma and skeletal muscle inflammation). iodine which binds to proteins of target cells and thereby kills their biological activities. Myositis → see Idiopathic inflammatory M myopathies (IIM) Myocrisin → see Gold salts Myositis ossificans progressive → see Myofibrils These are cylindrical organelles Fibrodysplasia ossificans progressive, Pro- found within muscle cells, consisting of bun- gressive type of myositis ossificans (myositis dles of actomyosin filaments attached to the ossificans progressiva) cell membrane at each end. They can be sub- divided into different types depending on Myotonia A symptom manifesting after their properties: nerve impulse or as a result of artificial mus- • type I – slow red fibres – SO (slow oxida- cle stimulus (electric or by tapping) in which tive). muscle contraction lasts longer than normal properties: abundance of mitochondria and muscle relaxation is slow. Persisting mus- and myoglobin, many capillaries, slow con- cle contractions have a typical electromyo- traction, low fatigability, static function, graphic (EMG) picture. Myotonia occurs in “tonic fibres” (slow fibres), certain inherited diseases: myotonia congen- • type II A – fast, white fibres – FOG (fast ita Thomsen, Becker, oxidative and glycolytic). Eulenburg, dystro- properties: more myofibrils, fewer mito- phia myotonica Curshman-Steinert, but can chondria, fast and very strong contraction, also develop after administration of certain rapid movement, “twitch fibres” substances having rather an experimental • type II B – fast red fibres – FG (fast glyco- significance. The diagnosis is established lytic). from the clinical picture and typical EMG properties: few capillaries and myoglobin, findings. All forms of myotonia are incur- fast contraction with maximal strength, able. rapid fatigability, N

Nailfold Capillaroscopy An examination ies per 1 mm2 at the edge of the nailfold and/ using widefield microscopy of the nailfold or per l mm2 from its proximal edge. The cap- capillary bed 10 to 200-point zoom. It has illary count varies between 9 and 13 per 1 been useful in diagnosing and observing the mm. progress of systemic connective tissue dis- Variability of the capillaroscopic picture eases, especially systemic sclerosis. Changes and morphology changes to capillaries can in capillaries can also be detected in diabetes also occur in healthy individuals, but are usu- mellitus, arterial hypertension, atherosclero- ally mild in degree, and between different fin- sis and other disorders. The simplicity, non- gers. They are often due to microtrauma (man- invasiveness and affordability are all advanta- ual work, influence of chemical agents, etc.). A geous. normal capillaroscopic finding is found in ap- The capillaries of the finger nail folds on proximately 80%. In healthy individuals, the the hands are the most appropriate for moni- microvasculature in the nailfold does not toring microvasculature in vivo as they run change greatly over long-term observation. parallel to the surface of the skin. The skin Nailfold capillaroscopy can assess functional transparency can be increased by local appli- disturbances in microcirculation in vivo using cation of an immersion oil. A capillaroscope a higher magnification, thus monitoring of the or videocapillaroscope capable of scanning flow of erythrocyte aggregates and plasma and recording the capillaroscopic picture by a gaps in the arterial and venous arm of the cap- camera can be used to record the picture. Al- illary loop. The examination should be per- ternatively, a stereomicroscope, a modified formed under resting conditions, because the standard microscope or an ophthalmoscope flow velocity varies with temperature and can be used. mental status, even during the examination. A microvasculature, including arterioles, precapillaries, capillaries and venules, are all Naive lymphocytes Lymphocytes which viewed by nailfold capillaroscopy. The shape have not met a specific antigen and therefore of the capillaries is evaluated in the morphol- did not have the opportunity to be activated ogy assessment. The capillaries may be dilated, by the antigen and subsequently be differen- coiled and branched or have the shape of a tiated into memory and efficient cells. All bush. Dilatation of the capillaries may be grad- lymphocytes that leave the pivotal (central) ed in a qualitative or quantitative way. Concur- lymphoid organs are naïve. Those leaving rent elongation and dilatation of the capillaries bone marrow are naive B lymphocytes and is referred to as capillary enlargement. those leaving the thymus are naive T lympho- Subpapillary venous plexus A reticular cytes. plexus visible proximally from the edge of the nailfold. Necrosis The local death of cells or tissues Microhaemorrhage Leaking of erythrocytes due to chemical or physical damage, or after from capillaries, often visible with the naked complete interruption of blood supply to the eye, growing out of the nailfold. affected tissue. It differs from apoptosis (bio- Avascular regions Areas lacking capillaries logically programmed death of cell). After on the distal edge of the nailfold. Their size is necrosis an inflammatory response develops, expressed in mm2. not after apoptosis. Migration of the inflam- Decreased number of capillaries This is matory response to the area of necrosis is me- evaluated by counting the number of capillar- diated by necrotaxis. necrosis of tibial tuberosity of the femur in children 142

Necrosis of tibial tuberosity of the fe- T-helper-lymphocytes (CD4+) are among the mur in children → see Osgood-Schlatter major indicators of the initial conversion disease from the asymptomatic phase of HIV-1 infec- tion to the clinical symptoms of AIDS. Negative thermal therapy Local cryo- therapy is used in inflammatory rheumatic Nerve A bundle of nerve fibres () diseases in order to suppress inflammatory forming part of the peripheral nervous sys- symptoms, provide pain relief, muscle re- tem. The majority of nerves consist of motor laxation, and reduce swelling. Systemic appli- and sensory fibres (mixed nerve). Certain cation of coldness is used in cases of hyperpy- contain only sensory fibres rexia and in cryochambers for the purpose of and serve for specific purposes like smell, vi- managing inflammation, e.g. in rheumatoid sion, hearing and vestibular function. arthritis. Cryotherapy has similar effects to thermal therapy (pain relief, muscle relax- Nervous system A complicated system of ation). nerve cells whose primary function is to monitor, protect and respond to changes in Neonatal Lupus A syndrome of dermal lu- the internal and external environment. The pus and inherited complete heart block in the system is divided into the central nervous newborn of some mothers with SLE, Sjögren’s system (CNS; brain and spinal cord); periph- syndrome or other connective tissue inflam- eral nervous system (PNS; cranial and spinal matory diseases caused by the transplacental nerves) and autonomous nervous system passage of maternal IgG antibodies against (ANS), which is a subdivision of spinal motor anti-Ro (SSA). Anti-La (SSB) antibodies and nerves. The ANS is subdivided into the sym- rarely also anti-U1RNP may also be present. pathetic system (prepares the organism for Anti-Ro (SS-A) antibodies are not only an extreme situations) and the parasympathetic important marker, but play a significant role system (restores and preserves physical ener- in the pathogenesis of the disease. Using an gy during rest periods). N indirect immunofluorescent technique, de- posits of immunoglobulins can be found in Neuralgia Pain localised in the area sup- the conduction system of the heart in the plied by one or more nerves. week 9 to 10 of pregnancy. Apart from the above mentioned clinical symptoms, inherit- Neurogenic pain Pain caused by damage ed heart defects, cardiomyopathies and myo- or intermittent impairment of the peripheral carditis may also be present as part of neonatal or central nervous system. The term is mainly lupus. Other symptoms include haematologi- used as a general name for peripheral or cen- cal disorders (haemolytic anaemia, leukope- tral nervous system lesions of various aetiolo- nia, and thrombocytopenia), hepatosplenom- gies. For more specific determination, the egaly, and occasionally pulmonary and neuro- term peripheral and central neurogenic pain logical symptoms. Clinical symptoms, except may be used. for complete heart block, usually disappear within one year of birth with the disappear- Neuron The neuron is an electrically excit- ance of the antibodies. able cell forming the basic structural and func- tional unit (nerve cell) of the nervous system. Neopterin A metabolite of guanosine It consists of a cell body, dendrites and axon. triphosphate (GTP) produced by macrophag- Functionally neurons can be divided into sen- es after IFN-γ stimulation. The level of neop- sory, motor or combined neurons. From a terin in serum and urine of HIV-1 infected structural point of view, the neuron can be individuals increases in proportion to the pseudo-unipolar, bipolar and multipolar (most progression of AIDS. An increased level of of them). The afferent neuron carries impulses neopterin along with a decreased number of from sensory receptors to the central nervous 143 NO synthase (nitric oxide synthase, NOS) system. Efferent neurons carry impulses from against extracellular pathogenic parasites and the central nervous system to effector organs are the first cells to appear in the area of in- (muscles and glands). flammation. As with macrophages, neutrophils can also be present in the three stages: quies- → see Char- cent (resting), pre-activated and activated. Ac- cot’s joint (neuropathic arthropathy) tivated neutrophils possess the most efficient antimicrobial and cytotoxic activity, which can Neuropathic pain Pain caused by damage also cause damage to their own tissues. to the peripheral or central nervous system. Pain due to peripheral nervous system lesions Neutrophilic dermatoses A group of (neuropathy) is usually burning or an electric non-infective diseases characterized by skin shock-like pain, due to firing of pain and lesions which on histopathological examina- non-pain sensory nerve fibres. tion show intense inflammatory infiltrates of mainly neutrophils. The term neutrophilic Neurotransmitters Chemicals localised in dermatosis is sometimes associated with a nerve axon terminals that are released into good response of these diseases to glucocorti- the synaptic gap where they induce excitatory coids and immunosuppressive agents. or inhibitory postsynaptic potentials. Acetyl- choline, dopamine, noradrenaline, glutamin- Nitric oxide (NO) A mediator of immune, ic acid, serotonin, endorphin, encephalin, nervous and the cardiovascular system. NO substance P and others belong to this group. is a product of NO synthase activity and a free radical containing one disparate electron. Neutrophils Belongs to granulocytes and also called neutrophil granulocytes or poly- NO synthase (nitric oxide synthase, morphonuclear neutrophils (PMN). They are NOS) Synthase of NO, an enzyme that re- present in peripheral blood (45 to 70% of cir- moves NO in the form of a free radical (NO.) culating leukocytes) or are either tethered to from the guanidine group of L-arginine, lead- the endothelium of blood vessels (so called ing to L-citrulline production. Subsequently N marginal pool) or deposited in tissues where other reactive products derived from nitro- they move particularly during inflammatory gen (reactive nitrogen intermediates [RNI]) reactions (inflammation). They are typical develop. In the human body, the enzyme is professional phagocytes as they have immu- present in three isoforms: constitutive neuro- noadherent receptors on their surface through genic NO synthase (nNOS), constitutive en- which they are effectively able to perform the dothelial synthase (eNOS) and inducible syn- phagocytosis of particles (including patho- thase (iNOS). nNOS is present in neurons genic microorganisms) opsonised by anti- and skeletal muscles, eNOS in endothelial bodies or by the iC3 fragment of complement. cells and iNOS mostly in macrophages, but The enzyme NADPH-oxidase, which initi- also in a number of cells of epithelial, myeloid ates the production of oxygen dependent an- or mesenchymal origin. NO has a number of timicrobial and cytotoxic substances (reactive physiological functions (involvement in de- oxygen intermediates [ROI]), is activated in fensive inflammation, immune responses, their cytoplasmic membrane during contact cardiovascular and nervous system regula- of the neutrophils with the particle or by tions) and pathological functions (injurious chemotactic factors. ROIs along with oxygen inflammation, direct toxic damage of tissues). independent factors (defensin, lactoferrin, In immune responses, it acts as a regulator neutral proteinases) kill phagocytosed cells. and an effector (injurious) molecule. NO Oxygen independent antimicrobial substanc- synthesised by eNOS is involved in the regu- es are present in their progenitor forms in the lation of blood pressure, causing relaxation of granules (granule of leukocytes). Neutrophil smooth muscles of vessels, whereas in the granulocytes are paramount in the defence nervous system NO plays the role of neu- nociception 144

rotransmitter of nitrergic (non-adrenergic kinetic properties, efficacy and adverse ef- and non-cholinergic) neurons. fects.

Nociception All processes due to nocicep- Non-steroidal anti-iflammatory drugs tor activation. Nociception does not always (NSAIDs) – advice for treatment in lead to painful sensation, and vice versa. The rheumatic disease The aim of NSAID pain does not always have to be caused by no- is pain relief and reducing the pe- ciception (pain without nociception like psy- riod of morning stiffness, leading to relief of chogenic pain). symptoms and improvement in the patient’s quality of life. Nociceptive pain → see Types of pain Advice for NSAID medication • the onset of analgesic effect is within sev- Non-inflammatory myopathies A group eral minutes or hours, of muscular diseases in which muscle fibres are • the onset of anti-inflammatory effect dur- subject to damage and necrosis. Electromyo- ing continual administration is up to 7 graphic examination confirms myogenic le- days, sions. Serum muscle enzymes become raised • strong COX-1 inhibitors have the most sig- during degradation of a large number of mus- nificant anti-aggregate effect, cle fibres. Biopsy of muscle confirms muscle • the minimum effective dose is recom- fibre atrophy which is non-neurogenic in ori- mended, gin, and the necrosis of muscle cells without • the length of treatment should be as short inflammatory changes. Some myopathies are as possible, hereditary, whereas the remainder are of toxic • two orally administered NSAIDs should origin (drugs). not be combined (increased gastrotoxici- Drug induced muscular diseases ty), Myopathies are caused by: • NSAIDs with selective COX-2 inhibition glucocorticoids (particularly fluoroglucocor- have less gastro-intestinal toxicity, but have N ticoids) a higher cardiovascular risk. The latter chloroquine, hydroxychloroquine, cyclospo rin, should be borne in mind when prescribing colchicine, ipecacuanha, them in the elderly. quinolones, aminocaproic acid (Amicar®), beta-blockers, Non-steroidal anti-inflammatory drugs cimetidine, clofibrate, etrenitate, Sodium (NSAIDs) – classification Commonly, they cromoglycate. are classified according to their chemical Polymyositis may be caused by: structure, their pharmacodynamic effect ac- • D-penicillamine, penicillin, sulfonamides, cording to the degree of inhibition of both • Cimetidine, isoenzymes of cyclooxygenase (COX-1 and • , , COX-2) and their biological half-life. A large • Propylthiouracil. group of NSAIDs can be easily divided into Myasthenia may be caused by: acids and neutral substances. The group of • D-penicillamine, neutral NSAIDs contains only , Chloroquine, hydroxychloroquine which as a pro-drug is metabolised in the liver into its effective substance of 6-meth- Non-steroidal anti-inflammatory drugs oxy-2-naphthyl acetoacetic acid. Acid forms (NSAIDs) They represent a heterogeneous of NSAIDs include most known agents and group of drugs with anti-inflammatory, anti- are divided into derivates of enol acids like pyretic and analgesic effects. They act by and , which are com- non-selective inhibition of the enzyme cy- monly characterised by long plasma elimina- clooxygenase. They differ from each other in tion half-life and frequently used derivates of their chemical structure, certain pharmaco- carboxyl acids. 145 non-steroidal anti-inflammatory drugs (NSAIDs)(nsaids) – clinical effect and indication

Classification of NSAIDs according to Table 6. Variability of NSAID effectiveness chemical structure Acid NSAIDs: Physical and chemical Lipid solubility properties • Derivates of enol acids: – pyrazolones – , oxyphenyl- Pharmacokinetics plasma half-life butazone, phenylbutazone, . Pharmacodynamics selectivity of COX-2 – oxicams –, , meloxi- inhibition cam, , , Dose selection and chronopharmacology application period • Derivates of carboxyl acids: – – acetylsalicyclic acid (As- Variability of disease elimination organ disorders pirin®), , , lysinsalicy- late, . Adverse effects, idiosyncrasy pharmacogenetic – acetoacetic acid – , acemeta- differences cin, , , indomethacin, , . – anthranilic acid –, niflu- mic acid. at the cellular level. Various factors such as – – , , physical and chemical properties of the drug, , , , pharmacokinetic parameters, the ability to naproxen, , . inhibit a particular isoform of cyclooxyge- Neutral NSAIDs: nase, selection of the form of application and • alkanone – nabumetone. the variability of the treated disease or symp- • coxibs – celecoxib, , , tom, all affect the variability of NSAID effec- . tiveness (see table 6). In clinical practice, the selection of a Non-steroidal anti-inflammatory drugs NSAID is subject to basic pharmacokinetic (NSAIDs) – clinical effect and indica- properties. Absorption of the majority of tion They are subject to common properties NSAIDs is rapid after oral administration N and these properties are very similar among (0.5 to 1.5 hours) unless it is an enteric-coat- different NSAIDs. After NSAID administra- ed or slow release form of the drug. The time tion, relief of pain, stiffness and other symp- of clinical effectiveness is usually determined toms occurs. Individual variations in the ef- by the plasma elimination half-life. Particular fectiveness of a particular NSAID can be ex- NSAID groups have different plasma elimi- plained by the pharmacokinetics of the drug nation half-life (table 7).

Table 7. Classification of NSAIDs based on plasma elimination half-life (Pavelka and Štolfa 2005)

Plasma elimination half-life of NSAIDs short (to medium-long) < 6 h long > 10 h aspirin 0.25 fenbufen 10 tolmetin 1.0 diflunisal 13 diclofenac 1.1 naproxen 14 1.4 sulindac 14 ketoprofen 1.8 azapropazone 15 ibuprofen 2.1 nabumetone 26 fenprofen 2.5 piroxicam 57 etodolac 3.0 tenoxicam 60 tiaprofenic acid 3.0 phenylbutazone 68 flurbiprofen 3.8 indomethacin 4.6 non-steroidal146 anti-inflammatorynon-steroidal drugs (nsaids) anti-inflammatory – common properties drugs (NSAIDs) – common properties146

NSAID groups have a broad range of indi- Non-steroidal anti-inflammatory drugs cations, due to their anti-inflammatory, anal- (NSAIDs) – common properties gesic, anti-aggregation and effects. • anti-inflammatory effect, Indications of NSAID treatment: • analgesic effect, • arthritic diseases including inflammatory • antipyretic effect, rheumatic diseases, systemic connective tis- • acid character,* sues diseases, reactive arthritis, irritative • fat soluble, synovitis, metabolic arthropathy (gout, • strong binding to plasma proteins, chondrocalcinosis), osteoarthrosis, trau- • inhibition of prostaglandin synthesis in matic synovitis, tenosynovitis, bursitis in macrophages and fibroblasts, extra-articular rheumatism, and acute lum- • inhibition of synthesis in bosacral disease. thrombocytes, * • acute and chronic nociceptive (somatic • inhibition of prostacyclin synthesis in en- and/or visceral) pain and malignancy as- dothelial cells, * sociated pain. • induction of apoptosis. • prevention of ectopic calcification devel- * selective COX-2 inhibitors and coxibs do not opment after total hip joint replacement. have significant effects • acute pain conditions, renal and biliary colic, migraine, toothache (pulpitis), post- Non-steroidal anti-inflammatory drugs operative pain, trauma pain; (NSAIDs) – mechanisms of action The • dysmenorrhoea, premature labour rever- NSAID group includes approximately 200 ac- sal; tive substances originating from about 20 • fever; chemically different groups. Their common • cardiovascular indications; property is the blockade of the cyclooxyge- • other: , juvenile idiopathic nase enzyme (COX) in a metabolic cascade of arthritis, closure of patent ductus arteriosus. arachidonic acid (figure 2) through unstable N

Figure 2. Metabolic pathways of arachidonic acid HPETE – hydroperoxyeicosatetraenoic acid HETE – hydroxyeicosatetraenoic acid HPETE and HETE are abbreviations in the table. 147 non-steroidalnon-steroidal anti-inflammatory anti-inflammatory drugs drugs (NSAID’s) (nsaids) – mechanisms of action endoperoxides to prostaglandins, thrombox- synthesis of proteoglycans in chondrocytes, anes and . The anti-inflammato- the production of superoxide radicals, the ry effect of NSAIDs is explained by inhibition transmembrane transport of anions, and in- of the cyclooxygenase enzyme and subsequent hibit aggregation and adhesion of neutro- blockade of prostaglandin synthesis. The ma- phils, the production of pro-inflammatory jority of NSAIDs inhibit transformation of cytokines and synthesis of NO. arachidonic acid into thromboxane (TXA2), Classification of NSAIDs based on pharma- prostaglandins (PGE2) and prostacyclins codynamic effect:

(PGI2). However, the mechanism of NSAIDs • selective inhibitors of COX-1 such as aspi- anti-inflammatory action is more complicat- rin (doses up to 300 mg/day), ed and includes the inhibition of the tran- • non-selective inhibitors of COX-1 and scription of a number of pro-inflammatory COX-2 such as aspirin (doses >500 mg/ genes, the products of which are significant day), ibuprofen, diclofenac, ketoprofen, mediators of inflammation, e.g. the pro-in- tiaprofenic acid, indomethacin and others, flammatory cytokines TNF, IL-1 and IL-6. • selective inhibitors of COX-2 such as eto- NSAID mechanisms of action: dolac, . • membrane enzymes inhibition: Gastrointestinal complications are among the – NADPH-oxidases of neutrophils (and most frequent adverse effects of NSAIDs and superoxide production), phospholipase along with renal complications are prosta- C of macrophages, glandin-dependent. In the group of typical – Peroxidases of 12-hydroperoxyeicosatet- NSAIDs (such as non-selective COX-2 and raenoic acid of thrombocytes; COX-1 inhibitors) the two mechanisms can- • entrapment of precursors of arachidonic not be separated from each other. New groups acid and its establishment to membranes of of selective COX-2 inhibitors (etodolac, macrophages; meloxicam) and specific COX-2 inhibitors • inhibition of transmembrane transport of (celecoxib, etoricoxib, lumiracoxib, parecox- ions in erythrocytes and in the cells of re- ib) have reduced the risk of gastrointestinal nal tubules; complications while preserving their anti-in- N • inhibition of oxidative phosphorylation in flammatory and analgesic effects. The risk of mitochondria; gastrointestinal complications is lower in • inhibition of aggregation and adhesion of drugs with higher selectivity for COX-2. Selec-

neutrophils; tivity for COX-2 is assessed by a IC50 COX-2/ • inhibition of lysosomal enzymes release; COX-1 ratio (ratio of half inhibitory concen- • inhibition of pro-inflammatory cytokines; trations of COX-2/COX-1). Therefore all • inhibition of NO synthase, particularly in NSAID groups have been tested and high se- endothelial cells; lectivity for COX-2 is the criterion for the de- NSAIDs interfere with pathways of inflam- velopment of new anti-inflammatory drugs. mation even more significantly than has been Selectivity of particular NSAID groups and reported. It has been confirmed that low dos- other new anti-inflammatory drugs blocking es of aspirin and newer forms of NSAIDs in- COX-2 hibit the biosynthesis of prostaglandins from • less than 5 times more selective for COX-2: arachidonic acid. Higher anti-inflammatory acetylsalicylic acid, flurbiprofen, naproxen, doses of aspirin (> 3.0 g/day) and sodium piroxicam, indomethacin, nabumetone, salicylate that do not inhibit cyclooxygenase ketoprofen, diclofenac, ibuprofen, tenoxi- and other NSAIDs act as anti-inflammatory cam, mefenamic acid. agents by inhibiting reactions that are not • 5 – 50 times more selective for COX-2: mediated by prostaglandins (NADPH-oxi- meloxicam, celecoxib, etodolac; dase inhibition, inhibition of phospholipase • More than 50 times more selective for C and peroxidase of 12-hydroperoxyeicosa- COX-2: etoricoxib, lumiracoxib. tetraenoic acid). At the same time they block Adverse effects of NSAID’s Nottingham health profile 148

Gastrointestinal symptoms couple of years of regular NSAID medication. Prolonged administration of NSAIDs is as- Elderly patients (>60 years old) are at higher sociated with a higher incidence of gastric risk as mild renal impairment may already by ulcer and subsequent tendency towards its present due to a physiological decrease in complications such as gastrointestinal bleed- glomerular filtration from nephrosclerosis ac- ing and perforation. A higher risk of gastroin- companying hypertension or diabetes. testinal complications associated with NSAID Bone marrow inhibition has been reported administration is seen in elderly patients (>60 mainly in association with pyrazolones ad- years of age), patients with a history of peptic ministration. ulcers or its complications, and patients tak- Central nervous system symptoms include ing glucocorticoids, anticoagulant or anti- tinnitus during salicylate medication and aggregate medication. chronic fatigue and headache after indo- Cardiovascular effects of NSAID and COX-2 methacin administration (especially in fe- inhibitors males). Increased bronchospasm can occur NSAIDs and COX-2 inhibitors increase with most NSAIDs, which is important in blood pressure (BP) or may de-stabilise BP. patients with asthma. The list of adverse ef- This has a clinical impact particularly in older fects is given in table 8. individuals among whom the prevalence of Adverse effects are relatively frequent and hypertension and osteoarthrosis is high. The serious in combination with anticoagulant BP should be regularly checked in patients treatment (table 9). with arterial hypertension and diabetes during treatment with NSAIDs and COX-2 inhibi- tors. NSAIDs and COX-2 inhibitors also in- Nottingham health profile → see Instru- crease the risk of congestive heart failure, par- ments of assessing (health status measure- ticularly in older individuals with ischaemic ments, outcome measurement) heart disease. There are differences within the group of NSAIDs and COX-2 inhibitors. A NSAIDs → see Non-steroidal anti-inflam- N higher incidence of cardiovascular complica- matory drugs (NSAIDs) tions (myocardial infarction) has been con- firmed, which is probably due to the imbal- NTX → see Crosslinked telopeptides of type I ance between inhibition of vascular prostacy- collagen, Markers of osteoresorption, Peptide clin synthesis and the absence of the impact fragments of collagen type I (NTX, CTX) on thrombocyte thromboxane synthesis. The thrombotic potential of COX-2 inhibitors de- Nuclear factors Proteins also referred to as pends on the cardiovascular profile of the par- transcription factors because they bind to the ticular patient, particular drug, its dose and promoter location (regulation units) of vari- the duration of treatment. The risk of cardio- ous genes and thereby stimulate (sometimes vascular complications is also present among also inhibit) transcription (transcription to non-selective NSAIDs. mRNA). Some of them are able to activate Renal complications other genes, the products of which are involved Inhibition of renal prostaglandins by in various physiological or pathological reac- NSAIDs leads to oedema, hyponatraemia and tions. A number of them are in an inactive impaired effect of diuretics and beta-blockers. phase under physiological conditions and can The incidence of kidney disease depends on be activated directly (viruses, various inflam- the length of NSAID administration. However, matory stimuli produced in tissue or cell dam- functional renal impairment may occur after age) or by various extra-cellular stimuli that act only a couple of days or weeks of NSAID ad- through receptors (e.g. antigens, hormones, cy- ministration, whereas interstitial nephritis af- tokines). The transcription factors can there- ter weeks to months of NSAID administration. fore be regarded as nuclear messengers trans- Analgesic nephropathy can develop after a forming external signals into long-term 149 nuclear factors

Table 8. Adverse effects of NSAIDs

Disease Mechanism Frequency Note Gastrointestinal Dyspepsia local irritation, Frequent Differences among ↓ synthesis of PG NSAIDs Erosion, ulcer Local irritation, 2 to 10% ↓ synthesis of PG Bleeding, perforation ↓ synthesis of PG, thromboxane More factors Hepatopathy dose-dependent or idiosyncratic Rare Differences Renal ↓ H20 and sodium retention synthesis of PG Dose ↓ renal perfusion ↓ synthesis of PG depen- acute renal insufficiency ↓ synthesis of PG dent interstitial nephritis dose-dependent, or idiosyncratic papillary necrosis dose-dependent or, idiosyncratic Rare Haematological Bone marrow inhibition dose-dependent or idiosyncratic Rare More frequently after pyrazolones Dermal Allergic reactions Multifactor origin Relatively Differences frequent Central Nervous System Fatigue, headache, vertigo, tinnitus (unknown origin, probably PG?), direct effect, e.g. indomethacin Increased bronchospasm (salicylates)

Table 9. NSAID interactions N

Agent Result of interaction Mechanism Serious bleeding Summation of effect on various receptors, release from plasma proteins binding, high levels of free agent Warfarin and other drugs bleeding complex – PG effect Oral hypoglycaemic agents hypoglycaemia Antihypertensive drugs reduced effect changes in gene transcription. ‘Alert’ cyto- cause of bronchial asthma, NF-κB and AP-1 kines (IL-1, TNF-α) and other chemotactic act synergistically. Glucocorticoid receptors factors that act via receptors as well as certain in the cytoplasm of cells belong to transcrip- bacterial products (e.g. LPS) belong to the tion factors. Activated glucocorticoid recep- group of inflammatory stimuli. They are as- tors inhibit the activity of other transcription sociated with activation of transcription fac- factors and so inhibit the initiation or poten- tors such as the nuclear factor kappa B (NF- tiation of the inflammatory process. Tradi- κB), activator protein-1 (AP-1), nuclear fac- tional aspirin acts mostly through inhibition tor of activated T cells (NF-AT) and signal of NF-κB. That is why the transcription fac- transduction activating transcription factors tors have been used as a target for novel anti- (STAT). A synergic relationship has been ob- inflammatory agents. The nomenclature of served among certain transcription factors. transcription factors is trivial and is derived For example, during inflammation that is the from a particular function. Basically they can nuclear scintigraphy of the skeleton (bone scintigraphy or bone scan) 150

be divided into two large groups: the group of ing inflammation of the synovial membrane factors that are present in a number of cells can be detected by increased accumulation of and the group of factors that are specific to a the radiopharmaceutical agent in the in- certain type of cells. flamed joint. Methylene diphosphonate la- belled by 99m Tc (osteotropic radiopharma- Nuclear Scintigraphy of the skeleton ceutical agent) is used for investigating bony (bone scintigraphy or bone scan) This structures, with increased activity in the skele- non-invasive method of nuclear medicine ton such as primary or metastatic tumours, consists of the intravenous injection of a ra- Paget’s disease, or healing fractures. diopharmaceutical agent where its increased (rarely decreased) accumulation in certain NZB/NZW mice (New Zealand black/ regions of the body can be detected through New Zealand white mice) F1-hybrid its emission of gamma rays by radiation de- mice in which a disease similar to human sys- tectors (gamma camera). The distribution of temic lupus erythematosus develops sponta- these tracers is dependent on the rate of bone neously. The disease is of genetic origin; anti- turnover and blood flow nuclear antibodies and immune complexes Technetium-99m Tc is used in the investi- develop, subsequently causing glomerulone- gation of soft tissues. Hyperaemia and in- phritis (membrane glomerulonephritis) and creased permeability of the vessel walls dur- shortening the life of these animals.

N O

Ochronosis → see Alkaptonuria and Ochro- calation of osteoresorption; calcium excre- nosis, Arthropathy in ochronosis tion by the kidneys is decreased and calcium absorption in the gut via parathormone Oestrogens These female sex steroids are (PTH) production of 1,25(OH)2D3 is in- more important to bone than the classical creased. The following rise of serum calcium calcitropic molecules (PTH, 1,25(OH)2 vita- causes a drop in PTH secretion and an in- min D and somatotropin-IGF-1). The prima- crease in calcitonin secretion. This process ry importance of oestrogens for bone integ- leads to decreased osteoresorption, decreased rity in both genders is likely to be associated intestinal absorption and increased calcium with the early development of specific intrac- excretion. A decrease in serum calcium oc- ellular (cytosol) receptors during evolution. curs, though within the physiological range. The effect of oestrogens on bone and cal- Oestrogen deficiency causes, via PTH effect, cium homeostasis is complex. They have an an increase of phosphate concentration in the inhibitory influence on bone resorption – blood. The decrease of PTH and increase of they protect against a proresorptive effect phosphate lead to a decrease in the produc- mediated by hormones and molecules (e.g. tion of 1,25(OH)2D3. All these adaptive , thyroid hormones and mechanisms contribute to the deepening of heavy metals) and inhibit the release of cy- the primary disturbance of bone in oestro- tokines from osteoblasts and peripheral gen-deficient conditions. An early menarche, monocytes. An effect on calcitonin and cal- the number of and hormonal citriol regulation is exerted via specific oe- contraception all have a protective influence strogen receptors on osteocytes. The absence against the occurrence of osteoporosis. As the of oestrogens causes an overproduction of in- pathophysiological overview shows, there is terleukin (IL)-1 by peripheral monocytes. an acceleration of bone loss after the meno- Tumour necrosis factor (TNF) alpha also in- pause. The yearly bone turnover in the pre- creases bone resorption. IL-1 and TNF alpha menopausal women affects approximately play a critical role in the pathogenesis of bone 2–5% of cortical bone and 15–25% of trabec- loss in the absence of oestrogens. Oestrogens ular bone. also suppress the production of IL-6, which is induced by IL-1 and TNF alpha. IL-6 is an Orthoses Orthopaedic devices that help lo- important stimulator of osteoclast produc- comotive system function. They hold body tion. Oestrogen receptors are present on the parts in their correct position or move them surface of mononuclear cells, osteoblast pre- into the correct position. Sometimes they cursors, osteoblasts and osteoclasts. At the compensate for lost function, or correct a same time, oestrogens stimulate the gene ex- deficit to a manageable level. pression of the growth factor TGF beta, which Depending on their purpose, orthoses are is an anabolic factor inhibiting the produc- divided into: tion of osteoclasts. Oestrogens also regulate • Therapeutic – can be used as temporary the production of prostaglandins (PG) which therapeutic or physiotherapeutic devices. influence the production and effectiveness of • Compensatory – they permanently com- cytokines. Except the afore-mentioned direct pensate a particular defect of the locomo- effect on bone, the absence of oestrogens tive system, e.g. different length of limbs. leads to alterations of the calcium–phosphate • Prophylactic – used, for example, in sport metabolism. Oestrogen deficiency causes es- to avoid unfavourable injury. orthopaedic shoes 152

Static orthoses (stability) patients with hands affected by a rheumato- • Supportive – they compensate for loss of logic process. load capacity. • Fixative – they maintain stability where Orthopaedic shoes Suitable for individu- there is pathologic damage to the locomo- als who owing to foot deformity (often in tive system; temporary (compensative) or- rheumatological diseases) cannot wear ordi- thoses help, for example, during sequential nary shoes. They are made for the purpose of therapy of fractures (plaster fixation), per- foot deformity correction, pain relief and gait manent orthoses are used when the muscle support, progression prevention and for cos- system does not hold the joint in the re- metic cover for a deformed foot. quired position as a consequence of a per- manent defect. Orthopaedic shoe inserts Orthoses that Dynamic orthoses are inserted into shoes in order to correct cer- • Correct defective posture – e.g. corsets in tain less serious foot defects. Correction in- the treatment of pathological curvature of serts help actively or passively correct flatten- the spine. ing of the arch of the foot. Relieving inserts • Movement control orthosis – e.g. orthosis contain holes for relieving the pain arising used with knee instability where the ortho- from sore areas (callosities). Correction inserts sis prevents mediolateral movement, but are used to correct different lengths of limbs. anteroposterior movement can occur. Orthoses influencing muscle work Oscar (OsteoClastS-Associated Recep- These are orthoses with dynamic func- tor) A product of gene coding for the leuko- tions. The function of weak muscles is taken cyte receptor complex. It is specifically ex- over by the orthosis, which utilises: pressed in preosteoclasts and mature osteo- • the transfer of work from healthy muscle clasts. OSCAR-L exprimed by osteoblast/ • springs and rubber tension apparatus stromal cells is its ligand. The presence of a • the elasticity of material from which the soluble form of OSCAR in the co-culture of orthoses are made osteoblasts and bone marrow cells inhibits • hydraulic or electric drive the formation of osteoclasts. OSCAR is there- O Orthoses of fingers fore a specific regulator of osteoclastic differ- Can be divided into fixative, redressive, re- entiation. tentive, substitute and movement regulating orthoses. A fixative or retentive orthosis is Osgood-Schlatter disease Necrosis of used in the rupture of the extensor pollicis tibial tuberosity of the tibia in children, es- longus muscle; the PIP (proximal interphala- pecially in 8 to 14 year old boys. The defect is geal) joint remains free. An extensive dynam- frequently bilateral. Patients complain of ic PIP orthosis enables the movement of the pain, particularly when climbing stairs. The joint against resistance (flexion or extension). pain is located in the area of the tibial tuber- The three-point correction principle is used osity, which is swollen and tender to pressure. in Boutonniere deformity (correction of flex- X-ray shows irregularity and calcification ion deformity in PIP and extension deformity around the insertion of the patellar tendon. in DIP – distal interphalangeal joint). In Swan Treatment heat, rest, a protective plaster is neck type deformity, the orthosis corrects ex- necessary in more serious cases. Improve- tension deformity in the PIP joint and the ment may take two or more years. flexion position in the MCP (metacarpopha- langeal) and DIP joint. deformans → see Paget’s disease A fixative thermoplastic splinter avoids ul- nar or possibly radial deviation in the MCP Osteoarthritis (OA) A very common de- joints. Spring extension splints of the fingers generative joint disease which progresses are used after orthopaedic hand operations in with age and characteristically affects the 153 osteoarthritis (OA) small joints of the hand, lower limb joints and dle phalanges is frequent. Once growth of the the vertebral column. OA embraces hetero- nodes stops, the affected joints become pain- geneous diseases of different aetiological ori- free. Compared with rheumatoid arthritis, gin, but with a similar biological, pathologi- hand function usually remains good, though cal, radiological and clinical picture. It mani- may be a problem in certain jobs or pastimes fests itself by joint dysfunction due to dys- (e.g. pianist). More often, it only causes cos- regulation of cartilage metabolism, which metic problems (knobbly looking hands). leads to changes in the mechanical properties Initially, the radiographs are normal, but later of cartilage. The pathological picture includes show unequal narrowing of the articular cav- focal destruction of the cartilage as well as ar- ity and osteophyte formation. It is very im- eas of remodelling in the form of osteosclero- portant to emphasise to the patient that it is sis and osteophyte formation. OA can be pri- not rheumatoid arthritis or gout. mary or secondary (e.g. due to metabolic, Treatment: Non-steroidal anti-inflamma- endocrine, haematological diseases). tory drugs, or intra-articular glucocorticoids, Risk factors of OA: are administered during inflammatory epi- • , particularly in the polyarticular sodes. The use of SYSADOA are other op- form of small joints of the hands, tions in more stubborn cases. Treatment may • Obesity, where it is associated with knee be supplemented by ultrasound administra- osteoarthritis, tion, thermotherapy (wax, mud) and thera- • Hypermobility accompanying collagen ab- peutic exercise. normalities, • Post-traumatic conditions, Osteoarthritis (OA) of the first carpo- • Sports with risk for joint injuries, metacarpal (CMC) joint (Rhizarthro- • Posture at work. sis) OA may occur only in the first CMC (OA Clinical symptoms: Pain is typically associ- of the thumb) and the trapeziometacarpal ated with exercise, and is associated with brief joint. Rhizarthosis is a common problem that morning and inactivity stiffness. Gradually affects mainly women in their 50s. The affec- reduced function and immobility develop. tion may be uni- or bilateral, with different The X-ray picture shows loss of joint space, clinical and radiological stages. As the cause the development of sub-articular cysts, sub- is generally unknown it is referred to as idio- O chondral sclerosis, osteophyte formation, and pathic. The most common symptom is pain, deformities. The course of OA is very vari- particularly in everyday movements at using able and in most cases progresses very slowly. the pinch function (touch the thumb with an- However, very rapid progression can occur. other finger) to turn keys, open a jar, a win- dow, turn a knob. Little by little the joint de- Osteoarthritis – hands (Heberden and teriorates and later it subluxes. The result is Bouchard type) A hereditary disease espe- then a characteristic deformation at the base cially affecting women. The DIP (distal inter- of the thumb. Treatment is the same as in all phalangeal) joints are affected producing He- other forms of OA but if conservative treat- berden’s nodes whilst involvement of the PIP ment is insufficient, surgery may be indicat- (proximal interphalangeal) joints cause ed. Bouchard’s nodes. It commonly manifests it- self between 40 to 60 years of age (menopaus- Osteoarthritis (OA) – pharmacological al). treatment The pharmacological treatment Clinical symptoms: Cartilaginous stiff of OA is represented by two large groups of nodes gradually grow on the opposite articu- drugs: lar surfaces on the dorsal articular margins. 1. SYRADOA (symptomatic rapid-acting The nodes are sore in the course of growth drugs of osteoarthritis) can be simple an- with intermittent inflammatory erythema algesics such as paracetamol, aspirin, and swelling. Deviation of the distal and mid- NSAIDs (non-steroidal anti-inflammato- osteoarthritis – primary generalised nodal osteoarthritis (GNOA) 154

ry drugs), opioids or intra-articular gluco- Treatment: Non-steroidal anti-inflamma- corticoids; tory drugs are administered during inflam- 2. SYSADOA (symptomatic slow-acting matory episodes. Afterwards, treatment is the drugs of osteoarthritis) such as intraartic- same as in other forms of osteoarthrosis. ular hyaluronate or oral glucosamine sul- phate, chondroitin sulphate, diacerein, Osteoarthritis (OA) – surgical treatment etc. (so-called chondroprotective agents). Surgical procedures play a key role in the treat- Initially, simple analgesics usually provide ment of OA. They are indicated when pharma- satisfactory pain relief. In advanced disease, cological and non-pharmacological treatment in order to suppress the inflammation and fails especially in severe hip and . ease pain, NSAIDs are prescribed. Treatment The indications for surgical treatment include with standard NSAIDs is associated with a permanent severe pain (including night pain) number of adverse effects, particularly gas- and greatly reduced function of the affected tropathy (gastric ulcer, bleeding). The risk of joint with very limited mobility. At present, to- gastrointestinal complications is increased in tal hip or knee joint replacements are the most elderly patients who often suffer from OA. effective and frequently used procedure. Most In terms of these complications, NSAIDs patients are able to return to their normal daily with strong selectivity to cyclooxygenase 2 activities after surgery. An improvement in the (COX-2) have a significantly lower incidence materials used in the development of the pros- of adverse gastrointestinal effects. In terms of theses guarantees their longer durability up to biological and biochemical properties, low 10 to 15 years. dose meloxicam belongs to this group. At the stage of painful OA, it is administered orally Osteoblasts Uninuclear cells whose main in a daily dose of 7.5 mg, but can be increased function is the production of bone tissue (os- to 15 mg daily if required. teoformation). They develop from a pluripo- Another specific COX 2 inhibitor is cele- tent mesenchymal cell that gradually matures coxib. Studies have shown that celecoxib is as to preosteoblasts and osteoblasts. From a effective as non-selective NSAIDs, when ad- morphological point of view, they have a ministered in a single daily dose of 100–200 rounded nucleus localised in the basal part of O mg (Bensen et al. 1999, Pavelka and Štolfa the cell. In the nucleus, receptors for oestro- 2005). The safety profile of celecoxib has been gens, vitamin D3, integrins and cytokines can extensively tested in comparative trial with be found. The nucleus is localised on the op- diclofenac, ibuprofen and naproxen. These posite side to the position of contact between trials confirmed the favourable safety of cele- the osteoblast and the bone surface. The cyto- coxib with less renal adverse effects and no plasm is heavily basophilic; the Golgi appara- increased cardiovascular risk. tus lies between the nucleus and the apical part of the cell. The endoplasmic reticulum is Osteoarthritis – primary generalised pronounced. The plasma membrane of active nodal osteoarthritis (GNOA) Initially, it osteoblasts contains a high concentration of manifests by inflammatory episodes of the alkaline phosphatase and receptors for para- DIP (distal interphalangeal) and PIP (proxi- thormone. Osteoblasts are localised on the mal interphalangeal) joints of the hand in rela- surface of trabeculae and in the osteons of tively young women (around 40 years old), compact bone where they are capable of pro- often peri-menopausal. Familial incidence is ducing osteoid in the places of active osteo- frequent. It never affects the MCP (metacar- formation. After completion of the osteofor- pophalangeal) joints but often affects the mation phase, osteoblasts are transformed knees, hips and intervertebral (facetal) joints. into lining cells or osteocytes. Initially, radiological changes are not visible, but typical osteoarthritic changes develop lat- Osteocalcin Osteocalcin, also known as er. Deviation of the phalanges occurs. bone Gla-protein (BGP), is a small non-colla- 155 osteocytes gen protein (MW 58 kDa) specific for bone Osteoclasts Large multicellular cells con- and dentin. It forms 1–2% of bone proteins. taining 4–20 nuclei. The main function of Osteocalcin is preferentially synthesised in osteoclasts is the resorption of mineralised osteoblasts under the control of 1,25-dihy- bone matrix. Osteoclasts are formed by a fu- droxyvitamin D3, and is then incorporated sion of unicellular phagocytic cells (mono- into the extracellular bone. A portion of new- cytes) following development from preosteo- ly-synthesised osteocalcin is released into the clasts. There are receptors for calcitonin and circulation and reflects the intensity of osteo- integrin in their cytoplasm. Osteoclasts con- formation. tain esterases and produce enzymes such as At present, osteocalcin, together with the tartrate resistant acid phosphatase, glucuroni- bone isoenzyme of alkaline phosphatase, is dase and carboanhydrase. They also possess the most utilised marker of osteoformation. colony stimulating factor (CSF-1). In the most frequently used method, the in- The nuclei of osteoclasts have no uniform tact molecule is determined by a method us- appearance. There are numerous Golgi appa- ing two monoclonal antibodies detecting the ratuses, mitochondria and transport vesicles intact molecule together with its N-terminal filled with lysosomal enzymes around the nu- peptide. clei. Once activated, osteoclasts move to areas Serum osteocalcin correlates with the in- of microfracture by chemotaxis and come to creased skeletal growth during puberty and is lie in Howship’s lacuna and osteons of com- elevated in various disturbances of bone me- pact bone. The osteoclast resorption area is tabolism associated with increased bone increased by a ruffled border from which is turnover (e.g. primary and iatrogenic hyper- secretes hydrogen ions and several hydrolytic thyroidism, hyperparathyroidism, acromega- enzymes including cathepsin and matrix ly and ). Likewise, the metalloprotease groups into the subosteo- level of osteocalcin is decreased in hypothy- clastic space. As a consequence of the low pH, roidism, hypoparathyroidism, in glucocorti- hydroxyapatite crystals dissolve allowing ex- coid-treated patients, in the osteoporosis in- posure of the bone matrix to the lytic en- duced by hepatic disorders, diabetes, in some zymes and its resorption. Osteoclast activity patients with multiple myeloma and malig- is regulated by several hormones including nant hypercalcaemia. In hypercorticism, the parathormone, calcitonin and interleukin 6 O synthesis of osteocalcin in osteoblasts is sup- (IL-6) and by osteoprotegerin and RANK li- pressed. Decreased levels have a diagnostic gand produced by osteoblasts. value and an increase of its level is a marker of successful treatment. Interestingly, in Pag- OsteoClastS-Associated Receptor → et’s disease, the concentration of osteocalcin see Oscar (OsteoClastS-Associated Recep- rises far less than the value of the bone isoen- tor) zyme of alkaline phosphatase. Generally, os- teocalcin reacts very sensitively to distur- Osteocytes These develop from osteoblasts bances of bone metabolism associated with and accumulate in the lacunae between the the endocrine disorders. lamellae of compact bone and inside trabecu- The serum osteocalcin level is also raised in lae. These cells were originally osteoblasts certain forms of osteoporosis. Pathologically entrapped in the bone matrix that they pro- increased values are found in postmenopausal duced and which was consequently calcified. women with rapid bone loss (fast-losers). The shape of osteocytes depends on their age Measurement of decarboxylated osteocalcin and activity. A young osteocyte has many fea- may be useful in determining the prognosis tures in common with its precursor – the os- following hip fracture in elderly women. teoblast, but is smaller with a smaller Golgi apparatus and endoplasmic reticulum. These Osteochondritis dissecans → see König’s changes are substantially more pronounced disease in older osteocytes with glycogen accumula- osteogenesis imperfecta (OI) 156

tion within the cytoplasm. Osteocytes pos- fecting cortical bone, and bone deformity are sess cytoplasmic processes that form a net of among the main symptoms. Callus formation cells in the bone channels. These processes after fractures is normal and bone remodel- facilitate the transport of cytokines, hor- ling is rapid. Every tissue containing type I mones, growth factors as well as signal trans- collagen may be affected, i.e. teeth, ligaments, mission. Osteocytes work as sensors reacting skin, sclera etc. Therefore, teeth development to changes in the flow of fluids in bone chan- may be defective – dentinogenesis imperfec- nels. They react to these stimuli, induced by ta. The teeth have a greyish even brownish- mechanical and environmental changes, by yellow colour, short and narrow roots, and synthesis of active substances influencing the tooth enamel is fragile. Occasionally, in some process of bone remodelling by gentle adjust- families patients present only with the teeth ments of osteoblastic and osteoclastic activity. defects (no fractures). Joint hypermobility The other function of these stimuli is the nu- with lax ligaments can lead to repeated dislo- trition of bone tissue. During osteoclastic re- cation. Conductive hearing impairment may sorption of bone, osteocytes undergo phago- occur in early middle age. Decreased synthesis cytosis. or impaired quality of collagen is reflected by increased capillary fragility associated with Osteogenesis imperfecta (OI) This re- bruising, haematomas and frequent epistaxes. presents a group of hereditary connective tis- Patients are prone to develop hernias. The sue diseases characterised by a qualitative or sclera of a number of patients have various quantitative defect of type I collagen. William shades of blue to greyish colour, may be very Vrolik (physician working in anatomy and slight. Bone deformities are represented by pathology, The Netherlands, 1801–1863) first curvature of long bones after repeated frac- described the symptoms of the disease in the tures and various degrees of thorax deformity Pathological anatomy handbook in 1844. (most frequently kyphoscoliosis). Individuals There are 8 main types of osteogenesis im- with severe forms of the disease also have a perfecta People with type I tending to have disproportionately large head and triangular- mild symptoms.. People with types IV, V, and shaped face. A squeaky voice, excessive perspi- VI tend to have more moderate symptoms. ration, constipation, mitral valve defects and O People with types II, III, VII, and VIII tend aortal insufficiency are among other variable to have severe symptoms, with type II being symptoms. Intelligence is always normal, even lethal in the perinatal period. Osteopenia in the most severely affected patients. and osteoporosis occurs to varying degrees. Diagnosis: A skin biopsy for fibroblast cul- In the differential diagnosis, children with ture to analyse the type I collegen genes and juvenile osteoporosis, secondary osteoporo- DNA testing for mutations in sis associated with other diseases and, last COL1A1 and COL1A2 can be helpful, but but not least, child abuse must all be taken may not be conclusive. into consideration. Personal and family his- Treatment: Although there are no curative tory, thorough physical examination, X-ray specific treatments, administration of bis- review and bone densitometry lead to the phosphonates appears to offer the best out- diagnosis. look. Pathogenesis: Synthesis or structured de- fects of pro-α1 and pro-α2 chains of type I Osteokines in Osteoporosis Interleukins collagen (encoded by the COL1A1, COL1A2, (IL) IL-1, IL-4, IL-6 and IL-11, macrophage CRTAP and LEPRE1 genes on chromosomes and granulocyte/macrophage (GM) colony 7, 17, 1 and 3 respectively) occur. Currently, stimulating factor (CSF) and tumour necrosis more than 200 mutations of these genes have factors (TNFs) belong to cytokines with im- been recognised. portant effects in the pathogenesis of osteo- Clinical symptoms: Osteopenia or osteo- porosis. These cytokines stimulate osteore- porosis with repeated fractures, mainly af- sorption. 157 osteomyelitis

IL-1 has a complex impact on osteoporosis. pear during childhood. Biochemically, pa- Elevated concentrations of IL-1 are found in tients have a raised serum alkaline phos- patients with severe osteoporosis. IL-1 stimu- phatase and low or normal calcium. Treat- lates the synthesis of IL-6 which increases the ment is directed at the cause, and correction osteoclast count. Oestrogens decrease the will often markedly improve the patient’s synthesis of both IL-1 and IL-6. TNF alpha quality of life. stimulates osteoresorption and replication of osteocytes. CSF plays a role in the maturing Osteomyelitis A bacterial infection of of osteoclasts and deficiency of GM-CSF-1 bone. Infectious agents include pyogenic bac- leads to osteoporosis. teria such as cocci (staphylococci, strepto- Bone remodelling is a complex process cocci, pneumococci), Escherichia coli, salmo- regulated by systemic hormones and local nella, Proteus and myobacteria. Infectious factors that have an important position in the agents usually reach the bone via blood maintenance of the dynamic balance (cou- spread during bacteraemia from a purulent pling) between the processes of osteoforma- focus elsewhere the body, or they may direct- tion and osteoresorption. The actual influ- ly invade the bone during open fractures or ence of the individual factors on bone contin- operations. The course of osteomyelitis can ues to be studied. Understanding their mech- be acute, sub-acute or chronic. Usually a fever anisms of action is the key to the development up to 40°C with significant localised pain and of new, more preventative and therapeutic decreased mobility occurs. Osteomyelitis is measures in fighting osteoporosis. mainly located in the areas of the most rapid enchondral growth with increased blood sup- Osteomalacia The essence of osteomalacia ply, thus in the metaphyses of long bones. De- is deficient mineralisation of bone tissue in pending on age, the infection can spread into adults. Consequently, the bone tissue is softer the joint (pyarthrosis) in children up to 1 year and bones are prone to deformities. In con- old in whom epiphysis and metaphysis have a trast, rickets is a defective mineralisation of common blood supply, whereas this is less the epiphyseal plates in children leading to likely in children over 12 months old when growth retardation and skeletal deformities. the blood supply mentioned above is sepa- The low concentration of minerals in bone rated. The growth cavity forms a certain bar- O tissue in osteomalacia is caused by deficient rier so the infection may expand under the mineralisation of newly formed bone so that periosteum and fistulate externally (sub-pe- this condition may be considered as “minor- riosteal abscess). Another form of abscess is mineralisation”, and not as demineralisation, the Brodie abscess (Sir Benjamin Brodie, sur- which is the term often used incorrectly for geon in London, 1783–1862), which mani- this condition. In the histological picture, the fests itself by pain, with the X-ray showing a affected bone shows non-mineralised bone clear round lesion with a sclerotic margin lo- matrix (osteoid) visible as concentric layers cated in the diaphysis and metaphysis. In os- in Haversian canals of compact bone and as a teomyelitis, sclerotising bony enlargement wide margin on the trabeculae of bone. The with periosteal apposition occurs predomi- total number of Haversian canals and trabe- nantly. culae as well as their size remain (in contrast A suspected diagnosis of osteomyelitis is to osteoporosis) normal. Symptoms can be confirmed by the clinical picture, X-rays, minimal, but include muscle weakness, bone bone puncture biopsy and cultivation to de- pain due to micro-fractures (looser zones on termine the pathogenic agent. Treatment X-rays) in weight bearing areas and fractures consists of long-term antibiotics administra- following little or no trauma. The main cause tion and immobilisation of the affected limb. is calcium and vitamin D deficiency due to In the chronic stage, treatment includes the poor diet or various malabsorption diseases, debridement of necrotic tissue, removal of rarely hereditary causes of osteomalacia ap- bone sequestrae, lavage and local administra- osteonecrosis (ON) 158

tion of antibiotics. Subsequently, covering of • serum calcium, albumin, phosphate and the defect with transfer of vascularised bone, alkaline phosphatase, skin and muscle flaps may be necessary. • liver transaminases, creatinine, protein electrophoresis, Osteonecrosis (ON) Cell death involving • chemical analysis of the urine, both the mineralised bone and bone marrow • 24 hour urinary calcium and phosphate ex- based on loss of bone’s blood supply. Osteone- cretion. crosis is not a specific clinical entity. It is a Specialised laboratory examinations: common final pathway of numerous diseases. • serum and urinary bone markers, Clinical symptoms: The most frequent • tests for a diagnosis of secondary osteopo- (and most serious) localisation of ON affects rosis: serum PTH, 25-OH Vitamin D, TSH, the femoral head but it may also occur at fT4, STH, IGF1, gonadotrophins (LH, other sites (humeral head, femoral condyles, FSH), prolactin, free cortisol in the urine, small bones of wrist and foot) and bilateral serum CTH, sex hormones (oestradiol, disease is common. Clinical symptoms are testosterone), bone biopsy, biopsy of the non-specific and particularly include persis- small intestine and specific antigliadin an- tent pain of varying intensity, though some- tibodies, oncomarkers. times the patients may be asymptomatic. Early X-ray changes of ON are not well rec- Osteopetrosis Belongs to skeletal diseases ognised, with typical changes becoming visible associated with hyperostosis or subsequently. An excellent method of detect- also known as Albers-Schönberg Disease ing progressive change is the use of magnetic (Heinrich Ernst Albers-Schönberg, German resonance imaging (MRI). Whereas early dis- radiologist, 1865–1921). Osteopetrosis causes ease may be curative, established disease is ir- bones that appear dense and cavities for bone reversible and requires surgical intervention. marrow do not form. At present, several forms of osteopetrosis can be distinguished. (ONJ) A very A ‘benign’ autosomal dominant adult type rare complication following administration with only mild symptoms, a ‘malignant’ auto- of bisphosphonates, most commonly in high somal recessive infantile type which, if not O doses parenterally, in the setting of poor den- treated, leads to death in infancy, and an ‘in- tal hygiene with or without dental proce- termediate’ autosomal recessive type which, dures. The risk with oral treatment is low. It in childhood, has many symptoms similar to presents with infection and necrosis of bone those of malignant osteopetrosis but patients in the mandible or maxilla. It is important to survive. Other types include carbonic anhy- check for good dental hygiene before admin- drase II deficiency previously described as istration of bisphosphonates, as treatment is osteopetrosis with and difficult. Conservative management with cerebral calcifications and certain extremely limited debridement, antibiotics and mouth rare types such as neuronal recurrent disease rinses assist healing. with malignant osteopetrosis, lethal or infan- tile transitory osteopetrosis. Osteopathies – Laboratory investiga- Pathogenesis: The gene for the adult type tions The aim of the biochemical examina- of osteopetrosis has been localised on chro- tion is the differential diagnosis of other os- mosome 1p21. The basic defect is similar in teopathies, the evaluation of phosphate – cal- all forms of disease with failure of osteoclasts cium metabolism, and the evaluation of bone to resorb bone. It results in a persistently cal- metabolism activity (it means differentiation cified matrix, which was formed by chondro- of fast-loser and slow-loser osteoporosis). blasts during enchondral ossification. Defec- Routine laboratory examinations: tive transformation of fibrous bone into com- • blood count, erythrocyte sedimentation pact bone, which is associated with defective rate, bone resorption, contributes significantly to 159 osteoporosis – definition increased bone fragility. Carbonic anhydrase dosis and cerebral calcification. The neuronal is vital for acid-base homeostasis. Its isoen- form is a combination of severe skeletal defect, zymes speed up the reaction of carbon diox- epilepsy and neurodegenerative changes. ide and water leading to carbonic acid pro- duction and subsequent release of hydrogen Osteopontin (OPN) Also known as ETA-1 cation and bicarbonate. Carbonic anhydrase (early T lymphocyte activator 1). OPN is a II is missing in erythrocytes in cases of osteo- human gene expressed in bone. It is an extra- petrosis with renal tubular acidosis and calci- cellular structural protein. OPN also has the fication in the brain. Rarely, osteopetrosis can property of a cytokine, which regulates cell- be associated with a neuronal degenerative mediated immune reactions. The expression disease due to accumulation of ceroid lipo- of osteopontin is located in bone and on the fuscin secondary to a lysosomal defect. epithelial surface, but also occasionally on the Clinical symptoms: Infantile osteopetrosis endothelium, smooth muscle cells and on the manifests in early childhood. Chronic nasal surface of mononuclear cells during the course obstruction due to malformation of parana- of pathological inflammation. They support sal sinuses and mastoid is among the first Th1 and inhibit Th2 expression of cytokines. symptoms. It is not rare for the disease to Osteopontin is a regulating factor of calcium manifest in infancy with clinical hypocalcae- deposition in bone and in areas of pathologi- mia. Narrowing of the cranial foramens cal inflammation (dystrophic calcification) through which the nerves run leads to visual and is also involved in the pathogenesis of impairment and paresis of oculomotor and atherosclerosis and tumour growth. facial nerves. The child often suffers from floating eye movement and/or strabismus, is Osteoporosis (OP) Skeleton disease char- generally unwell, and teething is delayed. The acterised by decreased bone strength with a skeleton looks dense on X-ray picture but subsequent increased risk of fractures. Bone bones are very fragile. In certain patients hy- strength is determined by the density of bone drocephalus develops, and sleep apnoea syn- mineral and the quality of bone tissue, i.e. by drome may occur. Apart from optic nerve the architecture of bone trabeculae, the inten- palsy, retinal degeneration contributes to vi- sity of bone turnover and the accumulation of sual loss. The bone marrow cavities apart from microfractures (NIH consensus conference O an abundance of osteoclasts, contain fibrous 2000). tissue so the child has a tendency towards Osteoporosis is usually diffuse. Based on spontaneous bleeding and the development of aetiology, it can be classified as primary, bruises, and suffers from frequent infections. which is present without a known disease or Severe anaemia occurs if hypersplenism and condition leading to structural or functional haemolysis are present. The necessity for blood defects of bones, or secondary, when it is in- transfusion before the third month of age is voked by a known disease, or by external fac- a sign of poor prognosis. On physical exami- tors. Primary OP includes postmenopausal nation the child is generally unwell and mac- OP (type I), senile OP (type II) and juvenile rocephaly, frontal bossing, and nystagmus are OP (rare). Secondary OP caused by genetic found. The child has an adenoid facies, hepa- abnormalities, endocrine disorders, nutri- tosplenomegaly (compensatory extramedul- tional disorders, renal diseases, inactivity, in- lary haematopoiesis) and genu valgum. Pe- flammation, tumours or certain drugs. De- ripheral leukocytes are unable to perform their creased bone formation and increased bone immune functions, and therefore untreated resorption occur in glucocorticoid induced patients usually die during the first decade of OP, leading to a rapid reduction in bone sub- their life from sepsis accompanied by severe stance and increased risk of fractures. anaemia and haemorrhagic diathesis. Autosomal recessive deficit of carbonic an- Osteoporosis – Definition A number of hydrase II is accompanied by renal tubular aci- diverse definitions of osteoporosis exist based osteoporosis – diagnosis 160

on specific diagnostic criteria. At present, the (due to osteoarthritis, joint prosthesis, etc). WHO definition (1994) has usually been Only a region of the forearm referred to as used as it takes into account the morphologi- 33% radius may then be used for diagnosing cal, as well as the clinical aspect. Osteoporosis osteoporosis. The peripheral bone mineral is defined as a metabolic disorder of bone densitometry at the heel is unsuitable for di- characterised by a low bone mineral density agnosing osteoporosis according to WHO. and disturbance of microarchitecture with a However it is still applicable as a method of consequent increase of fragility and risk of identifying patients at high risk. fracture. A low bone mineral density does not con- firm the diagnosis of primary postmeno- Osteoporosis – Diagnosis The aim of di- pausal osteoporosis even in a woman after agnosis is to define the group of patients with menopause. Likewise, normal values of the a low bone mineral density, in which the risk bone mineral density measured at a single of fracture is high enough for antiosteoporo- skeletal site by one method of measurement tic treatment to be considered. do not exclude osteoporosis in a given pa- The T-score reflects the number of stan- tient. It is important to exclude other relevant dard deviations (SD) compared with the bone disorders where a low bone mineral density mineral density in young healthy individuals and secondary osteoporosis may occur. of the same gender. This assessment of bone density applies only to postmenopausal wom- Osteoporosis – Epidemiology The con- en and men over 50 years of age (see table 10). temporary definition only allows indirect In premenopausal women, children and men measurement of the epidemiology of osteo- under 65 years of age the International Society porosis either on the basis of the prevalence for Clinical Densitometry (ISCD) recom- of osteoporotic-related fractures or osteopo- mends the use of the Z-score (Z-score reflects rosis defined by bone mineral densitometry. the number of standard deviations compared The risk of fracture, however, is determined with the bone mineral density in healthy age, not only by bone mineral density, but also a gender and ethnicity matched individuals) to whole range of other indicators within the assess low bone mineral density, with a rea- bone (quantity of bone mineral, microarchi- O sonable working definition of “low BMD” as tectural structure, properties of the material, a Z-score -2.0. dynamics of the bone turnover, etc.). Diagnosis of osteoporosis may be estab- The most frequent sites of osteoporotic lished by measurements in the following re- fractures are the forearm, vertebrae and hip. gions: lumbar spine in the AP projection, The life-long risk for any osteoporotic frac- femoral neck, greater trochanter and a region ture in a 50-year old woman is approximately referred to as total femur. Bone mineral den- 39% and in a man approximately 13%. sity measured in other regions may not be Hip fracture is the most serious complica- used for diagnosing osteoporosis, according tion of osteoporosis and is associated with to the WHO criteria. Forearm measurements high morbidity and mortality. Worldwide an may be accepted in patients where the other increase in number of these fractures from sites are non-measurable or uninterpretable 1.6 million in 1990 to 6.26 million in 2050 can be expected (Marcus et al. 2008). The 5-year survival is only 82% of the total popu- Table 10. WHO classification of bone density lation survival with mortality at its highest in Classification of decreased T-score the first 6 months. The lifetime risk of death bone density following a hip fracture is comparable to that of breast cancer and 4-times higher than Normal more than –1.0 uterine cancer. Osteopenia –1.0 to – 2.5 The epidemiology of vertebral fractures is Osteoporosis less than – 2.5 less well understood due to the lack of a uni- 161 osteoporosis in men versally accepted diagnostic criterion and a Osteoporosis – Genetic factors Genes high portion of asymptomatic fractures. Only participate in influencing the maximum peak about one third of vertebral fractures are seen bone density and in affecting bone remodel- in the outpatient clinic and only 2–8% require ling. Knowledge and practical application of hospitalisation. The prevalence of radiologi- genetics in osteoporosis are hampered by its cal fractures in people >50 years old is be- obvious polygenic inheritance. Two types of tween 8–25%, depending on the definition. research studies are involved; association Vertebral fractures are associated with a simi- studies searching for links between individual lar increase in 5-year mortality as hip frac- genes or their clusters and incidence of oste- tures. oporosis, and the description of definite ge- Fractures of the distal forearm, most of netic abnormalities in individual patients or them of Colles type, differ from the epidemi- families (Marcus et al. 2008).There are typical ological view from hip and vertebral frac- descriptions of changes in the genes for Os- tures. There is a significant predominance of terix, Sclerostin, LRP5 and others. A strong women (up to 4:1) with the incidence up to genetic component is confirmed by studies 85%. The distal forearm fractures are not as- on identical twin and daughters of oste- sociated with increased mortality or with a oporotic mothers (Marcus et al. 2008). The long-term disability. inheritance is strongest in the lumbar spinal Osteoporosis is socially the most severe lo- region. The collagen synthesising gene type I comotor system disorder due to its high inci- (COL1A1 gene), oestrogen receptor genes, dence and mortality. cytokines and growth factors are considered to be potentially responsible for influencing Osteoporosis – Fracture risk estima- bone turnover. Changes found in the allele tion There is a close correlation between the for the vitamin D receptor correlate with cal- bone mineral density and the risk of fracture. cium absorption from the gastrointestinal A decrease by 1 SD represents 1.5–2.5 times tract, the level of peak bone mass (PBM), as higher risk of fracture. This correlation, how- well as with bone turnover. Similar variability ever, has not been documented in premeno- have been assumed for the oestrogen recep- pausal women. It is known that many frac- tor gene and procollagen type I gene. These tures occur in the patients with osteopenia. hypotheses could explain the great variability O In deciding whether to start anti-osteoporotic of PBM in healthy subjects as well as differ- treatment, an assessment of risk is impor- ences in response to treatment with vitamin tant. D. However, further prospective studies are A prevalent vertebral fracture following in- needed. The gene coding for CaSR may also adequate trauma is the most significant fac- influence calcium and parathormone levels, tor. These patients have up to 5-times higher and thus bone mineral density. risk of another fracture and approximately 2-times higher risk of hip fracture. A second Osteoporosis in men The lower incidence vertebral fracture appears within one year in of osteoporosis in men compared to women 20% of patients. is caused by: Bone turnover is another significant factor. • a higher maximum BMD in adolescent A high bone turnover doubles the risk of males (thicker bones), fracture, independent of bone mineral densi- • slower and more uniform resorption of ty. BMD with age (no accelerated postmeno- The length of the femoral neck is directly pausal loss), proportional to the risk of fracture in this • shorter mean life expectancy in men. area as well. Evaluating the tendency to falls However, the difference in the incidence of is important as non-vertebral fractures, which fractures between women and men signifi- quantitatively dominate, occur almost exclu- cantly decreases with age. The aetiopatho- sively after trauma. genesis of osteoporosis in men is multifac- osteoporosis (OP)(op) in rheumatoid arthritis (ra)(RA) 162

toral and in contrast to women is secondary • synthetic oestrogen derivatives with com- in nature in more than 50%. Therefore, a sec- bined properties of oestrogens, gestagens ondary cause should be sort especially in and androgens (Tibolone) – STEAR, younger men. • selective oestrogen receptor modulators (SERM), Osteoporosis (OP) in rheumatoid ar- • calcitonin thritis (RA) Diffuse osteoporosis is very fre- • bisphosphonates quent, even in patients who have never been Stimulation of osteoformation: treated with steroids, which has been proved • anabolic steroids, by recent trials of monozygotic twins, from • parathormone, which only one suffered from RA. It is com- • fluoride salts. monly present in patients treated with gluco- Drugs with a dual mechanism of action (in- corticoids. hibition of the osteoresorption and stimula- Possible mechanisms of secondary OP are: tion of the osteoformation): • Systemic effect of inflammatory mediators • strontium ranelate, associated with disease activity (IL-1, IL-6, Drug decreasing the elimination of calcium TNF etc.), in the urine: • Changes in circulating hormone concen- • thiazide diuretics. trations, • Changes in , Osteoporosis – Non-medical treat- • Changes in skeletal load, ment Nutritional factors • Influence of drugs used in RA treatment. An adequate supply of nutritional elements Clinical symptoms: is one of the decisive factors in the prevention • Fractures of vertebrae, neck of femur, fore- and treatment of osteoporosis which becomes arm bones, even more significant in the postmenopausal • Chronic static pain in the spine, most fre- period. The intake of calcium is of key impor- quently between scapulae and in the lum- tance. Calcium has a beneficial influence on bosacral area, maximising bone mass in children and ado- • Acute sharp localised pain to the spine, oc- lescents. An abundance of vitamin D, ade- O casionally radiating to the front of the tho- quate supply of proteins (too high supply rax and abdomen, causes an increase of calciuria), phosphates • Kyphosis of the thoracic spine, (too high supply stimulates secretion of PTH) • Decrease in body height. and C and K (necessary for collagen synthesis) are also essential. An excessive Osteoporosis – Indications for treat- supply on sodium (calciuria), proteins, mag- ment Antiresorptive treatment (except of nesium, zinc, copper and manganese should calcium and vitamin D) is indicated: be avoided, which is usually no problem with • in patients where bone mineral densito- a normal dietary regime. An excessive supply metry has verified osteoporosis, of substances forming insoluble salts with • in patients with an osteoporotic related calcium, such as oxalic acid, phytic acid, lac- fracture (in sites where osteoporosis-based tose and certain proteins, is inadvisable. So- fractures occur following low energy trau- dium and glucose cause calciuria. Exposure ma). to aluminium, sulphur dioxide and other toxic waste products may worsen the status of Osteoporosis – Medical treatments bones. Drugs used in the treatment of osteoporosis Smoking Bone turnover inhibitors: Nicotine, similar to other components of • calcium, cigarettes, has a negative effect on the differ- • vitamin D and its active metabolites, entiation of osteoblasts. It is an important • oestrogens, risk factor, especially in slender women. 163 osteoporosis – risk factors

Smoking influences the bone via the fol- the incidence of falls and thus reduces the lowing mechanisms: risk of fractures independent of bone mineral • a negative influence on the protective ef- density. During excessive exercise, especially fect of oestrogens, in athletes, the development of amenorrhoea • earlier menopause, with its associated hormonal changes will ac- • malnutrition due to anorexia, celerate osteoporosis in spite of the physical • increased sensitivity to parathormone, activity. • acidosis due to toxic concentrations of car-

bon dioxide (CO2), Osteoporosis – Physical examination increased rate of respiratory infections and The findings on physical examination that facilitation of acidosis. should make one suspicious of a diagnosis of Alcohol osteoporosis include: a loss in height, en- Alcohol also has a direct toxic influence on hancement of the thoracic kyphosis, bulging bone. An increased amount of alcohol has a of the abdomen, low body weight (BMI un- negative influence on the synthesis and dif- der 19), thin stature and a reduced distance ferentiation of osteocytes. between the iliac crest and the last rib (less Alcohol influences the bone density by the than 3 fingers). In addition, there may be following mechanisms: physical finding indicating diseases leading • Malnutrition – lack of proteins and vita- to secondary osteoporosis (joint deformities mins, in RA, cushignoid habitus, etc). • Malabsorption of calcium, The physical findings may be typical of • Hepatopathy (through disturbance of vita- other metabolic osteopathies including the min D hydroxylation in the liver) bone deformities in Paget disease, blue sclera • Increased secretion of cortisol. in osteogenesis imperfecta, etc. None of the However, several observations have also above-mentioned parameters themselves or shown a reduction of fracture risk in persons their combination are able to unambiguously with a low alcohol intake compared with establish the diagnosis of osteoporosis, but nondrinkers. Due to the difficulty in defining should alert the physician‘s attention to its the exact protective dose of alcohol, osteo- possibility. porotic patients are advised to abstain from O alcohol completely. Osteoporosis – Prevention of Frac- Physical activity tures Osteoporosis prevention involves Physical activity has a positive influence on methods aimed to increase the activity of os- the increase in bone mineral density. Exercise teoblasts and prevent osteoresorption. The facilitates activation of remodelling processes most important factors are the following: ad- and increases in certain hormones (for ex- equate intake of calcium, vitamins D and C, ample oestrogens, gestagens, testosterone and exercise, a well-balanced diet, and exclusion growth hormone). It is hypothesised that of toxic influences (smoking, excessive alco- pressure caused by a load causes a piezoelec- hol intake, heavy metals and excessive supply tric event change to the transmembrane po- of phosphates). At the same time, the use of tential and leads to the stimulation of osteo- good fitting footwear, correction of vision blasts. On the other hand, a loss of mechani- and prevention of falls (obstacles on floors, cal stimulation of bone (physical inactivity) is elimination of vertigo, etc.) are important in associated with a significant decrease in bone reducing the incidence of fractures. mass. A beneficial effect of regular exercise on bone mineral density, however, persists Osteoporosis – Risk factors A meta- only during the activity. Swimming and gym- analysis of large clinical studies by the WHO nastics are reported as the most appropriate affiliated working group has considered the sports. Exercising at the same time improves following as the most significant risk factors: locomotor coordination, which can reduce age, previous fracture after an inadequate osteoporosis risk factors – modifiable 164

trauma (the so-called low-energy trauma), a prevailing extracellular form is a dimer. Os- family history of fractures, corticosteroid teoprotegerin is produced by osteoblasts. It is treatment, smoking, excessive alcohol intake a soluble substance that acts as a receptor and rheumatoid arthritis (WHO Scientific blocker binding to RANKL (receptor-activa- Group 2007). tor of nuclear factor κB ligand) and thereby preventing its action on osteoclasts and their Osteoporosis Risk factors – modifi- precursors. In the past RANKL was known as able osteoclastogenesis inhibiting factor, which • physical activity, defined one of his properties. It belongs to • physical inactivity – inactivity-induced os- the family of TNF-receptors, but does not teoporosis develops during complete im- have a transmembranous domain or sequence mobilisation. Depending of the intensity of that allows signal transduction and therefore bone metabolism in an individual patient, is denoted as a blocking receptor. By blocking significant loss of bone mineral density oc- the differentiation and activation of osteo- curs over weeks to months. clasts it prevents, for example, parathormone

• Dietary supply of calcium – insufficient or vitamin D3 induced hypercalcaemia. supply of calcium, a disturbance of its ab- sorption from the gastrointestinal tract and Ott’s sign → see Metric measurement of ver- increased excretion in the kidneys may tebral column in spondyloarthritis (SpA) lead to a negative calcium balance and in- creased bone loss. Overall status in rheumatoid arthritis • Body weight – Reduced body weight, often (OSRA) → see Instruments of assessing combined with other risk factors, increases (health status measurements, outcome mea- the risk of postmenopausal osteoporosis. A surement) BMI < 19 kg/m2 is an important risk factor for fractures. Overlap syndromes A term used to label patients with the diagnostic criteria of two or Osteoporosis Risk factors – unmodifi- more systemic connective tissue diseases, but able now more commonly called undifferentiated O • genetic predisposition – higher risk in connective tissue diseases (UCTD). Polymy- Caucasians and patients with a family his- ositis (PM), dermatomyositis (DM), systemic tory of osteoporotic fractures and thin stat- sclerosis (SSc), and less frequently rheuma- ure, toid arthritis (RA) and systemic lupus erythe- • age, matosus (SLE) are the most frequent compo- • gender – more significant risk in women nents of overlap syndromes. compared to men. Clinical symptoms: Depend on nosologi- cal units that form the overlap syndrome. The Osteoprotegerin (OPG) Alkaline glyco- most frequent symptoms are: protein with four potential N-glycoside • Raynaud’s phenomenon, arthralgia, arthri- bonds. It is released as glycoprotein (Mw tis, myositis, serositis, interstitial pneumo- 55 kDa), which is intracellularly transformed nia, by disulphide bonds into a dimer with (Mw • Antinuclear antibodies, antibodies against 110 kDa). It may also exist as a trimer but the ribonucleoproteins referred to as U1RNP. P

Paget’s disease A progressive disorder af- diographic findings and laboratory investiga- fecting a limited number of bones. It is charac- tions, though sometimes is only determined terised by progressive hypertrophy and osteo- in the differential diagnosis of an elevated al- sclerosis of bone tissue. It leads to an abnormal kaline phosphatase. Even in the early stages, increased bone turnover causing changes to there are localised areas of on X- bone formation. Its prevalence increases with ray. This finding in the skull is called osteo- age and in certain countries (especially the porosis circumscripta. Later, enlargement of Anglo-Saxon population) it affects up to 3% of bones, thickening of the cortex, sclerotic the population over 40 years of age. Men and changes and other findings appear. Increased women are affected equally. The aetiopatho- uptake on bone scintigraphy is highly sensi- genesis is unknown, but there has been specu- tive, but a nonspecific method of detecting lation that a viral (parvo-virus) infection may the regions of skeletal abnormalities. In the be implicated. The majority of osteoclasts con- blood tests, there is a typical (often very high) tain intracellular particles resembling paramyx- elevation of serum alkaline phosphatase level, oviral nucleocapsids. Other possible causes are especially of its bone isoenzyme. Osteore- an inborn error of metabolism or vascular ab- sorption products are also increased. normalities. Paget’s disease may be inherited in Treatment of Paget’s disease is aimed at an autosomal dominant trait, with the genetic suppression of bone pain (short-term) and abnormality localised to chromosome 18. preventing the progression and complica- Many patients remain asymptomatic. The tions (long-term). most frequent symptom is bone pain at rest The following are the indication for medi- or on weight bearing. The skin over the af- cal treatment: fected limb is usually warm. Enhanced vascu- • bone pain, larisation, mechanical stress and irritation of • prior to orthopaedic surgery, the periosteum by disturbed remodelling are • hypercalcaemia caused by immobilisation, the reasons for pain. Secondary osteoarthri- • symptomatic heart failure, tis, especially in the hip or knee may occur if • neurological deficit, the bone around the joint is affected. Other • prevention of future complications. typical findings include deformities of the fe- Modern treatment involves the administra- mur, tibia (sabre) and forearm. These late on- tion of a bisphosphonate (etidronate in a dose set deformities are asymmetrical and often 5 mg/kg/day for up to 6 months or rise- easy to diagnose. Pathological fractures can dronate 30 mg/day for up to 2 months) are occur after minimal trauma. Deformities of now considered more effective than calci- the skull cause changes to its shape resulting tonin. More recent data on suppression of in a lion face (leontiasis ossea), basilar invagi- disease activity and prevention of recurrence nation, hydrocephalus and compression neu- have indicated better results with either ti- ropathies leading to hearing and visual loss. ludronic acid (skelid) 400mg daily orally for Other complications include compression of 12 weeks or administration of zolendronic the spinal cord and nerve roots, compression acid in a single dose of 5 mg in a slow intrave- of the posterior fossa, osteosarcoma and gi- nous infusion over 15 minutes. ant-cell tumours, heart failure and hypercal- A surgical operation is reserved mainly caemia during immobilisation. for: The diagnosis of Paget’s disease may follow • total hip or knee joint prosthesis, the typical clinical picture, characteristic ra- • tibial osteotomy, Paget-Schroetter syndrome 166

• occipital craniotomy for the decompres- pecially visceral pain, is accompanied by sion of posterior fossa, vegetative changes. This is mainly because • decompression of the spinal cord and nerve of a number of vegetative system fibres, roots. mainly sympathetic, inside the body that influence pain. Paget-Schroetter syndrome → see Acute 4. motor It enables the avoidance of painful shoulder pain stimuli or fighting against it: “fight or flight”. Pain It is a fundamental component of hu- Types of pain man life. Despite its aversive character, the By time course: perception of pain is a basic condition for hu- Acute pain This is subject to actual or de- man survival. In an acute state, it serves as a veloping tissue or organ damage. It has a pro- positive warning signal for the body, indicat- tective function and is time-limited. Acute ing actual or potential tissue damage. Inten- pain has a sudden onset and subsides rapidly sive and prolonged pain, however, loses its after withdrawing. It provokes a number of biological significance and protective func- reflex responses such as muscle contraction tion. The pain itself becomes a source of fur- or activation of the autonomic nervous sys- ther, often more severe damage to the body. It tem (tachycardia, increased cardiac output, has a negative influence on the physical con- hypertension, increased gastrointestinal tract dition of the patient, disturbing his mental motility, vasoconstriction, , balance, leading to decompensation and dis- diaphoresis, etc.). Mental changes are mini- turbance of social communication. Persistent mal (anxiety, insomnia) and transient. Acute pain is the reason for repeated seeking of pain responds well to and non-opioid medical help and excessive use of medica- analgesics. Insufficient control of pain can ments, especially analgesics. The drop in lead to the prolonged course of the morbid physical activity and mental decompensation state (or postoperative state) and to undesir- cause gradual isolation of the patient and de- able emotional stress, which has a negative velopment of abnormal, often purposeful, influence on haemocoagulation, immune painful behaviour. Behavioural and psycho- system activity, cardiovascular and gastroin- social influences play an important role in the testinal function. processing of pain of whatever origin; how- Chronic pain This is pain defined as fol- P ever, their importance rises with chronicity. lows: Chronic pain is therefore considered a com- • pain lasting longer than expected healing plex bio-psycho-social phenomenon. time, Pain has four components: • pain associated with a chronic disorder, 1. sensory-discriminative Most information where the aetiology has not been ascer- is available about this component; when tained, and where the pain arises, how it is trans- • pain related to neoplastic disease – this is mitted and how it is processed in the cen- assigned as a separate type of pain. tral nervous system (CNS). Chronic pain is not strictly time-limited, with 2. affective-emotional Less knowledge is as much as 1/3 of patients not expressing known on this though the tracts transmit- signs of somatic disease. The activity of the ting it to the brain are understood. This autonomic nervous system decreases gradu- component determines interindividual ally with the duration of pain. Mental chang- variability (one is a coward, another a es, such as sleep disturbance, anxiety and de- hero). It is genetically determined, but pression, become prominent. Behaviour and anything can be substantially influenced personality changes appear. The physical sta- by education. tus deteriorates – muscle hypotrophy and at- 3. vegetative (autonomic) This is very impor- rophy, contractures, weakness, reduction of tant in visceral pain. Any kind of pain, es- mobility and immobilisation. The patient is 167 gradually isolated from working, social and one branch goes to the skin and the other to family life. Approximately 20% of patients try visceral organs or muscles. The to commit suicide. in the internal organs are activated by differ- The treatment of chronic pain is more ent stimuli (traction, ischaemia, distension, complex than acute pain. The aim is to inter- etc.). The visceral pain responds poorly to fere with all basic pain mechanisms – physio- analgesics. logical, behavioural, as well as cognitive. In Neuropathic pain This results from damage addition to drug therapy, which by itself is of the peripheral or central nervous system not so effective, psychotherapy and other (somatosensory tracts). It can be associated non-pharmacological procedures, such as with nerve dysfunction followed by distur- acupuncture, rehabilitation, transcutaneous bance of sensitivity or weakening of muscles electrostimulation etc, play an important role. innervated by a damaged nerve. Absence of The multidisciplinary approach of healthcare afferent inputs in the disrupted nerve causes and non-healthcare professionals is required. the reorganisation of central circuits. Tasker Chronic pain is not a uniform group. It is introduced the term “de-afferentation pain” often categorised according to length of time for states characterised by neuropathic pain. and pattern such as permanent, progressive, Interruption of the afferent nerve may cause recurrent or cyclic pain, etc. peripheral and central de-afferentations on The term “benign chronic pain” was intro- all levels of the CNS (dorsal horns, thalamus, duced in 1970 to distinguish a non-neoplastic and cortex). As a consequence of a lesion in pain. It should be considered of less severity sensory tracts, the central inhibitory control, with a view of intensity, course and progno- activated by stimuli from the periphery, is of- sis. Malignant pain is pain associated with ten decreased. It manifests by an increased oncological disease response to afferent stimuli as hyperesthesia, From a neurophysiological perspective hyperalgesia and allodynia. It is mostly un- (pain classification according to Lind- pleasant, burning, and often transposed. blom): Neuropathic pain responds weakly to analge- Nociceptive pain This is elicited by stimula- sics, while adjuvant treatment is more effec- tion of nociceptors in the somatic and vis- tive (tricyclic antidepressants, anticonvul- ceral organs. sants, NMDA receptor blockers). According Somatic pain The result of activation of no- to the location of damage, it can be divided ciceptors in somatic organs (tendons, mus- into central and peripheral. P cles, capsule, periosteum). It is mostly well Psychogenic pain It may have a psychogenic localised, dull, but occasionally sharp. It re- cause (anxiety), can be related to a psychoso- sponds well to all analgesics. matic disease, or may be an associated sign of Visceral pain The perception of pain is a mental disorder (schizophrenia). deep, prickly, gripping, or possibly spasmod- ic. Unlike somatic pain it is more diffuse – Painful arc Shoulder pain elicited on ab- likely as a consequence of the prevalence of duction of the arm between 60 and 120°. Pain C-fibres over A-delta fibres in the visceral af- occurring in this range is typical of supraspi- ferent nerves. It has a prominent autonomic natus tendon or subacromial bursa involve- component – sweating, nausea and hypoten- ment. Pain at the end of the arc between 160 sion. It is associated with reflex muscle and 180° indicates an affection of the acro- cramps and a secondary hyperalgesic phe- mioclavicular joint. nomenon due to sensitisation of dorsal horn neurons. Often it is transmitted to cutaneous Palindromic rheumatism Characterised regions innervated by the same nerve roots as by recurrent attacks of painful oedema the affected organs. The propagation of pain around the joints and soft periarticular struc- can be explained by a convergence of cutane- tures. The disease occurs mainly between the ous and visceral afferent horn ganglia, where third and sixth decade and equally affects panniculitis 168

both males and females. Attacks of palindro- Pannus Proliferating synovial tissue with mic rheumatism start suddenly, usually in- activated fibroblasts and inflammatory cell volve one to three joints and last for hours or infiltration (lymphocytes, plasma cells, acti- days before spontaneous remission occurs. vated macrophages and dendritic cells) which Prognosis is good, joint damage does not oc- intensively grows into the surrounding bone cur. on the joint margin causing local osteolysis. Clinical symptoms: The typical picture of bone erosion therefore • Short course of arthritis, develops. A frequent finding of multi-nucle- • Recurrent episodes of disease, ated cells with phenotypic characteristics of • Joints remain radiologically normal (non- osteoclasts in the interface between bone and destructive). pannus led to the presumption of direct in- volvement of the cells derived from the pan- Panniculitis Inflammation of subcutaneous nus in bone resorption. The focal inflamma- fatty tissue manifesting by the formation of tion in rheumatoid arthritis affects subchon- inflamed nodules, particularly in the lower dral and juxta-articular bone, where pannus extremities, thorax and gluteal area. It mainly development begins. affects women in early and middle age. Many forms of panniculitis with or without vasculi- Paracetamol One of the most frequently tis are described, including acute lobular used non-opioid analgesics. Missing an anti- panniculitis without vasculitis (Weber-Chris- inflammatory effect, it cannot be included in tian disease), and panniculitis associated with the group of non-steroidal drugs (NSAIDs), a connective tissue disease, pancreatic disease even though recently published trials suggest (pancreatitis or pancreatic carcinoma) or that paracetamol, particularly in the central lymphoma. It consists of a heterogeneous nervous system, inhibits the COX-3 isoen- group of symptoms, in which inflammation zyme. It does not affect the production of in fatty tissue occurs, particularly in subcuta- physiologically important prostaglandins in neous fatty tissue. The histopathologic pic- the stomach, bowel or platelets and therefore ture shows infiltration of neutrophils or lym- there are none of the typical adverse effects phocytes, later followed by histiocytic infiltra- observed when using NSAIDs such as in- tion, and possibly large cell infiltration. Lesions creased risk of gastrointestinal bleeding or an settle by fibrosis formation. In the phase of his- acute decrease in renal function. A daily dose P tiocytic infiltration, panniculitis can have higher than 5 g/day may cause fatal liver im- the property of granulomatous inflammation. pairment. The analgesic and antipyretic effect Subcutaneous fatty tissue has a lobular struc- is comparable to that of aspirin. Paracetamol ture. Central arteries pass through the fatty has neither an anti-inflammatory nor anti- lobules forming branches of arterioles and aggregate effect. The analgesic properties of capillaries, from which the blood is conducted paracetamol will last for around four hours through venules located in septa between par- due its short half-life of about two hours. Ad- ticular lobules. Panniculitis affecting venules ministration of higher doses (more than 2 in the septum between lobules can be sche- grams a day) may cause prolongation of the matically classified as septal (non-necrotiz- prothrombin time. Compared to aspirin, par- ing) panniculitis and lobular (necrotizing) acetamol has a lower ceiling effect. It can pass panniculitis, which affects the artery passing through the blood brain barrier and only a through the centre of the lobule. small amount is bound to plasma proteins (approximately 10%). It is metabolised in the Panniculosis A non-inflammatory disease liver and is eliminated via the kidneys in the of subcutaneous tissue incorrectly known as form of glucuronides and sulphates. cellulitis. It is a constitutional disorder of fatty tissue deposit predominantly occurring in Paraesthesia Decreased or tingling sensa- women during the menopause. tion of skin in particular dermatome. 169 parvo virus arthritis

Paraffin Wax A mixture with approximately activity of osteoclasts. The release of calcium 5% of paraffin oil, heated to 55 to 60°C, is is associated with the release of phosphate, used for therapeutic purposes. The heat that bone matrix and collagen. The changes in is released during transformation from a liq- bone with primary hyperparathyroidism are uid to a solid state is utilised. The manner of complex and include a subperiostal osteore- use includes soaking the limbs in paraffin sorption, osseous cysts, bone demineralisa- wax, transferring the paraffin wax using a tion and acroosteolysis. Spontaneous frac- paintbrush or suitable tissue soaked several tures are frequent complications. times in the paraffin wax and, most favourably, using plastics. It is necessary to keep the skin Parathormone Drug – Teriparatide The dry in the area of paraffin wax administration only pure osteoanabolic drug indicated for as different tolerability of the skin to paraffin the treatment of severe postmenopausal os- wax (60°C) and water (46°C) may cause burns. teoporosis (previous fracture and T score The mixture of paraffin with peloid sheets, so- <2.5 on BMD scan). A synthetic recombinant called parafango, is also frequently used. They aminoterminal fragment (1–34) of parathor- are indicated for chronic pain of the musculo- mone is used. When used in a therapeutic skeletal system, non-inflammatory arthrosis, dose of 20 micrograms/day subcutaneously, it extra-articular rheumatism, vertebrogenic does not produce osteoporosis as occurs in pain syndrome, , and hyperparathyroidism, but instead the osteo- rarely also for inactive ankylosing spondylitis blastic production of growth factors IGF-1 as a form of pre-heating before exercise. and TGF-β increases, without reducing the production of osteoprotegerin. Teriparatide Paraproteins Monoclonal immunoglobu- reduces the risk of vertebral and nonvertebral lins present in the plasma of patients with fractures and greatly increases BMD in the multiple myeloma or Waldenström‘s macro- most at-risk groups of patients. Treatment globulinaemia (gammopathy), monoclonal significantly improves pain and quality of life. gammopathy of undetermined significance, It is administrated for 18 months. cryoglobulinaemia, plasmacytoma, amyloi- dosis, heavy chain disease, lymphomas, leu- Paroxysmal nocturnal haemoglobin- kaemias and some other diseases. uria A rare form of haemolytic anaemia with intravascular haemolysis during sleep due to Parathormone The most important regu- a greater sensitivity of the erythrocytes to P lator of extracellular calcium, but also has a haemolysis by an autologous complement. As direct effect on bone. It influences the hy- well as affecting erythrocytes, neutrophils droxylation of vitamin D and reabsorption of and thrombocytes also have a higher sensitiv- calcium in the kidneys. The effect of PTH on ity to the haemolysis. The cytoplasmic mem- bowels is indirect via calcitriol (increase of branes of these cells are deficient in DAF, the calcium resorption from the bowel). decay-accelerating factor that protects against Parathormone affects calcium and phos- damage after spontaneous activation of com- phate metabolism via several mechanisms: plement. The disorder is characterised by • it stimulates the release of calcium and leukocytopenia, thrombocytopenia, and iron phosphate from bone, deficiency and often by the presence of blood • it stimulates the reabsorption of calcium (haemoglobin) in the urine from the glomerular filtrate and loss of phosphate to urine, Parvo virus arthritis Parvo virus B19 was • it stimulates the renal synthesis of 1,25- associated with clinical disease in the early (OH)2 vitamin D3 and thus the gastrointes- 1980’s. In children, it produces slapped- tinal absorption of calcium and phosphate. cheek disease (fifth’s disease, erythema in- A prolonged overproduction of parathor- fectiosum) but in female adults, it can pro- mone leads to an increase in the number and duce an acute arthralgia/arthritis mimicking pathergy phenomenon 170

rheumatoid arthritis. Symptoms usually settle soluble proteins including circulating im- within three weeks, though occasionally last mune complexes and as a fusogen in hybri- up to six months. The diagnosis can be con- doma technology of monoclonal antibod firmed by IgM antibodies to parvo virus production. within the serum. Only symptomatic treat- ment and reassurance is required, though Peptide fragments of collagen type I rarely it can produce a transient aplastic anae- (NTX, CTX) NTX and CTX are peptide frag- mia and miscarriage in pregnancy. ments of type I collagen from the telopeptide region of the collagen molecule used as a Pathergy phenomenon Scratching the measure to assess bone loss. skin using a sterile needle evokes a strong erythematous reaction with induration. The Perforins Glycoproteins with cytolytic test is positive in active Behcet’s disease as properties are located in the granules of cyto- a sign of skin impairment (vasculitis). It is toxic T lymphocytes and NK cells. After re- present more frequently in the Turkish popu- lease to the surface of target cells, perforins lation than in Europeans and Americans. undergo polymerisation to form polyperforins which perforate the phospholipid double layer Pauciarticular juvenile idiopathic ar- of the cytoplasmic membrane. The damaged thritis → see Juvenile idiopathic arthritis membrane causes cell death and lysis. The C9 (JIA) component of complement, defensins of neu- trophils, cytolysins of eosinophils as well as PCR (polymerase chain reaction) A certain viruses, microbial toxins (e.g. strep- laboratory technique that makes it possible in tolysin O) and insect toxins (e.g. mellitin of an automated way to gain millions of copies bees and wasps) or cation detergents act by a of a fragment of a DNA molecule by in vitro similar mechanism. enzymatic replication. The segment of dou- ble-chain DNA isolated from, for example, Peripheral Quantitative Computerised lymphocytes and containing the required Tomography (pQCT) The measurement gene is marked by complementary oligonu- of peripherally localised bones without a su- cleotides (primers). The segment undergoes perposition of the soft tissues. It is measured amplification by repeated cycles of denatur- in the area of forearm. Although a relatively P ation, cooling and primer attachments and simple method allowing the separate evalua- their subsequent prolongation using thermo- tion of trabecular and cortical bone as well as stable DNA-polymerase. One cycle takes ap- the examination of certain morphological pa- proximately 3 minutes and results in duplica- rameters it is, however, currently (due to ex- tion of a DNA fragment. This means that pense and high dose radiation) infrequently within 60 minutes thousands of copies of one used in the clinical practice. DNA fragment can be produced. PCR can be used in medical and biological research for Personage-Turner syndrome An acute prenatal and common diagnostics of genetic, neuropathy of the brachial plexus of unknown infectious and other diseases, in determining origin, which particularly affects young men. their pathogenesis, in the genetic determina- The pain radiates into the shoulder and scapu- tion of individuals and populations, and in la. Hyperaesthesia may develop in the arm and resolving the most fundamental problems of shoulder area. Passive ranges of movements of contemporary molecular biology and medi- the shoulder are normal but often paresis of cine. shoulder muscles develops. Depending on the particular muscles affected, active movements PEG Abbreviation for polyethylene glycol; a of the shoulder are limited. EMG confirms a synthetic molecule with variable relative mo- neurogenic lesion. The disease recovers spon- lecular weight. It is used for precipitation of taneously over several months. 171

Treatment: Bed rest, analgesics, gradually aged cell organelles), the process is referred to increased doses of oral glucocorticoids, vita- as autophagia. min B1, therapeutic exercise and physical therapy. Phalen’s test Maximal forced flexion of the wrist evokes paraesthesia in fingers on the ra- Perthes Disease → see Legg-Calve-Perthes dial aspect of the hand. Along with Tinel’s Disease sign, it is positive in carpal tunnel syndrome.

Pes equinus The foot is in a vertical posi- Pharmacorehabilitation A model of the tion, with toe tip towards the ground. If the synergic effect of two therapeutic procedures condition is caused by paresis, it can be cor- – rehabilitation and pharmacotherapy. The rected by a peroneal splints or orthosis. Fixed principle lies in relieving the patient of rest- pes equinus (with shortened Achilles tendon) ing pain and reducing exertional pain to a usually requires surgical intervention. bearable level. It plays an important role in chronic disorders such as rheumatic diseases. Pes excavatum (cavus) The longitudinal For example, rehabilitation in acute or chron- arc is significantly elevated, the plantar ic rheumatoid arthritis should be performed aponeurosis is shortened, and dorsal flexion despite the presence of certain limiting fac- at the ankle is limited. It is usually combined tors, while respecting the diurnal variation of with mallet toes. Treatment consists of arch symptoms, such as pain, stiffness and fatigue. underpacking, which allows the aponeurosis Analgesic treatment is adjusted so that the to stretch. therapeutic maximum is reached at the time set for rehabilitation. Pes varus The opposite of pes planovalgus or flat feet. The ankle is in a varus position Phosphate → see Phosphorus with supination and adduction of the anterior part of the foot. An external wing heel is ap- Phosphorus The sixth most frequent ele- plied as a treatment. ment of the human body and is present as phosphate in biologic systems. An adult body PET → see Positron emission tomography contains approximately 600 mg of phospho- (PET) rus. The distribution of phosphate in the in- dividual tissues differs substantially from that P Pfeiffer’s disease → see Infectious mono- of calcium. Approximately 85% of phospho- nucleosis rus is deposited in crystalline form in the skeleton. The other 15% is found in the soft Phagocytosis A protective mechanism that tissues and extracellular fluid. 90% (55% in belongs to the fundamental elements of natu- ionised form + 35% in complexes) of plasma ral immunity when phagocytes ingest micro- phosphate is ultra filtratable and only 10% is organisms and other particles with a diameter protein bound. The serum phosphate level greater than 0.5 μm. It is a complex process varies more than the serum calcium level consisting of several concurring intermediate with a circadian rhythm leading to 50% of the steps. The disturbance of one of them leads to value during the day. a deficiency of phagocytosis. The ability to Phosphate, similarly to calcium, plays a phagocytose is possessed by all nuclear cells structural role in the skeleton, except that it is in the human body, but protective phagocy- also contained in membrane phospholipids, tosis is performed mainly by professional nucleic acids, phosphoproteins, energy-rich phagocytes. If particles from the intercellular compounds (ATP, creatine-phosphate) and environment are ingested, the process is re- in the co-factors of some enzymes (NADP, ferred to as heterophagia; if the ingested ma- phosphoinositides). Basic physiological pro- terial comes from surrounding cells (dam- cesses such as gene regulation, modulation of physiatrics 172

enzymatic activities and maintenance of the elbow, temporomandibular joint and hands. integrity of cellular membranes are amongst The affected joint is swollen; roughened syn- its functions. Phosphate is irreplaceable in ovia resembles a foam structure. Synovial buffering systems to provide stability of the fluid is xanthochromic or sanguinous, with acid base balance. It also plays an important cell counts around 3,000/mm3, mainly mono- role in the metabolic processes of intermedi- nuclear cells. ary metabolism and in energy transmission. Biopsy of synovial membrane is diffusely brown with deposits of haemosiderin and the Physiatrics A field of medicine engaged in presence of multi-nuclear large cells. Opin- utilising various physical agents for the diag- ions about malignant transformation are still nosis, treatment and rehabilitation of various not consistent. Treatment consists mainly of disorders, or in the prevention of physical de- rheumatologic and orthopaedic interventions formities and disabilities. In physiological with subtotal synovectomy. terms, the reactions to these physical stimuli are protective reactions used by physiatry to Pilates technique → see Exercise tech- provoke one’s own reactions of the body. The niques effect of physiatric stimuli depends on the re- activity of the body, and also on the kind, PINP (procollagen I N-terminal pro- form, intensity and duration of the physical peptide) → see Procollagen peptides stimulus. Piper fatigue scale (PFS) → see Instru- Physiotherapy – forms Physiotherapy ments of assessing (health status measure- can be ments, outcome measurement) • natural For example solar radiation, atmo- spheric pressure, atmospheric electricity, Plantar fasciitis → see Calcaneal Spur effects of gravity, thermal climatic effects, natural radioactive radiation, magnetic ra- Plantogram An area print of the foot. It is diation. obtained by tracing the contour of the foot of • artificially prepared The sources of various a standing patient with a pen pointing verti- energies: mechanic, acoustic, electric, ther- cally on the paper. A plantogram is used to mal; sources of magnetic and electromag- obtain prints of the foot, where the patient P netic radiation. Also included are certain stands on the paper fixed above the base satu- manual activities such as classical and re- rated with paint. The plantogram shows the flex massages, passive movements, posi- distribution of pressures on the sole of the tioning, manipulation, mobilisation, acu- foot in the standing position. puncture, acupressure and active motion exercises – therapeutic physical training. Plasmocytoma and its musculoskele- tal symptoms (MM; multiple myelo- PICP (procollagen I carboxyterminal ma) One of the most frequent malignant propeptide) → see Procollagen peptides haematologic diseases characterised by ma- lignant transformation of mature plasma cells Pigmented A and their precursors (B lymphocytes, lym- rare benign, slowly progressive disease of un- phoplasmacytoid cells). known aetiology caused by proliferation of Clinical symptoms: Systemic symptoms synovial cells and mesenchymal connective (fatigue, bone pain, weight loss and frequent tissue of affected joints, tendon sheaths and infections) are prevalent in advanced disease. bursae. It is characterized by villous and nod- Depending on the grade of infiltration of ular growth of synovia. It mainly affects bone marrow with myeloma cells and their young to middle-aged adults. Most frequently metastatic and secretory activity, the follow- it affects the knee, hip, less frequently wrist, ing symptoms occur: 173 polyarteritis nodosa (PAN)

• haematologic symptoms (anaemia, throm- POEMS syndrome An acronym for this bocytopenia or pancytopenia due to in- multisystem multiorgan disease, which in- creased numbers of atypical plasma cells in cludes polyneuropathy (P), organomegaly (O), bone marrow with subsequent reduction endocrinopathy (E), monoclonal gammopa- of normal haematopoesis), thy (M) and skin abnormalities (S). Described • symptoms arising from paraproteinemia for the first time in 1956 by Crow, in 1968 by and a general increase in plasma protein Fukase and in 1983 by Takatsuki, it is also concentration markedly increased ery- known as Crow-Fukase-Takatsuki syndrome. throcyte sedimentation rate, hyperprotein- The major criteria consist of polyneuropathy emia, proteinuria, increased serum viscos- and monoclonal gammopathy (paraprotein- ity, increased concentration of monoclonal aemia), with minor criteria consisting of scle- Ig-paraprotein IgG, IgA, rarely IgM, IgE, rotic bone lesions, organomegaly, oedema, IgD and more frequently kappa, endocrinopathy, skin changes, and papilloe- • bone changes on X-ray with osteolytic le- dema. The complete form of POEMS syn- sions (approximately in 2/3 patients), path- drome requires the presence of at least the ological fractures or diffuse osteoporosis; two major criteria, otherwise it is referred to increased osteoclastic remodelling and sub- as the incomplete form. sequent bone resorption lead to hypercal- The neuropathy is of a distal, symmetric caemia and increased levels of collagen sensomotor type, with proximal progression. degradation products. Electromyography reveals denervation, de- myelination and axonal degeneration. Hepa- Platelet-derived growth factor (PDGF) tosplenomegaly and lymphadenopathy occur. A polypeptide acting as a systemic and local Symptoms and signs of endocrinopathy in- regulator of tissue growth. Its function is sim- clude impotence, testicular atrophy, gynaeco- ilar to FGF. It stimulates the replication of os- mastia, amenorrhea, hyperprolactinaemia seous cells and collagen synthesis. The syn- and hyperoestrogenaemia. Hypothyroidism thesis of locally produced PDGF is regulated and diabetes mellitus are usually present. The by growth factors. paraproteinaemia involves immunoglobulin IgA and free chains of the lambda type in 90% Plyometric exercises The principle of the of patients. Markers of increased osteoclastic exercise is the stretch-shortening cycle of resorption may be present. Skin changes in- muscle movement. Before the prime move- clude hyperpigmentation, hyperkeratosis, hy- P ment, e.g. flexion, the individual performs a pertrichosis, and Raynaud’s phenomenon. short quick movement in the opposite direc- tion, i.e. extension. It is applied mainly in Polarised light → see Birefringence (Dou- sports medicine when rehearsing extreme ex- ble refraction) ertion, e.g. jumps. Polyarteritis nodosa (PAN) A disease of Podiatry The field of health care involved in small and medium-sized arteries character- the study and treatment of disorders and de- ised by the involvement of all three layers of formities of the feet, ankle and lower leg. the vessel wall, leading to the formation of multiple , thrombi and infarctions. Podogram Examination of the footprint of Its aetiology is unknown but deposition of the bare planta pedis (sole) in the normal immune complexes in arterial walls is con- standing position. A podogram provides in- sidered to be an important pathophysiologi- formation on the patient’s skeletal and mus- cal mechanism. This inflammatory reaction cular system. A podogram has geometric (in- activates complement and neutrophils (im- forming mainly about body height) and dy- munopathology). It may be associated with namic signs (informing about body weight). certain viral infections such as hepatitis B. At present, two types of PAN are known: polyarthralgias 174

1. typical PAN is defined as necrotising in- amide, gold, thiazides and also termination flammation of medium and small sized of steroid therapy), arteries without vasculitis affecting arteri- • para-neoplastic syndrome, oles, capillaries or venules, and without • changes of atmospheric pressure (weather, glomerulonephritis, caisson disease), 2. microscopic polyarteritis or more precisely • joint hyperlaxity, polyangiitis is a necrotising vasculitis with • incipient generalised osteoarthrosis. minimal or total absence of immune com- Psychogenic rheumatism is a psychosomatic plex deposits; affects small vessels (capillar- disease with arthrodynia as a major symp- ies), venules or arterioles; concurrently, tom. Inflammatory symptoms are absent and necrotising arteritis of small and medium- organic disease can be ruled out. The patient sized arteries can be present. This second must be assured that he/she does not suffer form occurs considerably more frequently. from inflammatory joint disease. Depending Clinical symptoms: Apart from systemic on need, psychiatric referral and treatment symptoms, various polymorphic exanthemas should be considered. with typical livedo reticularis, non-specific arthralgias and even arthritis, involvement of Polyarticular juvenile idiopathic ar- peripheral nerves (asymmetric polyneuropa- thritis → see Juvenile idiopathic arthritis thy), kidneys (renal impairment and hyper- (JIA) tension) and gastrointestinal tract (bowel in- farction) can occur. Polychondritis → see Relapsing polychon- dritis Polyarthralgias Concurrent, mainly sym- metric, pain in several joints is referred to as Polymerase chain reaction → see PCR polyarthralgias, as long as symptoms of the (polymerase chain reaction) inflammation process are absent. Most frequent causes include: Polymorphism A phenomenon in biology • viral diseases, particularly their prodromal which occurs when several morphological period (e.g. hepatitis, rubella, influenza, forms exist within a single population of the AIDS), same species of organism. It also occurs at the • diffuse connective tissue diseases, polyar- level of protein molecules, when it is referred P thritis, particularly in prodromal period, to as genetic polymorphism. A locus of a par- Sjögren’s syndrome, systemic lupus erythe- ticular gene in individuals of a particular matosus, polymyositis, rheumatoid arthri- population may contain one of several vari- tis, ants (alleles). They therefore encode different • polyarthralgias associated with internal variants of a corresponding protein product. diseases (ulcerative colitis, Crohn’s disease, The major histocompatibility complex multiple myeloma, hypertrophic pulmo- (MHC) is considered to be the most poly- nary osteoarthropathy = HPOA, chronic morphic system. pancreatitis, myxoma of the heart, etc.), • metabolic diseases (hyperlipidaemia, Polymorphonuclear leukocytes Not an haemochromatosis), entirely clearly used term by which the ma- • endocrine disorders, menopause, hyper- jority of authors indicate neutrophils, where- thyroidism, hypothyroidism, hyperpara- as others indicate granulocytes. thyroidism, Cushing’s disease, acromegaly, • bacterial infections, sepsis, chronic infec- Polymyalgia rheumatica A clinical syn- tions, infectious foci (teeth, tonsils), bacte- drome, affecting individuals over the age of rial endocarditis, 50, characterised by myalgias and stiffness of • drugs (retinoids, cimetidine, fluorides, qui- the shoulder and/or pelvic muscles and is of- nolones, hydralazine, β-blockers, pyrazin- ten accompanied by non-specific systemic 175 post-isometric relaxation symptoms. The rapid response of clinical The position of the back is alternated with symptoms to low doses of glucocorticoids is the prone position. characteristic of this disease. 2. Either preventive splints fix the local Myalgias and muscle stiffness are usually standstill positioning of a joint affected by symmetrical, most often worse after rest and inflammation or if there are existing con- in the morning. Muscle strength is unaffected tractures must be positioned in a set of but may be limited by myalgias when exam- corrective splints. The period of corrective ining the patient. Musculoskeletal symptoms splinting is 5 to 30 minutes. The position- are frequently accompanied by systemic ing of affected joints can also be secured symptoms like fatigue, tiredness, loss of ap- by traction, which at the same time en- petite, loss of weight, and fever. Raised eryth- ables performance of movement therapy rocyte sedimentation rate (ESR) is the most without gravity. dominant laboratory test, other acute phase reactants (plasma viscosity, CRP) may be el- Positron emission tomography (PET) evated. Glucocorticoid treatment is necessary A method of nuclear medicine imaging based for several months sometimes up to two on the detection of photons of gamma-radia- years, though lifelong treatment may be tion, which are emitted during transforma- needed in some patients. tion of positron-emitting radioisotope that are administered into the body for diagnostic Polymyositis → see Idiopathic inflammato- purposes. These radioisotopes can be incor- ry myopathies (IIM), Non-inflammatory porated into molecules of many biologically myopathies active substances and thus enable monitoring of their metabolism and distribution in vari- Polyostotic fibrous dysplasia → see ous parts of the body. McCune-Albright syndrome (polyostotic fi- A detection scanner measures the distribu- brous dysplasia) tion of specific activity of the radio indicator in the body. A final tomographic picture can Poncet’s disease A reactive arthritis asso- be achieved from this data using computer ciated with acute tuberculosis. The presence analysis to create numeric reconstruction al- of mycobacterium in the joint has not been gorithms resulting in a three-dimensional proved. Synovial biopsy does not reveal myo- picture or a map of functional processes bacterial involvement, but shows non-specif- within the body. P ic inflammation. Treatment: Non-steroidal anti-inflamma- Post-dysenteric arthritis A sterile reac- tory drugs are administered in addition to tive oligoarthritis may occur 1 to 3 weeks af- treating the primary disease. ter dysentery induced Shigella flexneri infec- tion, and usually settles within a few weeks. Popliteal cyst → see Baker’s cyst Post-isometric relaxation This belongs Positioning Two basic positions are used in to neuromuscular techniques. Apart from rheumatic diseases: isometric muscle activation, it utilises main- 1. General standstill regime in bed when pa- ly inspiration and looking in a certain direc- tient is lying on his back, his upper ex- tion as a facilitating manoeuvre and expira- tremities are at an abduction of 30°, fore- tion while looking in the opposite direction arms in a middle position between prona- as an inhibitory manoeuvre. The initial po- tion and supination, with mild extension sition of particular segments of the locomo- of the wrists; lower extremities at an ab- tion system lets us target the facilitation and duction of 15°, knees straight and dorsi- inhibition into particular muscles or muscle flexion of 90° at ankles. The head rests on groups. a small pillow; shoulders are off the pillow. postmenopausal osteoporosis (type I) 176

Postmenopausal Osteoporosis (type I) the agent causing transitory diarrhoea with Oestrogen deficiency is regarded as the main mesenteric lymphadenitis, and after 1 to 3 pathophysiological mechanism for the devel- weeks oligo- or polyarthritis develops, often opment of postmenopausal osteoporosis. Its accompanied by myalgia, endocarditis, ery- onset is typically 15–20 years after the meno- thema nodosum, conjunctivitis, lymphade- pause with trabecular bone being mainly af- nopathy and splenomegaly. Arthritis of the fected. The main clinical manifestations are knee and/or ankle joints is characteristic. The fractures of bones with a higher trabecular joint is swollen and warm, and often associ- bone fraction (distal forearm, vertebrae), but ated with a fever. also involves cortical bone in the elderly, pre- Laboratory diagnostics: Besides evidence disposing to hip fractures. of inflammatory activity, the dynamics of the rise of anti-Yersinia antibody titre is crucial. Postmenopausal Osteoporosis – treat- Unilateral sacroiliitis can be observed. ment guidelines • general treatment and recommendations: a Prednisolone → see Glucocorticoids healthy lifestyle with adequate physical ac- tivity, sufficient dietary supply of calcium Priessnitz compress A cold compress at- and vitamin D, and prevention of falls. tached to the surface of the body in order to Minimising risks by avoidance of drugs achieve better local blood perfusion. The first with adverse effects on balance and calci- layer consists of a wet compress, the second um metabolism (hypnotics, long-term an- consists of waterproof material and the third ticonvulsants, anticoagulants, phosphate- one consists of a dry warm compress. The binding antacids, glucocorticoids, and oth- steam effect is thus achieved. Local vasodila- ers) are also important. tation develops within one hour (local hyper- • basic treatment: calcium and vitamin D aemia). In rheumatology, the Priessnitz com- supplementation, press is used particularly in degenerative dis- • specific treatment with antiresorptive agents ease of joints. Cold herbal infusion may be and stimulators of osteoformation. This used instead of cold water; thereby the steam type of treatment must be optimised to the effect is amplified (so-called Tripes com- age, health status and contraindications for press). Vincenz Priessnitz, also written the individual patient. Prießnitz, (1799–1851) lived in Austrian Sile- P sia (now Czech Republic) and is considered Post-Salmonella reactive arthritis This as the founder of hydrotherapy. reactive arthritis occurs 1 to 2 weeks after in- fection (diarrhoea) and is similar to post-Ye- Primary immunodeficiency Immuno- rsinia arthritis. In most cases the inflamma- deficiency is defined as a defect of the im- tory process affects the knee and/or ankle mune system due to the absence, decrease or joints, and fever may occur. The diagnosis is functional alteration of one of its compo- confirmed by a rising titre of antibodies nents. It is classified as primary or secondary against salmonella. The infectious agent can immunodeficiency. Primary immunodefi- be cultured in the stools. ciencies are usually genetic disorders due to a defect in embryonic development, an enzyme Post-vaccination arthritis In isolated defect, or of unknown cause. Secondary im- cases, arthritis with a clinical picture of reac- munodeficiencies develop due to impairment tive arthritis with a tendency to gradual re- of the existing evolved immune system as a gression occurs after administration of cer- consequence of various pathological condi- tain vaccines (rubella, BCG, hepatitis B). tions including malignancies, metabolic dis- eases, malnutrition, and drugs. Primary anti- Post-Yersinia reactive arthritis Yersinia body immunodeficiency comprises 50–70% of enterocolitica or Yersinia pseudotuberculosis is all primary immunodeficiencies. 177 progressive type of myositis ossificans (myositis ossificans progressiva)

Clinical symptoms: Both primary and Procollagen peptides Procollagen is a secondary immunodeficiencies have basical- precursor of collagen and the terminal pep- ly the same symptoms with recurrent and tides are released via proteolytic cleavage into chronic infections and frequently are associ- the circulation prior to the formation of col- ated with autoimmune diseases, e.g. perni- lagen fibrils. Procollagen has accessory pep- cious anaemia, autoimmune haemolytic tides on the C- and T-terminal ends, which anaemia, idiopathic thrombocytopenic pur- are referred to as the procollagen I N-termi- pura, thyroiditis, chronic active hepatitis, sys- nal propeptide (PINP) and procollagen I car- temic lupus erythematosus, Sjögren’s syn- boxyterminal propeptide (PICP). The serum drome, juvenile idiopathic arthritis or der- procollagen I carboxyterminal propeptide matomyositis. Aseptic non-erosive polyartic- (PICP) has been monitored as a marker of ular arthritis, suggestive of rheumatoid osteoformation. Its value falls in postmeno- arthritis, occurs in 10–30% of patients with pausal women. Antiresorptive treatment, as hypogammaglobulinaemia. Arthritis can be well as glucocorticoids, lowers the PICP con- the first clinical symptom of primary hypog- centration. Determination of these peptides ammaglobulinaemia. is utilised in the monitoring of disturbances of collagen synthesis (decreased levels in os- Primary hyperparathyroidism An au- teogenesis imperfecta and hypercorticism). tonomous overproduction of parathormone. The most frequent causes comprise adenoma, Progressive osseous heteroplasia A hyperplasia and rarely carcinoma of the para- very rare condition of children in which pro- thyroid glands. Clinically typical changes of gressive ossification occurs in subcutaneous bones, nephrolithiasis, nephrocalcinosis, gas- and deeper connective tissue. In contrast to troduodenal ulcer disease, acute pancreatitis, fibrodysplasia ossificans progressiva, the he- arterial hypertension and arrhythmias may reditary skeletal malformation is absent (see be present. Typically, the serum and urinary myositis ossificans progressive) and hetero- calcium levels are elevated in the presence of topic ossification is of an intramembranous an elevated parathormone level. The concen- than an enchondral feature. Ankylosis and tration of phosphate is decreased in the se- local defect in growth of the affected extrem- rum and increased in the urine. Surgical re- ity develop when a joint is involved. The dis- moval of affected parathyroid glands is the ease is autosomal dominant with variable ex- treatment of choice. pressivity. P

Prion Currently, it is the smallest known in- Progressive type of myositis ossificans fectious particle consisting only of protein (myositis ossificans progressiva) A rare causing universally fatal diseases affecting disease manifesting itself by the ossification brain and neural tissues. Prion invokes both of skeletal muscles, muscle fascia and aponeu- human diseases (Kuru disease, Creutzfeldt-Ja- rosis. The onset of the disease frequently oc- kob disease, Gerstmann-Sträussler syndrome) curs in childhood and is often associated with and animal diseases (sheep scrapie, bovine typical inherited skeletal abnormalities (mi- spongioform encephalopathy or BSE, infec- crodactyly or absence of digits affecting ei- tious mink encephalopathy). Prions are usually ther the hands or feet). A familial occurrence species specific, but BSE most probably origi- has been observed with an autosomal domi- nated when beef-cattle were fed with meat- nant type of heredity with variable expressiv- bone powder prepared from animals that per- ity. ished from scrapie and so the species barrier Clinical picture: Initially localised oede- was broken and BSE prion developed. Similar- ma, erythema and warm sensation, particu- ly, new variant Creutzfeldt-Jakob disease devel- larly in the neck and paravertebral area, occur. oped when BSE prion was transformed into At this stage patients suffer from severe pain. human prion, invoking such a disease. The inflammation subsides slowly within prolapsed lumbar intervertebral disc 178

a few days and subsequently fibrous changes viduals with properdin deficiency (less than with consequent ossification develop in the 2% of normal serum level) are more sus- next few weeks. Replacement of muscle tis- pectible to infections due to Neisseria. sues and tendons by osseous tissue leads to contracture and deformity. After the develop- Prostacyclin A metabolite of arachidonic

ment of osseous tissue, the subsequent chang- acid (PGI2) with inhibitory effects on platelet

es are minimal. Restrictive lung disease may aggregation. PGI2 is an effective vasodilatator develop due to involvement of thoracic mus- and increases vascular permeability. It has cles. Subsequently, respiratory impairment opposite properties to those of thrombox- develops, and associated pneumonias are the ane. major cause of death in patients with the pro- gressive type of myositis ossificans. Prostaglandins A family of biologically ac- tive lipids, which originate from arachidonic Prolapsed lumbar intervertebral disc acid by the influence of the enzyme cyclooxy- Prolapse of the intervertebral disc often de- genase. They belong to the group of local velops as a consequence of its chronic degen- hormones and are present in virtually all hu- eration. The fibrous ring surrounding the in- man and mammalian tissues. They are in- tervertebral disc becomes diseased and the volved in regulation of inflammatory reac-

inner softer part of the disc bulges out. It tions, particularly (PGE2),

most frequently involves the L4-L5 and L5-S1 which is an endogenous pyrogen, causing va- segments. Compression of the nerve root of sodilatation, a drop in blood pressure and

L5 or S1 respectively, is caused by dorsolateral increased vascular permeability. PGD2 with prolapse of the disc. Multiple root impair- similar properties, except the pyrogenic prop- ments develop in the case of medial prolapse erty, is released in the anaphylactic reaction

of the disc (cauda equina syndrome). Urgent mediated by IgE. Both PGE2 and PGD2 in- surgical intervention may be necessary. hibit platelet aggregation, and in addition,

Clinical symptoms: Long-term compres- PGD2 inhibits the expression of MHC (major sion of the cauda equina invokes permanent histocompatibility complex) class II mole- of the pelvic muscles with subse- cules on the surface of T lymphocytes and quent urinary and faecal incontinence. The macrophages. The involvement of prosta- clinical picture of intervertebral disc protru- glandins in the regulation of the inflamma- P sion with spinal root compression is charac- tory response is based on the fact that a typi- terised by pain in the corresponding lumbar cal anti-inflammatory drug, such as acetyl- area and root zone of the lower extremity. salicylic acid, acts through the inhibition of Spasm of paravertebral muscles on the side of cyclooxygenase which is the enzyme respon- disc protrusion occurs. The root palsy is sible for the biosynthesis of prostaglandins. manifested by sensory impairment in the corresponding dermatome, and by muscle Prosthesis An artificial extension that re- weakness and decreased, eventually absent places a missing part of the body. Prosthesis reflexes in the corresponding myotome. can be classified as epiprosthesis, whose func- tion is cosmetic replacement such as dental Proliferating cell nuclear antigen → see or eye prosthesis, or endoprosthesis with re- Anti-PCNA/cyclin antibodies (proliferating placement of parts of the body such as heart cell nuclear antigen) valves, blood vessels and partial or total joint replacements. Properdin Also referred to as factor P. It comprises the regulatory function in the Proteases Proteolytic enzymes that are ca- course of activation of complement via the pable of degrading protein chains into minor alternative pathway. This pathway was previ- fragments, even into amino acids. Depending ously known as the properdin system. Indi- on the localisation of the peptide bond within 179 the polypeptide chain, proteases are divided ence of neutropenia and an increased num- into two main groups; endopeptidases which ber of large granular lymphocytes in the pa- break the peptide bond inside the protein tient’s blood and bone marrow. Most patients chain thereby forming polypeptide fragments also suffer from thrombocytopenia, anaemia and exopeptidases which break only termi- and splenomegaly. The syndrome usually af- nal amino acids or hydrolyse small oligopep- fects elderly patients, and recurrent infections tides. Peptidases are further divided into car- are prominent and the major cause of death. It boxypeptidases (split terminal amino acids can occur relatively early in the course of ar- from C-ending of polypeptide chain) and thritis. Treatment is difficult, but consists of a aminopeptidases (split N-terminal amino combination of immunosuppressive drugs acids). Usually a number of proteinases are (including methotrexate and cyclosporin) or involved in the degradation of one particular glucocorticoids, either alone or in combina- protein. tion with an immunosuppressive agent. Sple- nectomy is contraindicated. Proteasome A cellular organelle located in the cytoplasm which plays a significant role Pseudogout → see Chondrocalcinosis, in antigen presentation in which HLA class Crystalline-induced arthropathy I molecules are involved. It is of spherical shape and consists of 12 to 14 circularly ar- Pseudohypoparathyroidism A group of ranged units. Proteasome contains proteolyt- inherited diseases characterised by laboratory ic enzymes, which are able to break antigens findings typical for hypoparathyroidism (hy- into peptide fragments. The most favourable pocalcaemia, hyperphosphataemia but with fragments are those consisting of 8 or 9 ami- an increased concentration of parathormone no acid subunits as these can optimally bind (PTH)). Fuller Albright (American physi- to binding channels of HLA class I antigens cian, 1900–1969) first described the condi- (antigen presentation). tion in 1942. The condition is due to a lack of effect of PTH on the target organs (bone and Protein A A protein located in the cellular kidney). Under normal circumstances, PTH wall of Staphylococcus aureus. It is able to binds to a specific receptor on the plasma bind onto the Fc domains of IgG molecules membrane of target cells. This receptor is (in humans except for IgG3 subclass). It is connected with the signal effector molecule suggested that the protein protects Staphylo- on the inner surface of the membrane by reg- P coccus against IgG antibodies by disabling ulating nucleotide guanine (G), which is at- their interaction with complement and Fc- tached to protein (Gs protein). The synthesis receptors on the surface of professional of many ‘secondary messengers’, including phagocytes. Protein A is utilised in IgG anti- cyclic adenosine monophosphate (cAMP), body purification, in the detection of these initiates rapidly after the hormone binds to antibodies using ELISA techniques, and also the receptor with subsequent activation of as a polyclonal mitogen of B lymphocytes. adenylyl cyclase and other enzymes. Cyclic adenosine monophosphate activates protein Protrusion of intervertebral disc Pro- kinase A, as well as stimulating other en- trusion of intervertebral disc reveals similar zymes, ion channels and proteins. Adminis- symptoms as prolapse but the pathological tration of PTH in a healthy individual leads picture is different. In disc protrusion, the fi- to a significant increase in nephrogenic brous ring surrounding the intervertebral cAMP excretion into the urine. Neither the disc remains intact but deformation causes it concentration of cAMP nor phosphaturia in- to bulge out. creases in the group of diseases referred to as pseudohypoparathyroidism type I, due to Pseudo-Felty’s syndrome A variant of mutations of the Gs alpha gene (GNAS1). Felty’s syndrome characterised by the pres- The excretion of cAMP into the urine in- psoriatic arthritis (psa)(PsA) 180

creases but the phosphaturic response is miss- The therapeutic efficiency and toxicity of ing after oral administration of PTH in the azathioprine are dose dependent and increase case of pseudohypoparathyroidism type II. proportionally to the administered dose. How- ever, patients with a genetic deficiency of thio- Psoriatic arthritis (PsA) Arthritis associ- purine methyltransferase (TPMT) are at in- ated with psoriasis, usually seronegative and creased risk of severe myelosuppression and without rheumatoid nodules. liver toxicity, so studies are looking at the ef- Clinical symptoms: ficacy of measuring the TMPT genotype and/ • Arthritis, frequently asymmetric, affecting or enzyme activity in patients prior to treat- DIP (distal interphalangeal) joints and ment (Pavelka 2000). Azathioprine is well joints of the anterior chest wall tolerated in pregnancy and is not associated • Dactylitis with congenital malformations in humans. In • Enthesitis spite of data showing that only very small • X-ray signs of new bone formation and amounts transfer into breast milk, its admin- erosions of terminal phalanges istration during breast-feeding is not recom- • Typical extra-articular manifestations mended. (ophthalmic). Adverse effects: Gastrointestinal symp- toms such as nausea and vomiting, leukope- Psychogenic pain → see Types of pain nia and increased liver transaminases. Clinical symptoms resolve after withdrawal of treat- Purine analogues Azathioprine and ment. Long-term treatment with azathioprine 6-mercaptopurine belong to purine ana- is associated with a higher risk of malignan- logues. Currently, neither azathioprine nor cies, particularly haematopoietic and lym- 6-mercaptopurine is the drug of first choice phoreticular malignancies. in the treatment of rheumatoid arthritis (RA) but they both remain a valuable therapeutic Pyoderma gangrenosum A rare derma- option for RA when complicated by vasculitis, tological ulcerative disease of unknown ori- glomerulonephritis or when other DMARDs gin which belongs to the group of non-infec- are not tolerated. tious neutrophilic dermatoses. Dosage: Azathioprine in RA is adminis- Clinical symptoms: tered orally in a daily dose from 1.5 to 2.5 mg/ • Typical lesions sometimes develop after P kg (75 to 200 mg daily). Its full effects take a minor injuries, have a dark red to purple couple of months. It is necessary to monitor colour, most commonly involving the legs the blood count and liver function tests dur- and their margin often overreaches the ul- ing treatment: every 14 days for the first two ceration (referred to as ‘undermined mar- months, and subsequently every 6–8 weeks. gin’) The occurrence of leukopenia is an indica- • Ulceration is usually very painful tion for withdrawal of treatment. • Systemic diseases (inflammatory bowel dis- Clinical efficiency: Several clinical trials ease, arthritis or lymphoproliferative disor- show comparable clinical efficiency of azathi- ders) are often associated with the pyoder- oprine with antimalarials, penicillamine, par- ma gangrenosum enteral gold, cyclophosphamide and cy- • The diagnosis of pyoderma gangrenosum closporin, but less when compared to metho- is confirmed when other conditions caus- trexate in RA. ing skin ulcerations are excluded Q

Quantitative Computerised Tomogra- risk of fracture, and is therefore a suitable phy (QCT) In contrast to DEXA, QCT mea- method for selecting patients with high risk of sures the volumetric bone density (mg/cm3). fracture. However, it is not suitable for con- It can separately measure trabecular bone. firming the diagnosis of osteoporosis based on QCT scans the whole region of interest using the WHO criteria. Low costs, portability and a multi-slice or spiral CT and specific soft- safety are all advantages of this method. The ware is needed. Its use is not recommended measurement has lower reproducibility and it in the diagnosis of osteoporosis. A greater er- is therefore not suitable for monitoring the ror of measurement occurs than with DEXA, effectiveness of treatment. Measurement only a relatively high radiation dose for the pa- in peripherally localised bones (heel, tibia) is tient, the high cost of the investigation and a a disadvantage of this method. In contrast to lower accessibility for diagnosing of osteopo- radiological methods, the measured value is rosis are all disadvantages of this method. influenced not only by the bone mineral den- Therefore, CT is used mainly in the differen- sity, but also by the structure of the measured tial diagnosis of bone changes. bone. Changes in bone architecture also in- fluence the mechanical firmness of bone, but Quantitative Ultrasound (QUS) This at present we are unable to interpret them un- has a relatively good predictive value for the ambiguously. R

Radiography The radiograph (X-ray) is Radioimmunoelectrophoresis An elec- still “a golden standard” of musculoskeletal trophoretic analysis with radioactive labelled system examination even in the era of novel antigen or antibody to identify the precipita- diagnostic imaging methods such as USS, CT tion line. and MRI. It enables evaluation and assess- ment of changes to the skeleton in arthritic Radioimmunoscintigraphy Monoclonal and orthopaedic disorders, monitoring the antibodies directed against antigens associat- potential progression of the disease over time ed with malignancies is used in this in vivo and assessment of their changes with respect diagnostic method. After the conjugation of to treatment. Projectional radiography is com- antibodies with radioactive nuclides and their monly used in examining the joints and the administration to a patient affected by a ma- spine and involves taking two X-rays, usually lignancy, these conjugates bind exclusively to at right-angles to each other, to produce 2D X- the malignant cells and identify them. Con- ray images. Image intensification may be used temporary radioimmunoscintigraphy is a sen- for targeted joint injections (e.g. hip joint or sitive method able to identify a tumour spinal injections) or in internal fixation of frac- weighing as low as 0.1–1.0 gram, including tures. Radiographic examination with contrast possible metastases. medium is used in rheumatology for diagnos- ing oesophageal dysmotility in systemic scle- RANK (receptor-activator of nuclear rosis. factor κ-B) A transmembrane protein con- Radiographic examination after an intra- sisting of 616 amino acids that is localised on articular application of contrast medium (ar- precursors of osteoblasts. Binding OPG-L thrography) is utilised less in the era of CT, (RANKL) to ODAR (RANK) leads to the dif- MRI and arthroscopy. Radiographic exami- ferentiation and activation of osteoblasts. nation of the vascular system after intrave- nous injection of a contrast medium (classi- RANKL (receptor-activator of nuclear cal angiography, digital subtraction angiogra- factor κ-B ligand) Produced by osteoblasts. phy – DSA) is utilised, for example, in the It belongs to the TNR-receptor family. Ini- diagnosis and assessment of vasculitis. tially it was called osteoclast differentiation factor, which represents its main role in the Radioimmunoassay An analytical meth- body. It is produced by osteoblasts in soluble od used to assess the concentration of soluble and membrane-binding forms. Binding to its antigens or haptens. In this method, the anti- receptor (RANK) on the surface of osteo- gen or hapten is labelled with a radioactive clasts and their precursors leads to the activa- isotope which competitively inhibits the tion of differentiation, maturation and pro- binding of unmarked antigen with specific duction of new osteoclasts and stimulation of antibody. The relation between the inhibition their osteolytic activity. and concentration of the analysed antigen is assessed by a set of standard solutions of un- Rapamycin A relatively new immunosup- marked antigen of known concentration. It pressive agent, originally developed as an an- was the first method to enable quantification tifungal agent, with a structure similar to tac- of various proteohormones, neuropeptides rolimus but with a different mode of action. It and other substances in complex biological inhibits the response to IL-2 and thereby fluids. blocks the proliferation of B and T lympho- 183 receptor cytes, the synthesis of lymphokines and re- velop after infection localised anywhere in sponsiveness of T cells. Its immunosuppres- the body and often the association between sive concentrations are significantly lower clinically and microbiologically defined pre- than those of tacrolimus and cyclosporin. vious infection and ReA may not be found. Main features of ReA: Rapid assessment of disease activity • Arthritis, eventually other musculoskeletal in rheumatology (RADAR) → see Instru- symptoms (myalgia, tendinitis, osteitis, en- ments of assessing (health status measure- thesopathy), ments, outcome measurement) • Skin and mucosal lesions, • Ophthalmic lesions (uveitis, conjunctivi- Raynaud’s phenomenon (RP) A sym- tis), metrical non-progressive vasospastic disor- • Organ lesions are rare (nephritis, carditis), der affecting the fingers and toes, which • The prognosis is usually favourable with manifests as paleness and/or cyanosis. Such spontaneous remission, a symptom is due to cold exposition or emo- • Chronic course of the disease with func- tional stress. Maurice Raynaud (1834–1881, tional impairment is rare, French physician) first described the phe- • Significant association with the HLA-B27 nomenon in 1862. antigen. Clinical symptoms: The typical clinical picture consists of three phases. In the first Reactive nitrogen intermediates (RNI) phase, the fingers become pale due to vasos- Nitric oxide, for which NO synthase is in- pasm of the digital arteries. In the second volved in its synthesis, is the main representa- phase, dilatation of the capillaries and venules tive RNI. NO is involved in a number of pro- occurs, leading to cyanosis due to blood sta- tective, regulatory and also harmful reactions sis and its subsequent deoxygenation. The in the immune, nervous and cardiovascular patient usually complains of cold sensations systems. Other oxides of nitrogen, anions of and paraesthesia during these phases of RP. peroxynitrous and nitrous acid and finally When heating the limb, vasospasm retreats anions of nitric acid can originate from nitric and blood perfusion dramatically increases. oxide. This phase of reactive hyperaemia is charac- terised by a bright red colour of the fingers Reactive oxygen intermediates (ROI) and is often associated with unpleasant pul- Unstable molecules that possess an uncou- sating sensations. The changes to the fingers pled electron (free radicals) or excited-state extend from distal parts towards proximal ar- electrons (singleton oxygen). The basic free eas and never proximal of the metacarpopha- radical derived from molecular oxygen is su- langeal joints. The fingers and toes are most peroxide from which hydrogen peroxide and R often affected, particularly the 2nd, 3rd and 4th subsequently hydroxyl radicals are formed. fingers of the hand, less frequently the toes. ROI are formed in higher concentrations, The acral part of the nose, the tongue and ear particularly in professional phagocytes (neu- can be affected. Infrared thermography can trophils, macrophages), where they are in- be used in the detection and quantification of volved in the destruction of phagocytosed RP. micro-organisms. They are also very effective cytolytic substances and may damage the Reactive arthritis (ReA) Aseptic immu- cells and tissues of the hosting organism dur- nologically mediated joint inflammation, ing immunopathological reactions. which develops in association with distant infection in the body. The disease has a sys- Receptor A complex of atoms or molecules temic character and usually develops after that form a site with stereochemically specific upper airway infections, urogenital or gastro- affinity for a particular substance known as intestinal infections. However, ReA may de- ligand (agonist in pharmacology). The recep- receptor-activator of nuclear factor κ-B 184

tors are usually present on the surface of cells Reflex arc The set of structures involved in but may also be located on the inner part of the reflex pathway. It consists of 5 components: the cytoplasmic membrane or in the cyto- receptor, afferent nerve pathway, integration plasm. The binding of ligand (agonist) to the centre, efferent nerve pathway and effector. receptor is the signal for the cell to perform The connection with the central nervous sys- certain physiological (in some cases patho- tem runs through the integration centre. logical) responses. The binding of an inhibi- tor (antagonist) to this receptor leads to inhi- Rehabilitation methods Rehabilitation bition of the receptor’s function. Neurotrans- methods in rheumatoid arthritis are focused mitters, hormones, antigens, cytokines, or on maintaining the scope of movement and other mediators transmit their signal through muscle strength. The patient must be taught receptors and thereby information is trans- the knowledge of how to protect affected mitted between cells. One cell can transfer joints by improving muscle power and how to the information to another cell directly with- improve their daily routine. The use of or- out the need for any chemical messenger. In thoses and various auxiliary instruments in such a case, the receptor of one cell reacts performing daily routines is, apart from reha- with the receptor (effector) of the other cell. bilitation, one of the basic components of joint protection. The resources of physical Receptor-activator of nuclear factor therapy (PT) need to be used to minimise the κ-B → see RANK (receptor-activator of nu- symptoms and signs of RA, such as pain, at- clear factor κ-B) rophy, decreases in local metabolism, spasms etc. Balneotherapy, both local and systemic, is Receptor-activator of nuclear factor also important in the management of RA. κ-B ligand → see RANKL (receptor-activa- tor of nuclear factor κ-B ligand) Relapsing polychondritis A very rare disease affecting a number of organs. The dis- Referred pain The pain felt in an area that ease is episodic, but occasionally progressive. is distinct from the affected area. It is com- It is an inflammatory process affecting struc- mon in lesions of visceral organs. It is usually tures of the cartilage and tissues with a high felt in the area that is innervated from the content of glycosaminoglycans. Clinical symp- same spinal segment as the involved viscus. toms appear in the areas of the pinna of the ear, nose, larynx, upper airways, joints, heart, Reflex A basic functional unit of the nervous blood vessels, inner ear, cornea and sclera. system function. It can be defined as an invol- Clinical symptoms: untary, rapid and stereotypic response to a • of ear, nasal, laryngotracheal, R peripheral stimulus. costal and joint cartilages, • Inflammation of eye and inner ear, Reflex sympathetic dystrophy → see Al- • Collapse of laryngotracheal structures, godystrophic syndrome (ADS) subglottic area leading to increased upper airways infections and , Reflexive massage The fundamental of • Concurrent presence of vasculitis or glom- this massage is the knowledge that functional erulonephritis may contribute to increased connections exist between skin and muscle morbidity and mortality, areas, bones, vessels, nerves and subcutaneous • Clinical symptoms, the course of disease tissue and inner organs, which are supplied and response to treatment vary. from the same spinal segments. Reflexive mas- sage can be used in both organic and function- Relaxation An essential component of reha- al disorders, particularly in the chronic stage. bilitation when both muscle and psychological The main indications are spinal pain syndrome relaxation occurs. Relaxation in the rhythm of and extra-articular rheumatism. breathing, autogenic training (Schultz’ auto- 185 rheumatoid arthritis (RA) genic training psychomotor relaxation thera- Rheumatic fever Systemic inflammatory py; Johannes Heinrich Schultz, German physi- disease which develops 2 to 5 weeks after in- cian, 1884–1970), Jacobsons’ relaxation meth- fection with group A beta-haemolytic strep- od (Edmund Jacobson, American physician, tococcus. It is characterised by a number of 1888–1983) and yoga elements are among pathological reactions in which the immune such techniques. system is involved and which affect mainly the heart and joints. Remitting seronegative symmetrical Clinical symptoms: The disease is charac- synovitis with pitting oedema) → see terised by fever, migratory arthritis and Syndrome RS3PE (remitting seronegative symptoms of rheumatic heart inflammation symmetrical synovitis with pitting oedema) (carditis). The inflammation may affect en- docardium, myocardium or pericardium – Reverse transcriptase An RNA depen- either selectively or completely (pancarditis). dent DNA polymerase, which is the enzyme In certain cases, permanent heart damage that synthesises DNA on the RNA chain ma- may develop, primarily rheumatic valve dis- trix and transfers the genetic information ease. Central nervous system involvement from RNA into DNA. RNA viruses contain can result in chorea, pneumonitis when the this enzyme. lungs are affected, and erythema marginatum when the skin is affected. Laboratory find- Rhesus blood group system The set of ings include increased titre of streptococcal antigens present on the surface of erythro- antibodies and the presence of elevated acute cytes in humans and Rhesus apes (that is why phase reactants. Rh). They are encoded by gene loci on chro- Jones criteria JONES is an abbreviation mosome 1 which possesses at least three al- summary often used to recall the major crite- lele pairs Dd, Cc and Ee. The most clinically ria (joints, o-shaped heart on imaging, nod- significant is antigen D, so individuals are ei- ules, erythema marginatum, Sydenham’s cho- ther Rhesus factor positive (RhD+) or Rhesus rea). The presence of two major symptoms or factor negative (RhD–) depending on wheth- 1 major + 2 minor symptoms are necessary to er they do or do not possess Rhesus factor on make a diagnosis of rheumatic fever: the surface of their erythrocytes. Individuals • Major symptoms: migratory polyarthritis, who do not possess this antigen (RhD–) and carditis, chorea, erythema marginatum, receive erythrocyte RhD+ transfusion will de- rheumatic nodules, velop alloantibodies directed against the anti- • Minor symptoms: fever, arthralgias, in- gen. Anti-RhD antibodies will evoke severe creased erythrocyte sedimentation rate, el- post transfusion reactions during another evated C-reactive protein, leukocytosis, the transfusion of RhD+ blood. In pregnant confirmation of beta-haemolytic strepto- R women who are RhD– and who have a foetus coccus infection, prolonged P-R interval with RhD+ erythrocytes (antigen RhD inher- on ECG (first degree heart block), a history ited from father), the transfer of foetal eryth- of rheumatic fever. rocytes into the maternal circulation (e.g. dur- ing labour or amniocentesis) may evoke the Rheumatoid arthritis (RA) A common formation of anti-RhD antibodies. Such al- inflammatory joint disease that affects indi- loantibodies will cause haemolytic disease in viduals of all ages, with maximal onset in newborns in subsequent pregnancies. Con- women around the menopause. The disease trary to alloantibodies against ABO blood is multifactorial in origin with certain genetic groups antigens, anti-Rh antibodies do not predispositions and unknown trigger factors. cause agglutination of Rh-positive erythro- It is characterised by chronic inflammation, cytes and that is why they must be detected which is initiated and maintained by immu- by a different method (Coomb’s test). nopathological mechanisms. The course of RA is very variable in pattern, but generally is rheumatoid arthritis (ra)(RA) – – aetiopathogenesis aetiopathogenesis 186

progressive and can lead to significant dis- from protein antigens of endogenous or ex- ability. ogenous origin. These antigens are conse- General features: quently recognised by T lymphocytes, which, • RA is not a benign disease as it shortens the by a number of interactions with other im- life of affected individuals by 5–10 years mune cells, initiate the immune response. It is • Joint erosion develops early – usually dur- unknown from which antigen the “arthrito- ing the first two years genic” peptide originates in RA. It is hypoth- • Early RA affects mainly joints, later sys- esised that the whole autoimmune process is temic symptoms may develop initiated by infection. • Therapeutic management is effective par- Pathogenesis: RA is definitely associated ticularly in the early stages of RA, with immune mechanisms and direct dam- • RA is a very variable disease; most forms age of target structures in the initial stages of progress slowly, have long periods of clini- the disease. Initially, T lymphocytes play a cal remission and a low tendency towards major role. Lymphocytes (especially CD4+) destruction; approximately 10% develop represent 50% of all cells present in the in- severe disease with joint destruction and flammatory infiltrate and accumulate in the deformities, leading to severe disabilities, synovial membrane. The profile of cytokines

• The course of RA is unpredictable but risk suggests that these cells belong to the TH1

factors associated with unfavourable prog- subpopulation. Insufficient synthesis of TH2 nosis have been defined based on large cytokines, particularly IL-4, IL-3 and IL-10 studies of patients (Rovenský et al. 2000, may contribute to an uncontrolled inflamma- Scott 2000, Plant et al. 1994). tory process, as these cytokines belong to the anti-inflammatory group of cytokines and so Rheumatoid arthritis (RA) – aetio- they may antagonise the unfavourable pro- pathogenesis The cause of RA is currently inflammatory cytokines IL-1, IL-6 and unknown. It is hypothesised that RA is a dis- TNF-α. TNF-α is a cytokine, which alone is ease that develops in individuals with a ge- responsible for the development of local and netic predisposition after induction by an systemic inflammatory reactions, and is also unknown microorganism. A genetic element the key regulating mediator of other cytok- is well established, particularly in the studies ines production. Another important cy- of concordance in monozygotic twins, which tokine, IL-7 increases the production of other is 12–15%, compared to 2–4% in dizygotic cytokines by acting on macrophages and syn- twins (Silman 1997, Seldin et al. 1999, Wiles oviocytes. Activated T lymphocytes are pres- et al. 1999). RA is a polygene-determined dis- ent particularly in the perivascular space, ease with major involvement of the HLA contrary to CD8+ T-lymphocytes, which are R complex, which is thought to account for up dispersed in synovial membrane. Macrophag- to 40–50%. RA is associated with the HLA- es are also present. With these features, the DR4 antigen. This antigen can be divided into conditions for initiation and maintenance of 5 subtypes: HLA-Dw4, HLA-Dw10, HLA- the immune response are assured, as particu- Dw13, HLA-Dw14, and HLA-Dw15. The as- larly macrophages, through their class II HLA sociation of RA with antigens HLA-DR4, antigens, present the pathogenic antigen to T HLA-Dw4 and antigens HLA-DR4, HLA- lymphocytes. Macrophages are important pro- Dw14 is typical for the Caucasian population. ducers of pro-inflammatory cytokines and However, only 70% of RA patients possess chemokines. Germinal centres typical for B the antigens HLA-DR4, HLA-Dw4 or HLA- lymphocyte areas of the lymph nodes are also DR4, HLA-Dw14 in the Caucasian popula- present in the synovial membrane. A number tion; other patients possess other antigens, of autoantibodies that after binding to their particularly HLA-DR1. autoantigens form immune complexes are The major biological function of HLA produced in the germinal centres. The im- molecules is to present peptides originating mune complexes subsequently induce an in- 187 rheumatoidrheumatoid arthritis arthritis (RA) (ra) – clinical symptoms flammatory process in which polymorpho- Rheumatoid arthritis (RA) – classifica- nuclear leukocytes are particularly involved. tion criteria Criteria suggested by Arnett et Neutrophils through the medium of prote- al. in 1987 are used for the purposes of the olytic enzymes and reactive oxygen and ni- ACR (American College of Rheumatology; trogen radicals damage the extracellular ma- table 11). A patient suffers from RA if at least trix and cartilage. The invasion of neutrophils 4 criteria are present, 1–4 criteria must last at into synovial fluid contributes to other typi- least 6 weeks. cal changes for RA, especially involving neo- vascularisation. Neovascularisation and pro- Rheumatoid arthritis (RA) – clinical liferation of synoviocytes are among the ma- symptoms The initial symptoms of RA can jor changes that contribute to development of involve the joints alone or be more systemic. the pathological process. Joint symptoms include pain of various in- Chronic inflammation of synovial mem- tensities with more intense pain occurring in brane leads to pannus formation. Such gran- the morning. Another prominent symptom is ulation tissue consists of a number of cells of morning stiffness, usually lasting more than different types, such as lymphocytes, mac- one hour, which distinguishes the pain from rophages, fibroblasts, synoviocytes and mast that occurring in osteoarthrosis. Systemic cells. The invasion of pannus and the synthe- symptoms include general malaise, tiredness, sis of proteolytic enzymes are directly respon- fatigue, subfebrile temperatures, weight loss sible for cartilage destruction, erosion of sub- and sleep disturbance. Metacarpophalangeal chondral bone and damage to periarticular (MCP), proximal interphalangeal (PIP) joints structures. Metalloproteinases (collagenase, and wrist (RC) are the most frequently af- stromelysin) and other proteolytic enzymes fected in early RA. (elastase, cathepsin B and G, gelatinase) re- Symmetric joint involvement is typical. leased from activated macrophages, fibro- The basic clinical signs of joint inflammation blasts, synoviocytes and chondrocytes in re- are soft tissue swelling and tenderness on pal- sponse to pro-inflammatory cytokines, par- pation. The joint is considered to be active ticularly IL-1 and TNF-α, are involved in from an inflammatory point of view when it damaging the tissues. Periarticular osteope- is swollen and sore during palpation. The nia is caused by increased activity of osteo- joint swelling can be intra-articular or peri- clasts, which are stimulated by IL-1 and IL-6. articular. Fluid can be found with intra-artic- ular swelling. Joint destruction can be detect-

Table 11. ACR classification criteria for diagnosis of rheumatoid arthritis 1987 R Criteria Definition • morning stiffness • morning joint stiffness that lasts at least 1 hour • arthritis of three or more joint groups • soft tissue swelling or fluid observed by a physician is present at least in 3 of 14 joint areas (right or left PIP, MCP, RC, elbow, knee, ankle, MTP joints) • arthritis of hand joints • swelling of at least one area – RC, MCP or PIP • symmetric arthritis • concurrent involvement of the same joints on both sides of the body • rheumatoid nodules • subcutaneous nodules over the bone eminences or extensor areas around joints observed by a physician • serum rheumatoid factor • verification by any method where outcomes are not positive in more than 5% of the normal population • X-ray changes • X-ray changes typical for RA that are visible on an X-ray picture taken in PA projection of the hand and wrist with the discovery of erosions or decalcification of affected joints or in their proximity rheumatoid arthritis disease activity index (RADAI) 188

ed clinically or radiologically. The course of Renal complications: the disease is very variable. RA is not a be- • Glomerulonephritis, nign disease; it shortens the life of affected • Secondary amyloidosis, individuals by 5 to 10 years. The diagnosis of • Pyelonephritis, RA is confirmed by the presence of ACR clas- • Interstitial nephritis. sification criteria, though early disease may Neurological complications: not fulfil four of these criteria. • Compressive syndromes (carpal tunnel syndrome, ulnar nerve compression, tarsal Rheumatoid arthritis disease activity tunnel syndrome), index (RADAI) → see Instruments of assess- • Distal sensory neuropathy, ing (health status measurements, outcome • Sensory-motor neuropathy. measurement) Soft tissue complications: • Tendinitis, Rheumatoid arthritis (RA) – extra-ar- • Tenosynovitis, ticular symptoms Ophthalmic complica- • Bursitis, tions in RA: • Myositis (non-specific). • Keratoconjunctivitis sicca (dry eyes), • Episcleritis, Rheumatoid arthritis pain scale (RASP) • , → see Instruments of assessing (health status • Uveitis, measurements, outcome measurement) • Episcleral nodules, • Peripheral ulcerative , Rheumatoid arthritis (RA) – patholog- • Secondary cataract, ical anatomy In RA, the inflammatory pro- • Glaucoma, cess is located in the synovial membrane, • Keratopathy, which normally plays a significant role in the • Retinopathy. nutrition of avascular hyaline cartilage in Cardiac complications in RA: synovial joints. The synovia of tendon sheaths • Pericarditis, and bursae are also affected by the inflamma- • Myocarditis, tion. The joint cartilage is gradually damaged • Disease of endocardium, as its nutrition and drainage of the articular • Coronary arteritis, cavity is affected by the inflammation. Pan- • Cardiac amyloidosis, nus tissue is formed in the area of the syn- • Vasculitis. oviochondral junction. The pannus expands Haematological abnormalities: into articular cartilage and gradually replaces • Anaemia accompanying chronic disease, the cartilage – initially at the margin. Tendon R • Anaemia due to , sheaths, ligaments and discs are affected sec- • Thrombocytosis, ondarily. • Thrombocytopenia, Macroscopic changes of synovial mem- • Felty’s syndrome (neutropenia) brane • Large granular lymphocyte syndrome, In the early stage of RA, the synovial mem- • Lymphadenopathy, brane is oedematous, hyperaemic and opales- • Lymphoproliferative disease. cent and straw-coloured synovial fluid leaks Pulmonary complications in RA: from the membrane. Villi and fibrin are pres- • Pleuritis, ent on the surface of synovia; ‘rice shaped’ • Rheumatoid nodules in the lung, particles may be present in the synovial fluid. • Caplan’s syndrome, The articular cavity may be obliterated (fi- • Diffuse interstitial pulmonary fibrosis, brosed ankylosis), but the presence of syn- • Bronchiolitis obliterans, ovial fluid frequently prevents the formation • Constrictive bronchiolitis, of adhesions. Synovial villi may atrophy over • Drug toxicity symptoms. time and the synovial membrane affected by 189 rheumatoid factors (RF) inflammation transforms into thin tissue marrow, lymph nodes, spleen and subcutane- membrane. ous rheumatoid nodules. RF’s can be of vari- Microscopic changes of synovial mem- ous immunoglobulin isotypes, i.e. besides brane IgM RF, there are also IgG RF, IgA RF and IgE A distinct hyperplastic layer of synovial RF. cells is typical. Blood plasma gradually leaks Agglutination tests are still the most popu- from dilated capillaries and venules into the lar methods for RF assessment. In routine articular cavity and along with infiltrating cells use, sheep erythrocytes bond with rabbit IgG forms an inflammatory exudate. Polymorpho- (Waaler-Rose haemaglutination test) are of- nuclear leukocytes and later also mononuclear ten replaced by inert latex particles, which are inflammatory cells migrate from vessels into coated with human IgG. A latex fixation test the interstitium of the synovial membrane and has a higher sensitivity for detecting RF but to synovial fluid. Fibrinogen, which leaked has a slightly lower specificity for diagnosing from blood vessels, forms polymerised aggre- RA. A greater frequency of positivity of the gates of fibrin on the synovial membrane. latex test is probably based on the fact that Deposits of fibrin, necrosis, poorly differenti- human IgG react also with anti-allotypic an- ated mesenchymal cells and decomposition tibodies and anti-Fab antibodies. The test of collagen fibrils are found in the synovial particularly detects pentametric IgM RF that, membrane. in view of the higher number of bonds, pro- duces macroscopically visible agglutination. Rheumatoid arthritis (RA) – remission The contribution of IgG RF and IgA RF to the criteria (according to American Col- positivity of the agglutination test is minimal. lege of Rheumatology; ACR) The result is taken as the highest titre of serum • Morning stiffness lasting less than 15 min- dilution when agglutination is apparent. A utes, titre higher than 1:80 is considered positive. • No tiredness, IgG present in the serum may during the • No joint pain, agglutination test compete with IgG coating • No joint tenderness or pain during passive the particles. In certain RF’s, the binding sites movement, of RF are already bound by normal serum • No soft tissue swelling of joints or tendon IgG and so the agglutination is negative. Such sheaths, RF’s are referred to as hidden rheumatoid • Erythrocyte Sedimentation Rate does not factors and can be detected by the latex fixa- exceed 30 mm/hour in women and 20 mm/ tion test only when the IgM fraction of serum hour in men. is separated from IgG fraction. Hidden RF’s Exceptions that exclude clinical remission in- are found more commonly in juvenile idio- clude the clinical manifestation of active vas- pathic arthritis. R culitis, pericarditis, pleuritis, myositis, weight Recently, the ELISA method, which has loss or fever which cannot be explained other a number of advantages, has been used more than in association with RA. frequently for detecting RF. In particular, ELISA allows the detection of immunoglobu- Rheumatoid factors (RF) Autoantibodies lin isotypes of rheumatoid factors depending that react with antigenic determinants on the on the specificity of the secondary antibody Fc-component of the IgG molecule. The pres- which is marked by enzyme; ELISA is also ence of IgM RF is a serological diagnostic cri- more sensitive in detecting IgM RF than the teria for rheumatoid arthritis (RA); it is pres- agglutination test. ent in 75 to 90% of cases. RF can be detected The presence of RF is not associated only either in serum or in various body fluids, in- with RA. Increased levels are found in certain cluding synovial fluid. Synthesis takes place other acute and chronic inflammatory dis- mainly in the lymphatic tissue of the joint af- eases. The frequency and level of rheumatoid fected by inflammation, but also in bone factors is increased in individuals over the rheumatoid nodules 190

age of 60, and so it is recommended to recon- monary rheumatoid nodules and pneumoco- sider the titre of a positive test, e.g. a positive niosis in patients with rheumatoid arthritis titre in the latex fixation test is 1:1280. Such (RA). The nodules are multiple and usually an increase in the frequency and levels of RF occupy the subpleural areas of pulmonary tis- is reduced again in individuals over the age of sue. The X-ray picture suggests massive pul- 80, probably due to the higher mortality of monary fibrosis. The nodules are visible as individuals with autoantibodies. concentric light and dark strips and consist of Permanently increased levels of RF are more a central necrosis, an inflammatory zone with frequently present in chronic bacterial infec- macrophages containing dust particles, a tions, such as subacute bacterial endocarditis, zone of fibroblasts and a surrounding layer of tuberculosis, syphilis or leprosy. They are usu- fibrous tissue. Caplan’s syndrome (Anthony ally temporarily increased in viral infections Caplan, English physician, 1907–1976) de- (e.g. infectious mononucleosis, hepatitis, in- velops in individuals with RA who have had fluenza, AIDS) or after vaccination. RF posi- considerable exposure to coal-dust. However, tivity can be also found in other systemic or a similar condition develops after silica and rheumatic diseases (systemic lupus erythema- asbestos exposure. tosus, scleroderma, Sharp’s syndrome, Sjögren’s syndrome, myositis), parasitic infections, pul- Rheumatoid-surgical treatment Syn- monary and liver diseases, sarcoidosis, mixed ovectomy, implantation of total joint prosthe- cryoglobulinaemia, hypergammaglobulinae- sis and joint arthrodesis belong to conven- mic purpura, Waldenström‘s macroglobuli- tional corrective rheumatoid-surgical treat- naemia, chronic lymphocytic leukaemia and ments. They are indicated in patients with finally, in some patients with malignancy. rheumatoid arthritis (RA) in order to reduce Low levels of RF can occur in all healthy indi- tissues affected by inflammation (synovecto- viduals. B lymphocytes with membrane- my), to provide pain relief and improve joint bound receptor with RF activity are a normal function. Synovectomy is indicated after fail- physiological finding and are presumably in- ure of courses of DMARD treatment and only volved in normal immune system function. short term benefit from intra-articular gluco- corticosteroids if only a few joints are affect- Rheumatoid nodules Occur in 20 to 35% ed. However, surgical synovectomy is often of of patients with positive rheumatoid factors. limited success as it is impossible to remove They usually accompany more active forms all inflamed synovium. Prophylactic synovec- of the disease. The nodules develop in areas tomy of the wrist with excision of the head of exposed to pressure, such as the olecranon the ulna should be considered in patients process, hand joints, sacral eminence or with severe wrist disease in order to prevent R Achilles tendon. Rheumatoid nodules often the rupture of extensor tendons. Other suit- bind tightly to the periosteum. Histologically, able rheumatoid-surgical interventions in- they consist of central necrosis surrounded clude total hip, knee and shoulder replace- by fibroblasts. The nodules are most likely the ments, replacement of metacarpal or proxi- consequence of vasculitis of a small vessel mal interphalangeal joints and resection of with fibrous necrosis, which forms the cen- metatarsal heads in patients with subluxation tral part of the nodule, surrounded by the of metatarsal joints, and finally operation of proliferation of fibroblasts. Rheumatoid nod- hallux valgum with bursitis affecting the first ules are benign and mainly represent a cos- metatarsal bone. In selected patients, recon- metic problem but if they develop in a prob- structive hand surgery on joints and tendons lematic location (e.g. the sole of the foot), may be very beneficial. In arthrodesis, the they may be surgically removed. joint pain is abolished but at the detriment of complete loss of joint mobility. Fusion of C1 Rheumatoid pneumoconiosis (Ca- and C2 vertebrae is indicated in atlanto-axial plan’s syndrome) Is characterised by pul- subluxation (>4 mms) with associated neuro- 191 rickets logical symptoms and signs. The rheumatolo- Rickets A generalised skeletal disorder oc- gist in liaison with an orthopaedic specialist curring in children characterised by inade- can recommend rheumatoid-surgical inter- quate mineralisation of bone matrix (os- ventions. teoid). Newly formed trabecular and cortical bone and the growth plate (in contrast to os- Rheumatological rehabilitation Has teomalacia, which does not interfere with the three functions: growth plate) are all affected. Clinically, its 1. Preventive – focusing on educating the pa- presentation varies with age. Rickets within tient to learn all the elements of rehabilita- the first year of life may present with craniota- tion treatment before the development of bes (thin deformed skull), and later with wid- functional deficits, ened epiphyses at the wrists and beading of the 2. Corrective – the aim is to influence revers- costochondral junction (rickety rosary). In ible functional deficits, older children, typical bow-leg deformities oc- 3. Maintaining – to maintain existing func- cur. A number of acquired and genetically con- tional levels. ditioned causes for rickets have been identified (table 12). From a biochemical perspective, Rhizarthrosis → see Osteoarthritis (OA) of rickets can be divided into those arising due to the first carpometacarpal (CMC) joint a calcium deficiency (hypocalcaemic rickets) (Rhizarthrosis) or phosphate depletion (hypophosphataemic

Table 12. Classification of rickets (modified according to a review of Kutilek et al., 1998)

Genetically hypocalcaemic: conditioned vitamin D-dependent (type I; an enzymatic defect in synthesis of the active form of vitamin D) vitamin D-dependent (Type II; pseudovitamin D deficiency caused by mutation in the gene encoding the vitamin D receptor) 25-hydroxylase deficiency magnesium-dependent vitamin D-resistant hypophosphataemic: vitamin D-resistant (X-linked or autosomal dominant types) hereditary hypophosphataemic with a hypercalciuria renal renal tubular acidosis (RTA type I; distal RTA) renal tubular acidosis (RTA type II; proximal RTA) Dent disease Lowe’s (oculocerebrorenal) syndrome R Inborn errors of metabolism (cystinosis, glycogenosis I, hypertyrosinaemia (tyrosinaemia type I), Wilson’s disease) Genetically hypocalcaemic: unconditioned vitamin D-deficiency calcium-deficiency magnesium-dependent vitamin D-resistant hepatopathy renal osteodystrophy anticonvulsant therapy hypophosphataemic: phosphate deficiency (metabolic osteopathy of the prematurely born, other acquired hypophosphataemias) oncogenic acquired Fanconi syndrome, acquired renal tubular acidosis (intoxications, interstitial nephritis) risedronate 192

rickets). Conventionally, blood tests show a ach and washed down with a cup of water in low serum calcium, phosphate and vitamin D an upright posture. The patient should not with an elevated alkaline phosphatase. sit, lie down or eat for thirty minutes after The most frequent cause of rickets is ac- drug ingestion. The normal drug regime is 35 quired deficiency rickets due to lack of vitamin mg once weekly or (rarely nowadays) 5 mg D. The disease occurs sporadically, particularly daily. in older breastfed children and toddlers. In most cases the cause is a combination of a lack Rolf technique → see Exercise techniques of calcium intake and borderline levels of vita- min D. Treatment is dependent on the cause, Rubella-associated arthritis Occurs in but many acquired rickets respond to calcium 15 to 20% of all rubella infections affecting and vitamin D replacement. Other types of adults. The arthritis can be divided into rickets are relatively rare. Hypophosphataemic mono-, oligo-, or polyarthritis. vitamin D resistant rickets linked to the X Clinical symptoms: Myalgias, suboccipital chromosome has an incidence of 1:20,000 and lymphadenopathy. Exanthema does not al- is the most frequent congenital type of rickets. ways occur. Laboratory diagnostic criteria: Prevalence Risedronate A bisphosphonate licensed for of mononuclear cells is typical in differential the treatment of postmenopausal osteoporo- blood account. Mononuclear cells are also sis to reduce the incidence of vertebral and found in synovial fluid. Serologic screening hip fractures. It is also licensed for the pre- reveals antibodies against the rubella virus. vention of glucocorticoid-induced osteopo- Treatment: The disease recovers sponta- rosis and is used in men with osteoporosis. neously, though symptomatic treatment may The drug should be taken on an empty stom- be needed.

R S

Sacroiliac block (SI block) Sacroiliac pain mandible may develop later on in the course is a frequent reason for vertebrogenic pain of the disease. Less frequently, ossification of syndrome. SI block is blockade of one or both the ribs, sternum and sternoclavicular joint SI joints. Symptoms can be confirmed as aris- occurs. Focuses of sterile osteomyelitis are ing from the sacroiliac joint by various meth- present in the histopathological picture. The ods, e.g. hyperabduction phenomenon ac- aetiology of the disease is unknown, though cording to Patrick, by springing the SI joints in a few cases disseminated infections due to in the prone and supine positions, by tender- Propionibacterium acne were reported. Treat- ness over the affected SI joint in the standing ment is non-specific; antibiotics are not effec- position tive. Non-steroidal anti-inflammatory drugs, sulphasalazine and methotrexate have bene- Sanfilippo’s disease → see Mucopolysac- fited certain patients. Recent studies have charidosis (MPS) shown significant improvement after intra- muscular administration of calcitonin or in- SAPHO syndrome It is characterised by a travenous pamidronate. The differential di- unique arthropathy predominantly affecting agnosis includes ankylosing spondylitis, pso- the sternocostoclavicular area and accompa- riatic arthritis, fibromyalgia, bacterial infec- nied by skin lesions of acne or pustulosis type tions and relapsing polychondritis (Schilling and chronic recurrent multifocal osteomyeli- et al. 2000, Olivieri et al. 2006). tis. The syndrome affects particularly the Eu- ropean and Japanese populations. The no- SARA → see Sexually acquired reactive ar- menclature SAPHO reflects synovitis, acne thritis (SARA) pustules, hyperostosis and osteomyelitis. Clinical symptoms include pain in the area of Sarcoidosis → see Musculoskeletal manifes- the sternum and the costoclavicular area. Os- tations of sarcoidosis sification of the costoclavicular ligaments may be visible on X-ray. The triad of sacroilii- Sausage toe → see Toe swelling/deformity tis, syndesmophytes and discitis is present and associated diseases when the vertebral column is affected. The skin lesions include palmoplantar pustulosis, Scheie’s disease → see Mucopolysacchari- acne conglobata or acne fulminans. Patho- dosis (MPS) logically, the skin lesions are referred to as neutrophilic pseudoabscesses. Joint impair- Scheuermann’s disease Juvenile kypho- ment is peripheral and symmetric. The symp- sis and idiopathic are severe disor- toms on the axial skeleton are similar to those ders of a growing vertebral column. Heredi- of seronegative spondyloarthropathy. There’s tary, hormonal, nutritional factors, blood no direct association with the HLA-B27 anti- supply impairment and mechanical overload- gen. ing cause of vertebral end The clinical picture is characterised by pain plates and herniation of the nucleus pulposus and oedema in the sternal area. The disease into vertebral bodies called Schmorl’s nodes leads to limited movement of the arms and (Christian Georg Schmorl, German patholo- shoulders. Pain localised to the acromio- gist, 1961–1932). The condition leads to clavicular joints may also be present. Osteo- wedging deformities of vertebrae, narrowing lytic lesions in the sternum and rarely in the of inter-vertebral discs and kyphosis of the Schmid’s dysplasia 194

thoracic spine compensated by significant the SOST gene. It shows radiologically as a cervical and lumbar lordosis. generalised hyperostosis and sclerosis lead- ing to a markedly thickened and sclerotic Schmid’s dysplasia An autosomal domi- skull, mandible, ribs, clavicles and all long nant hereditary asso- bones. Sclerostin is a protein product of the ciated with mild short-limbed dwarfism SOST gene competing with bone morpho- without shortening of the vertebral column. genic products (BMPs) for receptor types Epiphyses of long bones are denticulate; I and II of these proteins on osteoblasts. Scle- metaphyses are deformed in caliculus shape. rostin decreases the signalling induced by Affected individuals suffer from genu varum BMPs and suppresses the osteoblast-induced and coxa vara. Schmid’s dysplasia becomes mineralisation. The expression of SOST has obvious after the third year of life; initially the been detected in osteoblast cultures and in dysplasia may suggest rickets but serum lev- sites of mineralisation of the skeleton. A els of calcium, phosphate and alkaline phos- strong expression in osteocytes indicates that phatase are within the normal childhood through these cells sclerostin modulates bone range. homeostasis. Transgenic mice with increased expression of SOST have low bone stock and Schmorl’s nodes → see Scheuermann’s dis- decreased firmness of the bones. ease Sclerostin (SOST) A glycoprotein that is ho- Schober’s test → see Metric measurement mologous with other BMP (bone morphogenic of vertebral column in spondyloarthritis products) antagonists from the DAN (differen- (SpA) tial screening-selected gene aberrant in neuro- blastoma) family, such as noggin, gremlin Schober’s test modified → see Metric and dan. It plays an important role in bone ho- measurement of vertebral column in spondy- meostasis and a specific role in the differentia- loarthritis (SpA) tion of osteoblasts and osteoformation induced by these cells. It acts as an integration link for SCID → see Severe combined immunodefi- osteocyte-mediated regulation of osteoforma- ciency (SCID) tion. Sclerostin released from osteocytes may control the proliferation and differentiation of SCID mice (Severe Combined Immu- osteoprogenitor/preosteoblastic cells as well as nodeficiency mice) A species of mice with the activity of mature osteoblasts via inhibition serious genetic combined immunodeficiency of activity of BMP proteins. (SCID) which causes them not to develop an- tibody or T-cell immunity and so allow them Scoliosis The curvature of the vertebral col- to serve as “live test-tubes” for implanting umn in the frontal plain. Scoliosis is consid- S lymphocytes from other animal species. ered to be the lateral curvature of the verte- When, for example, human lymphocytes are bral column in a range greater than 11°. Sco- injected, they can produce antibodies of hu- liosis can be functional (the curves are not man isotypes after antigen stimulation. The fixed and can be corrected actively or pas- nature of the primary disorder is a mutation sively) or structural (the curves are fixed). on chromosome 16 causing deficient activity of an enzyme involved in DNA repair, lead- Scurvy → see Musculoskeletal symptoms in ing to failure of haematopoietic stem cells of scurvy the lymphoid line to mature. Secondary gout A condition in which Sclerosteosis A progressive autosomal re- gout is caused by hyperuricaemia secondary cessive disorder characterised by an excess of to overproduction of uric acid from increased bone stock due to insufficient expression of cellular turnover or decreased excretion of 195 selective oestrogen receptor modulators (SERM) uric acid by renal disease or effects of drugs. sis as a consequence of oestrogen deficien- Lymphoproliferative and myeloproliferative cy in this group) and growth hormone. diseases, certain malignancies (usually carci- • Osteoporosis due to excess of hormones – nomas in disseminated malignancies and hypercorticism, hyperthyroidism, hyper- more frequently in anaplastic malignancies) prolactinaemia, and hyperparathyroidism. and haemolytic anaemia belong to those con- • Osteoporosis caused by dietary deficien- ditions that are associated with overproduc- cies – insufficient calcium and vitamin D tion of uric acid. Chronic renal insufficiency, intake, disturbances of digestion and mal- chronic lead poisoning, drugs (diuretics, low absorption syndromes. dose salicylates, pyrazinamide, nicotinic acid • Renal osteopathy. and ethambutol) and also endocrinopathies • Inactivity-induced osteoporosis. (hyperparathyroidism, hypothyroidism) are • Osteoporosis due to chronic inflammatory among conditions associated with decreased disorders. renal elimination of uric acid. • Osteoporosis due to neoplastic disease. • Drug-induced osteoporosis – corticoster- Secondary hyperparathyroidism The oids, excess thyroid hormones, anti-con- increased concentration of parathormone is vulsants, heparin, cyclosporin A, and in response to calcium deficiency with the methotrexate. most frequent cause being a vitamin D defi- ciency. Treatment of the underlying cause is Selectins A family of glycoprotein leuko-ad- the treatment of choice. hesive molecules which consist of three mem- bers: L-selectin (CD62L, previously referred to Secondary Osteoporosis Develops as a as MEL-14), P-selectin (CD62P, previously re- result of another primary disorder or as a ferred to as PADGEM) and E-selectin (CD62E, consequence of treatment. In spite of its low previously referred to as ELAM-1). The no- prevalence, approximately 10%, it is impor- menclature is derived from the cell types, tant to rule it out as a cause of osteoporosis. which possess particular selectins on their sur- Exclusion of secondary osteoporosis is often face: L-selectin on leukocytes, P-selectin on demanding especially in patients in whom it platelets and after induction by cytokines on is suspected on the basis of the medical his- endothelial cells, and E-selectin on endothelial tory, clinical examination and laboratory cells. The molecules of selectin have the lectin findings, as well as in patients in whom the domain on the N-terminal of the molecule bone mineral density measured for age is low through which they can bind to the specific or the elapsed time since the menopause. In ligand. These are saccharides in adhesive mol- men, a thorough differential diagnosis is im- ecules similar to mucin. This is the fundamen- perative as several authors report its occur- tal of their biological function as such lectin- rence in more than 70% of cases. The impor- saccharide interactions (lectins) are particu- tance of distinguishing secondary osteoporo- larly involved in the binding of leukocytes to S sis often lies in a diametrically different thera- the vascular endothelium and subsequently in peutic approach. The most frequent causes of their migration from postcapillary venules to secondary osteoporosis include: disorders of the tissue affected by inflammation. the gastrointestinal tract, pancreas, liver and kidneys, endocrine and rheumatic diseases Selective Oestrogen Receptor Modula- and drug-induced osteoporosis. tors (SERM) At present, raloxifene is the only member on the market licensed for the treat- Secondary Osteoporosis – classifica- ment of osteoporosis. It acts on bone as an tion oestradiol agonist, producing a decrease in • Osteoporosis due to hormone deficiency – bone resorption and an increased proliferation deficiency of sex hormones (several au- of osteoblasts. As an oestradiol agonist, it influ- thors include postmenopausal osteoporo- ences the cardiovascular system (even though semiquantitative assessment of vertebral deformities 196

in contrast to oestradiol, it does not increase Senile Osteoporosis (type II) A mild de- the total HDL and CRP). Raloxifene is an oe- gree of atrophy of the bones is a physiological strogen antagonist of receptors in the endome- phenomenon and belongs to the normal in- trium and breasts. It significantly reduces the volution of ageing. A pathological state oc- risk of vertebral and nonvertebral fractures in curs when bone loss is excessively enhanced women with severe osteoporosis, and a reduced and the bone mineral density level decreases risk of invasive breast cancer (84%) is consid- below the osteoporosis limit defined in the ered an additive and very important effect. A individual age groups of men and women on possible positive influence on cardiovascular the basis of WHO criteria – see the entry di- events is promising. Raloxifene is also effec- agnostics of osteoporosis. tive in the prevention of osteoporosis. An in- Senile osteoporosis usually occurs in people creased risk of venous thromboembolism with older than 70 years. It affects women just a lit- raloxifene is comparable to oestrogens and hot tle more often than men. The most important flushes may also be accentuated. Therefore, it is pathogenic factors of senile osteoporosis in- not suitable for patients with a history (or fam- clude age-related decrease of osteoformation ily history) venous thrombembolism and for (decreased vitality and activity of both the os- women with climacteric problems. teoblasts and osteoclasts), circulation and neu- rotrophic disturbances of bone, age-related Semiquantitative assessment of verte- structural changes in bone collagen and sec- bral deformities The assessment of changes ondary hyperparathyroidism consequent on in the height of vertebral bodies in the lateral decreased absorption of calcium due to de- projection has a great significance, especially creased production of calcitriol. It is character- in predicting further fractures, in patients with ised by fractures, both in the cortical and tra- osteoporosis. A semiquantitative assessment, becular bones (hip, vertebrae, proximal hu- according to Genant, is the most frequently merus, tibia and other long bones). used method in clinical practice. A decrease of anterior height of a vertebra by 20 to 25% is Is caused by a group of assessed as 1st degree or mild fracture, with a bacteria: Staphylococcus aureus (more than decreased height by 25 to 40% as 2nd degree or 50%), Staphylococcus epidermidis, Streptococ- moderate vertebral fracture and a decrease by cus pyogenes (15 to 20%), Enterococcus fae- 40% and more as 3rd degree or severe fracture. cium, Enterococcus faecalis, Haemophilus in- fluenzae, Escherichia coli, Klebsiella pneumo- Senile shoulder Chronic shoulder pain niae, and Salmonella species. Bacterial arthritis with polytopic symptomatology. The pain is is most frequently caused by Staphylococcus caused by degenerative changes of periarticu- aureus, Streptococcus haemolyticus, Pseudomo- lar soft tissue in old age. Tendon ruptures and nas, and by Haemophilus influenzae and Es- atrophy of the rotator cuff are often present. cherichia coli in children. The risk factors are S listed in table 13. Table 13. Risk factors of septic arthritis

• elderly • underlying disease: RA, SLE, diabetes mellitus, liver cirrhosis, chronic nephropathy, malignancies, haemophilia, hypogammaglobulinemia • orthopaedic interventions • joint replacements • extraarticular infections: skin, pneumonia, pyelonephritis • long-term therapy using corticosteroids and immunosuppressive drugs • haemodialysis • IV drug abuse • acquired immunodeficiency syndrome • organ transplantations 197 serum amyloid A (SAA)

The onset of disease is acute with systemic ately after taking the sample of synovial fluid. symptoms such as shivering, fever, lethargy, Intravenous administration of antibiotics is and fatigue. Pain, oedema with erythema, lo- necessary to ensure effective concentrations cal hyperaemia and reduction of active and of the antibiotics in the serum and synovial passive locomotion in the affected joint are fluid. Oral, intra-articular or intramuscular dominant symptoms and signs of the disease. antibiotics are not suitable for the initial treat- Antalgic posture is frequent. Increased syn- ment of septic arthritis. ovial fluid is present in the joint (more than 90% of all cases). Clinical symptoms in the SERM → see Selective Oestrogen Receptor hip or sacroiliac joint may be atypical or Modulators (SERM) modified. Atypical symptoms occur in the newborn, drug abusers and individuals with Seronegative spondyloarthritis A rela- immunodeficiencies. The pain and oedema tively heterogeneous group of inflammatory localised in the pubic symphysis, sacroiliac rheumatic diseases in the course of which and the sternoclavicular joint in children and rheumatoid factors remain negative (serone- IV drug abusers may suggest Gram-negative gative) by the use of standard tests. Involve- infection. Micro-organisms of low virulence ment of the axial skeleton and major periph- may cause chronic synovitis. eral joints along with skin, mucosal, gastroin- Early diagnosis is very important, as joint testinal and urogenital symptoms are com- sepsis may lead to destruction of the affected mon clinical signs in this disease. joint, or even fatal septicaemia. Clinical symptoms: Laboratory findings: The laboratory pic- • Absence of subcutaneous nodules, ture includes a high erythrocyte sedimenta- • Inflammatory arthritis of peripheral tion rate, C-reactive protein and leukocytosis joints, referred to as left shift. Aspiration of synovial • Sacroiliitis, spondylitis (sometimes loca- fluid is diagnostically very important. The lised), fluid is usually opaque, and often purulent. • Skin, mucosal, ophthalmic, gastrointesti- The cell count is usually more than 3,000 and nal and urogenital symptoms, up to 50,000 WBC/mm3 with a majority of • Familial incidence polymorphonuclear cells. The X-ray picture • Frequent association with HLA-B27, initially only shows soft tissue swelling and • Ossification in areas of inflammatory en- an apparent increase in joint space where thesopathies (pelvis, os calcis etc.). there is significant synovial fluid. Later osteo- porosis, erosion and cartilage destruction de- Serum amyloid A (SAA) A family of poly- velop, the articular cavity gradually narrows, morphous proteins encoded by various genes or even disappears. Isotope scintigraphy (us- on chromosome 11 in a number of mammali- ing 67Ga or marked leukocytes) helps to con- an species. There are two human acute-phase firm the diagnosis in cases where affected SAA proteins (SAA1 and SAA2), with 5 iso- S joints are located in areas of difficult access forms of SAA1 and 2 isoforms of SAA2. The (sacroiliac and hip joint). physiological concentration of SAA in serum Treatment: Hospital admission to an or- is approximately 2 to 3 mg/L, but can increase thopaedic or rheumatology ward is necessary, by one thousand times in acute inflammation as apart from confirmation of diagnosis and (similarly to C-reactive proteins). In terms of assessment of antibiotic sensitivity, bed rest, function, SAA are small lipoproteins, which parenteral administration of antibiotics, pain during the acute phase of inflammation join management and monitoring of the clinical the third fraction of high density lipoproteins response must be ensured. Treatment with (HDL3) and become a dominant apolipopro- broad-spectrum antibiotics, which can be tein in such molecules. SAA inhibits throm- later modified according to the results of cul- bin-induced activation of platelets, as well as tures and sensitivity, must be started immedi- the activation of neutrophils to prevent oxi- severe combined immunodeficiency (SCID) 198

dative tissue destruction during the course of ing on the underlying cause, shock can be inflammation. SAA is beneficial in acute in- subdivided into traumatic, haemorrhagic, flammation, but is harmful in chronic in- cardiogenic, anaphylactic or endotoxic (sep- flammation (causing amyloidosis). tic) shock. Reduced tissue perfusion and in- sufficient oxygen delivery were considered as Severe combined immunodeficiency the typical cause. Lately, impaired mitochon- (SCID) This is a heterogeneous group of dis- drial function (defect of oxidative phospho- orders caused by defects in the development rylation) has been included. At present, de- of stem cells of the lymphoid line with the fects of certain mitochondrial enzymes, in- subsequent occurrence of serious disturbanc- creased synthesis of nitric oxide and reactive es in T- and B-lymphocyte functions. It is one oxygen intermediates, increased adhesion of of the most severe immunodeficiencies as neutrophils on endothelium and activation of there is almost complete absence of humoral proinflammatory cytokines are considered and cellular immunities. Children with SCID the main causes of hypotension. The condi- have very severe lymphopenia (decreased pe- tion of shock is thus the result of an imbal- ripheral lymphocyte count) with blood lym- ance between NO, superoxide and their me- phocytes being functionally inactive. A severe tabolites. agammaglobulinaemia develops within the first months of life. The thymus is either miss- Shoulder–hand syndrome → see Algo- ing or present only in remnants localised in dystrophic syndrome (ADS) untraditional anatomic sites. There are also numerous disturbances observed in phagocy- Shulman’s syndrome → see Eosinophilic tosis. Severe recurrent infections, including fasciitis (Shulman’s Syndrome) pneumonias, chronic otitis media, chronic di- arrhoea and sepsis begin soon after birth. The Sickness impact profile (SIP) → see In- body rapidly becomes overwhelmed by recur- struments of assessing (health status mea- rent infections and children with SCID usually surements, outcome measurement) do not live to see the second year of life. The development of infection can only be prevent- Signals of functional impairment ed by a sterile birth and complete isolation of (SOFI) → see Instruments of assessing (health the child in a sterile environment for its whole status measurements, outcome measure- life. SCID has several forms depending to the ment) type of cells affected and the molecular de- fects, especially in the activity of various en- Silicone synovitis Develops as a reaction zymes. Treatment is possible via bone mar- to a foreign body or to certain components of row transplantation or gene therapy (supple- silicone arthroplasties (silicone elastomer, di- menting missing or defective genes). methylpolysiloxane). Clinical symptoms in- S clude pain, stiffness and swelling of the joint Sexually acquired reactive arthritis with the implanted silicone prosthesis. Silicone (SARA) Reactive arthritis secondary to sexu- synovitis most frequently affects carpal and ally-acquired infection with chlamydia being metacarpal implants and radial prostheses. the most frequent pathogen. The diagnosis is confirmed on histological (inflammatory reaction to foreign body, large Sharp score → see Total Sharp score cell infiltration, silicone particles) or radio- logical findings (intramedullary destruction, Shock A systemic reaction of the body to erosion, destruction of surrounding bone). sudden and intensive non-physiological im- Ultrasound and magnetic resonance imaging pulses from the external or internal environ- significantly contribute to the diagnosis of ment. It is manifested particularly by hy- silicone synovitis. Treatment consists of re- potension and respiratory distress. Depend- moval of the implant. 199 spinal canal stenosis

Sjögren’s syndrome (SjS) A chronic in- Somatic pain → see Types of pain flammatory disease characterised by dimin- ished function of salivary and lacrimal exo- SOST → see Sclerostin (SOST) crine glands (Henrik Sjögren, Swedish eye doctor, 1899–1986). Lymphocytes infiltrate Spasticity Increased muscle tension with the functional component of the epithelium, increasing resistance during passive stretch- which leads to glandular and ductal atrophy. ing. The trigger point is a painful point in the Dry mucosa, particularly of mouth and con- muscle, which is formed by spastic fibres of junctiva, is a typical symptom. The disease skeletal muscle. Its irritation causes referred can be primary or secondary. Secondary SjS pain in the periphery. is associated with other autoimmune diseas- es, such as rheumatoid arthritis, systemic lu- Specific features of rheumatological pus erythematosus or primary biliary cirrho- rehabilitation Exercise according to: sis. Antibodies directed against small ribonu- • Buerger-Allan – to improve circulation of cleoprotein antigens SSA/Ro and SSB/La are the lower extremities, of diagnostic significance. Positive associa- • McIntry – to improve acral circulation of tions between HLA-DR3 and primary SjS, as the upper extremities, well as between HLA-DR4 and secondary • Codmann – to relax the articular sheath, SjS, accompanied by rheumatoid arthritis • Kohlrausche – exercise in sitting up posi- have been found. Approximately 90% of pa- tion without backrest used in ankylosing tients are women 40 to 60 years old. spondylitis (AS) and osteoarthrosis (OA), Clinical symptoms: Dry mouth (xerosto- • Kaltenborn – exercise for the back, mia) and dry eyes (xerophthalmia) develop. • Vale – spinal exercises, Glands of the gastrointestinal system, the re- • Guymans, Michel and Lewit (PIR) – facili- spiratory system, skin and vaginal mucosa, tation-mobility techniques, may also be affected. Skin symptoms, vasculi- • Nordemar, Harcom and Ekdahl – aerobic tis, Raynaud’s phenomenon, renal impair- exercise used in rheumatoid arthritis, OA ment, neuropathy and arthritis belong to the and AS, most frequent extraglandular symptoms of • Kubat – exercise for flatfoot and other foot Sjögren‘s syndrome. deformities.

Skin test A test in which a test substance Spinal Canal Stenosis The narrowing of (usually antigen) is injected into the skin or is the central spinal canal, lateral recesses and administered to the skin surface in order to neuronal foramen. The defect is either con- assess the immune response of the host. Tu- genital, evolutionary conditioned or due to berculin test or determination test of host degenerative, inflammatory, traumatic, meta- sensitivity to various allergens are the most bolic and endocrine changes of the vertebral frequently used methods. column. S Clinical symptoms: Narrowing of the spi- SLE → see Systemic lupus erythematosus nal canal manifests itself after reaching a (SLE) critical point – when compression of nerve and vascular structures of the spinal canal oc- Sly’s disease → see Mucopolysaccharidosis curs. Neurogenic claudication causing pain (MPS) located in the thigh and calf are among typi- cal symptoms of spinal stenosis. The claudi- Sm antigen → see Antibodies against cation is associated with weakness of the U1RNP and Sm antigen lower extremity muscles and paraesthesiae evoked when the patient walks or stands. A Snapping hip syndrome → see Coxa sal- typical sign of the disease is for symptoms to tans (snapping hip syndrome) disappear when the patient sits down, lies spondyloarthitis 200

down or leans forward. Long-term lumbago proximately 2 to 3% of infected patients with frequently appears before the development of a genetic predisposition to RF. claudication. Spontaneous erection of the pe- nis during walking or impotence is among Stress proteins Intracellular proteins, the less frequent symptoms. Initial neurological synthesis of which increases when the cell is symptoms appear only during exercise or exposed to stressful conditions. Most infor- during extension of the spine, and tend to mation is known about heat shock proteins, disappear during relaxation or spinal flexion. which are immediately produced by cells Progression of spinal canal stenosis increases (from bacterium to mammals, including hu- mechanical pressure on intraspinal structures mans) when exposed to a higher than opti- and symptoms can then occur as postural mal temperature, and glucose regulated pro- claudication or as nocturnal claudication. teins, the production of which is induced by a lack of glucose and by certain other factors. Spondyloarthitis → see Seronegative spon- dyloarthritis Strontium ranelate This drug contains 2 atoms of strontium and has a unique dual SRS-A Slow reacting substance of anaphy- mechanism of action. It stimulates prolifera-

laxis – the mixture of the leukotrienes LTC4, tion of the preosteoblasts (osteoanabolic ef-

LTD4 and LTE4 causing slow contractions of fect) and at the same time inhibits differentia- smooth muscle of bronchi and are involved tion of osteoclasts (antiresorptive effect). in the bronchospasm of bronchial asthma. Strontium ranelate has a documented effect on the reduction of vertebral and nonvertebral SSA → see Serum amyloid A (SAA) fractures. This effect is highlighted in the most-at-risk groups of postmenopausal wom- SSc → see Systemic sclerosis (SSc) en with osteoporosis. It is administered in a dose of 2 g/day in the form of granules, mixed Statins on bone metabolism Statins with water, preferably at bedtime. may inhibit the production and functional ability of osteoclasts interfering with the me- Structural components of joints Tenu- valonate pathway in synthesis of cholesterol. ous connective tissue, adipose tissue, dense A reduction in fracture risk has been docu- connective tissue, cartilage and bone belong mented in a number of observations on pa- to the group of tissues referred to as connec- tients taking statins longterm. tive tissue. Certain connective tissues (bone and dentine) are mineralised. All forms of Still’s disease → see Juvenile idiopathic ar- connective tissue are derived from embryonic thritis (JIA) tissue referred to as mesenchyme. The cells of mesenchyme are pluripotent cells, which dif- S Streptolysin O Bacterial cytolysin released ferentiate into specialised fibrocytes, chon- by group A beta-haemolytic streptococci. drocytes, osteocytes and adipocytes. Hae- They belong to perforins because after bind- matopoietic cells also originate from mesen- ing to the surface of target cells, the strep- chyme. tolysin O in the course of polymerization The presence of intercellular matter, which forms spiral tubes, which forms holes in the is located between particular cells or groups cytoplasm, leading to lysis of the affected cell of cells, is a typical feature of connective tis- (particularly the erythrocytes and leukocytes sue. The intercellular matter consists of fibres of the host). The detection of antibodies (collagen, elastic and reticular) and amor- against streptolysin O (antistreptolysin O, phous material referred to as matrix. The in- ASO) is a test used to detect infection caused tercellular matter is a non-living supportive by these streptococci, which may lead to the matter. Only certain types of connective tis- development of rheumatic fever affecting ap- sue cells are able to produce intercellular mat- 201 sulfasalazine (SSZ) ter. Such cells (e.g. fibroblasts, chondroblasts, Sudeck’s atrophy → see Algodystrophic osteoblasts) produce fibrous components and syndrome (ADS) amorphous matrix. Amorphous matrix con- sists of macromolecules, which used to be Sulfasalazine (SSZ) At present it is the sec- referred to as acid mucopolysaccharides, but ond most commonly used disease-modifying currently are referred to as glycosaminogly- drug (DMARD) in the treatment of rheuma- cans. Such a nomenclature better defines the toid arthritis. It is also successfully used in chemical structure of their polysaccharide the treatment of spondyloarthropathies, par- (glycan) chains. ticularly in peripheral joint disease. The most The part of the nomenclature – glycosami- favourable features of the drug include: no – suggests that the linear polysaccharide • Rapid onset of action within 3 to 4 days chain consists of repeated disaccharides; each • Absence of serious late adverse effects (e.g. containing uronic acid bound to a hexo- malignancies) samine (aminosaccharide) residue. Certain • Favourable application in combination glycosaminoglycans (e.g. sulphonated gly- with other DMARDs. cosaminoglycans) are covalently bound to Pharmacokinetics: Approximately 30% of proteins, whereby they are a component of SSZ is absorbed in the small intestine. As SSZ large macromolecules referred to as proteo- is subject to entero-hepatic circulation, its glycans. For example, heparan sulphate, biological availability is only around 10%. In- chondroitin sulphate and keratan sulphate tact SSZ reaches the large intestine, where by belong to sulphonated glycosaminoglycans. the action of intestinal microorganisms, the Hyaluronan represents non-sulphonated gly- double nitric bond of SSZ is broken, leading cosaminoglycans. Large glycoprotein laminin to the formation of 5-aminosalicylic acid is present in basal membranes. Chondronec- (PAS) and sulfapyridine. PAS is poorly ab- tin, which mediates adhesion of chondrocytes sorbed (around 30%), is subject to on type II collagen, is present in cartilage. before excretion, and the remainder is excret- The intercellular matter localised between ed via the stool. Sulfasalazine is well absorbed cells provides connective tissue with support- and its metabolites appear in the blood 3 to 6 ive and protective functions. hours after drug administration. It is metabo- lised in the liver and excreted in urine in con- Substance P A neuropeptide containing 11 jugated or unconjugated form. Different amino acid units. It is present particularly in types of acetylation phenotype of patients ex- the nervous system of vertebrates. It may ist – so called ‘rapid’ and ‘slow’ acetylators. have a supportive function as a neurotrans- The relationship between such a phenotype mitter and neuromodulator in the central and the presence of adverse effects has not nervous system, whereas in the peripheral been confirmed. SSZ has a high affinity to- nervous system and other tissues, it acts as a wards plasma proteins (>95%), the peak plas- local hormone (tachykinin). Substance P ma concentration is achieved 3 to 5 hours af- S causes hypotension and vasodilatation and ter drug administration, and the plasma may cause contraction of smooth muscles. elimination half-life is 6 to 7 hours. A steady Apart from the above, it is involved in a num- state is reached in 4 to 5 days. ber of immune mechanisms, including stimu- Mechanism of action Not clearly under- lation of phagocytosis of professional phago- stood, as the effective component of the drug cytes in a similar manner to tuftsin, stimula- is unknown. It is suggested that the whole tion of inflammatory cytokines (TNF-α, IL-1, molecule is the most effective anti-rheumatic IL-6) and prostaglandin production in cells of agent. SSZ, similarly to methotrexate, blocks the inflammatory reaction, particularly in dihydrofolate reductase and other folate de- cells of the mononuclear line. Substance P pendent enzymes. This may lead to adenos- acts through specific receptors (neurokinin 1 ine accumulation and to increased levels of receptor). pro-inflammatory interleukins. sulphasalazine 202

Adverse effects: of patients receiving both SSZ and corti- • Gastrointestinal, costeroids. • Skin reactions, • Haematological, Sulphasalazine → see Sulfasalazine (SSZ) • Hepatic. Frequent adverse effects: Superantibodies A group of antibodies, • Gastrointestinal – nausea, vomiting, an- which apart from their ability to bind an anti- orexia, abdominal pain, dyspepsia, gen, also possess other activities. They usually • Central nervous system – headache, pyrex- bind to insert the preserved (constant) parts ia, mild vertigo, tinnitus. of the variable domains and are able to bind Less frequent adverse effects: nucleotides and superantigens, mediate mu- • Systemic – hypersensitivity reactions, tual interactions and catalyse certain chemi- • Skin – exanthema (macular, papular, pruri- cal reactions. Similarly to superantigens of B tus), alopecia (1 to 5%), Stevens-Johnson lymphocytes that can bind a number of anti- syndrome, bodies with different specificity, superanti- • Ocular – yellow staining of the lens/cornea, bodies are able to bind various ligands to • Hepatic – elevation of liver enzymes, acute parts of their molecule other than the stan- hepatic reaction including serious dam- dard binding site for antigens. age, • Pulmonary – rare reversible pulmonary in- Superantigens These can, like ordinary an- filtrations with eosinophilia, fibrosing al- tigens, be divided into two groups: thymus de- veolitis, pendent and thymus independent. The com- • Haematological – leukopenia, neutropenia mon feature of superantigens is their ability to thrombocytopenia, aplastic anaemia, agra- non-specifically stimulate a number of T or B nulocytosis, lymphocyte clones. Thymus dependent anti- • Nervous system – irreversible changes to gens do not require modification in antigen central nervous system (very rare), presenting cells, they stimulate 5 to 25% of all • Kidneys – serious damage (very rare), or- T helper lymphocyte clones that are present in ange-coloured urine (from excreted me- the body by non-specific binding to the tabolite), β-chain of the antigenic receptor (TCR) and • Autoimmune symptoms – drug induced concurrently to the α-chain of the class II systemic lupus erythematosus. MHC antigens (major histocompatibility com- Interactions: plex). As a consequence of the binding, acti-

• Cimetidine has often been used to treat vated TH-lymphocytes release large amounts NSAID-gastropathy and its interaction with of cytokines, which have a negative influence SSZ is very important. Cimetidine increases on the host causing systemic toxicity and sup- the levels of sulfapyridine and thereby the pression of the specific immune response. An- S risk of nausea and vomiting. N-hydroxyme- other type of superantigens is the B cell type of tabolite of cimetidine may increase the hae- superantigens. matological toxicity of SAS. As well as exogenous superantigens of B • Corticosteroids were studied in patients lymphocytes, endogenous superantigens can treated with SSZ and receiving corticoster- stimulate B cells to continuous expansion. It oids or a placebo in Great Britain. In spite is suggested that superantigens play a key role of the fact that 20 patients were followed in the pathogenesis of certain neurodegenera- up for a period of one year, the supplement tive (multiple sclerosis) and autoimmune dis- of corticosteroids was of no clinical benefit eases (rheumatoid arthritis, insulin dependent and the authors suggest that this may be diabetes mellitus and psoriasis). due to biological interaction. This fact has not been confirmed by a Norwegian study; Superoxide radical Often referred to as . – fewer adverse effects occurred in the group superoxide anion or as superoxide ( O2 ), it 203 synovial fluid (SF) develops by single-electron reduction of mo- • Aged over 65, absence of IgM RF in the se- lecular oxygen by virtue of the enzyme rum NADPH oxidase. This enzyme is present • Symmetrical polysynovitis affecting the mainly in professional phagocytes but also in wrist, CMC (carpometacarpal), MCP the mitochondrial respiratory chain and so is (metacarpophalangeal) and PIP (proximal involved in certain other reactions. Hydrogen interphalangeal) joints, TC (talocrural) peroxide and other reactive forms of oxygen and MTP (metatarsophalangeal) joints, that are involved in antimicrobial and cyto- tenosynovitis of hand flexors and exten- toxic reactions originate during these reac- sors, tions. • Pitting oedema of hands and feet, • Morning stiffness, Sural nerve tunnel syndrome → see • Good response to glucocorticoids treat- Tunnel syndromes of foot ment, • Exclusion of other pathological diseases. Sweet’s syndrome → see Acute febrile neutrophilic dermatoses Synovectomy A surgical procedure to re- move inflamed synovial tissue by open joint Synapse A functional connection between surgery or arthroscopy. It is rarely fully suc- two neurons (in the central nervous system), cessful, as total synovectomy is difficult to or between a neuron and its effector cell in achieve. It is most effective if performed at an muscles (referred to as myoneural or neuro- early stage, before articular cartilage is dam- muscular connection) or glands. Most syn- aged and allows regression of the inflamma- apses function by the nerve impulse arriving tory process and improvement in joint func- at the afferent neuron releasing a neurotrans- tion. Indications are rheumatoid arthritis, mitter which then rapidly triggers the effer- ankylosing spondylitis, monoarthritis. ent neuron. A lack of neurotransmitter leads to diseases such as myasthenia gravis. Synovial chondromatosis The principle of the disease is cartilaginous tissue forma- Syndrome RS3PE (remitting seroneg- tion in the process of synovial membrane ative symmetrical synovitis with pit- metaplasia. Pain and limitation in the range ting oedema) A rare disease of unknown of joint movement predominate the clinical origin that predominantly affects older Cau- picture. Multiple shadows are visible on X- casian individuals. The disease is character- ray. Malignant transformation is very rare. ised by acute symmetrical polysynovitis par- ticularly affecting the radiocarpal joints and Synovial fluid (SF) The volume of synovial small joints of the hand, as well as the tal- fluid in a healthy joint is only about 0.1 to 0.4 ocrural joints and small joints of the foot. ml. SF forms a very thin layer (approx. 26 Rheumatoid factors are not detected in the μm) in the articular cavity of a healthy joint. S serum, and there are no joint erosions on X- Intraarticular pressure is subatmospheric ray. The disease has a good prognosis. The (negative) or slightly atmospheric (from –4 to synovitis subsides after low doses of glucocor- 1 mm Hg), so the intraarticular cavity is only ticoids or antimalarial agents. The drug-in- a potential space and capillaries of synovial duced remission is long-term, even after with- membrane are in very close proximity to the drawal of treatment. Such a fact distinguishes avascular articular cartilage. Furthermore, the RS3PE from rheumatoid arthritis and polymy- structure of the synovial membrane causes algia rheumatica. The RS3PE syndrome may synovial fluid to communicate directly with be present as a paraneoplastic symptom. Ma- the interstitial fluid of the synovial mem- lignancy should always be considered. The brane. diagnostic criteria of RS3PE suggested in SF is formed in the synovial membrane by 1994 are as follows: secretion of blood plasma and is then en- synovial fluid (SF) 204

riched by hyaluronan and other macromole- act as a unique lubricant of the cartilage, to cules. The synovial matrix can be considered transfer nutrients towards avascular articular as a special form of extracellular matrix with cartilages, fibrous cartilages, discs and menis- a high content of water, electrolytes and hy- cus and also carry metabolites away. aluronan. The content of synovial fluid re- SF is a clear, viscous, yellow fluid, which is flects the condition of the synovial membrane present in all diarthrodial joints. It maintains and avascular articular cartilage. The number lubrication of the cartilages of articulating of cells in a healthy joint is low. Gardner sug- bones. Healthy synovial membrane (SM) gests the following number of cells in normal transmits only substances of small molecular synovial fluid: cells with nucleus are less than weight (e.g. glucose); pathologically changed 750 in 1 μL; neutrophil granulocytes are found SM can transmit substances of higher molecu- around 200 in 1 μL; lymphocytes in small lar weight, e.g. proteins, complexes of oxygen amount; mononuclear phagocytes only a few radicals, cytokines etc. Hyaluronic acid, which and synovial cells very few. is synthesised by B cells of the synovial lining, SF represents a liquid medium that is re- is a component of SF. Depending on the num- sponsible for hydrodynamic changes in the bers of leukocytes, their differential picture course of joint movement. SF is of high vis- and bacteriological assessment, SF can be cosity; however, the physical properties of SF subdivided into four groups: non-inflamma- cause its viscosity to decrease during in- tory, inflammatory, septic and haemorrhagic creased loading. Such properties enable SF to (table 14).

Table 14. Findings in synovial fluid classified according to particular groups (Hüttl 1970, 1971)

Parameter Normal SF Group I Group II Group III (non-inflammatory) (inflamma- (septic) tory) Volume (mL) < 3,0 > 3,0 > 3,0 > 3,0 Viscosity High Higher Low Variable Colour Clear/Straw Amber Yellow Purulent Turbidity No No Present Significant Leukocytes < 200 200–2000 2000–50 000 > 50 000 Neutrophils/ < 25% < 25% > 50% > 85% Granulocytes Cultivations Negative Negative Negative Frequently positive Total proteins (g/L) 11–22 Normal value > 40 30–60 S Uric acid 180–116 Normal value Normal value Normal value (μmol/L) Glucose 3.3–5,2 Normal value Low in RA 1.1–1.6 (mmol/L) Lactate (mmol/L) 0.9–1,8 Up to 4.2 Up to 6.9 Up to 28.0 (except for gonococcal arthritis) LDH (U/L) < 333 Normal value > 333 > 501 Rheumatoid factors Negative Negative Positive/ Negative negative Immunoglobulins Approximately ½ of Approximately ½ of Increased Increased plasma concentration plasma concentration 205 synovial lining cells

Synovial fluid analysis This is a compre- Synovial lining cells The surface of the hensive histopathological, microscopic, bio- synovial membrane is composed of synovial chemical, immunological and bacteriological lining cells, which do not form a consistent assessment of synovial fluid, which provides layer, but have wide intercellular spaces be- diagnostic information and assistance for ap- tween them, filled by intercellular matter and propriate therapeutic management. A less interstitial fluid. No intercellular connections comprehensive analysis consists of macro- of desmosomal type exist between particular scopic examination (colour, turbidity and lining cells, and there is no basement mem- viscosity of SF), cytological assessment with brane under the synovial lining cells. The su- an emphasis on the number of nucleated cells perficial layer of the synovial membrane is re- and the leukocyte differential count, micro- ferred to as the synovial intima or the layer of scopic assessment focused on the presence or synovial lining cells (consists of two to three absence of microcrystals, and depending on layers of cells in various types of membrane). need, a bacteriological examination. The underlying subintimal or subsynovial layer of synovial membrane consists of fi- Synovial joints These joints provide a very brous, loosely areolar or fatty tissues. Three effective mechanical system and allow a wide major types of synovial membrane are distin- range of movement. They are approximately guished according to the structure of subsyn- 106 times exposed to load during the first year ovial tissue: areolar, adipose and fibrous. Syn- (each load is approximately three- to fourfold ovial membrane forms stratum synoviale, body weight) and remain effective for the re- which is continuously substituted by stratum mainder of life (approximately 70 years). fibrosum of the articular sheath. The bone terminals of synovial joints are Two morphologically different types of covered by cartilage, which is referred to as synovial lining cells can be recognized in the articular cartilage. The main mechanical intima: type A and type B cells. Such knowl- properties of synovial joints are due to the edge was first published in 1962 by Barland et presence of such cartilage. The articular car- al. The ultrastructure of type A cells suggest tilage can be considered as hydrated gel that they are phagocytosing cells with an strengthened by fibres, composed of a fibrous abundance of vacuoles, pinocytic vesicles, mi- microskeleton of collagen. The gel consists of tochondria and lysosomes. Type A cells belong proteoglycans, which is capable of retaining to the monocytomacrophage system and play huge amounts of water, and thereby act as a an important role in the homeostasis of the shock absorber. Articular cartilage reduces synovial environment. A typical feature of type the load applied to subchondral bone, and B cells is their well developed granular endo- provides contact areas with low friction that plasmic reticulum and Golgi apparatus. His- are resistant to attrition. Articular cartilage tochemical studies and tissue cultures indi- does not possess perichondrium. Synovial cate that these cells produce hyaluronan fluid as a component of the articular cavity is (Worrall et al. 1991, Momberger et al. 2005). S present between articular planes. The articular Capillaries are present in close proximity cavity is surrounded by the articular capsule, to the surface of the synovial membrane, di- which consists of two layers (external and in- rectly under the synovial lining cells. The ternal). The external layer (fibrous membrane) large number and superficial location of cap- consists of dense fibrous tissue and is adher- illaries explains the frequency of haemor- ent with the bone through collagen fibres. rhages into the articular cavity, as even a Dense fibrous tissue of the layer is substituted simple puncture of the joint cavity can cause by tenuous fibrous tissue of the synovial translocation of erythrocytes into synovial membrane. The synovial membrane possess- fluid. There are two types of capillaries in es plicae or digitiform villi, which protrude synovial membrane: continual and fenestrat- into the articular cavity. ed. The walls of fenestrated capillaries are very thin, endothelial fenestrations are locat- synovial sarcoma (synovioma) 206

ed in those parts of capillaries that are closest slow. The X-ray shows a picture of shadows of to the joint cavity. It is suggested that such soft tissues with calcification. As nearby joints vessels are specialised for the rapid exchange can react with secondary synovitis, synovitis of fluids and nutrients. Fenestrated venules due to rheumatoid arthritis, degenerative ar- have also been described in synovial mem- throsis, benign fibroma, fibrosarcoma, lipo- brane. It was found that dense corpuscular ma and liposarcoma must be ruled out. material (comparable to macromolecules of Treatment: Radical excision followed by antigen-antibody complexes) leaks from the radiotherapy. The tumour is very malignant blood circulation into the interstitium of the leading to development of metastases in synovial membrane and the joint cavity lymph nodes and lungs in 50 to 70% of pa- through the walls of fenestrated venules. It is tients. suggested that the permeability of fenestrated capillaries is not under the control of en- Synovioma → see Synovial sarcoma dothelium but the surrounding tissue. Lymphatic vessels of the synovial mem- Synovitis Inflammation affecting the syn- brane are not as numerous nor superficially ovial membrane of a synovial joint. Acute located as blood capillaries. Lymphatic capil- synovitis is accompanied by the typical symp- laries accompany postcapillary venules and toms and signs of inflammation, i.e. pain, form a system in the subintimal layer of the tenderness, heat, swelling, erythema and im- synovial membrane. They continue along the paired function. It is associated with an in- flexor aspect of the limb and communicate creased volume of synovial fluid. The micro- with the lymphatic plexus in the periosteum. scopic picture is characterised by the pres- The system of lymphatic vessels plays a sig- ence of polymorphonuclear leukocytes and nificant role in the homeostasis of the inter- macrophages in the interstitium of the syn- stitial connective tissue of the whole body. ovial membrane, as well as in the SF. Chronic Currently, it is well known that the lymphatic synovitis is characterised by thickening of the circulation significantly regulates the volume synovial tissue without or only a small amount of the extravascular fluid and proteins in the of fluid. Lymphoid follicles and multi-nucleat- tissues and forms pathways for the migration ed large cells and later also numerous mast and circulation of lymphocytes, and thereby cells occur in the synovium. Signs of hyper- contributes to optimisation of the immune trophy and hyperplasia of the synovial tissue response. The lymphatic system plays an im- develop following repeated exacerbations of portant role in metabolism of components of inflammation. The final outcome of this in- the connective tissue intercellular matter, es- flammatory process may be the development pecially hyaluronan (Rovenská et al. 2003). of fibrosis.

Synovial sarcoma (synovioma) Synovi- Syringomyelic arthropathy of shoul- S oma does not have a clear histology as epithe- der Syringomyelia can lead to a neuropathic lioid elements, spindle cellular particles, hya- osteoarthropathy with a progressive destruc- linised fibrosis and calcifications can be tive disease of the joints associated with loss present in this tumour. It occurs in the prox- of sensation, a decreased pain perception and imity of joints, particularly in the soft tissue, characteristic destructive changes on X-ray. It in the bursa of tendons, and rarely in conti- is characterised by soft tissue swelling, mild nuity with the synovial membrane. It occurs pain and rapid destruction of the shoulder in adolescents and young adults, more fre- joint. The disease is more frequent in men quently in men. between 20 and 40 years. Anaesthesia for Clinical picture: The tumour of soft elastic pain, warm and cold sensations with no de- consistency is found in the proximity of fect in the sensory function of deep sensa- joints, articular ends of bones or on tendon tions is present. Syringomyelic arthropathy sheaths. Growth of the tumour is relatively should be considered if the large joint of the 207 systemic lupus erythematosus (SLE) upper extremity is affected in a young patient, cesses. SET is also a component of complex especially if the patient complains of little oncology treatment. SET is different from pain despite severe destructive disease. , in which an intravenous thrombolytic agent (tissue plasminogen acti- SYSADOA; symptomatic slow acting vator) is infused as a clot buster in acute coro- drugs of OA Symptomatic rapid acting nary thrombosis. drugs are used in the treatment of osteoar- throsis (SYRADOA, symptomatic rapid act- Systemic lupus erythematosus (SLE) ing drugs of OA) in the form of analgesics. An autoimmune disease affecting most of the Slow acting drugs belong to the second group. important organs; however, particularly the Some of these drugs seem to be disease mod- skin, joints, cardiovascular system, kidneys, ifying drugs (DMOAD, disease modifying central nervous system and lungs. The dis- OA drugs) or more lately, structure disease ease is characterised by hyperactivity of B modifying drugs (SMOAD, structure disease lymphocytes leading to the formation of au- modifying OA drugs). Though their effects to-antibodies directed against organ non- have been disputed in many experimental tri- specific antigens. It is still not clear whether als, there are two studies of glucosamine sul- SLE is a syndrome whose common feature is phate and one study on chondroitin sulphate represented by the below mentioned symp- indicating a structure modifying effect (Ue- toms. belhardt et al. 1998, Reginster et al. 2001, Clinical symptoms: Pavelka et al. 2002). SYSADOA are slow act- • Clinical symptoms of the disease can be ei- ing drugs, but the effect lasts for up to two ther systemic or they can be due to inflam- months after their withdrawal. It is supposed mation of a particular organ or system, that they inhibit synthesis of lysosomal pro- such as skin, mucosa, joints, kidneys, brain, teases, decrease the formation of oxygen and serous membranes, lungs, heart and some- nitrous radicals and have a protective effect times the digestive system, on cartilage against the impact of pro-inflam- • The organs can be affected either individu- matory cytokines. ally or in combination, • Impairment of vital organs, particularly Systemic enzyme therapy (SET) A ther- the kidneys and the central nervous sys- apeutic management consisting of the ad- tem, must be considered a significant fea- ministration of a combination of enzyme ture influencing morbidity and the associ- agents (e.g. Wobenzym), usually by mouth. ated mortality, All preparations are in the form of tablets • The morbidity and associated mortality coated with an acid resistant cover to protect may be caused by the distribution and se- the contents from gastric acid. The tablet dis- verity of organ involvement by the under- solves in the small intestine where the en- lying disease process or due to its treat- zymes are partially absorbed and act systemi- ment. S cally in the body. Enzymes of SET prepara- Diagnostic (classification) criteria: The vari- tions belong to hydrolases and their major ability of clinical symptoms, signs and labora- representatives are proteolytic enzymes of tory findings and the need to monitor medi- animal and vegetable origin. They help in the cal observations internationally led to the es- degradation of immune complexes, the opti- tablishment of specific diagnostic criteria. misation of phagocytosis and the inflamma- The original proposals, on which specialists tory reaction, which determine their immu- had been working since 1972, were finally re- nonormalising effects. At present, SET is used viewed and released in 1982. The original particularly in surgical specialties, sport group of 14 signs was reduced to a final 11 medicine (injury treatment), vascular diseas- (table 15). es, the treatment of lymphoedema, and in- The above classification is based on the flammatory and immunopathological pro- presence of 11 criteria. In clinical trials, the systemic lupus erythematosus (SLE) 208

Table 15. ARA Diagnostic criteria of SLE

Criteria Definition 1. Facial erythema (malar) permanent, flat or raised, over the malar areas sparing the nasolabial folds 2. Discoid erythema erythematous raised patches on facial skin with adherent keratotic scaling and follicular plugging, atrophic scars develop in older lesions 3. Photosensitivity erythema as a consequence of increased reaction to sunlight in patient’s history or observed by a physician 4. Mouth ulcers oral or nasolaryngeal ulceration, usually painless, observed by a physician 5. Arthritis non-erosive arthritis affecting two or more peripheral joints character- ised by tenderness, swelling or effusion 6. Serositis a. pleuritis – typical pleural pain in the history or friction murmur, or pleural effusion, confirmed by a physician, or b. pericarditis – confirmed by ECG, rub or pericardial effusion 7. Kidney impairment a. proteinuria greater than 0.5 g/day, or greater than 3+ if quantitative evaluation has not been performed, or b. cellular casts, may be erythrocytes, haemoglobin, granular, tubular or mixed 8. Neurological disorder a. convulsions – if not due to an offending drug or known metabolic disorder, i.e. uraemia, ketoacidosis or electrolyte disturbance, or b. psychosis – if not due to an offending drug or known metabolic disorder, i.e. uraemia, ketoacidosis or electrolyte disturbance 9. Haematological a. haemolytic anaemia – with reticulocytosis, disorder defects or b. leukopenia (systemic) – less than 4.0 x 109/l, proved by at least two consequent examinations, or c. lymphopenia – less than 1.5 x 109/l, proved by at least two conse- quent examinations, or d. thrombocytopenia – less than 100 x 109/l, if not due to an offending drug 10. Immunological defects a. anti-DNA –presence of elevated levels of circulating antibodies against native DNA, or b. anti-Sm – the presence of circulating antibodies against nuclear Sm antigen, or S c. antiphospholipid antibodies – present in the serum, based on: – elevated serum concentrations of IgG or IgM anticardiolipin antibodies – positive test for lupus anticoagulant using standard method, or – false positive serological test for syphilis (Bordet-Wassermann reaction), proved positive for at least six months and confirmed by Treponema pallidum immobilization test or fluorescent trepone- mal antibody absorption test 11. Antinuclear antibodies abnormal titre of antinuclear antibodies proved by immunofluorescent test or by an equivalent method at any period of time and with no drug treatment which can induce lupus erythematosus 209 systemic lupus erythematosus diseasesystemic activity sclerosisindex (sledai) (SSc) diagnosis of SLE is confirmed when at least loss, subfebrile and general fatigue oc- four of these criteria are present, either simul- cur. taneously or serially over the time of moni- The clinical signs are characterised by scle- toring of the patient. rosis of the skin, Raynaud’s phenomenon, and Deposits of immune complexes in target gastrointestinal, lung and heart abnormalities. tissues (glomerulus, choroidal plexus etc.), Antibodies against DNA-topoisomerase I (an- along with cytokines and adhesive molecules, ti-Scl-70) are present in half the patients, more are involved in the pathogenesis of damaging frequently in patients with lung fibrosis, the inflammation. Proof of double-stranded DNA diffuse form of SSc, heart abnormalities, joint (anti-dsDNA) antibodies, anti-Sm antibodies, contractures and progressive disease. Anti- ribosomal ribonucleoprotein (anti-U1 RNP) centromere antibodies are present in approx- antibodies (overlap syndrome), antibodies to imately 20% of patients with SSc, a half of Ro (SSA) or La (SSB), antiribosomal P pro- whom suffer from a limited form; the anti- tein antibodies (cerebritis) or antiphospho- bodies are most frequently present in CREST lipid antibodies is crucial to the diagnosis of syndrome (in 90% of patients). The course of SLE. Many however are also present in other the disease is more favourable in patients connective tissue diseases (ie SSA/SSB anti- with anticentromere antibodies; damage to bodies in Sjögren’s syndrome). the lungs and kidneys is less frequent and se- vere. Prognosis is worse in patients with pro- Systemic lupus erythematosus dis- gressive lung fibrosis, pulmonary hyperten- ease activity index (SLEDAI) → see In- sion and renal disease with malignant hyper- struments of assessing (health status meas- tension. urements, outcome measurement) The principal subsets of SSc are: • Diffuse cutaneous SSc (dcSSc) Systemic sclerosis (SSc) Previously • Limited cutaneous SSc (lcSSc) known as diffuse scleroderma or progressive • SSc sine scleroderma in which patients systemic sclerosis is a chronic systemic dis- have only internal organ involvement ease affecting the skin, locomotor system and • Environmentally-induced scleroderma internal organs. It is characterised by fibro- • Overlap syndromes in which features of productive changes of connective tissue, col- SSc coexist with elements of other rheu- lagen overproduction, microvascular abnor- matic disorders malities and defects of humoral and cellular The use of disease modifying drugs is not well immunity. The disease affects women four established, but those that influence the me- times more commonly than men. It most fre- tabolism of collagen (D-penicillamine) and quently manifests itself between the ages of suppress the immune response, are often used 45 to 65 years. Annually, there are 5 to 10 in treatment, particularly cyclophosphamide, newly diagnosed cases in a population of one methotrexate and cyclosporin. Indications for million individuals. corticosteroids include the early oedematous S The first symptom of SSc is usually Ray- cutaneous stage, in patients with myositis, ar- naud’s phenomenon. Arthralgias, joint stiff- thritis and serositis. Vasoactive drugs, ACE ness, arthritis, myalgia and myositis occur in inhibitors and prostaglandins E1 are also used about half the patients. In most cases, systemic in treatment. Physical therapy is a component symptoms, such as loss of appetite, weight of the multi-disciplinary management. T

Tai-chi exercise This is an undemanding ing pain of the first and second toe of the but effective type of exercise for older people foot. Hypo or hyper aesthesia is present on aimed at improving movement coordination, the medial side of the first and second toe. increasing functional capacity and global The strength of the extensor digitorum brevis well-being. It also helps prevent traumas, es- muscle is weakened. pecially falls, because it leads to awareness of Medial tarsal syndrome the body and its parts, as well as positions in The tibial nerve is compressed by the flexor which the body is situated. reticulatum behind the medial malleolus near the heel bone. Pain radiates either to the Takayasu’s arteritis (TA) A chronic in- whole foot or only to one half of the foot and flammatory disease affecting large arteries, rarely just to the area of the heel. Hypo or hy- particularly the aorta and its main branches. per aesthesia is present over the whole foot or The disease mainly affects young women. only on medial or lateral side. Clinical symptoms: The phase of vessel Treatment: Glucocorticoids are adminis- obliteration, manifested by upper extremity tered locally or the nerve is released surgi- claudication, headaches, postural cally in both syndromes. and visual defects follows the phase of sys- temic symptoms. Weak or absent pulsation Temporal Arteritis (TA) (Giant Cell Ar- and bruits over the large arteries are typical. teritis) Vasculitis of unknown aetiology which affects both the external and internal Taping The use of special adhesive tapes in carotid arteries (and other intracranial arter- order to fix the supportive the fibro-tendinous ies) of individuals over the age of 50. It can apparatus of joints. It is used particularly in lead to sudden blindness if not recognised sports medicine in cases of swelling, joint and treated with high dose corticosteroids. subluxation, tendinitis and tenosynovitis. Its Clinical symptoms: The main clinical application is short term only, e.g. before symptoms include fatigue, unilateral fronto- overloading the joint or during various phas- temporal headache, , visual es of rehabilitation, after trauma or opera- disturbances, scalp tenderness, polymyalgia tions in the area of the locomotor system. rheumatica and aortic arch syndrome. Taping requires an appropriate application Diagnosis: The clinical picture associated technique in order to produce beneficial out- with a high erythrocyte sedimentation rate comes and avoid problems (callosities, pus- (ESR > 60mm/h) should give a strong suspi- tules, defects of circulation). The main areas cion. Temporal artery biopsy should be un- of application include the tibial area and the dertaken though may be normal in many pa- fingers. Taping in rheumatology is also ap- tients, due the nature of the disease affecting plied in knee pain when the patella is shifted the artery in skip lesions. medially by the use of tape, which leads to Treatment: Treatment with high dose significant pain relief. prednisolone (40 to 60 mg daily) should be started as soon as the diagnosis is strongly Tarsal tunnel syndromes suspected to avoid sudden blindness or Anterior tarsal syndrome stroke. The dose should be tapered slowly The deep peroneal nerve is compressed by and treatment is often required for twelve the cruciform ligament on the anterior tarsal months or longer. side. The patient complains of a sharp burn- 211 thalassaemias

Tendinopathy (tendonosis, tendope- elasticity and tonicity of the rubber strap. It is riostosis, enthesopathy) A progressive also used in patients with rheumatic diseases degenerative change within the tendon inser- to exercise the long muscles of the extremi- tions with gradual deposition of calcium. ties. Independent exercises at home after pro- Causes include trauma, microtrauma and viding the patient with instructions is an ad- overloading. Genetic and metabolic factors vantage of this method. also play an important role in their develop- ment. They can be diagnosed from the medi- Testosterone Does not have the same caus- cal history, and palpation and movement of al relation to osteoporosis in men as oestro- the affected muscle against resistance. Spon- gens have in women. In men, ageing is associ- taneous pain is not usually present. Tendi- ated with changes in the hypothalamus-pitu- nopathies can also affect the spinous and lat- itary-gonadal axis with a consequent signifi- eral processes of vertebrae. cant decrease in total as well as free testosterone. Testosterone has a direct stimulatory influence Tendinopathy of the rotator cuff A defect on the production and activity of the osteo- to the insertion area of the rotator cuff of the blasts, shown by the finding of androgen re- shoulder joint, most frequently affecting the ceptors on their surface. Also, androgens act tendons of the supraspinatus and infraspinatus via growth factors. Testosterone deficiency muscles, and less frequently the subscapularis reduces the secretion of calcitonin and syn- muscle. Impairment of a particular insertion thesis of calcitriol. Testosterone deficiency is can be distinguished by movement against re- one of the commoner causes of osteoporosis sistance according to the movement pattern of in men. The administration of testosterone the particular muscles (pain occurs), by palpa- derivatives increases bone mineral density tion and frequently also by a typical painful arc. and reduces the risk of fractures. Treatment: Physical therapy, non-steroidal anti-inflammatory drugs, local infiltration of Teufel’s bandage A support to correct corticoids. posture, which is used in Scheuermann’s dis- ease and cases of increased curvature of the Tendomyosis A frequent form of extra-ar- vertebral column in the sagittal plane due to ticular rheumatism. Myalgia and pain of habitual incorrect posture, e.g. at work. muscle and/or tendon insertions, which are worsened by various physical and psycho- TGF (transforming growth factor) Two logical factors, such as changes in the weather, TGF’s are well identified, TGF-α and TGF-β, cold, fear, depression etc. are typical symp- though they are not related to each other toms. Painful muscles show increased tone structurally or genetically and act through and areas of abnormal hardening of tissues – different receptors. TGF-α is a small polypep- so called myogelosis – can be present. The tide growth factor, which affects cell division, causes include overloading and incorrect load- wound healing and stimulates angiogenesis, ing of the muscles during work and sporting and is upregulated in some forms of human activities, incorrect posture, incorrect move- cancer. TGF-β exists in three subtypes, TGF- T ment habits, postural defects and others. β1, TGF-β2, and TGF-β3 and is commoner than TGF-α. The main feature of TGF-β is its Tensilon test → see Myasthenia gravis involvement in the regulation of transforma- tion of normal cells into malignant cells, reg- Teriparatide → see Parathormone – Teri- ulation of embryonic development, wound paratide healing, inflammatory and other immune re- sponses, and is involved in cell apoptosis. Terraband (dynamoband) Terraband (rubber strap) is used to perform exercises, Thalassaemias → see Haemoglobinopathies the difficulty of which can be adjusted by the and involvement of the locomotor organs thermal therapy 212

Thermal therapy The delivery of heat to if strict standard conditions are adhered to. the body for medical purposes. It can be re- Thermography can also be utilised to evalu- ferred to as positive (systemic application ate thermal changes due to pharmacotherapy with warm bath, mud, sauna or local applica- (temperature over affected joints) and physi- tion with wax, infrared radiation, diathermy, cal medicine (local changes of micro- and ultrasound) or negative (referred to as cryo- macrocirculation). It is used in rheumatolo- therapy using special bags, ice, cold air or gy, neurology, paediatrics, orthopaedics, gy- gas) thermal therapy. Systemic cryotherapy is naecology and reflexive therapy. administered in special chambers at a tem- perature of –120°C for a few minutes only. Thoracic outlet syndrome A compres- Positive thermal therapy is performed in sion syndrome due to compression of the three basic ways: neurovascular bundle as it passes from the 1. conduction (heated wax), thoracocervical region into the axilla. It can 2. convection (hyperthermal bath), be caused by muscle hypertrophy, increased 3. conversion (infrared lamp – conversion of tone of the scalene muscles, weakness of the radiation energy into heat). longissimus cervicis muscle and longus colli Heat is used in the treatment of the majority muscle or by bone or other fibrous surround- of rheumatic diseases, particularly for pain ing structural abnormalities. The syndrome relief, muscle relaxation, improving circula- manifestation includes various sensory, mo- tion, increasing tissue metabolism, and to tor, or vasomotor symptoms suggesting cer- increase collagen fibre elasticity. vicobrachial syndrome.

Thermographic index (TI) A frequently Thymosins The group of approximately 30 used index in rheumatology used for quanti- polypeptide immunohormones released from tative evaluation of thermal changes in the the thymus. They regulate maturation and region of interest (ROI). It is described as the various activities of lymphocytes. They origi- increase in the basal temperature over the nate from the larger precursors prothymosins.

monitored area and the temperature of iso- The most common is thymosin α1, whose therm multiplied by the surface of isotherm molecule consists of 28 amino acid units. It to total surface of ROI. The final TI is achieved stimulates activity of T helper lymphocytes, by the sum of TI of particular isotherms. The the humoral immune response, antiviral, an- normal TI value is 2, osteoarthrosis is 4, rheu- tifungal and anticancer immunity. Its serum matoid arthritis is >4; with acute gout giving concentration decreases with age. It is sug- the highest TI. TI is relevant for evaluating gested that loss of thymosins is one of many the efficiency of pharmacotherapy. causes of ageing.

Thermography (TMG) A complementary Thymulin A zinc-dependent peptide hor- imaging method by which the distribution of mone (previously known as serum thymic heat on the surface of subjects, including the factor) produced in the thymus from where it T human body, is detected. The principle is vi- is released into the circulation. It increases sualisation of infrared radiation with a ther- the activity of certain T lymphocytes subpop- mographic camera. Two methods are used: ulations (particularly suppressor and cyto- contact TMG (liquid crystal encapsulated in toxic activities). Thymulin is able to renew foil), and non-contact (thermovision sys- the responsiveness of lymphocytes to mito- tems). In rheumatology, it is used to detect gens in animals after thymectomy. local hyperthermia (induced by inflamma- tory mediators), local hypothermia caused by Thymus The endocrine gland producing nociceptive afferentation, or hypothermia thymosins, thymopoetins, thymulin and oth- due to vasospasm or obstruction of vessels. A er immunohormones. It is the primary lym- relevant thermal picture can be obtained only phatic organ where maturation and differen- 213 T lymphocytes tiation of T lymphocytes, which are able to (antigen) CD3 molecule, is a fundamental detect antigens, occurs. Concurrently, elimi- feature of T lymphocytes. nation of the majority of autoreactive clones T cells are a heterogenous population but of T lymphocytes, which is one of the most consist mainly of two basic subpopulations: important mechanisms of tolerance to au- helper T lymphocytes (TH) and cytotoxic T toantigens development, also occurs in the lymphocytes (TC). The abbreviation of cyto- thymus. The thymus consists of a cortex and toxic T lymphocytes is CTL. The differentiat- medulla. The cortex, which represents ap- ing determinants CD2 and CD3 are found on proximately 85% of gland weight, consists of the surface of all T cells, but TH lymphocytes thymocytes, epithelial cells and macrophages. also possess the CD4 determinant and CTL The medulla comprises mainly of thymo- possess the CD8 determinant. The nomen- cytes. The gland reaches its maximum in ad- clature ‘helper’ T lymphocytes is derived olescence (30 to 40 g), and decreases in size from their function, the fundamental of thereafter. which is the help they provide for B lympho- cytes during detection of the majority of anti- Thyroid disease → see Arthropathy in thy- gens and induction of humoral immune re- roid disease sponse. Cytotoxic T lymphocytes are typical effector cells whose major task is to kill cells Tietze’s syndrome and costochondri- infected by viruses or other intracellular par- tis Tietze’s syndrome is characterised by asites, to kill malignant cells or cells with for- painful swelling of one or more costochon- eign histocompatibility antigens on their sur- dral joints. face. Such target cells are detected by a spe- Clinical picture: The course of the disease cific manner in cooperation with class I HLA is benign, but relapses are frequent. The de- antigens (restriction of MHC). They are also velopment of painful swelling may be acute involved in rejection after organ or tissue or gradual. Pain may radiate to the shoulder, transplantation from non-identical donors. the arm, and is exacerbated by sneezing, Contrary to this, exogenous antigens after coughing, deep inspiration and thoracic rota- transformation in antigen presenting cells tion. In approximately 70% of cases, the dis- (antigen presentation) are recognised by ease affects only a limited area, most fre- helper T lymphocytes in cooperation with quently the second or third costochondral class II HLA antigens. Apart from helper and joints. Other joints – costosternal, manu- cytotoxic T lymphocytes, the population of briosternal and xiphisternal – are rarely af- these cells also contain memory T lympho- fected. cytes, which are referred to as TM-cells. A subpopulation of suppressor T lymphocytes

Tinel’s sign Palpation applied to the palmar (TS cells) was considered in the past. Accord- aspect of the wrist (transverse carpal liga- ing to contemporary opinions, suppressor T ment) evokes pain or paraesthesiae of the lymphocytes belong to the group of regula- first three fingers. It is positive in carpal tun- tory and cytotoxic T lymphocytes. T nel syndrome. Neither subpopulation of TH cells is ho- mogenous, but is divided into four groups – T lymphocytes Lymphocytes are a subset TH1, TH2, TH3 and TR cells, which release of white blood cells, which after development various groups of cytokines. The precursors from pluripotent haemopoietic stem cells in of TH1 and TH2 are naive (virgin) TH0 cells, bone marrow, acquires immunocompetence which have not yet come into contact with within the thymus gland, i.e. typical morpho- antigen and possess CD4 and CD45RA dif- logical and functional properties. They are ferentiating determinants. TH cells, which also referred to as T cells. The presence of have already been in contact with antigen, specific antigen receptors, which are in the possess the differentiating determinants CD4 complex with differentiating determinant and CD45RO and are referred to as memory T lymphocytes – activation 214

Table 16. Production of cytokines and cytotoxins by the subpopulations of TH-lymphocytes and

TC-lymphocytes, respectively

Cytokines TH1TH2TH3TH0CTL IL-2 ++ – – + +/– IFN-γ ++ – +/– + ++ IL-3 ++ ++ + + + GM-CSF ++ + – + + TNF-α ++ +/– – +/– + IL-4 – ++ – + – IL-5 – ++ – – – IL-6 – ++ – – – IL-9 – ++ – + – IL-10 – ++ +/– + – IL-13 – ++ – – – IL-17 + – – – – TGF-β – + ++ – – Cytotoxins Lymphotoxin (TNF-β) ++ – – – ++ Perforins – – – – ++ Granzymes – – – – ++

cells. TH3 cells produce transforming growth They originate from precursors of cytotoxic factor TGF-β and are involved in autotoler- T lymphocytes after recognising immuno- ance. genic peptide, which developed from endog- enous antigen, originating from target cells T lymphocytes – activation The process infected by viruses, or from malignant cells, by which clone expansion (proliferation of a and after subsequent activation by IL-2. After

particular clone) of naive TH cells is initiated, contact with the target cell and activation, T and thereby their involvement in specific hu- lymphocytes release cytotoxic perforins and moral or cellular immunity is enabled. For proteolytic enzymes (granzymes) onto the this purpose, the antigen receptor of a particu- surface of the target cell. As a consequence, lar clone of cells in cooperation with class II an influx of sodium ions and water and an MHC (major histocompatibility complex) an- outflux of potassium ions occur, leading to tigens must recognise specific immunogenic osmotic swelling and subsequent cell lysis. peptide, which originates from the presenta- T tion of exogenous antigen via the antigen pre- T lymphocytes – suppressor A subpop- senting cell. This primary stimulation signal ulation of lymphocytes, whose function is to must be confirmed at least by one other co- suppress the humoral immune response of T stimulating signal, which may be presented by cells, as well as inhibit the specific cellular re-

certain molecules on the surface of antigen sponse carried out by TH and TC cells. At

presenting cells and helper T lymphocytes. present, it is suggested that TS lymphocytes do not exist as an independent subpopula-

T lymphocytes – cytotoxic A subpopula- tion; however, natural regulator Treg lympho-

tion of T lymphocytes with CD8 differentiat- cytes and inducer Tr1 and TH3 lymphocytes ing determinant on their surface. These cells carry out their function. are effector cells of specific cellular immunity. 215 toxic shock syndrome

TNF receptor-associated factor 6 → see planes of the small joints of hand, and Achil- TRAF6 – TNF receptor-associated factor 6 les tendon. Less frequently, tophi occur on the eyelids, the tongue, in the lungs, and rare- Toe swelling/deformity and associat- ly in the pericardium and on heart valves. ed diseases Oedema of one toe can be as- Bone tophi occur in subchondral bone and sociated with gout, which manifests itself by can be seen on X-rays where they have a typi- acute inflammation, erythema and tender- cal cystic structure in the form of significant ness of the first metatarsophalangeal (MTP) transparency. joint (podagra). Treatment: See treatment of gout. Total Sharp score (TSS) A scoring system Hallux valgus Develops mainly due to flat- used to quantify the radiological changes in foot and osteoarthrosis. The deformity is patients with rheumatoid arthritis. The sys- typical and the joint is painful during palpa- tem describes erosions and narrowing of the tion. The X-ray picture is pathognomic. In joint space of 27 small joints of the hand, in- long standing cases, treatment may require cluding the carpal bones. Van der Heide et al. surgical intervention. modified the method in 1985 when feet Digitus rigidus Most frequently, stiffness of joints, which in some patients are affected the first MTP joint occurs. Treatment con- earlier than hand joints, were included in the sists of wearing good fitting shoes with spe- scoring system. Sixteen areas for erosions and cially shaped insoles. fifteen areas for joint space narrowing on Hammer toe Caused by chronic diseases each hand were established by the fusion of such as rheumatoid arthritis and other chron- the Sharp and van der Heide scoring system. ic inflammatory rheumatic diseases. The erosion is evaluated from 0 to 5 points (1 Sausage toe Most frequently occurs in reac- = discrete changes, 2 to 3 = greater changes; tive arthritis or psoriatic arthritis. score >3 includes the size of the erosions). The narrowing of the joint space is evaluated Tomesa (balneophototherapy) The from 0 to 4 points (0 = normal space, 1 = sus- name for combined treatment with balneo- pect narrowing, 2 = global narrowing <50% therapy and selective UV radiation is deduced of original space, 3 = global narrowing >50% from the German words “TOtes MEer SAlz” of original space or subluxation and 4 = ar- meaning the use of Dead Sea salts in the bath- ticular ankylosis or total luxation). The maxi- ing water. This modality imitates the micro- mum score for hand joints erosions is 160 climate of the Dead Sea. It is prepared as an 8 and for feet joints erosions 120; the maximum to 15% sodium chloride solution in a shallow score for narrowing of hand joints’ spaces is bathtub, in which the patient turns around so 120 and for feet joint spaces 48 (total maxi- the skin exposed to radiation is constantly mum score is 448). The system is not univer- wet. The dosage of radiation depends on the sal, certain other scoring systems are also type of skin pigmentation and is gradually used, e.g. Raua score. increased up to 30 minutes. It is used espe- cially in the treatment of psoriasis and psori- Toxic shock syndrome Caused by a bacte- T atic arthropathy. rial toxin produced by Staphylococcus aureus. The toxin belongs to the superantigens Tophus It is a deposit of sodium urate crys- (TSST-1 – toxic shock syndrome toxin). Symp- tals. It is divided into bone tophus and tophus toms include fever, arthralgias and exanthema of soft tissues. The typical localisation of soft accompanied by oedema of the hands, face tissue tophi are the pinna of the ear (helix, and conjunctivae. Mouth ulcers and desqua- less frequently antihelix), metatarsophalan- mation on the hands and feet occur in the sec- geal joint of toe, ulnar margin of forearm, el- ond phase of the disease. TSST-1 affects many bows (they may cause sack like dilatation of organs. Symptoms may include hypotension, the olecranon bursa), above the extensor arthralgias, nausea, vomiting, neurological toxin 216

symptoms, and even adult respiratory distress legs. The effect of such traction is increased syndrome. In certain cases, the symptoms are by the warm environment of the water. only mild, suggesting an influenza-like ill- ness. Traction test A test performed in the re- gion of the cervical and lumbar spine before Toxin A poisonous substance of biological manual or device traction. The aim is to de- origin, which is usually immunogenic and termine the most suitable direction of trac- therefore able to induce synthesis of antibod- tion that provides patient with the best pain ies. The antibodies are referred to as antitox- relief. ins and are able to neutralise the harmful ef- fects of the toxin, against which the antibody TRAF6 – TNF receptor-associated fac- is directed. Toxins can be the products of tor 6 RANK, as with other members of the micro-organisms (tetanus toxin, diphtheria family of TNF receptors, controls its intracel- toxin, botulinum toxin etc.), herbs (e.g. ricin, lular signalling via a group of proteins known abrin) or animals (snakes, scorpions, bees, as TRAF – TNF receptor-associated factors. wasps). To date, 6 TRAF factors, mostly without specificity for a certain receptor, have been Toxoid A microbial toxin that has inactivat- described. TRAF6 is an exception as it links ed toxicity (harmful effects), but has main- only with RANK and CD40 and transmits tained its immunogenicity. It is therefore used signals from these receptors. Knockout mice as an antigen to induce protective immunity for a gene coding for TRAF6 are character- against microbial exotoxins, such as tetanus ised by severe osteopetrosis, which confirms or diphtheria toxoid. that TRAF6 plays an essential role in osteo- clastogenesis. Träbert currents Rectangular impulses lasting 2 ms with a 5 ms pause between single A synthetic opioid, the structure impulses, leading to a frequency of approxi- of which is similar to . Its analgesic ef- mately 143 Hz. The intensity of the current is fect is similar to pethidine and has 1/10 of the mediated depending on the patient’s toler- efficacy of morphine. The ratio between par- ance (increases up to the first perception of enteral and oral efficacy is 1:3. It is one of the the current). Träbert currents mainly are suit- most widely used opioids for grade II analge- able for pain relief in the area of the locomo- sia and is suitable for the treatment of mild tor system. and moderately acute or chronic pain. Its me- tabolite mono-O-desmethyltramadol is phar- Traction Traction of cervical spine Performed macologically active, with a higher affinity by staged traction using a Glisson loop. The for receptors than tramadol itself. The anal- traction can be continuous or intermittent, gesic effect is conditioned by activation of applied in a sitting or lying position, and per- μ-1, δ and κ receptors, but it also influences formed manually, which is a safer and more pain by non-opioid mechanisms – stimulates T effective technique. serotonin release and inhibits the reuptake of Traction of lumbar spine Performed after a serotonin and noradrenalin by nerve end- traction test on a traction table either in ex- ings. This mechanism explains its greater ef- tension (with extended lower extremities) or ficiency in neuropathic pain. It is well toler- in flexion (with flexed hip joints and knees at ated at therapeutic doses, with milder and a 90° angle). This traction can also be per- less frequent adverse effects. The risk of drug formed manually, which is particularly suit- is low. It can be administered par- able for painful conditions. enterally, rectally or orally in conventional Traction of the spine in a vertical position and slow release forms. is performed in baths; the patient wears a floating collar and a load is attached to the 217 tremor

Transforming growth factors (TGF) in the area of the activity is higher with local These are glycoproteins originally described therapy than with systemic administration. as products of cells transformed by viruses Avoidance of the gastrointestinal system and that change (transform) the phenotype of nor- the liver to major concentrations of the drug mal cells to a neoplastic phenotype. They are by the use of transdermal therapy is particu- found in normal as well as neoplastic cells and larly beneficial to elderly patients. belong to two families: TGF-α and TGF-β. They are cytokines regulating tumorigenesis, Transduction The transfer of a specific part embryonic development and the healing pro- of the DNA chain (encoding a specific gene cess of damaged tissues. TGF-β also partici- or its part) from a donor cell to a recipient cell pates significantly in the regulation of im- by the use of a virus. This new genetic infor- mune responses. mation will then alter the recipient cells phe- notype. Transcription Transcription of genetic in- formation from DNA into mRNA. Transient coxitis It may affect children and teenagers after upper airway infection, prob- Transcutaneous Electrical Nerve Stim- ably caused by a viral infection. Perthes’ dis- ulator (TENS) Treatment with low frequen- ease or slipped epiphysis should be taken into cy rectangle currents with impulses shorter consideration as a differential diagnosis. Labo- than 1 ms, which are used for pain relief, par- ratory results are not diagnostic. The radio- ticularly in extraarticular rheumatism and in logical picture is normal, but fluid accumula- radicular pain. Electrodes are placed in a po- tion in the joint can be proven by ultrasound. sition where the running current stimulates Treatment: The disease recovers sponta- either the area of maximum pain (trigger neously; non-steroidal anti-inflammatory points) or part of a specific nerve. Independ- drugs can help to alleviate symptoms. ent use by the patient after instruction is ad- vantageous. The effect can be explained in Translation Translation of genetic informa- two ways. Selective stimulation of type tion encoded in the sequence of nucleotides A nerve fibres, which conduct sensation, pre- of the mRNA molecule into the sequence of vents the transfer of pain through thin type B amino acids (primary structure) of the poly- fibres, which are designed to conduct pain peptide protein chain. (70 ms, 70 Hz). The second theory is based on the principle of selective stimulation of B Traumatic arthritis This can be caused by fibres using longer lasting impulses (around a hit, distortion or strain. Articular fluid can 100 ms, with frequency of 10 Hz), which be sanguinous, but, this does not need to be leads to increased synthesis of endorphins due to intra-articular structure trauma (e.g. (with their generally accepted influence on meniscus) but most frequently is caused by pain perception). partial or total rupture of a cruciate ligament, or possibly by rupture of a joint bursa. Transdermal therapy with NSAIDs Treatment: Bed rest, splintage, non-steroi- T (non-steroidal anti-inflammatory dal anti-inflammatory drugs, joint aspiration drugs) Although NSAIDs are commonly as needed, glucocorticoids (intra-articularly), given by mouth, they can also be adminis- later mobilisation and physiotherapy. tered locally in the form of creams, gels, sprays and patches. These latter methods are Tremor An involuntary rhythmic muscle used with advantage in the treatment of the contraction of agonists and antagonists of early stage of osteoarthrosis in order to certain parts of the body. Although the com- achieve pain relief of painful areas, such as monest tremor is not associated with pathol- muscle insertions, tendons and ligaments. ogy (essential tremor), most other tremors The concentration of the effective substance are related to underlying pathology (Parkin- Trendelenburg’s test 218

son’s disease, dystonias, cerebellar disorders, be distinguished. The synovial form of joint etc) and can be diagnosed clinically. tuberculosis has three stages. The initial syn- ovitis, with insidious onset and mild pain Trendelenburg’s test A positive Trende- only, usually without any symptoms of active lenburg’s test indicates weakness of the glu- inflammation affects one joint with swelling teus medius muscle on the side of the lifted of its soft tissues and production of joint flu- leg. The patient stands on one leg with the id. The next stage is characterised by granu- examiner standing behind and observes lating synovitis, hyperaemia, synovial hyper- whether the patient is able to hold the pelvis plasia, development of fibrocaseous changes on the side of the lifted leg in the plane or and xanthochromic synovial fluid. In severe whether the pelvis tilts downwards. This tilt cases, the synovium is roughened and irregu- indicates weakness of the gluteus medius mus- lar layers of fibrin cover its surface. In the cle. A positive test signifies muscle imbalance third stage, arthritis becomes prominent with of the pelvis and a possible pathological pro- the inflammatory process gradually affecting cess in the hip of the standing leg. the cartilage and bony structures. This leads to chondral and subchondral destruction and Triamcinolone → see Glucocorticoids dissection of cartilage, bone sequestration and fistula formation. Trigger points Hyperirritable areas in the The primary bone form is associated with skin, subcutaneous tissue, muscles or on the extravasation into the joint with the gradual periosteum, which are asymptomatic at rest, development of arthritis. The secondary bone but are activated by muscle and joint activity form originates from primary tenosynovitis and evoke nociceptive reactions leading to and bursitis if the inflammation affects joint limitation of movement and pain. The trigger structures. It affects mainly weight-bearing points are sensitive to pressure and can be joints. The X-ray picture shows little change identified by the use of specific techniques, in the early stages, but later cystic changes such as Kibler diagnostic fold, Dick-Leube and marginal destruction in peri-articular technique or Vogler technique. The trigger bone due to the presence of granulation and points can be influenced by reflexive massage, caseous substances can be visible. Due to the acupuncture, acupressure, or by local anaes- absence of proteolytic enzymes in mycobac- thetic injections. terial organisms, the joint configuration is preserved with little sclerosis of the adjacent T-score → see Osteoporosis – Diagnosis, bone for a relatively long period of time in the Bone Mineral Density (BMD) Measurement early active stage. Later sequestration and sig- – evaluation nificant structural destruction can be seen. Diagnosis may be difficult without a good Tuberculin Sterile solution of proteins ob- synovial biopsy and/or appropriate synovial tained from the medium, in which Mycobac- fluid culture. terium tuberculosis was cultivated. It is used Clinical forms of tuberculous arthritis: T for a tuberculin skin test. • Chronic synovitis, • Chronic arthritis, Tuberculous arthritis A progressive • Caries sicca (more commonly seen with chronic low grade monoarthritis, sometimes syphilis), clinically intermittent, which if untreated • BCG arthritis. leads to abscess and fistula formation in the Other forms of musculoskeletal tuberculosis: established stages of the disease. It is usually • Spondylitis, due to lymphohaematogenous spread from a • Osteitis and osteomyelitis, primary pulmonary or gastrointestinal focus. • Spina ventosa/dactylitis, Depending on the location of the initial fo- • Tenosynovitis/bursitis, cus, the primary synovial or bone disease can • Poncet’s disease. 219 tunnel syndromes of foot

Tuftsin A Thr-Lys-Pro-Arg tetrapeptide pro- in parathormone levels. The disease can start duced by enzymatic cleavage of the Fc-domain as calcific bursitis, later spreading into sur- of the heavy chain of immunoglobulin G (po- rounding the fascia. Trigger factors can in- sitions 289–292) in the spleen. It acts as a cy- clude tissue damage with adipose necrosis. tokine regulating the chemotaxis, phagocyto- Increased local synthesis of calcitriol in gran- sis and respiratory activation of neutrophils ulomatous tissue leads to increased calcium and macrophages. Deficiency develops after absorption and decreased parathormone se- splenectomy. cretion. Clinical picture: The disease affects chil- Tumour necrosis factors (TNF) There dren mainly of African and Afro-American are two TNFs: TNF-α (cachectin) and TNF-β descent. Initially, hyperplastic fibrous tissue (lymphotoxin). They have cytostatic and cy- with ectopic calcifications does not cause totoxic effects not only on neoplastic cells, pain and grows at varying rates. With time, but also on other biological activities. TNF-α this creates a mechanical obstacle, causing is a typical cytokine acting as a trigger of the nerve compression, joint movement limita- inflammatory reaction, as an endogenous py- tion or skin ulcerations, which can become rogen and endogenous mediator of the toxic infected. Accompanying symptoms include effects of endotoxins of Gram-negative bacte- anaemia, lymphadenopathy, increased body ria. It is able to induce pathological emacia- temperature, splenomegaly, and eventually tion (). Lymphotoxin is a prototype amyloidosis. The disease is lifelong. of a new group of substances referred to as cytotoxins. Tunnel syndromes of foot Metatarsal tunnel syndrome (Morton’s metatarsalgia) Tumoral calcinosis The main features of The common plantar digital nerve is com- this hereditary disease are periarticular meta- pressed under the transverse metatarsal liga- static calcifications. Their appearance is in ment. Clinical symptoms include a sharp the soft tissue mass in the area of the large burning pain, which most frequently radiates joints, particularly the hip and shoulder. Usu- to the third and fourth toe. It does not cause ally, the disease is autosomal recessive, but an hypo- or hyper-aesthesia or muscle weakness. autosomal dominant form is also possible. Typical pain occurs when pressure is applied Pathogenesis: The genetic background is laterally to the metatarsophalangeal (MTP) still unclear, but appears to be due to a muta- joints (lateral pressure test). tion leading to a disorder of phosphate me- Sural nerve tunnel syndrome tabolism regulation via FGF23 (fibroblast Causes pain radiating from the lateral as- growth factor 23). One of the significant fac- pect of the ankle distally to the little toe. tors in the development of the disease is in- Treatment: Glucocorticoids are adminis- creased phosphate reabsorption in the kidney tered locally or the nerve is released surgi- tubules, which is not associated with changes cally in both syndromes. T U

U1RNP → see Antibodies against U1RNP early erosive changes around joints. Doppler and Sm antigen mode enables assessment of blood flow.

UCTD → see Undifferentiated connective tis- Undifferentiated connective tissue sue disease (UCTD) disease (UCTD) The term undifferentiated connective tissue disease applies to the com- Ultrasound The principle is the transfor- plex of symptoms that occur in patients with mation of the electrical energy of a high fre- a systemic connective tissue disease which quency current into mechanical energy of does not meet diagnostic criteria for any of longitudinal vibration of the physical envi- the recognised systemic connective tissue ronment with a frequency above the level of diseases, i.e. MCTD (mixed connective tissue audibility (approximately 20,000 Hz). The vi- disease). bration of all atoms and molecules, or of en- Clinical symptoms: The following symp- tire cells, occurs in the trajectory of the ultra- toms may occur in UCTD: sound ray leading to micro-massages with • Non-specific clinical symptoms (arthral- subsequent dispersal effects (the transforma- gia, myalgia, photosensitivity, overall weak- tion of gel into fluidity, gel fluidisation) and ness, subfebrile body temperatures, Ray- the transformation of mechanical energy into naud’s phenomenon), thermal energy, and thereby to the heating up • Symptoms relatively specific for systemic of deep tissues. connective tissue diseases (arthritis, myo- sitis, Raynaud’s phenomenon with finger Ultrasound in rheumatology (ar- ulceration, morning stiffness, erythema throsonography) A diagnostic method and exanthema of face and extremities, se- using ultrasound to measure the varying de- rositis). gree of its reflection when passing through tissues of the body and produces two- or (URV) A disease mani- three-dimensional reconstruction images of festing itself by recurrent rashes with the histo- the examined area. It is a promising non-in- logical finding of leukocytoclastic vasculitis. vasive method, which is easily available, re- Apart from the skin, the disease may affect producible and economically advantageous, many organ systems. It occurs mainly in wom- but is dependent on a well trained operator. It en in the fourth decade of life. is particularly used in the detection of joint Clinical symptoms: The main symptoms effusions, changes in muscles, periarticular include urticaria and papular exanthema, pru- structures, ligaments, tendons, bursae, carti- ritus, arthralgia and systemic diseases such as lage and the bone surface. High frequency glomerulonephritis, gastrointestinal and bron- probes (above 10 to 15 MHz) can detect the chopulmonary diseases. V

Vaccine Active, but attenuated or dead originate from the vertebral column or from pathogenic microorganisms or viruses, vac- its surrounding soft structures (muscles, liga- cine particles or products, which contain an- ments, fascia, and insertions). Nociceptive tigens able to stimulate a specific humoral or stimulation evokes a pathological process in T cell immune response, producing immuni- the affected spinal segment with radiating ty against these microorganisms or viruses. pain, muscle spasm and the development of hyperalgic skin and muscle zones which are Vasculitis Vasculitis is an inflammatory dis- referred to as vertebrogenic algic syndrome. ease of blood vessels leading to thickening Contrary to radicular vertebrogenic algic and/or fibrosis of the wall, with subsequent syndrome, there are no signs of spinal nerve obliteration of its lumen. palsy. Clinical symptoms: Clinical syndromes Common symptoms are present in both are the consequence of ischaemia of tissues types of syndrome: supplied by the affected vessels associated • Algic syndrome with reflex symptoms in with systemic symptoms (fever, weight loss, muscles, skin and subcutaneous tissue anorexia). (muscle spasm, painful trigger points, hy- Classification: Most frequently done on peralgic zones, vegetative defects) the basis of the size of blood vessels affected. • Impairment of static and kinetic functions Large: Giant cell arteritis, Takayasu arteri- of the vertebral column (changes of curva- tis. ture in the sagittal and frontal planes, re- Medium: Polyarteritis nodosa, Kawasaki duced mobility) in morphological defects disease, isolated CNS vasculitis. which frequently attack nerve roots, impair- Small: Wegener’s granulomatosis, microsco- ment of motor and sensory functions, pic polyarteritis, Churg-Strauss syndrome, He- trophic changes of muscles and reduced noch-Schönlein purpura, essential cryoglobuli- muscle tone in the affected segment; posi- naemic vasculitis, hypersensitivity vasculitis, tive stretch tests are almost obligatory signs vasculitis associated with connective tissue dis- of nerve root compression. eases, vasculitis due to viral infection. Diagnosis is established by the clinical pic- Viral arthritis An inflammatory arthritis or ture, blood tests including serum ANCA, and tenderness of the soft structures of the loco- biopsy of relevant tissues. motor system may occur in the course of a viral disease, which is usually short lived and Vertebrogenic algic syndrome This has a good prognosis. represents a common diagnostic and thera- Clinical picture: Most cases of viral arthri- peutic problem in neurology, rheumatology, tis are usually acute short lived arthritis with orthopaedics and rehabilitation therapy. Two a good prognosis, often associated with in- types of disease should be distinguished, name- creased body temperature, skin symptoms ly those with morphological defects (with and haematological abnormalities. Chronic symptoms and signs of locomotor system dis- polyarthritis suggestive of rheumatoid arthri- ease on X-ray or in laboratory findings) and tis is rare (usually due to parvovirus B19). those with functional defects without mor- Exanthema is a typical accompanying sign of phological and laboratory changes. togavirus infections (rubella); however, it can Vertebrogenic algic syndrome is a com- also occur in arthritis associated with hepati- mon term used for all painful conditions that tis B (urticarial rash). virulence 222

Virulence Refers to the quantitative degree (disturbance of hydroxylation in hepatic dis- of pathogenicity of a microbe or virus to eases) and then, in the kidneys, 1,25-dihydroxy cause disease in certain animal species. vitamin D3 and 24,25-dihydroxy vitamin D (disturbance of hydroxylation in renal disor- Virus An infective particle which consists of a ders) are synthesised via relevant hydroxylases. single or double chain of DNA or RNA and is The bone and intestines are the main target or- covered by a protein coat known as capsid. Vi- gans of calcitriol. It stimulates the absorption of ruses do not possess a proteosynthetic appara- calcium and phosphate in enterocytes, and tus, and therefore can only undergo replication stimulates the reuptake of calcium in the kid- inside animal or plant cells which they have in- neys. Calcitriol increases the mineralisation as vaded through specific receptors. They cause well as osteoresorption of bone. 24,25-dihy- a number of human, animal and plant diseases. droxy vitamin D on the contrary inhibits osteo- resorption induced by PTH. Vitamin D plays Vitamin D This vitamin influences bone me- an important role in calcium homeostasis. A tabolism in a complex way and has an essential number of cells possess receptors for vitamin D. role in the normal development of the skeleton. The concentration of 25(OH) vitamin D3 is a Small stature and development of rickets are relevant indicator of the total vitamin D status the consequences of its deficiency in childhood. in the body as it represents the amount of vita- In adults, vitamin D deficiency leads to the de- min D synthesised and ingested. velopment of secondary hyperparathyroidism The recommended daily intake of vitamin with a resulting mobilisation of calcium from D is approximately 800 I.U. and over 1000 I.U bone and the development of osteoporosis or for treatment. Some authors recommend osteomalacia or their combination. Several even higher doses. A daily intake up to 2000 studies have confirmed a high prevalence of hy- I.U. is generally considered safe. povitaminosis D in the European population, It is possible to give cumulative doses of vi- especially in the elderly (MacFarlane et al. 2004, tamin D up to 15000–20000 I.U. per week. A Hirani and Primatesta 2005). Chronic hepatic, supplementation of medium-level doses of vi- renal disorders and several drugs influence vi- tamin D appears to be safe and effective in pa- tamin D metabolism or its clearance leading to tients at risk of vitamin D deficiency and is 1,25-dihydroxy vitamin D3 deficiency. also effective in patients with mild-to-moder- Vitamin D deficiency develops predomi- ate renal insufficiency due to age or a renal nantly in the following conditions: disease. The beneficial effect of administration • increased demands (children, pregnancy, of vitamin D on reducing the incidence of menopause), fractures has been unambiguously shown in • low dietary intake, the elderly, where a deficit in exposure to sun- • inadequate exposure to sunlight (UVB ra- light, nutritional deficiency and disturbance of diation), renal hydroxylation of vitamin D is hypothe- • disturbances of intestinal absorption (dis- sised. Vitamin D supplementation is indicated turbance of lipid absorption, disturbance in all cases where deficiency may be assumed of secretion of bile and pancreatic enzymes, or determined (for example winter months). post-resection conditions, etc.), • disturbances of vitamin D metabolism V region of immunoglobulins The vari- (disorders of the liver and kidneys, treat- able region of polypeptide chains of immu- V ment with anticonvulsants) noglobulin molecules, which form a variable • resistance to vitamin D. domain. The sequence of amino acids of this As well as the dietary intake, the synthesis of region is not constant but variable, as various vitamin D3 () in skin by sunlight antibodies have different amino acids in par- is the main source of vitamin D in humans. Fol- ticular positions of the region. This is the es- lowing hydroxylation in the liver, it is trans- sence of the enormous variability of antibody formed into 25-hydroxy (25-OH) vitamin D3 specificity of immunoglobulin molecules. W

Weber-Christian disease → see Pannicu- Western Ontario and McMaster uni- litis versities osteoarthritis index (WOMAC) → see Instruments of assessing (health status Wegener’s granulomatosis A necrotis- measurements, outcome measurement) ing systemic vasculitis which primarily af- fects the upper and lower respiratory systems Williams-Beuren syndrome The original and kidneys. It is more frequent in men, usu- description of children with supravalvular ally between 50 and 60 years of age. aortic stenosis and ‘troll face’ has been com- Systemic symptoms, such as tiredness, pleted by the presence of transient hypercal- weight loss and subfebrile temperatures, are caemia during the first year of life. At present, frequent. Upper airways involvement in- it is suggested that a number of abnormalities cludes epistaxis, chronic rhinitis and sinus- exist within the syndrome; however, they itis. Otitis media and conductive hearing im- need not necessarily all be fully expressed. pairment are also frequent. Symptoms from Approximately 2/3 of children suffer from the lower airways include cough, haemopty- low birth weight and many are born after sis or chest pain. Renal damage (glomerulo- term. Small and defective dentition, large nephritis) is frequent and may lead to renal lower lip, long philtrum, short nose, epican- impairment. Ocular diseases include conjunc- thus, skull asymmetry with temporal depres- tivitis, episcleritis, corneal ulcers, retinal vasc- sion and microcephaly are present in children ulitis, optic nerve neuropathy and exophthal- with ‘troll face’ abnormality. The voice of the mos. Mononeuritis multiplex is the most fre- children is squeaky. The children suffer from quent form of peripheral nerve involvement. hypotonia and retardation of motor develop- Gastrointestinal symptoms include diarrhoea, ment. They are very friendly to strangers. haemorrhage, abdominal pain, and rarely Apart from a heart defect, they can also suffer bowel perforation. from stenosis of peripheral organ arteries and Anaemia, leukocytosis and thrombocyto- hypertension is diagnosed in some of them at sis are often present in laboratory findings. breastfeeding age. Hypercalcaemia, if pres- Other findings include increased erythrocyte ent, spontaneously recovers towards the end sedimentation rate, elevated levels of C-reac- of the first year of life. Hypercalciuria is rela- tive protein and hypergammaglobulinaemia, tively frequent. Approximately 1/3 of patients mainly IgA. The presence of ANCA (anti-neu- have radioulnar synostosis, which is the rea- trophil cytoplasmic antibodies) either c- son for inadequate development of the upper ANCA (anti-PR3 antibodies) or p-ANCA extremity. Genetic studies have localised the (anti-MPO antibodies) is found in 90% of pa- defect causing the syndrome to the q11.2 re- tients, however, anti-proteinase 3 (PR3) ac- gion of chromosome 7. The exact pathogen- tivity is more frequent. esis of the disease still remains unclear (Joyce Treatment consists of a combination of et al. 1996). corticoids and cyclophosphamide, often ini- tially active disease must be treated by the use Wiskott-Aldrich syndrome A rare reces- of corticoids pulse therapy and cyclophosph- sive immunodeficiency linked to the short amide. High doses of intravenous immuno- arm of the X chromosome. Affected boys suf- globulins or plasmapheresis are indicated in fer from suppressed T cell immunity, late sen- patients who are resistant to cyclophosph- sitivity reaction and decreased synthesis of amide. antibodies against polysaccharide antigens. wiskott-aldrich syndrome 224

The number of B lymphocytes in the periph- (CD43) a membrane glycoprotein involved in eral blood is normal. Serum IgM levels are activating and regulating processes is missing significantly decreased, whereas IgA and IgE on the surface of lymphocytes. The disease fre- levels are increased, and the IgG level is usually quently leads to malignancies, particularly of normal. The syndrome manifests during the the lymphatic system and epithelial tumours. first year of life by severe thrombocytopenia The patient’s condition may improve after leading to haemorrhagic symptomatology, re- transplantation of bone marrow. However, the current infections and eczema. Sialophorin overall prognosis is unfavourable.

W

W X

Xenogenous (Xenogenic) An adjective a different animal species, is referred to as a referring to the different genetic relationship xenograft or xenotransplant. It possesses xe- between individuals of two different animal noantigens against which xenoantibodies are species. It is used particularly in transplanta- formed. tion terminology. Skin graft or organ trans- plant, which has been donated by a donor of X-ray → see Radiography Z

Zidovudine A 3’-azido-3’-deoxythymidine, Zoledronate A bisphosphonate with a inhibitor of reverse transcriptase, the enzyme unique administration in the form of once a that is necessary for transcription of genetic year intravenously. Currently, it is indicated information from viral RNA to host DNA. It for the treatment of the Paget’s disease and is used in the treatment of AIDS. bony metastases. Its effect in the treatment of osteoporosis has been completed in clinical Zinc This element plays a significant role in trials. A single intravenous infusion of 5 mg the normal functioning of the immune sys- of zoledronate is administered in the treat- tem. It is complementary to many enzymes ment of Paget’s disease. and other substances involved in the synthesis of nucleic acids and proteins. Reversible dys- Z-score → see Osteoporosis – Diagnosis, function of T lymphocytes, thymus atrophy, Bone Mineral Density (BMD) Measurement selective decrease in the number of circulating – evaluation T helper lymphocytes, decreased synthesis of antibodies, as well as functional defects of Zymosan A complex polysaccharide isolat- macrophages and granulocytes develop in ed from the cellular wall of the Saccharomyces cases of . All this leads to an cerevisiae yeast. It contains mainly β-D-glucans increased risk of infections and to poor and mannans. It activates the complement by wound healing. the alternative pathway and binds to the re- ceptors for C3b fragment of complement. References

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