Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 3628-3641 Pruritus in selected dermatoses

K. OLEK-HRAB 1, M. HRAB 2, J. SZYFTER-HARRIS 1, Z. ADAMSKI 1

1Department of Dermatology, University of Medical Sciences, Poznan, Poland 2Department of Urology, University of Medical Sciences, Poznan, Poland

Abstract. – Pruritus is a natural defence mech - logical self-defence mechanism similar to other anism of the body and creates the scratch reflex skin sensations, such as touch, pain, vibration, as a defensive reaction to potentially dangerous cold or heat, enabling the protection of the skin environmental factors. Together with pain, pruritus from external factors. Pruritus is a frequent is a type of superficial sensory experience. Pruri - symptom associated with dermatoses and various tus is a symptom often experienced both in 1 healthy subjects and in those who have symptoms systemic diseases . Acute pruritus often develops of a disease. In dermatology, pruritus is a frequent simultaneously with urticarial symptoms or as an symptom associated with a number of dermatoses acute undesirable reaction to drugs. The treat - and is sometimes an auxiliary factor in the diag - ment of this form of pruritus is much easier. nostic process. Apart from histamine, the most The chronic pruritus that often develops in pa - popular pruritus mediators include tryptase, en - tients with cholestasis, kidney diseases or skin dothelins, substance P, bradykinin, prostaglandins diseases (e.g. atopic ) is often more dif - and acetylcholine. The group of atopic diseases is 2,3 characterized by the presence of very persistent ficult to treat . Persistent rubbing, scratching or pruritus. It is found in almost all patients with pinching leads to the formation of secondary skin or urticaria. Cutaneous T-cell lesions such as excoriations, erosions, eschars, lymphoma is another group of pruritic diseases hyperpigmentation or patches of discolouration, where the symptom of pruritus develops at an ear - impetiginisations or even scars, which results in ly stage and becomes intensified as the disease the creation of the -scratch cycle and self- progresses. Other dermatoses include psoriasis, stimulation of the pruritic mechanism and parasitic diseases and also systemic diseases in which pruritus is often the first and the only symp - scratching. Very often traditional methods for the tom suggesting an internal health problem. Cases treatment of chronic pruritus provide no success, of pruritus in healthy subjects, possibly associated and therefore better understanding of the neuro - with skin dryness or in women, have al - physiological aspects of pruritus can contribute so been reported. This paper presents mecha - to the development of new therapeutic methods. nisms responsible for pruritus and the most im - Pruritus can be induced by chemical, physical portant dermatoses in which this symptom is or thermal agents. In addition, pruritus can devel - found. Treatment of pruritic dermatoses is difficult op in peripheral nerves that have pathological and always requires an interdisciplinary approach. Not all dermatoses can be successfully treated changes and also in the central nervous system. with antihistamine drugs, particularly if patients The skin has the structure of a dense network suffer from cutaneous T-cell lymphoma, liver or of highly specialized sensory fibres of afferent kidney diseases. For this reason, the problem of and efferent autonomic nerve branches. The au - pruritus is the focus of attention of many scien - tonomic system consists of a small number of fi - tists, and the subject of interdisciplinary studies. bres and is responsible for the innervation of ec - Key Words: crine, apocrine, and sebaceous glands, hair folli - Atopic dermatitis, Cutaneous T-cell lymphoma, Itch, cles and blood vessels. The activation is followed Parasitic diseases, Pruritus, Pruritic dermatoses, Psoriasis. by the secretion of acetylcholine (ACh) or epi - nephrine, which activate target cells, muscarinic or catecholamine receptors. The sensation of burning pain, heat or pruritus are transmitted via Introduction nociceptive non-myelinated C-type neurons with a speed of 0.5-2.0 m/s and via A- δ fibres. Non- Pruritus is defined as an unpleasant sensation myelinated C-type nerve fibres are responsible that provokes the desire to scratch. It is a physio - for the transmission of information about itching

3628 Corresponding Author: Karolina Olek-Hrab, MD; e-mail: [email protected] Pruritus in selected dermatoses in an unspecified location, while the second type tems involved in the pathogenesis of pruritus are of fibres (A- δ) transmit precise information on also involved in the neurotransmission of pain the location and time of the itch’s onset. Itch re - (Table I) 5. Histamine is the most frequently list - ceptors, which are non-myelinated nerve end - ed and important mediator. It is released from ings, are located in the papillary layer of the epi - mastocytes or keratinocytes and plays an impor - dermis, with the highest number in the epider - tant role in many dermatoses, mainly in those mis/dermis transition layer. When itch receptors caused by allergic factors. Histamine is one of are stimulated, the elicited neural impulse is the most important mediators of pruritus but not transmitted to the dorsal roots of the spinal cord. the only one with a significant role. Many hista - The impulse is transmitted further via the spinal mine receptors have been identified in pruritus, cord and in the central nervous system. Interest - such as H 1, H 2 and H 3, and the recently discov - ingly, rubbing or scratching offers temporary re - ered H 4 receptor. About 70 years ago, Lewis et lief from the itch. This phenomenon has not yet al demonstrated that the intradermal administra - been fully investigated. tion of histamine caused and oedema. Acetylcholine is another mediator and is the ma - Mediators of Pruritus jor neurotransmitter between the autonomous Pruritus can be evoked directly by mechanical nervous system and muscarinic or nicotinic re - stimuli, or by thermal or chemical agents. How - ceptors. Intradermal administration of ACh ever, it can arise directly through the stimulated causes pain rather than pruritus. Bradykinin is degranulation of mastocytes and intensified hist - another mediator of pruritus. It belongs to the amine release 4. Most mediators and receptor sys - class of kinines and binds to bradykinin recep -

Table I. Mediators of pruritus and pain 8.

Mediator Receptor Pruritus Pain

Histamine H1, (H2), H4 Direct activation of receptors After intradermal administration of higher doses or deeper (subcutaneous) injection Tryptase PAR2 Direct activation of receptors Endothelin Endothelin A-receptors Direct activation of endothelin Direct activation of endothelin receptors receptors IL-2, IL4, IL-6, IL-31 IL-2R and IL-6R receptors Direct activation of specific Sensitization of nerve fibres on nerve fibre endings receptors on nerve fibre endings Substance P NKR1-3 neurokinin Direct activation of receptors Central sensitization, receptors on nerve fibre endings and neurogenic inflammation mast cells (release of histamine and proteases) Capsaicin, heat, TRPV1 on nerve fibre Direct activation Direct activation low pH endings Bradykinin B1 and B2 bradykinin Sensitization of nerve fibres Activation of receptors, receptors sensitization Prostaglandins Prostaglandin receptors Sensitization, aggravation Sensitization of histamine-induced pruritus NGF TrkA on mast cells and nerve Sensitization, stimulation of Peripheral and central fibre endings histamine and protease release sensitization Opioids µ-, κ-receptors µ-agonists induce pruritus, µ-agonists inhibit pain antagonists inhibit it, - agonists inhibit pruritus Cannabinoids Cannabinoid receptors Inκhibition of pruritus Peripheral and central (CB1, CB2) analgesic effect Acetylocholine Muscarinic receptors Intradermal administration Intradermal administration (M1-M5) to patients with AD causes to healthy people causes pain pruritus

3629 K. Olek-Hrab, M. Hrab, J. Szyfter-Harris, Z. Adamski

tors (B 1-B 2 type). Intradermal administration of dothelial cells, hair follicles and the endings of bradykinin more often causes pain than pruritus, thin sens ory fibres in the skin. When PAR2 re - 6 which is mediated by B 2 receptors . Apart from ceptors are stimulated their structure becomes that, bradykinin sensitizes nerve fibres to other permanently modified, and this fact can open chemical stimuli. Bradykinin-mediated stimula - the way to studies on chronic pruritus in many tion significantly increases the release of sub - pruritic dermatoses 12 . Mast cell degradation re - stance P (SP), a calcitonin gene-related peptide sults in the release of tryptase, which stimulates (CGRP), and prostaglandin E 2, while serotonin PAR2 receptors and this leads to an increase in and prostaglandin E 2 have no effect on the re - intracellular calcium level and the activation of lease of neuropeptides 7. Serotonin has been the protein kinase C. These reactions lead to the known for years for its stimulating effect on no - relea se of neuropeptides, mainly SP, neurokinin ciceptive C-type nerve fibres. Intradermal admin - A (NKA) and CGRP 13 . Prostaglandins and istration of serotonin or the application of leukotrienes also play a role in the induction of ionophoresis during the intervention evokes pru - pruritus. Leukotriene injected intradermally into ritic reaction but it is less intensive than that in - mice was shown to induce the scratching reflex. duced by histamine 8. Serotonin type 3 receptors The inhibition of leukotriene receptors is corre - are widely distributed within the central and pe - lated with a less intensive scratch reflex, particu - ripheral nervous system, and for this reason, they larly in patients with atopic dermatitis, while can play a role in various pruritic diseases. En - prostaglandins, mainly PGE2, cause the dilation dothelin is another mediator of pruritus. It be - of blood vessels and induce pruritus. longs to the group of peptides, has a number of biological properties and is synthesized by en - Primary Cutaneous Lymphomas dothelial cells. Endothelin 1, 2 and 3 stimulate Pruritus is a common symptom in patients neurogenic inflammation associated with burning with hematological diseases. In patients with cu - itch. Neuropeptides deserve special attention as taneous T-cell lymphoma, it is often found be - mediators of pruritus. They are important factors fore the onset of other clinical symptoms of the in the pathogenesis of many dermatoses, includ - disease. The problem of pruritus in this group of ing atopic dermatitis, psoriasis, eczema, acne dermatoses is not fully understood and has not rosacea and nodular . In intact skin, most been fully investigated. Cutaneous T-cell lym - nerve fibres containing neuropeptides are located phoma (CTCL) is a heterogeneous group of lym - in the papillary layer, around skin appendages phoproliferative disorders characterized by vary - and blood vessels. The most important neuropep - ing degrees of malignancy. Lymphomas are de - tides include SP, CGRP, somatostatin, neuropep - fined as primary if no abnormalities are found in tide Y, bradykinin and vasoactive intestinal pep - the lymph nodes, the bone marrow or visceral or - tide (VIP). For example, the intradermal admin - gans at the time of diagnosis. Mycosis fungoides istration of SP is followed by the development of (MF) is the most common type of T-cell lym - oedema and pruritus at the injection site. The phoma. Sézary syndrome, characterized by three mechanism of this reaction depends on the re - dominant symptoms: , lym - lease of histamine and tumor necrosis factor al - phadenopathy and the presence of Sézary cells in pha (TNF α) following the stimulation of masto - the peripheral blood, lymph nodes or the skin, is cytes by SP 9. In our continuous studies on the much less common. For a long time the disease pathogenesis of pruritus, we discovered that pro - has very few and mild symptoms, and lesions on teases can mediate the onset of pruritus. Proteas - the skin are limited to patches without infiltrates. es cause the degradation of many mediators of Along with the progression of the disease, pa - pruritus but also take part in its induction. tients present with intensified skin manifestations Tryptases and bacterial proteases are released and a distinct increase in the pruritus, which do from the mastocytes and induce neurogenic in - not respond well to the applied treatment (mainly flammatory condition after PAR receptors are antihistamine drugs, emollients or topical corti - stimulated. The expression and function of PAR costeroids) 14 . There are single reports published differ depending on the location of these recep - across the world dealing with this problem. tors. PAR1 receptors are involved in homeostatic The recently identified histamine H4 receptor processes and induce peripheral or central anaes - seems to be important in the development of pru - thesia in chronic inflammation 10,11 . PAR2 is ritus in CTCL. The receptor is expressed in he - found in many cells, such as keratinocytes, en - mopoietic cells, mainly in dendritic cells, masto -

3630 Pruritus in selected dermatoses cytes and eosinophils. It plays a role in regulating Pruritus is a very common symptom in patients the functions of immune system cells such as with cutaneous T-cell lymphoma, and it may trig - chemotaxis, cytokines and chemokines expres - ger the onset of pathological lesions or present in sion. Some in vivo studies demonstrated the role patients at advanced stages of the disease. In pa - of H4R in natural and acquired cellular immune tients with MF stages IIB to IV pruritus is fre - response 15 . It was found in particular that the H4R quently described as a burning pain resistant to receptor stimulated the Th 2 response under in vi - treatment with topical drugs and emollients. A vo and in vitro conditions, and the use of H4R an - published study carried out in the United States tagonists reduced lung inflammation in mice. by Demierre et al 21 qualified 309 patients with These and other studies allow us to expect that CTCL to complete a survey. The majority of pa - H4R will be helpful in the successful treatment of tients (88%) reported pruritus, with 41% also re - allergies and autoimmune or inflammatory dis - porting some pain. In primary cutaneous T-cell eases. Apart from the effects listed above, the H4 lymphoma pruritus can occur without any skin le - receptor was also found to be directly responsible sions, making the diagnostic process even more for pruritus in studies carried out in mice 16 . It has difficult. It can often take years before the correct been shown that histamine-induced pruritus in diagnosis is made based on clinical symptoms, Balic BALB/c mice through the stimulation of histopathological evaluation of skin biopsy taken the H4 receptor, and the use of the H4R antago - from the lesion, and a number of molecular tests. nist provided better outcomes in suppressing pru - A detailed understanding of the mechanisms re - ritus in mice than H1 receptor antagonists. The sponsible for pruritus in this group of diseases protease-activated receptor 2 (PAR2) is another will help us to develop better methods for the receptor important for the development of pruri - treatment of CTCL 22 . tus. It has been shown that proteases not only suppress pruritus and an inflammatory condition Atopic Dermatitis in the skin, but can also cause pruritus through Pruritus is very common in patients with atopic the activation of specific PAR2 receptors. dermatitis (AD). It is considered one of the major Tryptases and bacterial proteases released from diagnostic criteria for AD according to Hanifin the mastocytes can cause pruritus by inducing a and Rajka 23 , but is also a part of a scoring system neurogenic inflammatory condition after PAR2 used in scientific studies for the comparison of receptors are stimulated. These receptors are also groups of patients, or assessment of disease course found in nerve endings, and it seems that they can in individual patients at various time intervals, also induce pruritus directly by stimulating senso - both a few days long and a several years long 24 . ry nerves. After stimulation, the PAR2 is perma - The severity of pruritus is also a feature consid - nently modified and, therefore, its role in chronic ered in the severity scoring of clinical disease pruritus has been claimed 17 . symptoms using SCORAD and EASI indices 25,26 . The role of interleukins as mediators of pruri - The pathomechanism of pruritus in AD has not tus in CTCL should also be mentioned. In Sézary been fully explained. AD was found to be associ - syndrome T-cells synthesize IL-3, IL-4, IL-5, IL- ated with disorders within the dermis/epidermis 6 and IL-10, enhancing the secretion of Th2 cy - barrier, which result in the onset of characteristic tokines 18 . IL-2 and IL-6 have been described as skin lesions in the locations typical for this der - histamine-dependent mediators of pruritus. matosis 27,28 . Different forms are considered, in - There are reports on the role of histamine and cluding neurogenic pruritus, psychogenic pruritus mast cells as mediators of pruritus in MF, particu - and neuropathic pruritus. Neurogenic pruritus is larly in more advanced stages of the disease. Hist - induced centrally without any damage to the ner - amine, secreted by mast cells, has been known for vous system, while neuropathic pruritus is induced a long time as a factor responsible for pruritus. as a result of damage to the afferent impulse trans - Other mediators secreted by mast cells, such as mission pathway 29 . Psychogenic pruritus can also serotonin, are neuromediators causing pruritus in accompany many diseases in which the nervous certain diseases, including lymphomas 19 . In 1996, system plays an important role. Patients with AD Vermeer and Willemze 20 reported in their paper a often find pruritus unbearable. In AD pruritus is case of two patients with MF who suffered an ex - not caused by histamine alone, because the admin - acerbation of skin symptoms after the administra - istration of drugs inhibiting histamine receptors tion of fluoxetine, an antidepressant acting as a does not offer full relief and elimination of this selective serotonin reuptake inhibitor. persistent symptom. Scratching is a natural re -

3631 K. Olek-Hrab, M. Hrab, J. Szyfter-Harris, Z. Adamski sponse, and it leads to the formation of excoria - onset and sometimes accompanied by angioede - tions, erosions and erythema, also contributing to ma. Urticaria is more often seen in women than in skin damage and the creation of the itch-scratch men (3:2). About 20-30% of the total population cycle. Emotional and mental factors are also im - may experience a single episode of acute urticaria portant in AD. Ständer et al 30 carried out a valu - in life. Statistics for chronic urticaria persisting for able study on the pathophysiology of pruritus in longer than 6 weeks from the onset of the first AD. The researchers presented the results of stud - episode are slightly different, as it occurs in about ies supporting a certain role of the central nervous 1-4% of the total population. Wheals (raised areas system in the mediation of pruritus in AD. Raised surrounded by a base) from urticaria have porce - plasma levels of beta-endorphin and skin levels of lain or light pink colour and result from the limit - ACh were found in patients with AD. ACh is a ed oedema of the dermis. Oedema results from the neurotransmitter in sensory nerves surrounding dilation of blood vessels and increased permeabili - eccrine sweat glands, and is released and synthe - ty of their walls. Regardless of the type of ur - sized in vitro by keratinocytes. Intradermal admin - ticaria the common feature of these disorders is istration of ACh to patients with AD into the le - the activation and release of mediators from mast sion and apparently intact skin results in slightly cells in the skin. Released mastocytes are accumu - different skin reactions. In the first case pruritus lated directly near blood vessels and contain char - and burning pain is provoked, but in the second acteristic metachromatic granules. Different stim - case pruritus only. Does this mean that pruritus is uli trigger the release of preformed mediators (his - caused by different mechanisms in the same pa - tamine, heparin, various enzymes) and mediators tient with AD? We can only speculate that in skin synthesized directly after activation (TNF-alpha, lesions more intense pruritus is associated with IL-8). In urticaria, there is a direct correlation be - excessive perspiration caused by the effect of tween the nervous system and mast cells. Neuro - ACh. One certain fact is that neuropeptides play a transmitters, including substance P, cause the re - very important role in the pathomechanism of pru - lease of histamine, which can affect sensory nerve ritus in AD. Abnormalities in the innervation of fibres and provoke pruritus in this dermatosis. In skin with lesions in patients with AD include an cold-induced, pressure-induced and increased number of sensory nerve fibres, an in - there are also other factors responsible for the creased expression of SP and CGRP, as well as a degradation of mast cells. Important mediators, higher number of neurofilaments. The increased apart from histamine, in these types of urticaria in - secretion of the nerve growth factor (NGF) by the clude serotonin, bradykinin, leukotrienes C 4, D 4 epithelial cells in the basal skin layer results in the and E 4, prostaglandins and proteolytic enzymes. hypertrophy of nerve endings 31 . The causes of acute urticaria are often unknown, The role of histamine in the pathomechanism while 25% of cases of chronic urticaria are caused of pruritus in patients with AD continues to be by infections, allergic or pseudoallergic reactions the subject of many studies and debates. Initially, and autoimmune disorders. Physical urticaria ac - histamine was considered the major mediator of counts for another 25% of cases, and idiopathic pruritus in atopic diseases, but further studies do urticaria, in which no causative factor can be iden - not fully support this standpoint. Another reason tified despite full diagnostic process, account for for this is the fact that the administration of H1 50% 33 . Severe pruritus, apart from urticarial receptor antagonists to patients with AD does not wheal, is a very characteristic symptom of this offer relief from the persistent scratching 31 . Per - disorder. Pruritus is most severe in the phase of haps this problem can be attributed to the role of wheal formation and is rare in children. No exco - interleukins, including IL-2 or IL-31, because the riations are found on the skin, as patients rub le - intradermal administration of IL-2 provokes pru - sions rather than scratch them. Exacerbation of ritus in patients with AD with more severity than symptoms in the evening can be attributed to the in healthy people 32 . reaction of the parasympathetic system 34 . Other Allergic Diseases Contact dermatitis results from the skin’s reac - Urticaria tion to external factors triggering inflammation. Urticaria is a disease manifested by skin erup - Two types of this dermatosis have been de - tion in the form of wheals. Acute urticaria is the scribed and, depending on the provoking factor, most common skin disease, characterized by rapid these are irritant contact dermatitis and allergic

3632 Pruritus in selected dermatoses contact dermatitis. Irritant contact dermatitis re - common, although chronic reactions have also sults most often from cutaneous reaction to toxic been reported. Certain predispositions include al - substance acting directly on the skin. Allergic lergic diseases, but also skin injury leading to the contact dermatitis results from hypersensitivity development of allergic reactions. The immune to toxic substances, usually mediated by T lym - mechanism of contact reaction has been investi - phocytes. Skin lesions occur after repeated expo - gated in detail. At the first stage (induction sure of the skin to an irritant. In this type of reac - phase), the antigen is presented to T lymphocytes tion the dose of the provoking factor plays no sig - in regional lymphatic nodes, and Langerhans nificant role, but it is important that the reaction cells are involved in this process. Sensitized cells spreads beyond the site exposed to the allergen, in return to the skin. Repeated exposure to the mini - contrast to irritant contact dermatitis, in which mum dose of the allergen results in the onset of a skin lesions occur only at the site of exposure. hypersensitivity reaction. Receptors of T helper cells identify the specific antigen, then cytokines Irritant Contact Dermatitis are released, mainly IL-2, IL-4, IL-6 and IL-8, There are two types of this dermatitis – acute which activate other inflammatory cells. The list and chronic. Acute irritant contact dermatitis is of allergens is very long and continues to grow. found in people who are exposed to an irritant for Depending on the needs, standard and extended a sufficiently long time. The corneous layer cre - allergen test kits can be used. The clinical mani - ates a direct protection against harmful sub - festation of contact dermatitis varies and depends stances. The protective potential depends on its on the type of allergen provoking the reaction, thickness and the presence of skin appendages. exposure time, and the surface on which skin le - The face, genital organs and intertriginous areas sions develop. The most common symptoms de - are most susceptible to this dermatitis. Major fac - velop within 24-48 hours and include lesions of tors provoking acute reaction include alkali, acids, erythematous and exfoliating nature, excoria - organic solvents, detergents, UV radiation, ioniz - tions, lichenification, persistent pruritus and in - ing radiation, phototoxic factors, certain foods (as - flammation. Finding the causative factor for this paragus, mustard), plants and animals (agave, sea reaction and elimination of responsible allergen anemone), and military gases. Clinical manifesta - are very important, otherwise treatment will not tion is variable and depends on the provoking fac - be successful. Pruritus in these dermatoses is a tor, but various severity erythema with blisters, very common symptom, is persistent, and does bleeding, urticarial wheals and erosions are al - not respond to available treatment methods. Be - ways observed, and these lesions are accompanied cause of the continuous scratching skin lesions by pruritus. In chronic contact dermatitis the ma - do not subside and chronic inflammation devel - jor aetiological factor is repetitive exposure to ops. Skin patch tests offer very valuable informa - gentle irritants. This results in disorders within the tion, and in some cases, a diagnostic biopsy of lipid skin layer, leading to the development of the skin lesions might be recommended. symptoms such as lichenification, cracking and There is only scarce literature data on the exfoliation. More acute reactions can also devel - prevalence of contact allergy in children with op, with the formation of eruptions, oedema and atopic dermatitis. In one of the papers, the authors eschars. These reactions are most often caused by research assess the prevalence of contact allergy detergents, chemicals, physical factors and secre - among children with atopic dermatitis, seborrhoe - tions, including sweat and saliva. Pruritus is a fre - ic dermatitis and in a population of healthy chil - quent symptom associated with these dermatoses. dren. The statistically significant positive results Continuous scratching leads to the exacerbation of in the highest proportion of patch tests in the clinical symptoms and secondary infections or youngest age subpopulation of children with lichenification. The introduction of relevant topi - atopic dermatitis, and detection of contact allergy cal and oral treatment reduces inflammatory most commonly in the youngest subgroup of symptoms and the severity of pruritus. Avoiding healthy children, may suggest nonspecifically pos - contact with the irritant is very important 33 . itive results associated with the immaturity of the epidermal barrier during the first years of life 35 . Allergic Contact Dermatitis This dermatosis occurs in about 15% of the Drug Eruptions population. Lesions form in the reaction induced Drug eruptions are frequent disorders, and it by an allergen, and the acute type is the most should be kept in mind that any drug can cause

3633 K. Olek-Hrab, M. Hrab, J. Szyfter-Harris, Z. Adamski an adverse reaction. Acquiring a detailed patient ered with eschar. Lesions heal leaving no marks, history, covering not only days before the onset although hyper- or hypopigmentation may some - of skin lesions but also the ten or more past days, times occur on the affected skin. The administra - plays an important role. It should be remembered tion of antihistamine drugs is recommended be - that adverse drug reactions can, depending on the cause of the severe pruritus, and insect bites, active substance of the drug, lead to skin lesions varicella and scabies should mainly be consid - caused by all four immune mechanisms. The ad - ered in differential diagnosis 33 . ministration route also plays an important role. Subacute prurigo ( subacuta, At topical administration hypersensitivity re - strophulus adultorum) is another type of disease. It sponse at the drug application site can be expect - usually affects women aged 30-40 years and ed, oral or nasal administration stimulates the women during menopause. Subacute prurigo af - synthesis of immunoglobulins A and E, while in - fects men aged over 50 years. The etiology has not travenous administration can lead to anaphylactic been fully understood. There may be many causes shock. The drugs most often responsible for ad - but major listed agents include concurrent dis - verse reactions include antibiotics, non-steroid eases, such as renal and liver disorders, diabetes, anti-inflammatory drugs, diuretics, certain car - and prurigo dermographica. diovascular drugs and drugs acting on the CNS. The major characteristic symptom of this disease Because there is a possibility of an immune aller - is very intense itching subsiding after scratching gic reaction, and also a non-immune reaction, which results in bleeding of the lesion. Excoria - various skin lesions can be observed. Symptoms tions perceptible on the skin almost never affects of urticaria or are the most common. the adjacent intact skin. The disease is manifested Other common disorders include lesions resem - by an eruption in the form of a pink exudative bling lichen planus, acne, psoriatic-like lesions, nodule with a characteristic papule on the top. Le - eczema, blisters and pigmentary changes. Le - sions usually occur on the extensor surface of the sions are often associated with pruritus of vari - trunk or shoulder girdle. Characteristically, the ar - ous severity. The treatment method involves the eas between skin eruptions remain intact, which elimination of the provoking factor and the use helps to differentiate this disease from atopic der - of topical medications plus antihistamines. matitis or other disorders. Skin lesions do not oc - cur on mucous membranes, hands or feet 33 . Prurigo occurs in patients with This is a group of disorders of various aetiolo - chronic pruritus. It is often found in patients with gies, manifested by the formation of usually atopic dermatitis or other atopic diseases. It may small urticarial exudative nodules. The small occur in women during menopause due to the de - nodules are swollen and red at their base, some - velopment of depression symptoms and psy - times with a minor blister filled with serous flu - chosocial disorders. Prurigo may also develop id. In contrast to urticaria, these lesions do not because of underlying self-injury disorders. subside completely within a few hours. Scratching results in local proliferation of skin Acute prurigo (prurigo simplex acuta, strophu - nerves and an increase in the levels of neuropep - lus infantum) usually occurs in children aged 2 to tides. This process leads to increased secretion of 8 years. It may be associated with insect bites, proinflammatory cytokines, and stimulation of because acute prurigo tends to occur during sum - keratinocytes and fibroblasts, which can explain mer, and tests with insect allergens carried out in epidermal fibrosis and hypertrophy. Papules ob - patients often provide a positive response. The served clinically tend to form solid nodules most disease is manifested by clinical symptoms simi - often located on distal parts of lower extremities, lar to urticaria, and in healthy children very itchy buttocks and, rarely, on the trunk. Skin lesions papules develop rapidly on the skin, with pale may accompany atopic diseases, but also lichen pink infiltration on the margin. Lesions most of - planus, chronic contact dermatitis, crural eczema ten occur on the trunk and extremities. A barely and scabies. Because of the coexisting chronic perceptible papule that increases its size to a pruritus lesions are often scratched and covered clearly visible form (strophulus bullosa) may de - with crust. velop within the nodular lesions. Usually, the ex - udative papule grows and forms a hard nodule. Psoriasis These lesions are accompanied by intense itching Psoriasis is one of the most common chronic that leads to the formation of excoriations cov - and recurrent skin diseases and its cause is not

3634 Pruritus in selected dermatoses fully understood. It has been estimated that in statistically significant differences were found highly developed countries psoriasis affects between patients with pruritic psoriasis and pa - about 1-2% of people. There are many factors tients with non-pruritic psoriasis. that may influence the onset of psoriasis and ex - acerbate symptoms. These include genetic but al - Pruritus in Systemic Diseases so environmental factors, mainly stress, tobacco Pruritus can also be a symptom of systemic smoking, and certain drugs or alcoholic bever - conditions in the human body. It is most com - ages 36 . Stress may trigger exacerbation of psoria - mon in patients with cholestasis, liver dysfunc - sis in a number of ways. It can activate the hypo - tions, uraemia and renal diseases. thalamus-pituitary-adrenal axis and stimulate the secretion of corticoliberin (CRH), which has a Pruritus in Renal Diseases proinflammatory effect and can activate masto - Uraemic pruritus affects about 40 to 70% of cytes, stimulate angiogenesis and modulate im - patients on dialysis. It often has a generalized mune cells. Increased levels of CRH and its re - manifestation and is exacerbated during the ceptors were found in the skin of patients with night. The cause of uraemic pruritus has not been psoriasis. Stress can also be responsible for the fully understood, but a significant role is attrib - aggravation of disease by stimulating the release uted to skin dryness in these patients. The term of many proinflammatory neuropeptides such as uraemic pruritus is not correct, as there is no cor - SP, CGRP, VIP or somatostatin from nerve end - relation between the level of urea and the severi - ings in the skin 37 . In psoriasis, however, the con - ty of pruritic symptoms. In addition, pruritus nection between histamine and pruritic symp - may occur in patients with normal renal parame - toms is not completely clear. No correlation was ters. Increased levels of IL-6 were found in pa - found between the severity of pruritus and hista - tients with uraemia in comparison to patients mine plasma levels in patients with pruritic pso - without renal disorders[ 42 ]. The role of histamine riasis versus a group of patients without pruri - or serotonin is arguable, and carried out studies tus 38 . In addition, treatment with antihistamine have not provided conclusive evidence support - drugs rarely offers improvement, and any im - ing these assumptions. Attempts to treat this con - provement which does occur is most likely asso - dition with antihistamines or selective serotonin 39 ciated with the sedative effect of these drugs . receptor inhibitors 5-HT 3 offered no success. Reich et al 40 found no significant difference in This may be attributed to disordered clearance of plasma levels of SP, CGRP or VIP between pa - medium molecular weight proteins leading to pe - tients with pruritic psoriasis and patients with ripheral neuropathy, or to the effect of parathor - psoriasis who did not report pruritus. A negative mone or calcium and phosphorus ions[ 43 ]. In correlation was found between the plasma levels some studies increased mastocyte count and hist - of SP and VIP and severity of pruritus in patients amine levels were reported in patients with with psoriasis. This most likely results from the uraemic pruritus. The accumulation of endoge - increased activity of enzymes degrading neu - neous opioids and other compounds not removed ropeptides and, therefore, reduced plasma level during dialysis may be a causative factor for pru - of these neuropeptides. Nakamura et al 41 carried ritus in these patients. Because of the multifacto - out a study focused on pruritus in patients with rial pathogenesis of uraemic pruritus, researchers psoriasis, and they demonstrated an increased continue their studies to identify agents causing number of nerve fibres containing SP near blood this persistent symptom in patients. vessels, and reduced the activity of enzymes de - grading SP. The researchers also found that pa - Pruritus in Liver Diseases tients with pruritic psoriasis had an increased ex - Patients with liver conditions and cholestasis pression of NGF and TrkA receptors on ker - are often affected by pruritus. All the causes of atinocytes in the basal layer and in nerve fibres have not yet been identified. within inflammatory infiltrates in comparison to However, the role of bile salts, progesterone patients who had non-pruritic psoriasis. Chang et metabolites and histamine have been considered. al analyzed the expression of receptors for select - Beyond any doubt, many studies demonstrated ed neuropeptides (SP, NGF, VIP and CGRP) on that mediators of cholestatic pruritus are secreted keratinocytes from the psoriatic skin and found with bile and reabsorbed from the intestines into the expression considerably increased. Despite the bloodstream. Cholestatic pruritus is more many studies on the role of IL, mainly IL-2, no common in women, particularly during menstru -

3635 K. Olek-Hrab, M. Hrab, J. Szyfter-Harris, Z. Adamski al bleeding or those on hormone replacement cludes neurogenic pruritus and neuropathic pruri - therapy 44 . This may be associated with sterolic tus. Neurogenic pruritus develops after inducing metabolites acting as mediators of cholestatic the pathway transmitting the itch sensation but pruritus. Fatty acids can cause degradation of with no neural damage. Neuropathic pruritus is mast cells and the release of histamine. There - chronic in most cases and responds poorly to treat - fore, histamine plays a certain role in this condi - ment. Here we can list tumours of the CUN, main - tion, and its increased plasma levels were found ly cavernous angioma and ependymoma, abscess - in patients with cholestasis 45 . es of this area and ischaemic diseases. Pruritus in these diseases is unilateral, located opposite to the Pruritus in Endocrine and Metabolic injured hemisphere, and is associated with other Disorders perceptive disorders. Patients with multiple sclero - Pruritus may also be associated with thyroid sis (MS) may suffer paroxysmal attacks of itching disorders, both hypothyroidism and hyperthy - located symmetrically and lasting from several roidism, as well as with diabetes mellitus. Con - seconds to several minutes. Paroxysmal pruritus in trol of hormonal parameters is most important in patients with MS can cause sleep disruption at endocrine disorders and can contribute to im - night and may be an early, and the only, symptom proved clinical skin state and reduce itching. Pru - of MS. is another type of ritus occurs in 4-11% of patients with hyperthy - neuropathic pruritus. Lesions occur on the dorso- roidism and may be associated with increased lateral side of the arm. The affected skin is intact, blood flow to the skin. In hypothyroidism pruri - but post-inflammatory discolourations can some - tus accompanies the dryness of the skin which is times develop. Interestingly, symptoms become very typical of this condition. Diabetes mellitus aggravated after exposure to sunlight. The patho - is another endocrine disorder, and generalized genesis of this disease is not fully understood. One pruritus may be its first and only symptom. It certain fact is that an important role is attributed to may be a symptom associated with disorders sec - the compression of nerve roots at the C5-C8 level, ondary to diabetes, such as candidiasis or dryness or other pathology of the spinal cord at this level 47 . of the skin 46 . Diabetic patients may present with Notalgia parasthetica is a pruritic disease localized skin lesions caused by atherosclerosis, such as is - unilaterally in the interscapular area (Th2-Th6 der - chemia and ulcerations. Neuropathy leads to matomes) with coexisting increased sensitivity of trophic lesions, cracking and dryness of the skin the skin to sensory stimuli. Skin patches affected on the lower extremities. Patients taking drugs by pruritus often show abnormal pigmentation reducing blood sugar level may develop urticari - caused by persistent scratching of this area. The al skin lesions or eruptions. Phototoxic reactions primary role in this disease is attributed to injury of are sometimes observed. the posterior rami of spinal nerves arising in T2 During pregnancy, women experience many through T6 corresponding with degenerative hormonal changes. Pruritus is one symptom of changes in the thoracic section. This problem is this process, particularly in the second and third rather rare in young people, but if diagnosed it may trimester of gestation. It may be associated with be one of the symptoms of multiple endocrine neo - pregnancy-related complications and dermatoses plasia type 2A (MEN 2A). Treatment of pruritus in characteristic for this period, but may also be due these nervous system disorders is difficult and re - to skin dryness and stretching in certain body quires a multidisciplinary approach 48 . parts as a response to enlargement in areas of the abdomen, thighs and buttocks. In the latter case, Psychiatric Disorders pregnant women can achieve fast relief from pru - The diagnostic process focused on pruritus in ritus by using vitamin A-free emollients with a psychiatric disorders often requires consultation moisturizing effect. However, if pruritus persists with a psychiatrist. Pruritus occurs most often in in a pregnant woman despite using moisturizers, patients suffering from stress, fatigue or anxiety, diagnostic tests have to be carried out to rule out and is apparently reported more frequently by cholestasis, renal disorders or gestosis. women. Patients may be affected by pruritus with - out developing any skin lesions, but there are also Neurological Disorders cases of patients with excoriations and injuries Many disorders of the central nervous system from scratching. It is noteworthy that pruritus and can cause pruritus. According to the current classi - the skin lesions associated with it may give rise to fication the category of neurological pruritus in - symptoms of depression and breakdown 49 . Gener -

3636 Pruritus in selected dermatoses ally, psychogenic pruritus is diagnosed after ruling Bed bug (Cimex lecularius) out other causes. Precise criteria for diagnosing Bed bugs are active at night, and during the psychogenic pruritus have been proposed by the day they lodge in furniture crevices, floors or French Psychodermatology Group. paintings. Skin lesions appear as groups of sever - al erythematous nodules or urticarial changes. Parasitic diseases and skin lesions Lesions are located on the extremities and face. Induced by contact with insects Urticarial lesions transform into hard nodules that persist for several days with accompanying Diseases Caused by Arthropods severe pruritus. Treatment involves the control of There are many dermatoses in which pruritus is a pruritus with topical antipruritic medications. significant and persistent symptom. The most im - portant that have to be mentioned are scabies, inva - Human flea (Pulex Irritans) sion by intestinal parasites, larva migrans, pediculo - Human fleas are a considerable problem; they sis, human flea and skin lesions induced by insects. can jump and also fly. They tend to live in Arthropods are the largest group within the animal crevices, carpets and furniture. The human flea is kingdom. From the medical point of view insects small (2-4 mm) but can jump up to 50 cm into and arachnids are the largest group. Arthropods can the air and 60 cm in distance. Bites by human have a negative effect on their host through bites fleas cause the development of numerous wheals (lice, mosquitoes, flies, fleas, centipedes and spi - and nodules arranged irregularly. Diascopic ex - ders) or stings (bees, hornets and wasps). amination reveals the presence of puli - cosa. In rare cases reactions to a bite can have a Pediculosis bullous appearance or resemble bullous pem - There are three lice species important for hu - phigoid. Lesions are associated with severe itch man pathologies: head louse ( Pediculus humanus and, therefore, acute urticaria, lichen urticatus, capitis ), body louse ( Pediculus humanus cor - prurigo or bites by other insects should be con - poris ) and pubic louse ( Phthirus pubis ). The sidered at a differential diagnosis. head louse is most common in children of pre- school and school age. It is transmitted from hu - Nematodes man to human by direct contact and on combs, hair brushes or other hair accessories. Lesions Cutaneous Larva Migrans are generally found on the scalp, and less com - Cutaneous larva migrans, also called the monly on the eyebrows, eyelashes and beard. ‘plumber’s itch’ is a disease known worldwide, Lice are usually located in the retroauricular but is more common in countries of the tropical area, and after biting induce the formation of in - and subtropical regions. Infection is caused by tensely pruritic nodules. Severe itch and scratch - the contact with soil contaminated by animal fae - ing leads to the inflammatory condition defined ces. This usually occurs at the beach, to people as louse eczema. In skin areas affected by lesions working in the mining industry, in tunnels, and to secondary bacterial infection and contagious im - plumbers. The disease is caused by various petigo may develop. Pediculosis corporis is a dis - species of nematodes, which penetrate the skin, ease associated with poor personal hygiene and but are not able to mature there, or move to deep - is most common in homeless people. The irritant er layers to infest body organs. Shortly after a effect of lice saliva results in the development of larva penetrates the skin intense itch, oedema, erythema, urticarial lesions and itchy nodules small nodules and eruptions develop. Larvae cre - and pustules. Persistent pruritus leads to excoria - ate the typical red wormlike burrows visible un - tions with secondary infection and reactive lym - derneath the skin accompanied by severe pruri - phadenopathy. Because of the skin’s appearance, tus. Larvae may be removed sometimes as a re - this condition is also called vagabond’s disease. sult of scratching. This condition is usually con - The pubic louse, the smallest of all lice species, fined to the skin of the feet. is transmitted sexually and infests the genital and axillary areas due to the presence of apocrine Enterobiasis glands. In this condition pruritus is the least in - This condition has no association with any so - tense of all types of pediculosis. Blue spots that cioeconomic level, race or culture and is common - appear at the feeding site caused by pubic lice ly transmitted via the faecal-oral route. Parasites are a characteristic sign of infestation. live in the colon, duodenum and rectum. Female

3637 K. Olek-Hrab, M. Hrab, J. Szyfter-Harris, Z. Adamski pinworms, after leaving the small intestine, and ants. Each of these insects can cause a emerge from the anus and deposit eggs in the peri - painful bite and provoke a very dangerous aller - anal area and genitals (in women). Then eggs are gic response, including anaphylactic shock. Hon - then ingested and reach the human gastrointestinal ey bees, unlike wasps or hornets, can sting their tract, where larvae hatch already in the duodenum. victim only once in their lifetime. The venom of Patients feel well and the disease is often asymp - Hymenoptera has a complex structure and can tomatic. The major clinical symptom is perianal cause various reactions when introduced into the pruritus, intensifying during the night. Scratching human body. Desensitization to Hymenoptera can result in self-infection as patients transfer pin - venom is very difficult and requires extensive worms on dirty hands to the mouth. Erosions and knowledge and experience. A honey bee sting excoriations develop on the scratched skin. Enter - causes redness, itch, pain and a burning sensa - obiasis should be considered when making a dif - tion. Swelling often develops after the sting and ferential diagnosis in patients with perianal pruri - it may persist for a few days. Stings to the face or tus. Treatment is uncomplicated and requires per - mouth may cause immediate and acute anaphy - sonal hygiene and oral medication. lactic reaction. Ascariasis Arachnids – Scabies This is the most common human disease caused The itch mite is a human parasite, and is trans - by intestinal parasites, and infection occurs usual - mitted by direct human-to-human contact, partic - ly by ingestion of unwashed fruit and vegetables ularly in pre-schools, nurseries and schools, but or through contact with soil contaminated by fae - also among adults at workplaces. Scabies is typi - ces containing eggs of the parasite. The parasite cally manifested by an intense itch, becoming lives in the small intestine, where newly ingested more severe after an increase in body tempera - eggs hatch, and then larvae burrow through the ture, retiring for bed, and at night. Skin lesions gut wall to the blood system, and migrate via are typically located between fingers, on the skin veins to the lungs. In the lungs, the parasites can of wrists, soles, and around nipples and genital cause Löffler’s syndrome (eosinophilic pneumo - organs. Secondary papules develop in reaction to nia). After 10 days the parasites migrate along the mite faeces, located on lateral parts of the trunk, trachea to the larynx and are reingested to reach on extremities, in the gluteal cleft, and on the the small intestine, which starts the life cycle waist. In children skin lesions may occur on the again. Most infections are asymptomatic, but scalp, hands, soles and face. Lesions are eczema - some patients present with symptoms of intestinal tous and lichenoid in nature and transform into obstruction or pains resembling appendicitis. nodules, eruptions and pustules. Itchy red nod - ules contribute to the onset of urticarial allergic Skin Lesions Induced by Contact reactions. Intense pruritus causes the formation with Insects of lichenoid patches 50,51 . Treatment has to cover all family members, and requires the laundering Mosquitoes (Culicidae) and ironing of all the clothing used by the people Mosquitoes can transmit infectious diseases. occupying a dwelling. Parasites can also be suc - Their life cycle takes place in water bodies, either cessfully controlled by topical preparations. large, or small like a paddle or dumped tyres. Mosquitoes have a role in spreading diseases such Other Dermatoses Accompanied as malaria, filariasis, yellow fever, dengue fever, with Pruritus and encephalitis of various etiology. Skin lesions There are many dermatoses accompanied by after mosquito bites are numerous and itchy. Sec - pruritus. These include infectious diseases such ondary bacterial infection can occur due to as zoster, seborrhoeic disorders, e.g. simple acne, scratching. Children often present with a bullous acne rosacea, and also other dermatoses, like se - form of the disease. Treatment involves control of borrhoeic dermatitis and pemphigus, particularly the scratching reflex by the use of topical antihist - Duhring’s disease. Other diseases that should be amine medications. mentioned are ichthyosis and keratosis follicu - laris. Lichen planus is a distinct type of disease, Bees and Wasps (Hymenoptera) in which pruritus is very intense and is used as a This group of Hymenoptera includes insects diagnostic criterion. Pruritus can be caused by a such as wasps, honey bees, bumble bees, hornets reaction to drugs or be associated with hepatic

3638 Pruritus in selected dermatoses

Table II. Other selected pruritic dermatoses.

Lichen planus Macular amyloidosis Lichen sclerosus et atrophicus Nodular amyloidosis Dermatitis herpetiformis Pemphigoid Pityriasis rosea Gibert Herpes Pityriasis pilaris Zoster Xerosis (skin dryness) Varicella Ichthyosis Tinea glabrosa Keratosis pilaris Cutaneous mastocytosis Darier’s disease Lichen amyloidosus Grover’s disease diseases, and both these causes are considered to will help us to better understand the pathomech - be factors intensifying pruritus. Lichen sclerosus anism of pruritus and will contribute to advances et atrophicus is a specific type of connective tis - in this important domain of medical science. sue disorder, and skin lesions are located mainly in the genital area and are accompanied by un - –––––––––––––––– –-– –– Conflict of Interest pleasant and persistent pruritus, resistant to topi - cal treatment, including phototherapy. The Authors declare that they have no conflict of interests. Cutaneous mastocytosis can also be associated with pruritus. Mast cells become accumulated only in the skin. The disease affects mainly chil - References dren, the prognosis is good and lesions often sub - side spontaneously. Urticaria pigmentosa occurs 1) STÄNDER S, W EISSHAAR E, S TEINHOFF M. S CHMELZ M, in infants and children. It is clinically manifested METTANG T, H ANDWERKER H, L UGER TA. Pruritus-- by nodules and patches of abnormal pigmenta - pathophysiologie, klinik und therapie--An tion which after rubbing transform into urticarial overview JDDG 2003; 1: 105-118. WEISSEHAAR E, K UCENIC MJ, F LEISCHER AB J R. wheals (Darier’s symptom). Lesions are most of - 2) Pruritus: a review. Acta Derm Venerol Suppl 2003; 213: 5- ten located on the trunk, and rarely occur on 32. soles, hands and face. Major symptoms include 3) STÄNDER S, S TEINHOFF M. Pathophysiology of pruri - fever and pruritus, but other symptoms may oc - tus in atopic dermatitis: an overview. Exp Derma - cur, such as diarrhoea, vomiting, tachycardia and tol 2002; 11: 12-24. less often respiratory symptoms. All symptoms 4) STÄNDER S, S TEINHOFF M, S CHMELZ M, W EISSHAAR E, are mainly caused by mediators released from METZE D, L UGER T. Neurophysiology of pruritus. activated mast cells in the skin. Selected diseases Cutaneous elicitation of itch. Arch Dermatol 2003; accompanied by pruritus are listed in Table II. 139: 1463-1470. 5) STÄNDER S, S CHMELZ M. Chronic itch and pain – sim - ilarities and differences. Eur J Pain 2006; 10: Conclusions 473-478. 6) HALL JM. Bradykinin receptors: pharmacological properties and biological roles. Pharmacol Ther Because of the complex nature of the mecha - 1992; 56: 131-190. nisms involved in the induction of pruritus this 7) AVERBECK B, R EEH PW. Interactions of histamine problem requires more comprehensive and de - and bradykinin on polymodal C-fibres in isolated tailed analysis. Focus on the life quality of pa - rat skin. Eur J Pain 2001; 5: 97-106. tients with pruritic disorders is vital. In many 8) WEISSHAAR E, Z IETHEN B, G OLLNICK H. Can a sero - cases pruritus is also a significant psychological tonin type 3 (5-HT3) receptor antagonist reduce 38 experimentally-induced itch? Inflamm Res 1997; problem . Therefore, it is very important to un - 46: 412-416. derstand the mechanisms responsible for the de - 9) REICH A, S ZEPIETOWSKI J.C. The importance of se - velopment of this symptom. In many dermatoses, lected neuropeptides in neurogenic inflammation the mediators of pruritus have not been clearly of the skin. Dermatol Klin 2006; 8: 103-107. defined, which prevents the introduction of tar - 10) IKOMA A, S TEINHOFF M, S TANDER S Y OSIPOVITCH G, geted and effective treatment. We hope that mul - SCHMELZ M. The neurobiology of itch. Nat Rev tiple studies carried out on this difficult subject Neurosci 2006; 7: 535-547.

3639 K. Olek-Hrab, M. Hrab, J. Szyfter-Harris, Z. Adamski

11) TERESIAK -M IKOŁAJCZAK E, C ZARNECKA -O PERACZ M, S ILNY Evoluation of selected skin barier functions in W. Current views on the pathogenesis and treat - atopic dermatitis in relations to the disease ment of pruritus in chronic inflammatory der - severity and pruritus. Post Derm Alergol 2012; matoses. Post Derm Alergol 2009; 1: 56-64. 5: 373-377. 12) STEINHOFF M, N EISIUS U, I KOMA A. Proteinase-acti - 28) PASTUSZKA M, M ATYCH M, K ASZUBA A, P OZNANSKA - vated receptor-2 mediates itch: a novel pathway KUROWSKA K, K ASZUBA A. Microorganisms in the for pruritus in human skin. J Neurosci 2003; 23: etiopathogenesis of atopic dermatitis. Post Derm 6176-6180. Alergol 2012; 3: 215-221. 13) RICHARDSON JD, V ASKO M. Cellulary mechanisms of 29) TERESIAK -M IKOŁAJCZAK E, C ZARNECKA -O PERACZ M, J EN - neurogenic inflammation. J Pharmacol Exp Ther - EROWICZ D, S ILNY W. Neurogenic markers of the in - ap 2002; 302: 839-845. flammatory process in atopic dermatitis: relation 14) KISIEL K, K ASZUBA A. Alclometasone dipropionate: to the severity and pruritus. Post Derm Alerg properties and clinical uses. Post Derm Alergol 2013; 5: 286-292. 2011; 2: 107-119. 30) STÄNDER S, S TENHOFF M. Pathophysiology of pruri - 15) ZAMPELI E. T ILIGADA E. The role of histamine H4 re - tus in atopic dermatitis: an overview. Exp Derma - ceptor in immune and inflammatory disorders. Br tol 2002; 11: 12-24. J Parmacol 2009; 157: 24-33. 31) AK -P RELICH M, S YSA -J DRZEJOWSKA A. Pruritus, atopic 16) MOMMERT S, G SCHWANDTNER M, G UTZMER R W ERFEL T. dermatitis--therapeutic problem. Medipress Der - The role of the histamine H4 receptor in atopic der - matol 2003; 7: 11-16. matitis. Curr Allergy Asthma Rep 2011; 11: 21-28. 32) LIPPERT U, H OER A, M OLLER A, R AMBOER I, C REMER B, HENZ BM. 17) RATTENHOLL A, S TEIHOFF M. Proteinase-activated re - Role of antigen induced cytokine re - ceptor-2 in the skin: receptor expression, activa - lease in atopic pruritus. Int Arch Allergy Immunol tion and function during health and disease. Drug 1998; 116: 36-39. News Perspect 2008; 21: 369-381. 33) BURGDORF WHC, P LEWIG G, W OLFF HH, L ANDTHALER M 18) DUMMER R, H EALD PW, N ESTLE FO, L UDWIG E, L EINE E, (Eds.). Braun-Falco’ Dermatology. Springer, 2010. HEMMI S, B URG G. Sézary Syndrome T-cell clones 34) KAPLAN AP. Chronic urticaria: pathogenesis and treat - display T-helper2 cytokines and express the ac - ment. J Allergy Clin Immunol 2004; 114: 465-474. cessory factor-1 (interferon gamma receptor be - 35) SI LNY W, B ARTOSZAK L, J ENEROWICZ D, UKIEWICZ - ta-chain). Blood 1996; 88: 1383-1389. SOBCZAK V, G O DZIEWSKA M. Prevalence of contact 19) KRAJNIK M, Z YLICZ Z. Understanding pruritus in sys - allergy in children suffering from atopic dermatitis, temic disease. J Pain Symptom Manage 2001; seborrhoic dermatitis and in healthy controls. Ann 21: 151-168 Agric Environ Med 2013; 20: 55-60. 20) VERMEER MH, W ILLEMZE R. Is Mycosis fungoides ex - 36) WIELOWIEYSKA -S ZYBI SKA D, W OJAS -P ELC A. Psoriasis: acerbated by fluoxetine? J Am Acad Dermatol course of disease and treatment. Post Derm Aler - 1996; 35: 635-636. gol 2012; 2: 118-122. 21) DEMIERRE MF, G AN S, J ONES J, M ILLER DR. Significant 37) RAYCHAUDHURI SP, F ABER EM. Neuroimmunologic as - impact of cutaneous T-cell lymphoma on patients’ pects of psoriasis. Cutis 2000; 66: 357-362. quality of life. Cancer 2006; 107: 2504-2511. 38) WI NICKA B, S ZEPIETOWSKI JC, R EICH A. Histamine, 22) WOJEWODA K, B RENNER J, S OKOŁOWSKA -W OJDYŁO M, substance P and calcitonin gene-related pep - BARA SKA -R YBAK V. Treatment of primary cutaneous lym - tide plasma concentration and pruritus in pa - phoma with reference to the latest therapeutic con - tients suffering from psoriasis. Dermato Psych sensus of the Polish Lymphoma Research Group 2004; 5: 73-78. (PRLG). Post Dermatol Alergol 2012; 2: 63-68. 39) SZEPIETOWSKI JC, R EICH A, W ISNIECKA B. Itching in pa - 23) HANIFIL JM, R AJKA G. Diagnostic features of atopic tients suffering from psoriasis. Acta Dermatoven - dermatitis. Acta Dermatol Venereol 1980; 92: 44-47. erol Croat 2002; 10: 221-226. 24) SILNY W, C ZARNECKA -O PERACZ M, S ILNY P. The new 40) REICH A, O RDA A, W I NIECKA B, S ZEPIETOWSKI J. Plasma scoring system for evaluation of skin inflamma - neuropeptides and perception of pruritus in psori - tion. Entent and severity in patients with atopic asis. Acta Dermatol Venerol 2007; 87: 299-304. dermatitis. Acta Dermatovenerol Croat 2005; 13: 41) NAKAMURA M. T OYODA M, M OROHASHI M. Prurito - 219-224. genic mediators in psoriasis vulgaris: compera - 25) HANIFIN JM, T HURSTON M, O MOTO M, C HERILL R, tive evaluation of itch-associated cutaneous TOFTE SJ, G RAEBER J. The eczema area and severity factors. Br J Dermatol 2003; 149: 718-730. index (EASI): assessment of reliability in atopic 42) KIMMEL M, A LSCHER DM, D UNST R, B RAUN N, M ACHLEI - dermatitis. EASI Evaluator Group. Exp Dermatol DT C, K IEFER T, S TÜLTEN C, VAN DER KUIP H, P AULI -M AG - 2001; 10: 11-18. NUS C, R AUB U, K UHLMANN U, M ETTANG T. The role of 26) EUROPEAN TASK FORCE ON ATOPIC DERMATITIS . Severity micro-inflammation in the pathogenesis of scoring of atopic dermatitis: the SCORAD index. uraemic pruritus in haemodialysis patients. Dermatology 1993; 186: 23-31. Nephrol Dial Transplant 2006; 21: 749-755. 27) POLA SKA A, D A CZAK -P AZDROWSKA A, S ILNY W, J EN - 43) DUQUE MI, T HEVARAJAH S, C HAN YH, T UTTLE AB, EROWICZ D, O SMOLA -M ANKOWSKA A, O LEK -H RAB K. FREEDMAN BI, Y OSIPOVITCH G. is as -

3640 Pruritus in selected dermatoses

sociated with higher kt/V and serum calcium con - 47) STANDER S, P OGATZKI -Z AHN E, R AAP U. What is bra - centration. Clin Nephrol 2006; 6: 184-191. chioradial pruritus? Acta Dermato Venereol 2009; 89: 689. 44) KREMER AE, B EURES U, O UDE -E LFERINK RP, P USL T. Pathogenesis and treatment of pruritus in 48) SZEPIETOWSKI J, R EICH A. Itching patomechanism, cholestasis. Drugs 2008; 68: 2163-2182. clinic and treatment. Termedia, 2010. 45) WINOGA M, K ŁOS M, M INISZEWSKA J, Z ALEWSKA -J ANOWS - 49) KRETZMER GE, G ELDOF M, K RETZMER G. Idiopathic KA A. Health-related quality of life in dermatologi - pruritus in psychiatric inpatients: an explorative cal and allergo-dermatological patients. Post study. Gen Hosp Psychiatry 2008; 30: 344-348. Derm Alergol 2012; 2: 69-73. 50) CHOSIDOW O. Scabies and pediculosis. Lancet 46) EDMONDS EV, L IAZ ST, F RANCIS N. Nodular prurigo re - 2000; 355: 819-826 sponding to topical tacrolimus. Br J Dermatol 51) CHOSIDOW O. Clinical practices scabies. N Engl J 2004; 150: 1216-1217. Med 2006; 345: 1718-1727.

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