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Systemic Sclerosis (Scleroderma)

Systemic Sclerosis (Scleroderma)

Systemic sclerosis ()

Author: Doctor Panayiotis G. Vlachoyiannopoulos1 Creation Date: November 2001

Scientific Editor: Professor Haralampos M. Moutsopoulos

1Medical School, Department of Pathophysiology, National University of Athens, 75 Mikras Asias street, 11527 Athens, Greece. [email protected]

Abstract Keywords Disease name and synonyms Excluded diseases Diagnostic criteria Definition Differential diagnosis Prevalence Clinical description Clinical findings Management Etiology Diagnostic methods Genetic counseling Antenatal diagnosis Unresolved questions References

Abstract Systemic sclerosis (SSc) is an autoimmune systemic disease characterized by small vessel involvement that leads to tissue ischemia and stimulation resulting in accumulation of () in the skin and internal organs. The peak incidence of the disease is found between the third and fifth decade of life. The male to female ratio is 5:1. Annual incidence is 14.1 cases per million. Prevalence ranges from 19 to 75 cases per million. No well-defined treatment has been found. However several types of treatment exist and can be classified as such A) systemic and B) - specific therapies. Systemic therapies are subdivided into vascular therapies, immunomodulating therapies and antifibrotic therapies. Organ-specific therapies are subdivided into of pulmonary interstitial fibrosis, therapy of , therapy of SSc renal crisis. Most of the above-mentioned therapies have been tested in open clinical trials. Systemic sclerosis is more common in coal and gold miners and miners exposed to vinyl-chloride, epoxyresins and aromatic hydrocarbons. However, these factors do not explain the spontaneously developed disease. Recently, CD34 stem cells of child origin were detected in women with SSc more commonly than in normal women. Furthermore, the SSc women display histocompatibility in most of the HLA loci with their children.

Keywords , fibrosing alveolitis, pulmonary hypertension, renal crisis, / transplantation therapy.

Disease name and synonyms Excluded diseases Systemic sclerosis (SSc), Scleroderma, The clinical manifestations of the disease are Progressive systemic sclerosis. vascular and skin changes. Vascular changes include Raynaud's phenomenon, digital

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-SSc.pdf 1

ischemia, ulcers and gangrene. Raynaud's mainly against cell nuclear enzymes, like DNA phenomenon is the episodic, reversible, topoisomerase -1 (anti -Topo I) and RNA sequential expression of pallor, cyanosis, polymerases, as well as centromeric , redness of the digits, ears or nose, due to (anticentromere antibodies, ACA). vasospasm/dilatation repeated attacks, in response to cold exposure or to emotion. Skin Differential diagnosis changes include puffy or tight and atrophic skin. As shown in Table 2, differential diagnosis is Relying on the vascular changes in scleroderma, based on the exclusion of diseases showing the following diseases should be then excluded: vascular, skin and visceral changes similar to primary Raynaud's phenomenon, systemic SSc [2,3]. Physical trauma, chemical exposure, erythematosus (SLE), drugs and other autoimmune diseases are / (DM/PM), accompanied by Raynaud's phenomenon and Sjögren's syndrome (SS), polyarteritis nodosa should be excluded by history, physical and (PN), . Relying on the skin laboratory evaluation. Several forms of localized changes in scleroderma, the following diseases scleroderma (i.e without affecting internal should be then excluded: localized scleroderma, organs), constitute a single circumscribed or undifferentiated connective tissue disease linear area of tight skin without signs of visceral (UCTD), SLE, DM/PM, overlap syndromes of involvement, Raynaud's phenomenon or ANAs. SSc with other autoimmune diseases like SLE, Diseases resembling the early phase of SS, DM/PM, or rheumatoid (RA); chronic scleroderma or overlapping with it should be graft-versus-host disease (GVHD); POEMS recognized on the basis of additional clinical (polyneuropathy, organomegaly, signs, the type of organ involvement, the endocrinopathy, monoclonal gammopathy, skin profile and biopsy findings. Renal changes); eosinophilic fascitis, biopsy, in particular, allows the distinction syndrome and metabolic - genetic between SSc and SLE, , diseases as presented in "differential diagnosis". cryoglobulinemia, and SS. The analysis of skin/subcutaneous tissue/fascia and muscle Diagnostic criteria biopsies helps to distinguish between SSc and In order to include patients into specific clinical DM/PM or diffuse fasciitis with eoshinophilia or trials or cohort studies, a person will be classified eosinophilia - myalgia syndrome. Scleroderma- as having SSc if one major, two or more minor like changes in the skin or in the lung in a patient criteria are present (see Table 1). [1] who underwent bone marrow transplantation are indicative of GVHD. Pulmonary fibrosis in Table 1: Criteria for the classification of scleroderma is associated with antibodies to systemic sclerosis Topo -I while idiopathic pulmonary fibrosis is not. A. Major criteria Furthermore, idiopathic pulmonary fibrosis has a Proximal scleroderma: symmetric thickening, tightening and rapidly progressive course. Blood glucose level induration of the skin of the fingers and the skin proximal to allows the exclusion of diabetes mellitus which is the metacarpophalangeal or metatarsophalangeal . The changes may affect the entire extremities, face, neck associated with scleroderma, sclerosis and and trunk. arthropathy. Serum electrophoresis with B. Minor criteria or without immunofixation can rule out 1. Sclerodactyly: the above-mentioned skin changes are paraproteinemias, like amyloidosis and POEMS. limited to the fingers. Amyloidosis is diagnosed histologically after 2. Digital pitting scars or loss of substance from the finger pad. Depressed areas at tips of fingers or loss of digital pad staining procesure with Congo red, birefringence tissue as a result of ischemia. characteristic is seen under polarizing 3. Basilar pulmonary fibrosis: bilateral reticular pattern of microscopy. Amyloidosis diagnosis biopsy can linear or lineonodular densities most pronounced in basilar be made on the following biopsies: gingiva, bone portions of the on standard chest roentgenogram, not attributable to primary lung disease. marrow, rectum, subcutaneous , and liver [2,3]. Definition SSc is a multisystemic, affecting small , microvessels and resulting in vascular obliteration, collagen accumulation and scarring (fibrosis) of skin and internal organs. This leads to hidebound skin and damage of , lungs, heart and kidneys. The serological specifity of the disease is the presence of antinuclear antibodies (ANAs) which are directed

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-SSc.pdf 2

Table 2: Differential diagnosis of systemic Clinical description sclerosis Clinically, the condition may be divided into Based on the vascular changes different subtypes [4]. • Diffuse cutaneous SSc (dcSSc) • Primary Raynaud's phenomenon The onset of symptoms is more abrupt. • Physical trauma (e.g. jackhammer operator) Raynaud's phenomenon is common but may • Chemical exposure (vinyl - chrolide, follow other features. The earliest coal/silica/gold/heavy metal miners, organic solvents) phenomenon is thickening on the trunk and • Drugs/toxins [toxic oil syndrome (ingestion of acral skin edema, presence of tendon adulterated, rapessed oil, Madrid, 1982), arsenic, friction rubs, pulmonary fibrosis, oliguric , cisplatin, ergotamine, beta-blockers (high renal crisis, diffuse gastrointestinal disease dose), 5-hydroxytryptophan, carbidopa] and or cardiac arrhythmia. • Other autoimmune connective tissue diseases (SLE, DM/PM, vasculitis, RA, SS, cryoglobulinemia) Antibodies to Topo-I or to RNA-polymerases I, II, III are present while ACA [4] are absent. • Limited Cutaneous SSc (lcSSc) Based on skin changes Raynaud's phenomenon occurring many years before the onset of skin changes. Skin • Localized scleroderma (morphea, linear scleroderma induration is limited to hands, face and feet; with atrophy of the affected extremity, "en coup de sable" with and without facial hemiatrophy). pulmonary hypertension, skin calcification • Scleroderma - like skin changes and occuring at a later date, o UCTD ACA are highly prevalent. This subset also o with eosinophilia includes a subgroup of patients previously o Eosinophilia myalgia syndrome classified as patients with CREST syndrome o Overlap syndromes (scleroderma, with SLE, or (calcinosis, Raynaud's phenomenon, SS, or DM/PM, or RA) esophageal hypomotility, sclerodactyly, o Chronic form of GVHD telangiectasia) [4]. • Metabolic - genetic disorders o Scleredema/Scleremexedema • Systemic sclerosis sine scleroderma o Insulin-dependent diabetes mellitus (scleredema, (ssSc) digital sclerosis) It is characterized by visceral disease o POEMS and other paraproteinemias without cutaneous involvement [4]. o Amyloidosis Clinical findings Based on visceral involvement Raynaud's phenomenon affects almost all the patients. The skin is initially swollen and • Aging and diabetes mellitus (esophageal hypomotility) becomes tight later on. Musculoskeletal • Idiopathic pulmonary fibrosis involvement is evident in 1/3 to 1/2 of the • Idiopathic (primary) pulmonary hypertension patients and is expressed as symmetric • Sarcoidosis polyarthritis resembling rheumatoid arthritis and • Amyloidosis muscle weakness. Carpal tunnel syndrome and • Infiltrative cardiomyopathies tendon friction rubs are due to the fibrotic thickening of the tendon sheaths. Muscle • Malignant hypertension weakness occurs just in 5% of the lcSSc patients • Other autoimmune connective tissue diseases but in 50% of the dcSSc patients. It is due to: a) diffuse atrophy with and morning stiffness in the majority of patients, Prevalence b) scleroderma non associated with The disease has a worldwide distribution and elevated muscle enzymes affects all races. It is more frequent and severe c) full-blown (6%) with elevated muscle in young black women. The peak incidence is enzymes indistinguishable from PM/DM (overlap found between the third and the fifth decade of of SSc with PM/DM) [2,3,5]. life. The female to male ratio is approximately Gastrointestinal manifestations are common in 5:1. Annual incidence is 14.1 cases per million. scleroderma (> 50% of patients); they include Prevalence ranges from 19 to 75 cases per gastroesophageal reflux due to hypomotility of 100,000 people. For reasons that have not been the distal part of the , , well understood, the highest prevalence has odynophagia, burning pain in the epigastric and been reported in the Choctaw Native Americans retrosternal regions and regurgitation of gastric in Oklahoma (472/100,000 persons) [3]. contents, especially when the patient is lying flat or bending over [1-3,5]. Dysmotility of the may lead to abdominal pain and

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-SSc.pdf 3

and muscular atrophy of the large patients [1-3,5]. It affects mainly male patients bowel wall which may lead to wide-mouth with dcSSc who have antibodies to RNA diverticula. Pulmonary involvement occurs in polymerase III and who also suffer from cardiac 25% of the lcSSc and in more than 50% of the involvement (especially pericarditis) or take dcSSc patients. It has mainly three forms: prednisolone at levels of 25mg daily or higher. a) pulmonary interstitial fibrosis (PIF), Renal involvement takes the form of b) pulmonary hypertension and isolated scleroderma renal crisis, which is defined as reduction of of the lung follows: «a rise in diastolic blood pressure above [expressed as isolated impairement of carbon 110 mmHg and decreasing clearance during the monoxide transfer factor for whole lung (TLCO)]. final week of observation associated with Pulmonary alveolitis precedes PIF and can be or or retinal hemorrhages detected by high-resolution computed or microangiopathic hemolytic anemia or tomography (HRCT) of the lung as increased papilledema». Occasionally, renal crisis may lung density or patchy air-space opacification occur with normal blood pressure. Creatinine with reticular and nodular patterns (ground levels above 3mg/dL, during the episode, male glass). It can also seen by bronchoalveolar sex and older age at disease onset are lavage (BAL), which recovers increased associated with poor outcomes. Incidence and numbers of alveolar macrophages, neutrophils, poor outcome of renal crisis have been reduced eosinophils and CD8 positive T lymphocytes. after the introduction of treatment with PIF can be evident by chest X-ray or HRCT as angiotensin converting enzyme (ACE) inhibitors linear and reticular densities, leading to honey- [1-3]. combing appearance affecting prominently the lower two thirds of the lung (reticular pattern). Management PIF is associated with the dcSSc and anti-Topo-I It can be divided into two major parts: antibodies [5-7]. PH affects a small number of A) Systemic therapy, patients with lcSSc and ACA [5]. The most B) Organ-specific therapies. common symptom is exertional dyspnea and/or Systemic therapy can be divided into: vascular dry, non productive cough. On clinical therapy, immunomodulation and antifibrotic examination bilateral basilar rales may be therapy. present. In the case of PIF, spirometric Organ-specific therapies can be divided into the evaluation reveals decreased forced vital therapy of PIF; PH; peripheral vascular disease; capacities (FVC) and decreased total lung cardiac disease; renal crisis; gastrointestinal capacities (TLC), while in case of PH, only the involvement; skin involvement; musculoskeletal TLCO and the partial pressure of blood oxygen involvement [9]. are decreased. PH leads to right-sided heart failure, which has very poor prognosis. Clinically Systemic therapies evident cardiac involvement occurs in nearly 10% of the lcSSc patients and more than 20% of Vascular therapy the dcSSc patients, it is mainly due either to Smoking is completely prohibited. Drugs, such abnormalities of the intra-myocardial circulation as ß-blockers, which aggravate vasoconstriction (common) or to cardiomyopathy resulting from and Raynaud's phenomenon should be avoided. myocardial fibrosis (rare). It is manifested as: Calcium chanel blockers reduce cellular uptake a) conduction system abnormalities of calcium and therefore inhibit the contraction of (arrhythmias) [8], smooth muscle cells. at doses 10 mg b) left-sided heart failure, tid (ter in die) or in the tablets retard (40-60 mg c) pericardial effusion (usually silent). daily, divided into two doses) may reduce the However, ultrasound, electrophysiologic and frequency and the severity of the ischemic thallium scanning studies revealed that attacks. Frequent adverse affects include arrhythmia, or reperfusion abnormalities of the tachycardia, nausea, flushing, headaches, intra-myocardial circulation occur in respectively pretibial edema. The doses for the other drugs of 80% and 95% of patients [1-3,8]. the same category are diltiazem (60mg, tid), Hypoxia/reperfusion injury due to vasospasm of nicardipine (20mg, tid), amlodipine (5 mg per distal coronary vessels («cardiac» Raynaud's day) [10]. phenomenon), leads to the areas of contraction Prostaglandins and their analogues: band . Cardiac involvement has a poor prostaglandins are derived from arachidonic acid prognosis. For reasons not fully understood, (AA), which is released primarily from the pericarditis is a precipitating manifestation of phospholipids phosphatidylinositol and renal crisis. Renal involvement occurs in nearly phosphatidylcholine of the cell membrane, via 2% of the lcSSc and 6%-30% of the dcSSc the enzyme phospholipase A2. Once released,

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-SSc.pdf 4

AA can be converted into prostaglandins (PGs), morbidity such as cough, asthma, alveolitis and thromboxanes (TXs) or leukotrienes (LTs), interstitial fibrosis. depending on tissue type, enzyme Photophoresis is based on the inhibition of the concentrations and milieu. Biologically activated T cells by extracorporeal active PGs are PGD2, PGI2, (), photoactivated 8-methoxypsoralen. The patients PGE2, and PGF2a. They act via cell - surface receive the photosensitizing component 8- receptors and have important vasoactive methoxypsoralen and then undergo properties. Stimulation of PGE2, PGI2 and leukophoresis. Peripheral blood in an extra PGD2 receptors leads to smooth muscle cell corporeal flow system is exposed to ultraviolet A relaxation while stimulation of PGF2a, and TXA2 (UVA). T lymphocytes sensitized by 8- receptor activates smooth muscle cell methoxysporalen are sensitive to UVA and their contraction [10]. The short half-life of PGs made function. The results of various studies are their pharmacologic use difficult and led to the conflicting regarding the efficacy of discovery of prostaglandin analogues with longer photophoresis. Controlled studies are currently half-life. in progress [9]. Carboprostacyclin (), a synthetic Autologous stem cell transplantation aims at analogue of prostacyclin, has proven to be eliminating the active (including autoreactive) T useful in reducing severe ischemia which can lymphocytes and «reprogramming» the immune lead to digit amputation. The drug should be system by infusing their progenitor cells, known used on an inpatient basis by slow intravenous as CD34 positive stem cells. Improvement in infusion at doses ranging from 0.5 to 2 ng/kg/min skin score in 69% of the cases was reported. for 6 hours per day for 4 weeks [11]. In addition Lung function was not improved in a recent to vasodilatation, the drug inhibits study while 17% of the patients died from the aggregation, decreases blood viscosity and procedure [16]. This procedure still remains an alters neutrophil function [9]. For the experimental therapy. management of Raynaud's phenomenon [12], oral iloprost shows the same efficacy than Antifibrotic therapy placebo. D-Penicillamine [17], interferons (α-and - ß) [9], Antagonists of angiotensin II receptor, type 1; recombinant human relaxin [18] have been Losartan compared with nifedipine in a tested in controlled trials which did not show any randomized, parallel group, controlled trial was benefit. shown to be effective as a short-term treatment of Raynaud's phenomenon [13]. Organ specific therapies

Immunomodulation Pulmonary Interstitial fibrosis (fibrosing alveolitis) Activation of the immune system plays a key-role Prednisolone, , either per os at disease onset and on the disease-related or in intraveinous (IV) pulses, azathioprine and organ damage. home oxygen have been used with limited Cyclosporine A suppresses cell-mediated success. Their efficacy has not been tested in immunity and collagen synthesis by activated controlled trials. Spirometry and PIF score on SSc derived fibroblasts. The major response HRCT are response parameters. parameter evaluated in open studies was the Cyclophosphamide either as monthly IV 2 severity and the extent of skin involvement, injections at a dose of 0.750 g to 1 g/m or as a known as «skin score» [14]. Hypertension, 50mg to 125 mg oral daily dose has shown hypertrichosis and deterioration of renal function some benefit in open studies [19]. Controlled are common side effects. Arteriolar hyalinization studies are in progress. Many experts add small and interstitial fibrosis have been reported in the doses of prednisolone, (20 mg daily or less) to kidney of patients treated with cyclosporine. In the above-mentioned regimen. addition, endothelial cell stimulation of Corticosteroids have been widely used for the production by cyclosporine was treatment of interstitial lung disease with described. Relying on these findings, this drug conflicting results [9]. should not be recommended for the treatment of Azathioprine at a daily dose of 2.4 mg/kg has SSc [9]. been used following a 3-month induction phase , 15mg per week, reduces the with cyclophosphamide, especially in females extent of skin involvement. However, its effect is who are at child bearing age [9]. not sufficient to consider the drug as significantly Therapy is required for PH, especially when effective for the treatment of dcSSc [15]. In pulmonary pressure is above 50 mmHg addition, methotrexate may induce pulmonary and TLCO < 70%. Evidence for long-term

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-SSc.pdf 5

efficacy for the regimens described below is Cardiac involvement lacking. It is treated on an empirical basis, depending Calcium chanel blockers and ACE inhibitors. upon its type. Short- and medium- term efficacy has been shown for nifedipine and captopril, as detected Etiology by a decrease in mean pulmonary vascular SSc is rather common in coal and gold miners resistance [9]. and in workers exposed to vinyl-chloride, Carboprostacyclin (Iloprost) has been used by epoxyresins and aromatic hydrocarbons. direct infusion into the , then by Individuals taking pentazocin, bleomycin and oral and inhaled delivery. One of the main products containing L-tryptophan develop SSc- problems is the need for sustained drug release like features [2,3,9]. However, all these factors for years and the decreasing of systemic do not explain the spontaneously developed vascular resistance which may precipitate a fall disease. The activation of the immune system is in cardiac output [9]. an outstanding disease feature. Prostacyclin (epoprostenol) in continuous, and perivascular lymphocytic (mainly CD4 intravenous infusion improves the exercise positive T lymphocytes) infiltrates indicate capacity of the patients after 12 weeks of activation of the immune system. The CD4 therapy compared to conventional therapy alone positive T cells can be activated by endothelial [20]. basement membrane components like laminine Warfarin increases survival in primary PH, but and type IV collagen. Consequently, these cells the drug has not been tested in PH secondary secrete an endothelial cytotoxic factor, named to SSc. granzyme, as well as tumor necrosis factor Oxygen was shown to reduce pulmonary (TNF) which activates endothelial cells and vascular resistance for a short period of time. transforming growth factor - β (TGF-β) which Single lung or heart/lung transplantation is still activates fibroblasts to express TGF- β and an experimental therapy, although there are platelet-derived growth factor (PDGF). PDGF encouraging results from a small number of activates fibroblasts to secrete increased transplanted patients [9]. amounts of collagen. The chronic form of GVHD (a T-cell dependent disease) shares clinical Renal disease features with SSc. This observation supported Management of renal disease requires a high the hypothesis that alloreactive T cells derived index of suspicion, especially the first 4 years [9]. from the child survive for a long time in the Doses of prednisolone above 20mg daily should mother's body and vice-versa. This phenomenon be avoided. Blood pressure should be controlled is called «». Chimeras may by ACE inhibitors. In case of renal crisis the survive longer if histocompatibility exists patient should be hospitalized and high doses of between mother and fetus [3,9]. Recently, CD34 captopril or endlapril should be prescribed with stem cells of child origin were detected in the aim to reduce both, systolic and diastolic women with SSc more commonly than in normal blood pressure. Short-term should women. Furthermore the SSc women display be considered if necessary. The degree of histocompatibility on most of the HLA loci with microangiopathic hemolytic anemia should be their children [3]. monitored carefully [9]. Diagnostic methods Gastrointestinal manifestations Only clinical examination allows the diagnosis of H2-blockers and proton pump inhibitors are scleroderma. important therapeutic agents to eliminate dysphagia, odynophagia and gastroesophageal Genetic counseling reflux symptoms. The hypomotility of the small Genetic counseling cannot be carried out. intestine responds to long-acting somatostatine analogue octreotide and also to metoclopramide. Antenatal diagnosis Therapeutic measures for malabsorption include Antenatal diagnosis cannot be carried out. antibiotics, nutritional supplements, and low-residue diets. Pseudo-obstruction of the Unresolved questions large bowel should be treated carefully, after Regarding etiology, pathogenesis and the hospitalizing the patient and giving fluids therapeutic potential of various regimens. intravenously [9]. References 1. Wiglew FM: Systemic sclerosis and related syndromes-clinical features, in: Primers on the

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001. http://www.orpha.net/data/patho/GB/uk-SSc.pdf 6

rheumatic diseases 11th Edition, Klippel JH (ed) comparison of two doses of intravenous iloprost Arthritis Foundation USA, 1997; 20: 267-272. in the treatment of Raynaud's phenomenon, 2. Le Roy EC: Systemic sclerosis (scleroderma), secondary to connective tissue diseases. Ann Cecil's Textbook of , Bennet JC, Plum F Rheum Dis 1991; 50: 800-804. (eds) 20th Edition, Philadelphia 1996; 241: 1483- 12. Wigley FM, Korn JH, Csuka ME, Medger 1488. TAJr, Rothfield NF, Ellman M et al: Oral iloprost 3. Gilliland BC: Systemic sclerosis treatment in patients with Raynaud's (scleroderma), Harrisson's Principles of internal phenomenon secondary to systemic sclerosis: a Medicine, Fauci AS, Braunwald E, Isselbacher multicenter, placebo-controlled, double-blind KJ, Wilson JD, Martin JB, Kasper DL, Hauser study. Arthritis Rheum 1998; 41: 670-677. SL, Longo DL (eds), 14th Edition, New York, 13. Dziadzio M, Denton CP, Smith R, Howell K, McGraw - Hill, 1998; 314: 1888-1890. Blann A, Bowers E et al: Losartan therapy for 4. Le Roy EC, Black C, Fleischmajer R, Raynaud's phenomenon and scleroderma: Jablonska S, Krieg T, Medger TAJ et al: clinical and biochemical findings in a fifteen Scleroderma (systemic sclerosis): classification, week, randomized, parallel-group, controlled subsets and pathogenesis. J Rheumatol 1988; trial. Arthritis Rheum 1999; 42: 2646-2655. 15: 202-205 14. Clements PJ, Lachenbruch PA, Sterz M et 5. Vlachoyiannopoulos PG, Dafni V, Pakas I, al:, Cyclosporine in systemic sclerosis. Arthritis Spyropoulou - Vlachou M, Stavropoulos - Giokas Rheum 1993; 36: 75 - 83. C, Moutsopoulos HM: Systemic scleroderma in 15. Pope JE, Bellamy N, Seibold JR, Baron M, Greece: low mortality and strong linkage with Ellman M, Carrete S et al: A randomized, HLA-DRB1*1104 allele. Ann Rheum Dis 2000; controlled trial of methotrexate versus placebo in 59: 359-367. early diffuse scleroderma. Arthritis Rheum 2001; 6. Manoussakis MN, Constantopoulos SH, 44: 1351-1358. Gharavi AE, Moutsopoulos HM: Pulmonary 16. Binks M, Passweg JR, Furst D, McSweeney involvement in systemic sclerosis. Association P, Sullivan K, Besenthal C et al: Phase I/II trial with anti-Scl70 antibody and digital pitting. Chest autologous stem cell transplantation in systemic 1987; 92: 509-513. sclerosis procedure related mortality and impact 7. Rizou C, Ioannidis JP, Panou-Pomonis E, on skin disease Ann Rheum Dis 2001; 60: 577- Sakarellos-Daitsiotis M, Sakarellos C, 584. Moutsopoulos HM, Vlachoyannopoulos PG: B 17. Clements PJ, Furst DE, Wong WK, Mayes cell epitope mapping of DNA-Topoisomerase I MD, White B, Wigley F et al: High-dose versus defines epitopes strongly associated with low-dose D-Penicillamine in early diffuse pulmonary fibrosis in systemic sclerosis Am J systemic sclerosis: analysis of a two-year Respir Cell Mol Biol 2000; 22: 344-351. double-blind, randomised, controlled trial. 8. Gottdiener JS, Moutsopoulos HM, Decker JL: Arthritis Rheum 1999; 42: 1194-1203. Echocardiographic identification of cardiac 18. Seibold JR, Koen JH, Simms R, Clements abnormalities in scleroderma and related PJ, Moreland MD et al: Recombinant human disorders. Am J Med 1979; 66: 391-398. relaxin in the treatment of scleroderma. A 9. Black CM, Denton CP: Therapy of systemic randomized, double-blind, placebo-controlled sclerosis in Therapy of systemic Rheumatic trial. Ann Intern Med 2000; 132: 871-879. Disorders, van de Pute LBA, Furst DE, Williams 19. Pakas I, Ioannidis JPA, Malagari K, Skopouli HJ, van Riel PLCM (eds) 1998, Marcel Dekker F, Moutsopoulos HM, Vlachogiannopoulos PG: Inc, New York USA, 1998; 26: 495-531. Cyclo-phosphamide with low-or -high-dose 10. Finch MB, Dawson J, Johnston GD: The prednizolon for systemic sclerosis lung disease. peripheral vascular effects of nifedipine in J Rheum 2001, in press. Raynaud's syndrome associated with 20. Badesch DB, Tapson VF, McCoon MD, scleroderma: a double blind cross-over study. Brundage BH, Rubin LJ, Wigley FM et al: Clin Rheumatol 1986; 5: 493-498. Continuous intravenous epoprostenol for 11. Torley HI, Madhok R, Capell HA et al: A pulmonary hypertension due to the scleroderma double-blind, randomised, multicentre spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132: 425-434.

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