ACE inhibitors in SSc patients display a risk factor for scleroderma renal crisis-a EUSTAR analysis.

OBJECTIVES: To investigate the effect of ACE inhibitors (ACEi) on the incidence of scleroderma renal crisis (SRC) when given prior to SRC in the prospectively collected cohort from the European Scleroderma Trial and Research Group (EUSTAR). METHODS: SSc patients without prior SRC and at least one follow-up visit were included and analyzed regarding SRC, arterial hypertension, and medication focusing on antihypertensive medication and glucocorticoids (GC). RESULTS: Out of 14,524 patients in the database, we identified 7648 patients with at least one follow-up. In 27,450 person-years (py), 102 patients developed SRC representing an incidence of 3.72 (3.06-4.51) per 1000 py. In a multivariable time-to-event analysis adjusted for age, sex, disease severity, and onset, 88 of 6521 patients developed SRC. The use of ACEi displayed an increased risk for the development of SRC with a hazard ratio (HR) of 2.55 (95% confidence interval (CI) 1.65-3.95). Adjusting for arterial hypertension resulted in a HR of 2.04 (95%CI 1.29-3.24). There was no evidence for an interaction of ACEi and arterial hypertension (HR 0.83, 95%CI 0.32-2.13, p = 0.69). Calcium channel blockers (CCB), angiotensin receptor blockers (ARB), endothelin receptor antagonists, and GC-mostly in daily dosages below 15 mg of prednisolone-did not influence the hazard for SRC. CONCLUSIONS: ACEi in SSc patients with concomitant arterial hypertension display an independent risk factor for the development of SRC but are still first choice in SRC treatment. ARBs might be a safe alternative, yet the overall safety of alternative antihypertensive drugs in SSc patients needs to be further studied.

There is a need for new systemic sclerosis subset criteria. A content analytic approach.

OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

Increased release of soluble CD163 by the peripheral blood mononuclear cells is associated with worse prognosis in patients with systemic sclerosis.

PURPOSE: CD163 is a scavenger receptor which is exclusively expressed on monocytes/macrophages and participates in modulation of inflammatory response. We aimed to evaluate ex vivo production of soluble CD163 (sCD163) by peripheral blood mononuclear cells (PBMC) from patients with systemic sclerosis (scleroderma, SSc). MATERIAL/METHODS: Concentration of sCD163 was measured by commercially available ELISA kit in the PBMC suparnates from 23 SSc patients and 16 age- and sex-matched healthy controls (HC). Eighteen SSc patients were subsequently followed for at least three years or until death whichever happened earlier. Disease progression was defined as death due to SSc-related organ complication, development of a new or progression of pre-existing SSc-related organ involvement. RESULTS: PBMC from SSc patients released significantly greater amounts of sCD163 as compared with HC (p<0.05). No significant associations between release of sCD163 by PBMC and baseline clinical or laboratory parameters of the disease could be found. However, concentration of sCD163 in cell culture supernates was significantly higher in 6 SSc patients who experienced subsequent progression of the disease as compared with 12 SSc patients with stable disease course over a 3-year follow-up period (p<0.05). CONCLUSIONS: We show, for the first time, that PBMC from SSc release significantly greater amounts of sCD163 than do PBMC from healthy subjects. Evaluation of sCD163 production by PBMC ex vivo may serve as a new biomarker of disease progression. Further studies are required to evaluate the role of sCD163 in the development of SSc.

Peripheral blood mononuclear cells from patients with systemic sclerosis spontaneously secrete increased amounts of vascular endothelial growth factor (VEGF) already in the early stage of the disease.

PURPOSE: To investigate the capacity of the peripheral blood mononuclear cells (PBMC) from patients with systemic sclerosis (SSc) to produce vascular endothelial growth factor (VEGF), and to identify clinical associations of altered production of VEGF by PBMC in SSc. In addition, correlation with another pro-angiogenic cytokine, TNF-related weak inducer of apoptosis (TWEAK), was evaluated. METHODS: PBMC were isolated from 25 patients with SSc and 17 healthy controls (HC). VEGF and TWEAK were measured in the supernatants of cultured PBMC using commercially available ELISA kits. RESULTS: PBMC from SSc patients spontaneously released significantly greater amounts of VEGF as compared with HC. Production of VEGF was comparable between patients with early SSc and those with longer disease duration, and in both SSc groups higher than in HC. Patients without active digital ulcers produced significantly greater amounts of VEGF as compared with HC, while there was no significant difference in the production of VEGF between SSc patients with active digital ulcers and HC. VEGF/TWEAK ratio was significantly higher in PBMC from SSc patients than in HC indicating that high production of VEGF is not paralleled by increased release of TWEAK in SSc. CONCLUSIONS: PBMC form SSc patients produce increased amounts of VEGF already in the early stage of disease. There is an imbalance in the profile of pro-angiogenic mediators produced by PBMC in SSc which might contribute to the pathogenesis of SSc. Further studies should address clinical significance of our findings.

Use of methotrexate in patients with scleroderma and mixed connective tissue disease.

Systemic sclerosis (scleroderma, SSc) and mixed connective tissue disease (MCTD) are chronic autoimmune diseases characterised by a broad spectrum of clinical manifestations including different forms of musculoskeletal involvement, skin and vascular changes, as well as internal organ complications. Clinical course and outcomes might vary from mild forms with good clinical prognosis to severe rapidly progressive life-threatening diseases. At present, immunosuppressive therapies are considered a cornerstone in the treatment of MCTD, and are frequently used in clinical practice in SSc despite limited evidence from clinical trials. The aim of the present review is to discuss available data concerning efficacy of methotrexate therapy in SSc and MCTD.

Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database.

OBJECTIVE: To determine the prevalence of and independent factors associated with joint involvement in a large population of patients with systemic sclerosis (SSc). METHODS: This study was cross-sectional, based on data collected on patients included in the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) registry. We queried this database to extract data regarding global evaluation of patients with SSc and the presence of any clinical articular involvement: synovitis (tender and swollen joints), tendon friction rubs (rubbing sensation detected as the tendon was moved), and joint contracture (stiffness of the joints that decreased their range of motion). Overall joint involvement was defined by the occurrence of synovitis and/or joint contracture and/or tendon friction rubs. RESULTS: We recruited 7286 patients with SSc; their mean age was 56 +/- 14 years, disease duration 10 +/- 9 years, and 4210 (58%) had a limited cutaneous disease subset. Frequencies of synovitis, tendon friction rubs, and joint contractures were 16%, 11%, and 31%, respectively. Synovitis, tendon friction rubs, and joint contracture were more prevalent in patients with the diffuse cutaneous subset and were associated together and with severe vascular, muscular, renal, and interstitial lung involvement. Moreover, synovitis had the highest strength of association with elevated acute-phase reactants taken as the dependent variable. CONCLUSION: Our results highlight the striking level of articular involvement in SSc, as evaluated by systematic examination in a large cohort of patients with SSc. Our data also show that synovitis, joint contracture, and tendon friction rubs are associated with a more severe disease and with systemic inflammation.

The challenge of early systemic sclerosis for the EULAR Scleroderma Trial and Research group (EUSTAR) community. It is time to cut the Gordian knot and develop a prevention or rescue strategy.

Early diagnosis of systemic sclerosis (SSc) may allow the start of treatment that could slow disease progression. For this reason early diagnosis of the disease is of pivotal importance. However, the lack of diagnostic criteria and valid predictors significantly limit patient evaluation and the use of potentially effective drugs in the earliest phase of SSc. Early SSc may be suspected on the basis of Raynaud's phenomenon, puffy fingers, autoantibodies and SSc capillaroscopic pattern. In practice, the aim is to have criteria for the diagnosis of very early SSc. The criteria that are proposed are obviously provisional and need to be validated: (a) initially through a Delphi technique; (b) thereafter perhaps using already available datasets; but (c) of critical importance, through prospective studies. Only after prospective studies can these potential criteria be considered validated. The consensus on criteria for the classification of very early SSc might be part of the evolving EULAR/ACR project of reclassification of SSc.

EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR).

PURPOSE: The optimal treatment of systemic sclerosis (SSc) is a challenge because the pathogenesis of SSc is unclear and it is an uncommon and clinically heterogeneous disease affecting multiple organ systems. The aim of the European League Against Rheumatism (EULAR) Scleroderma Trials and Research group (EUSTAR) was to develop evidence-based, consensus-derived recommendations for the treatment of SSc. METHODS: To obtain and maintain a high level of intrinsic quality and comparability of this approach, EULAR standard operating procedures were followed. The task force comprised 18 SSc experts from Europe, the USA and Japan, two SSc patients and three fellows for literature research. The preliminary set of research questions concerning SSc treatment was provided by 74 EUSTAR centres. RESULTS: Based on discussion of the clinical research evidence from published literature, and combining this with current expert opinion and clinical experience, 14 recommendations for the treatment of SSc were formulated. The final set includes the following recommendations: three on SSc-related digital vasculopathy (Raynaud's phenomenon and ulcers); four on SSc-related pulmonary arterial hypertension; three on SSc-related gastrointestinal involvement; two on scleroderma renal crisis; one on SSc-related interstitial lung disease and one on skin involvement. Experts also formulated several questions for a future research agenda. CONCLUSIONS: Evidence-based, consensus-derived recommendations are useful for rheumatologists to help guide treatment for patients with SSc. These recommendations may also help to define directions for future clinical research in SSc.

European League Against Rheumatism (EULAR) Scleroderma Trial and Research group (EUSTAR) recommendations for the treatment of systemic sclerosis: methods of elaboration and results of systematic literature research.

OBJECTIVE: To describe methods and procedures used for the development of the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trial and Research group (EUSTAR) recommendations for the treatment of systemic sclerosis. In particular, the results of a web-based Delphi exercise aimed at selection of research questions and evidence from systematic literature research, as parts of the development of these recommendations, are presented in detail. METHODS: In agreement with the EULAR standard operating procedures a Task Force was created that consisted of the EUSTAR board members, 10 systemic sclerosis (SSc) experts invited from outside the EUSTAR board and representing Europe, the USA and Japan, a clinical epidemiologist, 2 patients with SSc and 3 fellows for literature research. All EUSTAR centres were invited to contribute to the development of recommendations through submission and preliminary selection of the research questions. The systematic literature research was performed using the Pubmed, Medline, EMBASE and Cochrane databases. Retrieved trials were evaluated according to the Jadad classification, and the level of evidence was graded from 1 to 4. Outcome data for efficacy and adverse events were abstracted and effect size, number needed to treat (NNT) and number needed to harm (NNH) were calculated when appropriate. RESULTS: In all, 65 EUSTAR Centres provided 304 research questions concerning SSc treatment. These questions were aggregated, subdivided into 19 treatment categories and then subjected to preliminary selection by a web-based Delphi technique. The final set of 26 research questions was created by the Expert Committee based on the results of the Delphi exercise and the expert's experience. CONCLUSIONS: This paper is a comprehensive summary of the methods we used to build recommendations for the drug treatment of systemic sclerosis, combining an evidence based approach and expert opinion.

Geographical variation of disease manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research (EUSTAR) group database.

BACKGROUND: Systemic sclerosis (SSc) is a vasculopathy with increased tissue deposition of collagen. The aetiology is unknown. Genetic and environmental susceptibility factors have been implicated. It is unknown whether disease presentation varies within Europe. AIMS AND METHODS: The baseline data of all SSc patients entered in the EULAR Scleroderma Trials and Research (EUSTAR) database up to April 2007 were analysed for geographical differences with regard to organ involvement, and geographical clusters with regard to clinical subsets (diffuse vs limited SSc) and autoantibodies (anticentromere vs anti-Scl70). RESULTS: 3661 patients from 79 centres in 62 cities and 23 countries were analysed. There was no clear trend between geographical coordinates and SSc subsets, although there appeared to be an increased prevalence of Scl70 in the more eastern centres. There was no association between geographical longitude or latitude and the age at the onset of Raynaud's phenomenon or the onset of non-Raynaud's symptoms. There was also a trend for the more eastern centres to care for patients with a higher prevalence of more severe organ manifestations (pulmonary arterial hypertension, cardiac involvement). Between different centres within one city there was a large variability in the frequency of organ complications. CONCLUSION: This analysis suggests that eastern centres care for more severe SSc manifestations in Europe. Large differences in patient referral account for a large local variability of SSc presentations and preclude the identification of genetic or environmental factors.

Screening for PAH in patients with systemic sclerosis: focus on Doppler echocardiography.

It is well established that patients with CTDs such as SSc carry a considerable risk of developing pulmonary arterial hypertension (PAH). Such SSc-PAH patients have an even worse prognosis than patients with only one of these two conditions. In view of the high incidence and prevalence of PAH in SSc, and the available treatment options that improve quality of life, exercise capacity and possibly survival, systematic screening has been recommended. The present article reviews current recommendations from PAH guidelines, focusing on studies that used Doppler echocardiography for screening, and describes limitations associated with the procedure. Furthermore, characteristics and parameters used to identify patients at high risk of developing PAH are summarized.

Outcome measures in pulmonary arterial hypertension associated with systemic sclerosis.

SSc is complicated in approximately 10% of the patients by pulmonary arterial hypertension (PAH), a rare dyspnoea-fatigue syndrome caused by an increase in pulmonary vascular resistance. The prognosis of SSc-PAH is particularly poor, with estimated survival rates of approximately 50% at 2 yrs without pulmonary circulation-targeted therapies. Prostacyclins, endothelin receptor antagonists and phosphodiesterase-5 inhibitors have been shown to be efficacious in PAH, with persistent long-term benefit and approximate doubling of survival rate, and these encouraging results appear transposable to the SSc-PAH subcategory. However, PAH as well as SSc-PAH remain incurable, with insufficient functional improvement in many patients. More progress is needed, and this will require more effective drugs and adapted outcome measures.

Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database.

BACKGROUND: Systemic sclerosis (SSc) is a multisystem autoimmune disease, which is classified into a diffuse cutaneous (dcSSc) and a limited cutaneous (lcSSc) subset according to the skin involvement. In order to better understand the vascular, immunological and fibrotic processes of SSc and to guide its treatment, the EULAR Scleroderma Trials And Research (EUSTAR) group was formed in June 2004. AIMS AND METHODS: EUSTAR collects prospectively the Minimal Essential Data Set (MEDS) on all sequential patients fulfilling the American College of Rheumatology diagnostic criteria in participating centres. We aimed to characterise demographic, clinical and laboratory characteristics of disease presentation in SSc and analysed EUSTAR baseline visits. RESULTS: In April 2006, a total of 3656 patients (1349 with dcSSc and 2101 with lcSSc) were enrolled in 102 centres and 30 countries. 1330 individuals had autoantibodies against Scl70 and 1106 against anticentromere antibodies. 87% of patients were women. On multivariate analysis, scleroderma subsets (dcSSc vs lcSSc), antibody status and age at onset of Raynaud's phenomenon, but not gender, were found to be independently associated with the prevalence of organ manifestations. Autoantibody status in this analysis was more closely associated with clinical manifestations than were SSc subsets. CONCLUSION: dcSSc and lcSSc subsets are associated with particular organ manifestations, but in this analysis the clinical distinction seemed to be superseded by an antibody-based classification in predicting some scleroderma complications. The EUSTAR MEDS database facilitates the analysis of clinical patterns in SSc, and contributes to the standardised assessment and monitoring of SSc internationally.

Platelet activation in allergic asthma patients during allergen challenge with Dermatophagoides pteronyssinus.

BACKGROUND: Animal models of allergic asthma indicate that intravascular platelet activation is necessary for the development of allergen-induced chronic airway inflammation. OBJECTIVE: To evaluate whether the development of a late asthmatic response (LAR) in allergic asthma patients challenged with a relevant allergen is consequent to platelet activation. METHODS: Thirty-three house dust mite sensitive asthmatic patients were challenged intrabronchially with Dermatophagoides pteronyssinus (Dp) extract. Twelve non-atopic healthy subjects (HC) were used as controls. Platelet count and plasma levels of beta-thromboglobulin (beta-TG), platelet factor-4 (PF-4) and soluble P-selectin (sP-selectin) were assessed before the challenge (T(0)) and 30 min (T(EAR)), 6 h (T(LAR)) and 24 h (T(24)) after the challenge. RESULTS: Eleven patients responded to allergen challenge with an isolated early asthmatic response (single responders, SR). In 22 patients dual asthmatic response was demonstrated (dual responders, DR). At T(0) neither the platelet count nor the mean plasma level of beta-TG in DR or SR were different from HC, the mean plasma level of PF-4 in SR was significantly greater than in HC (P=0.01) or DR (P=0.001), the mean plasma level of sP-selectin was significantly greater in DR than in HC (0.0002) but not statistically different from SR (P=0.055). A significant decrease in the platelet count and increase in the plasma level of all the studied markers was seen at T(EAR), which was followed by a gradual return to the baseline values in the SR. Elevated plasma levels of platelet activation markers and decreased platelet count were seen in the DR even at T(24). Strong correlation was found between the increase in plasma concentration of beta-TG at T(EAR) and the maximum fall in forced expiratory volume in 1 s at T(LAR) (r=-0.57; P=0.0006). CONCLUSION: In allergic asthma patients development of prolonged airway inflammation after allergen challenge is associated with intravascular platelet activation.

Cyclophosphamide reduces neutrophilic alveolitis in patients with scleroderma lung disease: a retrospective analysis of serial bronchoalveolar lavage investigations.

OBJECTIVES: To determine whether cyclophosphamide is beneficial for patients with scleroderma lung disease (SLD). METHODS: The effect of 6 months' treatment with intravenous cyclophosphamide on the functional capacity of patients, lung function tests, high resolution computed tomography of the lungs, and cytology of bronchoalveolar lavage was evaluated in 21 patients with SLD. RESULTS: The treatment was well tolerated and all patients completed 6 months' treatment. Intravenous cyclophosphamide stabilised or improved the patients' functional status and lung function tests. The extent of the lungs affected remained unchanged, as assessed with HRCT of the lungs. Patients with SLD and neutrophilic alveolitis (NA) showed greater improvement than patients with normal levels of granulocytes in the bronchoalveolar lavage fluid (BALF). Significant reduction of neutrophils was also seen in the patients with SLD and NA, whereas no significant change was seen in the level of granulocytes in patients with SLD and an initially normal percentage of granulocytes. CONCLUSIONS: Previous reports that patients with SLD with increased levels of granulocytes in BALF are more likely to benefit from treatment with intravenous cyclophosphamide are confirmed. Additionally, clinical improvement in this group of patients is accompanied by a significant decrease in the percentage of granulocytes in BALF.

The prevalence and clinical significance of antiphospholipid antibodies in the patients with systemic sclerosis--preliminary report.

PURPOSE: The aim of our study was to evaluate the prevalence of anticardiolipin and anti-beta2-glikoprotein I (anti-beta2GPI) antibodies in patients with systemic sclerosis (SSc) and to correlate the presence of these antibodies with clinical and serological features of the disease. MATERIAL AND METHODS: 22 patients (21 women and 1 man) fulfilling the ACR classification criteria of SSc were included into the study. In all SSc patients a detailed clinical evaluation including skin and internal organ involvement was performed. Moreover, the measurements of antitopoisomerase I (anti-Scl-70) and anticentromere (ACA) antibodies were done in all patients studied. Anticardiolipin antibodies in IgM and IgG class and anti-beta2GPI antibodies in IgM, IgG and IgA class were evaluated using ELISA kits (Hycor Biomedical and DiaSorin). RESULTS: Anticardiolipin antibodies were found in 10/22 (45.5%) patients with SSc, in 6/12 (50%) with diffuse SSc and in 4/10 (40%) with the limited SSc. Anticardiolipin antibodies in the IgG class were observed in 4/22 (18.2%) patients, and in the IgM class in 9/22 (40.9%) subjects. Anti-beta2GPI antibodies were found in 9/22 patients (40.9%), of which 3/22 (13.6%) had antibodies in IgG class, 4/22 (18.2%) in IgM class and 3/22 (13.6%) in the IgA class. Anti-beta2GPI antibodies were found exclusively in the patients in whom the anticardiolipin antibodies were also present. An association between the presence of antiphospholipid antibodies and internal organ involvement (pulmonary fibrosis, pulmonary hypertension and the alterations of oesophageal function) was not significant. No significant correlation was found between the presence of anticardiolipin or anti-beta2GPI antibodies and the presence of anti-Scl-70 or ACA antibodies. CONCLUSIONS: The results of our study indicate that the prevalence of anticardiolipin antibodies and anti-beta2GPI antibodies is relatively high in patients with SSc. A more detailed assessment of the relationship between the presence of antiphospholipid antibodies and the clinical and serological features of SSc requires further studies on the larger group of patients and a several years of follow-up.

The importance of early diagnosis of systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease which etiology and pathogenesis is still unknown. The vascular and immunological changes are the major elements of the SSc. The preliminary ACR criteria of SSc are the oldest criteria for rheumatic diseases and are not sensitive enough in respect to early SSc. Many authors suggest that these criteria should be extended by capillaroscopic and immunological changes. In 2001 LeRoy and Medsger proposed new criteria for SSc that could help to identify SSc patients with early stage of the disease. This will give the opportunity for the early and proper treatment.

Concentration and microheterogeneity of acute-phase glycoproteins in patients with systemic lupus erythematosus.

PURPOSE: To determinate glycosylation of selected acute-phase glycoproteins (AGP, ACT, CP) and serum concentration of this proteins in Systemic Lupus Erythematosus (SLE) patients. PATIENTS AND METHODS: The study was carried out on 35 patients with active SLE and 15 healthy volunteers. The immunological measurements were performed at first day of hospitalisation, before receiving treatment. The concentration of CRP, AGP, ACT and CP were evaluated by electroimmunoassay using anti-AGP, anti-ACT, anti-CP antibodies. CRP levels were determined by radial immunodiffusion with anti-CRP antibodies. The microheterogeneity of the acute phase proteins was assessed by agarose affinity electrophoresis using Con A as a ligand, as was described by Bøg-Hansen. RESULTS: Between SLE patients and control group statistically significant differences (p < 0.01) were observed in serum concentration of all investigated parameters. There were no significant differences in serum acute-phase proteins levels with regards to patient's age, sex and disease activity. The reactivity coefficients: AGP-RC, ACT-RC, CP-RC in SLE patients were similar to the healthy group. The precipitate curves were similar in both groups. The main difference was in the area of the precipitant, which was bigger in the SLE patients. CONCLUSIONS: Configuration of analysis serum concentration and heterogeneity of acute-phase proteins is one of important diagnostic tests in SLE.

Endothelin receptor antagonism--new perspectives in the treatment of systemic sclerosis.

Endothelin-1 is a naturally occurring polypeptide which possesses a broad range of activities including vasospastic, proinflammatory and profibrotic properties. Systemic sclerosis is a multisystem connective tissue disease characterized by vascular damage, inflammatory infiltrates and progressive fibrosis of the skin and internal organs. The results of the recent studies indicate that endothelin-1 may be a key element of the pathogenesis of systemic sclerosis. Accordingly, new class of drugs, endothelin receptor antagonists have been introduced for treatment of patients with systemic sclerosis. This article reviews the role of endothelin-1 in the pathogenesis of systemic sclerosis and the implications of endothelin receptor antagonism in the treatment of systemic sclerosis.