Background Preclinical studies showed that endothelin signalling is a major factor in perpetuating fibrotic responses in systemic sclerosis (SSc). Positive effects of endothelin-1 receptor antagonists (ETRA) have been demonstrated in pulmonary arterial hypertension, in the prevention of digital ulcers, but not in SSc-associated interstitial lung disease. One small, open-labeled, uncontrolled trial demonstrated that bosentan might improve skin fibrosis. Given the promising preclinical, but inconsistent clinical data, studies with a larger number of patients are needed.
Objectives To evaluate the effect of ETRA on skin fibrosis using data derived from the EUSTAR cohort.
Methods Patients with SSc from the EUSTAR cohort who fulfilled ACR classification criteria and had at least 3 follow up visits (pre-study visit without ETRA treatment, baseline and follow-up visit with ETRA treatment) were included. Data were obtained prospectively with post hoc retrospective analysis. The control group consisted of SSc patients with the same inclusion criteria, but without ETRA treatment. The change of the modified Rodnan skin Score (mRSS) between baseline and follow up was the primary endpoint of this study. Nonparametric data are shown as median and interquartile range and were analyzed by Mann-Whitney or the Wilcoxon paired test.
Results Data on 84 ETRA treated (79 bosentan, 4 sitaxsentan, 1 ambrisentan) and 962 control patients were collected from the EUSTAR database. Baseline characteristics were as follows: ETRA group: 77 female/7 male, 42 diffuse/42 limited, age 62 (47-71) years, disease duration 9.7 (4.2-11.5) years, median follow-up 27 (24-32) months, 31 received DMARDs. Control group: 859 female/103 male, 349 diffuse/613 limited, age 59 (47-67) years, disease duration 7.1 (3.4-12.7) years, median follow up 28 (25-33) months, 75 received DMARDs. Change of the mRSS between baseline and follow-up did not show any significant difference between the ETRA group and the control group (0 (0-2) vs. 0 (-1-3); p=0.6). To reflect clinical practice and inclusion criteria for randomized controlled trials for skin fibrosis, further analyses for patients with diffuse SSc and patients with extended disease (mRSS>16) were performed. Similarly, patients with diffuse SSc did not show differences in the change of mRSS between the ETRA group and the control group (n=42; 0 (0-3.2) vs. n=349; 1 (-1-4), p=0.7). Patients with extended disease showed a reduction of the mRSS at follow up versus baseline in both the ETRA (n=22; 23.0 (18.0-27.0) vs. 20.5 (17.7-24.2); p=0.02) and the control group (n=124; vs. 21.5 (18.0-25.0) vs. 18.0 (14.0-22.0); p<0.0001). Again, there was no difference between the ETRA group and the control group (-2.5 (-7.2-0) vs. -4 (-8-0); p=0.4).
Conclusions This is the first controlled study on the effects of ETRA on skin fibrosis in SSc. Our observational cohort real-life study with a large sample size demonstrates no positive effect of ETRA on skin fibrosis in the scleroderma EUSTAR cohort.
Disclosure of Interest S. Jordan: None Declared, J. Distler: None Declared, B. Maurer: None Declared, U. Walker: None Declared, D. Huscher: None Declared, G. Riemenkasten: None Declared, O. Distler Grant/Research support from: Actelion, Pfizer, Ergonex and Sanofi, Consultant for: Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis,United BioSource Corporation, Medac, 4D Science, Boehringer-Ingelheim, Active Biotech and Roche, Speakers Bureau: Actelion, Pfizer, Encysive and Ergonex
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