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SAT0513 Progressive skin fibrosis is associated with a decline in lung function and poorer survival in patients with diffuse cutaneous systemic sclerosis: a european scleroderma trials and research (EUSTAR) analysis

Background Short disease duration and low baseline modified Rodnan skin score (mRSS) have been identified as independent predictors of progressive skin fibrosis in patients with diffuse cutaneous systemic sclerosis (dcSSc) using the EUSTAR database.1 However, whether worsening of skin fibrosis is an appropriate surrogate marker for new-onset or deterioration of visceral organ disease and overall survival in dcSSc has been questioned. Objectives To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality in dcSSc patients during follow-up. Methods We performed a survival analysis of the EUSTAR database including patients with dcSSc, fulfilling the ACR 1980 criteria, with baseline mRSS ≥7 in 2009 or later, valid mRSS at 12±3 months after baseline and ≥1 available annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 units and ≥25% from baseline to 12±3 months later. Disease outcome was defined as occurrence of one of the following new events during follow-up based on expert group consensus: relative decrease in forced vital capacity (FVC) ≥10%; left ventricular ejection fraction (LVEF) <45% or relative decrease in LVEF >10% for patients with baseline LVEF <45%; pulmonary hypertension globally judged on echocardiography by the treating physician; renal crisis; all-cause death. The association between skin progression and disease outcomes over follow-up was evaluated by Kaplan–Meier analysis, log-rank test and multivariate Cox regression. Multiple imputation was used to handle missing values. Results Among 1021 eligible dcSSc patients, 78 (7.6%) had progressive skin fibrosis within 1 year (defined as progressors). The median follow-up period was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors (figure 1). These significant associations between skin progression and FVC decline and all-cause death were also observed in the subgroup of patients with either baseline mRSS ≤22/51 or disease duration ≤15 months. Multivariate Cox regression confirmed that skin progression was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09).Abstract SAT0513 – Figure 1 Kaplan-Meier survival plots for A) pulmonary progression and B) all-cause death during follow-up for skin progressors and non-progressors Conclusions In patients with dcSSc, progressive skin fibrosis within 1 year is associated with a decline in lung function and worse survival over follow-up. This evidence-based finding is helpful for cohort enrichment in clinical trials for both skin and lung fibrosis, and for risk stratification in clinical practice. Reference [1] Maurer B, Graf N, Michel BA, et al. Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database. Ann Rheum Dis2015;74(6):1124–31. Acknowledgements The authors thank Gill Hill for editing the abstract. Disclosure of Interest W. Wu: None declared, S. Jordan: None declared, N. Graf: None declared, J. Pena Employee of: Bayer HealthCare Pharaceuticals Inc, J. Curram Shareholder of: Bayer AG, Employee of: Bayer Plc, Y. Allanore Grant/research support from: Actelion Pharmaceuticals US, Bayer AG, Bristol-Myers Squibb, Inventiva, Medac, Pfizer Inc, Roche Pharmaceuticals, Genentech and Biogen IDEC Inc. Sanofi-Aventis Pharmaceutical, Servier, Consultant for: Actelion Pharmaceuticals US, Bayer AG, Bristol-Myers Squibb, Inventiva, Medac, Pfizer Inc, Roche Pharmaceuticals, Genentech and Biogen IDEC Inc., Sanofi-Aventis Pharmaceutical, M. Matucci-Cerinic Grant/research support from: Pfizer, Bristol-Myers Squibb, Actelion, UCB Pharma, Consultant for: Actelion, Bayer, ChemomAb, Genentech/Roche, Inventiva, Lilly, Pfizer, J. Pope Grant/research support from: Actelion, Bayer AG, Bristol-Myers Squibb, Merck, Pfizer Inc, Roche, Consultant for: Actelion, Bayer AG, Bristol-Myers Squibb, Merck, Pfizer Inc, Roche, C. Denton Consultant for: Actelion Pharmaceuticals US, Bayer AG, GlaxoSmithKline, CSL Behring, Merck-Serono, Roche Pharmaceuticals, Genentech and Biogen IDEC Inc., Inventiva, Sanofi-Aventis Pharmaceutical, Boehringer Ingelheim, Speakers bureau: Actelion Pharmaceuticals US, Bayer AG, GlaxoSmithKline, CSL Behring, Merck-Serono, Roche Pharmaceuticals, Genentech and Biogen IDEC Inc., Inventiva, Sanofi-Aventis Pharmaceutical, Boehringer Ingelheim, D. Khanna Shareholder of: Eicos, Grant/research support from: Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech/Roche, NIH, Pfizer, Sanofi-Aventis Pharmaceuticals, Consultant for: Actelion Pharmaceuticals US, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Chemomab, Corbus, Covis, Cytori, Eicos, EMD Serono, Genentech/Roche, Pfizer, Gilead, GlaxoSmithKline, Sanofi-Aventis Pharmaceuticals, and UCB Pharma, O. Distler Grant/research support from: Actelion, Bayer, Biogen Idec, Boehringer Ingelheim, ChemomAb, EspeRare Foundation, Genentech/Roche, GlaxoSmithKline, Inventiva, Lilly, Medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Sinoxa, and UCB in the area of potential treatments of scleroderma and its complications. Patent mir-29 for the treatment of systemic sclerosis licensed, Consultant for: Actelion, Bayer, Biogen Idec, Boehringer Ingelheim, ChemomAb, EspeRare Foundation, Genentech/Roche, GlaxoSmithKline, Inventiva, Lilly, Medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Sinoxa, and UCB in the area of potential treatments of scleroderma and its complications.