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. 2019 May;78(5):648-656.
doi: 10.1136/annrheumdis-2018-213455. Epub 2019 Mar 9.

Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort

Wanlong Wu  1 , Suzana Jordan  1 , Nicole Graf  2 , Janethe de Oliveira Pena  3 , John Curram  4 , Yannick Allanore  5 , Marco Matucci-Cerinic  6 , Janet E Pope  7 , Christopher P Denton  8 , Dinesh Khanna  9 , Oliver Distler  10 ; EUSTAR Collaborators
Collaborators, Affiliations

Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort

Wanlong Wu et al. Ann Rheum Dis. 2019 May.

Abstract

Objectives: To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc).

Methods: We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression.

Results: Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up 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. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year 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).

Conclusions: Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice.

Keywords: all-cause death; diffuse cutaneous systemic sclerosis; lung function decline; progressive skin fibrosis; visceral organ progression.

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Conflict of interest statement

Competing interests: OD has obtained research support from Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion and Pfizer. He is a scientific consultant for 4D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, ChemoAb, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, Medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm and Sinoxa, and has a patent licensed on mir-29 for the treatment of systemic sclerosis. DK has consultancy relationships and/or has received grant/research support from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech/Roche, NIH, Pfizer, Sanofi-Aventis Pharmaceuticals, Actelion Pharmaceuticals US, Chemomab, Corbus, Covis, Cytori, Eicos, EMD Serono, Gilead, GlaxoSmithKline and UCB Pharma. He is a shareholder of Eicos. CPD has consultancy relationships with and/or has received speakers’ bureau fees from Actelion Pharmaceuticals US, Bayer AG, GlaxoSmithKline, CSL Behring, Merck-Serono, Roche Pharmaceuticals, Genentech and Biogen IDEC Inc., Inventiva, Sanofi-Aventis Pharmaceuticals and Boehringer Ingelheim. JEP has consultancy relationships with and/or has received grant/research support from Actelion, Bayer AG, Bristol-Myers Squibb, Merck, Pfizer Inc. and Roche. MM-C has consultancy relationships and/or has received grant/research support from Pfizer, Bristol-Myers Squibb, Actelion, UCB Pharma, Bayer, ChemomAb, Genentech/Roche, Inventiva and Lilly. YA has consultancy relationships with and/or has received 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 Pharmaceuticals and Servier. JdOP and JC are employees of Bayer. WW, SJ and NG have nothing to disclose.

Figures

Figure 1
Figure 1
Kaplan-Meier survival plots for (A) time to FVC decline ≥10%, (B) time to FVC-DCLO composite endpoint, (C) time to all-cause death and (D) time to overall disease progression during follow-up depending on the presence or absence of skin progression within 1 year. DLCO, diffusing capacity for carbon monoxide; FVC, forced vital capacity.
Figure 2
Figure 2
Kaplan-Meier survival plots for FVC decline ≥10% during follow-up depending on the presence or absence of skin progression within 1 year in subgroups of patients with (A) baseline mRSS ≤22/51 units, (B) baseline mRSS >22/51 units, (C) disease duration ≤15 months and (D) disease duration >15 months. FVC, forced vital capacity; mRSS, modified Rodnan skin score.
Figure 3
Figure 3
Kaplan-Meier survival plots for all-cause death during follow-up depending on the presence or absence of skin progression within 1 year in subgroups of patients with (A) baseline mRSS ≤22/51 units, (B) baseline mRSS >22/51 units, (C) disease duration ≤15 months and (D) disease duration >15 months. mRSS, modified Rodnan skin score.
Figure 4
Figure 4
Kaplan-Meier survival plots for overall disease progression during follow-up depending on the presence or absence of skin progression within 1 year in subgroups of patients with (A) baseline mRSS ≤22/51 units, (B) baseline mRSS >22/51 units, (C) disease duration ≤15 months and (D) disease duration >15 months. mRSS, modified Rodnan skin score.
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