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Ann Rheum Dis. 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.

Collaborators (153)

Matucci-Cerinic M, Guiducci S, Walker U, Jaeger V, Bannert B, Lapadula G, Becvarare R, Cutolo M, Valentini G, Siegert E, Rednic S, Allanore Y, Montecucco C, Carreira PE, Novak S, Czirják L, Varju C, Chizzolini C, Allai D, Kucharz EJ, Cozzi F, Rozman B, Mallia C, Gabrielli A, Bancel DF, Airò P, Hesselstrand R, Martinovic D, Balbir-Gurman A, Braun-Moscovici Y, Hunzelmann N, Pellerito R, Mauriziano O, Caramaschi P, Black C, Damjanov N, Henes J, Santamaria VO, Heitmann S, Seidel M, Pereira Da Silva JA, Stamenkovic B, Selmi CF, Tikly M, Denisov LN, Müller-Ladner U, Engelhart M, Hachulla E, Riccieri V, Ionescu RM, Mihai C, Sunderkötter C, Kuhn A, Schett G, Distler J, Meroni P, Ingegnoli F, Mouthon L, Keyser F, Smith V, Cantatore FP, Corrado A, Ullman S, Iversen L, Pozzi MR, Eyerich K, Hein R, Knott E, Wiland P, Szmyrka-Kaczmarek M, Sokolik R, Morgiel E, Madej M, Alegre-Sancho JJ, Krummel-Lorenz B, Saar P, Aringer M, Günther C, Anne E, Westhovens R, Langhe E, Lenaerts J, Anic B, Baresic M, Mayer M, Üprus M, Otsa K, Radominski SC, Müller CS, Azevedo VF, Popa S, Stebbings S, Highton J, Mathieu A, Vacca A, Stamp L, Chapman P, O'Donnell J, Solanki K, Doube A, Veale D, O'Rourke M, Loyo E, Li M, Rosato E, Amoroso A, Gigante A, Oksel F, Yargucu F, Tanaseanu CM, Popescu M, Dumitrascu A, Tiglea I, Foti R, Visalli E, Benenati A, Amato G, Ancuta C, Chirieac R, Villiger P, Adler S, Dan D, de la Peña Lefebvre PG, Rubio SR, Exposito MV, Sibilia J, Chatelus E, Gottenberg JE, Chifflot H, Litinsky I, Venalis A, Saketkoo LA, Lasky JA, Kerzberg E, Montoya F, Cosentino V, Limonta M, Brucato AL, Lupi E, Spertini F, Ribi C, Buss G, Martin T, Guffroy A, Poindron V, Chung L, Schmeiser T, Zebryk P, Riso N, Riemekasten G, Rezus E, Puttini PS, Yavuz S11.

Author information

1
Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
2
Graf Biostatistics, Winterthur, Switzerland.
3
Clinical Development Pulmonology, Bayer US LLC, Whippany, New Jersey, USA.
4
Data Science and Analytics, Bayer plc, Reading, UK.
5
Rheumatology A Department, Paris Descartes University, INSERM U1016, Sorbonne, Paris Cité, Cochin Hospital, Paris, France.
6
Division of Rheumatology, University of Florence, Florence, Italy.
7
Department of Medicine, Division of Rheumatology, University of Western Ontario, St. Joseph's Health Care, London, Western Ontario, Canada.
8
Department of Rheumatology, Royal Free Hospital, University College London, London, UK.
9
Scleroderma Program, Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA.
10
Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland oliver.distler@usz.ch.
11
University of Marmara, Altunizade-Istanbul, Turkey

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

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.

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