Article Text

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
  1. Wanlong Wu1,
  2. Suzana Jordan1,
  3. Nicole Graf2,
  4. Janethe de Oliveira Pena3,
  5. John Curram4,
  6. Yannick Allanore5,
  7. Marco Matucci-Cerinic6,
  8. Janet E Pope7,
  9. Christopher P Denton8,
  10. Dinesh Khanna9,
  11. Oliver Distler1
  12. EUSTAR Collaborators
    1. 1 Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
    2. 2 Graf Biostatistics, Winterthur, Switzerland
    3. 3 Clinical Development Pulmonology, Bayer US LLC, Whippany, New Jersey, USA
    4. 4 Data Science and Analytics, Bayer plc, Reading, UK
    5. 5 Rheumatology A Department, Paris Descartes University, INSERM U1016, Sorbonne, Paris Cité, Cochin Hospital, Paris, France
    6. 6 Division of Rheumatology, University of Florence, Florence, Italy
    7. 7 Department of Medicine, Division of Rheumatology, University of Western Ontario, St. Joseph’s Health Care, London, Western Ontario, Canada
    8. 8 Department of Rheumatology, Royal Free Hospital, University College London, London, UK
    9. 9 Scleroderma Program, Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
    1. Correspondence to Dr Oliver Distler, Department of Rheumatology, University Hospital Zurich, Zurich 8091, Switzerland; oliver.distler{at}


    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.

    • diffuse cutaneous systemic sclerosis
    • progressive skin fibrosis
    • visceral organ progression
    • lung function decline
    • all-cause death

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    • Handling editor Josef S Smolen

    • Presented at Shown as a poster on the ACR/ARHP Annual Meeting in San Diego 2017 (Abstract No. 732).

    • Collaborators EUSTAR Collaborators (numerical order of centres): Marco Matucci-Cerinic, Serena Guiducci, University of Florence, Italy; Ulrich Walker, Veronika Jaeger, Bettina Bannert, University Hospital Basel, Switzerland; Giovanni Lapadula, School of Medicine University of Bari, Italy; Radim Becvarare, 1st Medical School, Charles University, Prague, Czech Republic; Maurizio Cutolo, University of Genova, Italy; Gabriele Valentini, Policlinico U.O. Reumatologia, Naples, Italy; Elise Siegert, Charité University Hospital, Berlin, Germany; Simona Rednic, University of Medicine & Pharmacy, 'Iuliu Hatieganu' Cluj, Cluj-Napoca, Romania; Yannick Allanore, University Cochin Hospital, Paris, France; C Montecucco, IRCCS Policlinico S Matteo, Pavia, Italy; Patricia E Carreira, Hospital 12 de Octubre, Madrid, Spain; Srdan Novak, KBC Rijeka, Croatia; László Czirják, Cecilia Varju, University of Pécs, Hungary; Carlo Chizzolini, Daniela Allai, University Hospital Geneva, Switzerland; Eugene J Kucharz, Medical University of Silesia, Katowice, Poland; Franco Cozzi, University of Padova, Italy; Blaz Rozman, University Medical Center Ljublijana, Slovenia; Carmel Mallia, 'Stella Maris', Balzan, Malta; Armando Gabrielli, Istituto di Clinica Medica Generale, Ematologia ed Immunologia Clinica, Università Politecnica delle Marche Polo Didattico, University of Ancona, Italy; Dominique Farge Bancel, Hôpital Saint-Louis, Paris, France; Paolo Airò, Spedali Civili di Brescia Servizio di Reumatologia Allergologia e Immunologia Clinica, Brescia, Italy; Roger Hesselstrand, Lund University Hospital, Sweden; Duska Martinovic, Clinical Hospital of Split, Croatia; Alexandra Balbir-Gurman, Yolanda Braun-Moscovici, B. Shine Rheumatology Institute, Rambam Health Care Campus, Haifa, Israel; Nicolas Hunzelmann, Universitätshautklinik Köln, Germany; Raffaele Pellerito, Ospedale Mauriziano, Torino, Italy; Paola Caramaschi, Università degli Studi di Verona, Italy; Carol Black, Royal Free and University College London Medical School, London, UK; Nemanja Damjanov, Institute of Rheumatology Belgrade, Serbia and Montenegro; Jörg Henes, Medizinische Universitätsklinik Abt. II, Tübingen, Germany; Vera Ortiz Santamaria, Rheumatology Granollers General Hospital, Barcelona, Spain; Stefan Heitmann, Marienhospital Stuttgart, Germany; Matthias Seidel, Medizinische Universitäts-Poliklinik, Bonn, Germany; José Antonio Pereira Da Silva, da Universidade, Coimbra, Portugal; Bojana Stamenkovic, Institute for Prevention, Treatment and Rehabilitation Rheumatic and Cardiovascular Disease Niska Banja, Serbia and Montenegro; Carlo Francesco Selmi, University of Milan, Italy; Mohammed Tikly, Chris Hani Baragwanath Hospital and University of the Witwatersrand, Johannesburg, South Africa; Lev N. Denisov, VA Nasonova Institute of Rheumatology, Moscow, Russia; Ulf Müller-Ladner, Kerckhoff Clinic Bad Nauheim, Germany; Merete Engelhart, University Hospital of Gentofte, Hellerup, Denmark; Eric Hachulla, Hôpital Claude Huriez, Lille, France; Valeria Riccieri, 'Sapienza' Università di Roma, Italy; Ruxandra Maria Ionescu, St. Maria Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Carina Mihai, Ion Cantacuzino Clinical Hospital, Bucharest, Romania; Cord Sunderkötter, Annegret Kuhn, University of Münster, Germany; Georg Schett, Jörg Distler, Universitätsklinikum Erlangen, Germany; Pierluigi Meroni, Francesca Ingegnoli, Istituto Gaetano Pini, University of Milano, Italy; Luc Mouthon, Hôpital Cochin, Paris, France; Filip De Keyser, Vanessa Smith, University of Ghent, Belgium; Francesco Paolo Cantatore, Ada Corrado, U.O. Reumatologia-Università degli Studi di Foggia, Ospedale 'Col. D’Avanzo', Foggia, Italy; Susanne Ullman, Line Iversen, University Hospital of Copenhagen, Denmark; Maria Rosa Pozzi, Ospedale San Gerardo, Monza, Italy; Kilian Eyerich, Rüdiger Hein, Elisabeth Knott, TU Munich, Germany; Piotr Wiland, Magdalena Szmyrka-Kaczmarek, Renata Sokolik, Ewa Morgiel, Marta Madej, Wroclaw University of Medicine, Poland; Juan Jose Alegre-Sancho, Hospital Universitario Dr Peset, Valencia, Spain; Brigitte Krummel-Lorenz, Petra Saar, Endokrinologikum Frankfurt, Germany; Martin Aringer, Claudia Günther, Erler Anne, University Medical Center, Carl Gustav Carus, Technical University of Dresden, Germany; Rene Westhovens, Ellen De Langhe, Jan Lenaerts, University Hospital Leuven, Skeletal Biology and Engineering Research Center, Leuven, Belgium; Branimir Anic, Marko Baresic, Miroslav Mayer, University of Zagreb, School of Medicine, University Hospital Center Zagreb, Croatia; Maria Üprus, Kati Otsa, East-Tallin Central Hospital, Tallin, Estonia; Sule Yavuz, University of Marmara, Altunizade-Istanbul, Turkey; Sebastião Cezar Radominski, Carolina de Souza Müller, Valderílio Feijó Azevedo, Hospital de Clinicas da Universidade Federal do Parana, Curitiba, Brazil; Sergei Popa, Republican Clinical Hospital, Chisinau, Republic of Moldova; Thierry Zenone, Unit of Internal Medicine, Valence, France; Simon Stebbings, John Highton, Dunedin School of Medicine, New Zealand; Alessandro Mathieu, Alessandra Vacca, II Chair of Rheumatology, University of Cagliari-Policlinico Universitario, Cagliari, Italy; Lisa Stamp, Peter Chapman, John O’Donnell, University of Otago, Christchurch, New Zealand; Kamal Solanki, Alan Doube, Waikato University Hospital, Hamilton, New Zealand; Douglas Veale, Marie O’Rourke, St. Vincent’s University Hospital, Dublin, Ireland; Esthela Loyo, Hospital Regional Universitario Jose Ma Cabral y Baez, Clinica Corominas, Santiago, Dominican Republic; Mengtao Li, Peking Union Medical College Hospital (West Campus), Beijing, China; Edoardo Rosato, Antonio Amoroso, Antonietta Gigante, Sapienza Università di Roma, Università La Sapienza, Policlinico Umberto I, Roma, Italy; Fahrettin Oksel, Figen Yargucu, Ege University, Bornova, Izmir, Turkey; Cristina-Mihaela Tanaseanu, Monica Popescu, Alina Dumitrascu, Isabela Tiglea, Clinical Emergency Hospital St. Pantelimon, Bucharest, Romania; Rosario Foti, Elisa Visalli, Alessia Benenati, Giorgio Amato, A.O.U. Policlinico Vittorio Emanuele La U.O. Di Reumatologia, A.O.U. Policlinico V.E. Catania Centro di Riferimento Regionale Malattie Rare Reumatologiche, Catania, Italy; Codrina Ancuta, Rodica Chirieac, GR.T. Popa Center for Biomedical Research, European Center for Translational Research, University of Medicine and Pharmacy, Rehabilitation Hospital, Iasi, Romania; Peter Villiger, Sabine Adler, Diana Dan, University of Bern, Switzerland; Paloma García de la Peña Lefebvre, Silvia Rodriguez Rubio, Marta Valero Exposito, Hospital Universitario Sanchinarro, Madrid, Spain; Jean Sibilia, Emmanuel Chatelus, Jacques Eric Gottenberg, Hélène Chifflot, University Hospital of Strasbourg, Hôpital de Hautepierre, Strasbourg, France; Ira Litinsky, Tel Aviv Sourasky Medical Center, Israel; Francesco Del Galdo, University of Leeds, Chapel Allerton Hospital, Leeds, UK; Algirdas Venalis, State Research Institute for Innovative Medicine, Vilnius University, Lithuania; Lesley Ann Saketkoo, Joseph A Lasky, Tulane/University Medical Center Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, Louisiana, USA; Eduardo Kerzberg, Fabiana Montoya, Vanesa Cosentino, Osteoarticular Diseases and Osteoporosis Centre, Pharmacology and Clinical Pharmacological Research Centre, School of Medicine, University of Buenos Aires, Ramos Mejía Hospital, Buenos Aires, Argentina; Massimiliano Limonta, Antonio Luca Brucato, Elide Lupi, USSD Reumatologia, Ospedali Riuniti di Bergamo, Italy; François Spertini, Camillo Ribi, Guillaume Buss, Department of Rheumatology, Clinical Immunology and Allergy, Lausanne, Switzerland; Thierry Martin, Aurélien Guffroy, Vincent Poindron, Nouvel Hôpital Civil, Strasbourg, France; Lori Chung, Stanford University School of Medicine, California, USA; Tim Schmeiser, Krankenhaus St. Josef, Wuppertal-Elberfeld, Germany; Pawel Zebryk, Poznan University of Medical Sciences, Poland; Nuno Riso, Unidade de Doencas Autoimunes—Hospital Curry Cabral, Centro Hospitalar Lisboa Central, Lisbon, Portugal; Gabriela Riemekasten, Universitätsklinik Lübeck, Germany; Elena Rezus, University of Medicine and Pharmacy 'GR.T.Popa' Iasi, Rehabilitation Hospital, Iasi, Romania; Piercarlo Sarzi Puttini, University Hospital Luigi Sacco, Milan, Italy.

    • Contributors Study conception and design: OD, WW, SJ, YA, DK, CPD, MM-C, JEP, JdOP, JC. Acquisition of data: OD, WW, YA, CPD, MM-C, EUSTAR co-authors. Analysis and interpretation of data: NG, OD, WW, SJ. Drafting the article: WW, OD, SJ. Revising the article: NG, YA, DK, CPD, MM-C, JEP, JdOP, JC.

    • Funding This study was supported by a grant from Bayer AG.

    • Disclaimer Bayer did not have any influence on the interpretation of the data.

    • 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.

    • Ethics approval All contributing EUSTAR centres have obtained approval from their respective local ethics committee for including patients’ data in the EUSTAR database and written informed consent was obtained in those centres, where required by the ethics committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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