Article Text

Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis
  1. Mike Becker1,
  2. Nicole Graf2,
  3. Rafael Sauter3,
  4. Yannick Allanore4,
  5. John Curram5,
  6. Christopher P Denton6,
  7. Dinesh Khanna7,
  8. Marco Matucci-Cerinic8,
  9. Janethe de Oliveira Pena9,
  10. Janet E Pope10,
  11. Oliver Distler1
  12. EUSTAR Collaborators
    1. 1 Department of Rheumatology and the Centre of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland
    2. 2 Graf Biostatistics, Winterthur, Switzerland
    3. 3 Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
    4. 4 Rheumatology A Department, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, Paris, France
    5. 5 Data Science and Analytics, Bayer plc, Reading, UK
    6. 6 UCL Division of Medicine, Royal Free Campus, London, UK
    7. 7 Division of Rheumatology, Department of Internal Medicine, University of Michigan Scleroderma Program, University of Michigan, Ann Arbor, Michigan, USA
    8. 8 Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
    9. 9 Bayer US LLC, Whippany, New Jersey, USA
    10. 10 Department of Medicine, Division of Rheumatology, University of Western Ontario, St. Joseph's Health Care, London, Ontario, Canada
    1. Correspondence to Dr Oliver Distler, Department of Rheumatology, University Hospital Zurich, Zurich 8091, Switzerland; oliver.distler{at}


    Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database.

    Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression.

    Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model.

    Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.

    • systemic sclerosis
    • disease worsening
    • mortality
    • predictive factors

    This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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    • Handling editor Prof Josef S Smolen

    • 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 Ljubljana, 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, Lasi, Romania; Piercarlo Sarzi Puttini, University Hospital Luigi Sacco, Milan, Italy.

    • Contributors Study conception and design, acquisition of data, analysis and interpretation of data and drafting and revising the article: OD and MB; analysis and interpretation of data: OD, MB, RS and NG. All authors have critically reviewed and approved the final submitted version to be published.

    • Funding This study was supported by a grant from Bayer AG. Bayer employees are coauthors of this paper and supported the study design and interpretation of the data, but otherwise Bayer had no influence on the study.

    • Competing interests MOB declares no conflict of interest. OD has had consultancy relationships with Actelion, Bayer, Biogen Idec, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Sinoxa and UCB in the area of potential treatments of scleroderma and its complications. OD has received research funding from Actelion, Bayer, Boehringer Ingelheim, Mitsubishi Tanabe Pharma and Roche in the area of potential treatments of scleroderma and its complications. OD has a patent for mir-29 licensed 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. NTG has nothing to disclose.

    • Patient consent for publication Not required.

    • 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.

    • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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