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Update of EULAR recommendations for the treatment of systemic sclerosis
  1. Otylia Kowal-Bielecka1,
  2. Jaap Fransen2,
  3. Jerome Avouac3,
  4. Mike Becker4,5,
  5. Agnieszka Kulak1,
  6. Yannick Allanore3,
  7. Oliver Distler5,
  8. Philip Clements6,
  9. Maurizio Cutolo7,
  10. Laszlo Czirjak8,
  11. Nemanja Damjanov9,
  12. Francesco del Galdo10,
  13. Christopher P Denton11,
  14. Jörg H W Distler12,
  15. Ivan Foeldvari13,
  16. Kim Figelstone14,
  17. Marc Frerix15,
  18. Daniel E Furst6,
  19. Serena Guiducci16,
  20. Nicolas Hunzelmann17,
  21. Dinesh Khanna18,
  22. Marco Matucci-Cerinic16,
  23. Ariane L Herrick19,20,
  24. Frank van den Hoogen2,
  25. Jacob M van Laar21,
  26. Gabriela Riemekasten22,
  27. Richard Silver23,
  28. Vanessa Smith24,
  29. Alberto Sulli7,
  30. Ingo Tarner15,
  31. Alan Tyndall25,
  32. Joep Welling26,
  33. Frederic Wigley27,
  34. Gabriele Valentini28,
  35. Ulrich A Walker25,
  36. Francesco Zulian29,
  37. Ulf Müller-Ladner15
  38. EUSTAR Coauthors
    1. 1 Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
    2. 2 Radboud University Medical Center, Nijmegen, The Netherlands
    3. 3 Rheumatology A Department, Cochin Hospital, Paris Descartes University, Paris, France
    4. 4 University Hospital Charité, Berlin, Germany
    5. 5 University Hospital Zurich, Zurich, Switzerland
    6. 6 University of California at Los Angeles, Los Angeles, California, USA
    7. 7 Research Laboratories and Clinical Division of Rheumatology, Department of Internal Medicine, University of Genova, IRCCS AOU San Martino, Genova, Italy
    8. 8 Department of Rheumatology and Immunology, Medical Center, University of Pecs, Pecs, Hungary
    9. 9 University of Belgrade, Belgrade, Serbia
    10. 10 University of Leeds, Leeds, UK
    11. 11 University College London, London, UK
    12. 12 University of Erlangen-Nuremberg, Erlangen, Germany
    13. 13 Hamburg Centre for Pediatric and Adolescence Rheumatology, Hamburg, Germany
    14. 14 FESCA, London, UK
    15. 15 University of Giessen, Bad Nauheim, Germany
    16. 16 University of Florence, Florence, Italy
    17. 17 University of Cologne, Cologne, Germany
    18. 18 University of Michigan School of Medicine, Ann Arbor, Michigan, USA
    19. 19 University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
    20. 20 NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester, UK
    21. 21 Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
    22. 22 University of Lübeck, Lübeck, Germany
    23. 23 Medical University of South Carolina, Charleston, South Carolina, USA
    24. 24 Ghent University Hospital, Ghent University, Ghent, Belgium
    25. 25 Basel University, Basel, Switzerland
    26. 26 FESCA Patient Research Partner, The Netherlands
    27. 27 Johns Hopkins University, Baltimore, Maryland, USA
    28. 28 Second University of Naples, Naples, Italy
    29. 29 University of Padua, Padua, Italy
    1. Correspondence to Professor Otylia Kowal-Bielecka, Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Ul. M. Sklodowskiej-Curie 24A, Bialystok 15-276, Poland; otylia.bielecka{at}


    The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

    • Systemic Sclerosis
    • Treatment
    • Cyclophosphamide
    • Methotrexate

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    • Handling editor Tore K Kvien

    • Acknowledgements The project was funded by a research grant of EULAR to the EUSTAR SSc recommendation group.

    • Collaborators EUSTAR Collaborators (numerical order of centres): Thomas Daikeler, Rheumatology, University Hospital Basel, Switzerland; Elisabetta Lanciano, Rheumatology Unit-DiMIMP School of Medicine University of Bari, Bari, Italy; Radim Bečvář, Michal Tomcik, Institute of Rheumatology, 1st Medical School, Charles University, Praha, Czech Republic; Ewa Gińdzieńska-Sieśkiewicz, Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland; Giovanna Cuomo; Michele Iudici, Dipartimento Medicina Clinica e Sperimentale ‘F-Magrassi’ II Policlinico U.O. Reumatologia, Napoli, Italy; Simona Rednic, Clinica Reumatologie, University of Medicine & Pharmacy ‘Iuliu Hatieganu’ Cluj, Cluj-Napoca, Romania; Panayiotis G. Vlachoyiannopoulos, Department of Pathopysiology Medical School, National University of Athens, Athens, Greece; Roberto Caporali, Unita’ Operativa e Cattedra di Reumatologia, IRCCS Policlinico S Matteo, Pavia, Italy; Patricia E. Carreira, Servicio de Reumatología, Hospital 12 de Octubre, Madrid, Spain; Srdan Novak, Department of Rheumatology and Clinical Immunology, Internal Medicine, KBC Rijeka, Rijeka, Croatia; Tünde Minier, Department of Rheumatology and Immunology, Medical Center, University of Pécs, Pécs, Hungary; Eugene J. Kucharz, Department of Internal Medicine and Rheumatology, Medical University of Silesia, Katowice, Poland; Armando Gabrielli, Gianluca Moroncini, Dipartimento di Scienze Cliniche e Molecolari, Clinica Medica, Università Politecnica delle Marche, Ancona, Italy; Paolo Airo’, U.O. Reumatologia ed Immunologia Clinica, Spedali Civili, Brescia, Italy; Roger Hesselstrand, Department of Rheumatology, Lund University Hospital, Lund, Sweden; Duska Martinovic, Mislav Radić, Daniela Marasovic-Krstulovic, Department of Internal Medicine, Clinical Hospital of Split, Split, Croatia; Yolanda Braun-Moscovici, Alexandra Balbir-Gurman, B Shine Department of Rheumatology, Rambam Health Care Campus, Haifa, Israel; Andrea Lo Monaco, Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Ferrara, Ferrara, Italy; Paola Caramaschi, Rheumatology Unit, AOUI, Verona, Italy; Jadranka Morović-Vergles, Melanie I. Čulo, Division of Clinical Immunology and Rheumatology Department of Internal Medicine, School of Medicine University of Zagreb, Dubrava University Hospital, Zagreb, Croatia; Jörg Henes, Medizinische Universitätsklinik, Abt. II (Onkologie, Hämatologie, Rheumatologie, Immunologie, Pulmonologie), Tübingen, Germany; Vera Ortiz Santamaria, Rheumatology Granollers General Hospital, Barcelona, Spain; Stefan Heitmann, Department of Rheumatology, Marienhospital Stuttgart, Germany; Dorota Krasowska, Małgorzata Michalska-Jakubus, Department of Dermatology, Venereology and Pediatric Dermatology, Medical University of Lublin, Lublin, Poland; Matthias F. Seidel, Medizinische Klinik III, Oncology, Hematology and Rheumatology, Bonn, Germany; Paul Hasler, Klinik für Rheumatologie, Kantonsspital Aarau, Aarau, Switzerland; José A. Pereira Da Silva, Maria J. Salvador, Rheumatology Department, Hospitais da Universidade Coimbra, Coimbra, Portugal; Bojana Stamenkovic, Aleksandra Stankovic, Institute for treatment and rehabilitation Niska Banja, Medical School, University of Nis, Serbia; Mohammed Tikly, Rheumatology Unit, Department of Medicine Chris Hani Baragwanath, Hospital and University of the Witwatersrand, Johannesburg, South Africa; Lidia P. Ananieva, VA Nasonova Institute of Rheumatology, Moscow, Russian Federation; Lorenzo Beretta, Scleroderma Unit, Referral Center for Systemic Autoimmune Disease, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy; Gabriella Szucs, Szilvia Szamosi, Division of Rheumatology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary; Carlos de la Puente Bujidos, Servicio de Reumatología, Hospital Ramon Y Cajal, Madrid, Spain; Øyvind Midtvedt, Anna-Maria Hoffmann-Vold, Department of Rheumatology, Rikshospitalet University Hospital, Oslo, Norway; David Launay, University Lille, Inserm, CHU Lille, U995, Centre national de référence maladies systémiques et auto-immunes rares (sclérodermie systémique), Lille, France; Eric Hachulla, Department of Internal Medicine, Hôpital Claude Huriez, Lille, France; Valeria Riccieri, Dipartimento di Medicina Interna e Specialita’ Mediche, Universita’ Sapienza, Roma, Italy; Ruxandra Ionescu, Daniela Opris, Department of Rheumatology-St. Maria Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Carina Mihai, Department of Internal Medicine and Rheumatology Clinic, Ion Cantacuzino Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Ilka Herrgott, Department of Dermatology University of Münster, Münster, Germany; Christian Beyer, Department of Internal Medicine 3, University Hospital Erlangen, Erlangen, Germany; Francesca Ingegnoli, Division of Rheumatology, Istituto Gaetano Pini, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Carlos Alberto von Mühlen, Rheuma Clinic, Porto Alegre, Brazil; Juan José Alegre-Sancho, Emma Beltrán-Catalán, Hospital Universitario Dr Peset, Valencia, Spain; Martin Aringer, Julia Fantana, Nicolai Leuchten, Anne-Kathrin Tausche, Division of Rheumatology, Department of Medicine III, University Medical Center Carl Gustav Carus TU Dresden, Dresden, Germany; Ellen De Langhe, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration KU Leuven; Rheumatology, University Hospitals Leuven, Belgium; Marie Vanthuyne, Cliniques Universitaires Saint-Luc, Rheumatology Department, Université Catholique de Louvain, Brussels, Belgium; Branimir Anic, Marko Barešić, Miroslav Mayer, University Hospital Centre Zagreb Division of Clinical Immunology and Rheumatology Department of Medicine, Zagreb, Croatia; Maria Üprus, Kati Otsa, East-Tallin Central Hospital, Department of Rheumatology, Tallin, Estonia; Sule Yavuz, University of Marmara, Department of Rheumatology, Istanbul Bilim University, Altunizade-Istanbul, Turkey; Brigitte Granel, Service de Médecine Interne, Hôpital Nord de Marseille, Marseille, France; Valderilio F. Azevedo, Carolina Muller, Hospital de Clínicas da Universidade Federal do Paraná, Curitiba—Paraná, Brasil; Sergio A Jimenez, Scleroderma Center, Thomas Jefferson University, Philadelphia, USA; Serghei Popa, Svetlana Agachi, Department of Rheumatology, State University of Medicine and Pharmacy ‘Nicolae Testemitanu’, Chisinau, Republic of Moldova; Thierry Zenone, Department of Medicine, Unit of Internal Medicine, Valence, France; Simon Stebbings, Joanne Dockerty, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Alessandra Vacca, II Chair of Rheumatology, University of Cagliari-Policlinico Universitario, Monserrato, Italy; Joanna Schollum, Waikato University Hospital Rheumatology Unit, Hamilton, New Zealand; Douglas J. Veale, Department of Rheumatology, St. Vincent’s University Hospital and University College Dublin, Ireland; Sergio Toloza, Hospital San Juan Batista, Catamarca, Argentina; Dong Xu, Department of Rheumatology, Peking Union Medical College Hospital (West Campus), Chinese Academy of Medical Sciences, Beijing, China; Jacek Olas, Malopolskie Centrum Reumatologii, Immunologii i Rehabilitacji, Cracow, Poland; Edoardo Rosato, Centro per la Sclerosi Sistemica-Dipartimento di Medicina Clinica, Università La Sapienza, Policlinico Umberto I, Roma, Italy; Rosario Foti, U.O. di Reumatologia, A.O.U. Policlinico Vittorio Emanuele, Catania, Italy; Sabine Adler, Diana Dan, Department of Rheumatology and Clinical Immunology/Allergology Inselspital, University of Bern, Bern, Switzerland; Ewa Wiesik-Szewczyk, Marzena Olesińska, Department of Connective Tissue Disease, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland; Cristiane Kayser, Universidade Federal de São Paulo-Disciplina de Reumatologia, São Paulo, Brasil; Nihal Fathi, Assiut and Sohage University Hospital, Rheumatology Department Assiut University Hospital, Assiut, Egypt; Paloma García de la Peña Lefebvre, Hospital Universitario Madrid Norte Sanchinarro, Madrid, Spain; Bernard Imbert, Vascular Medicine Unit-Department of Medicine, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.

    • Contributors The authors as listed on the title page of the manuscript have all made substantial contributions which qualifies them as authors. All authors have finally approved the submitted version to be published.

    • Funding EULAR (CLI066)

    • Competing interests OK-B: consultancies or speakers bureau: AbbVie, Actelion, Bayer, Inventiva, Pfizer, Roche; JA: grant/research support from BMS, Pfizer, Roche/Chugai, Sanofi-Aventis, Actelion; MB: consultant for Actelion; YA: consultant for: Bayer Pharmaceuticals, Actelion, Pfizer, Inventiva, Medac, Servier, Boehringer Ingelheim, Sanofi-Aventis, CSL Behring, Roche; OD: consultant for: 4D Science, Actelion, Active Biotec, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer Ingelheim Pharma, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation; MC: Mundipharm, Actelion, BMS, Horizon, Pfizer, Biogen, Celltrion, Cellgene; LC: consultant for Actelion and Pfizer; CPD: consulting fees from Roche, Actelion, GSK, Bayer Pharmaceuticals; IF: constultant: Bayer, Roche/Chugai; MF: Actelion; DEF: grant/research support from AbbVie, Actelion, Amgen, BMS, NIH, Novartis, Pfizer, Roche/Genentech and consultancy with AbbVie, Actelion, Amgen, BMS, Cytori, Novartis, Pfizer, Roche/Genentech; NH: lecture fees from Actelion, Bayer, Roche; DK: consultancy with Actelion, BMS, Bayer, Covis, Cytori, Genentech/Roche, Gilead, Sanofi-Aventis and grant from NIH/NIAID, NIH/NIAMS, Bayer and BMS; ALH: consultant/speaker/research funding: Actelion, consultant: Apricus; JMvL: honoraria from MSD, BMS, Pfizer, Eli Lilly, Roche; GR: lecturers fees from Bayer, Pfizer, Novartis, Actelion, GSK, BMS and research grants from Actelion; RS: consultant for: Entelligence Program, supported by Actelion; inPractice Rheumatology, grant support: BMS, Bayer; AS: research grant from Actelion; IT: Actelion; UM-L: grant/research support from: EULAR grant, consultant for: Actelion, GSK, Bayer, Medac, Roche/Chugai.

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