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Revised European Scleroderma Trials and Research Group Activity Index is the best predictor of short-term severity accrual
  1. Serena Fasano1,
  2. Antonella Riccardi1,
  3. Valentina Messiniti1,
  4. Paola Caramaschi2,
  5. Edoardo Rosato3,
  6. Britta Maurer4,
  7. Vanessa Smith5,
  8. Elise Siegert6,
  9. Ellen De Langhe7,
  10. Valeria Riccieri8,
  11. Paolo Airó9,
  12. Carina Mihai10,
  13. Jerome Avouac11,
  14. Elisabetta Zanatta12,
  15. Ulrich A Walker13,
  16. Florenzo Iannone14,
  17. Paloma García De la Peña Lefebvre15,
  18. Jörg H W Distler16,
  19. Alessandra Vacca17,
  20. Oliver Distler18,
  21. Otylia Kowal-Bielecka19,
  22. Yannick Allanore11,
  23. Gabriele Valentini1
  1. 1 Department of Precision Medicine, Section of Rheumatology, University of Campania Luigi Vanvitelli, Naples, Italy
  2. 2 Department of Rheumatology, University of Verona, Verona, Italy
  3. 3 Dipartimento di Medicina Traslazionale e di Precisione, Sapienza University of Rome, Roma, Italy
  4. 4 Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  5. 5 Department of Rheumatology, University Hospital Ghent, Gent, Belgium
  6. 6 Department of Rheumatology, Charit University Hospital, Berlin, Germany
  7. 7 Department of Development and Regeneration, Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium
  8. 8 Clinical Medicine and Therapy, Sapienza University of Rome, Rome, Italy
  9. 9 Rheumatology and Clinical Immunology Department, Spedali Civili di Brescia, Brescia, Italy
  10. 10 Department of Rheumatology, Carol Davila University of Medicine and Pharmacy, Bucarest, Romania
  11. 11 Department of Rheumatology, Paris Descartes University, Rheumatology A and INSER U1016, Cochin Hospital, Paris, France
  12. 12 Dipartimento di Medicina, DIMED, Universita degli Studi di Padova, Padova, Italy
  13. 13 Department of Rheumatology, Basel University, Basel, Switzerland
  14. 14 Department of Rheumatology, University of Bari, Bari, Italy
  15. 15 Department of Rheumatology, Ramon y Cajal University Hospital, Madrid, Spain
  16. 16 Department of Internal Medicine III, University of Erlangen, Erlangen, Germany
  17. 17 Chair and Rheumatology Unit, University Clinic AOU Cagliari, Monserrato, Italy
  18. 18 Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  19. 19 Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
  1. Correspondence to Dr Serena Fasano, Università degli Studi della Campania Luigi Vanvitelli, Napoli 80131, Italy; serena.fasano{at}


Background The European Scleroderma Trials and Research Group (EUSTAR) recently developed a preliminarily revised activity index (AI) that performed better than the European Scleroderma Study Group Activity Index (EScSG-AI) in systemic sclerosis (SSc).

Objective To assess the predictive value for short-term disease severity accrual of the EUSTAR-AI, as compared with those of the EScSG-AI and of known adverse prognostic factors.

Methods Patients with SSc from the EUSTAR database with a disease duration from the onset of the first non-Raynaud sign/symptom ≤5 years and a baseline visit between 2003 and 2014 were first extracted. To capture the disease activity variations over time, EUSTAR-AI and EScSG-AI adjusted means were calculated. The primary outcome was disease progression defined as a Δ≥1 in the Medsger’s severity score and in distinct items at the 2-year follow-up visit. Logistic regression analysis was carried out to identify predictive factors.

Results 549 patients were enrolled. At multivariate analysis, the EUSTAR-AI adjusted mean was the only predictor of any severity accrual and of that of lung and heart, skin and peripheral vascular disease over 2 years.

Conclusion The adjusted mean EUSTAR-AI has the best predictive value for disease progression and development of severe organ involvement over time in SSc.

  • systemic sclerosis
  • autoimmune diseases
  • outcomes research

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Key messages

What is already known about this subject?

  • The European Scleroderma Trial and Research (EUSTAR) group task force recently succeeded in constructing a revised activity index (AI).

  • The predictive value of EUSTAR-AI for disease severity accrual has not been evaluated.

What does this study add?

  • The adjusted mean EUSTAR-AI reliably captured all variations in disease activity during the observation period in patients with SSc and has the best predictive value for short-term disease progression and development of severe internal organ involvement over time.

How might this impact on clinical practice?

  • Identifying patients at risk has important implications for clinical care, because it helps the clinician in managing patients with SSc, monitoring disease state with rapid adjustments in treatment to prevent irreversible organ damage.


Systemic sclerosis (SSc) is a multisystem autoimmune disease with the highest case-specific mortality among rheumatic diseases.1 2 Predicting outcome and tailoring treatment and surveillance in patients with a potentially unfavourable evolution may improve quality of life and survival.3 In that regard, a number of adverse prognostic features as assessed at presentation and predictive of shortened survival have been identified.4–9 However, predicting severity accrual in the short term is still a poorly accomplished task. Recently, the Canadian Scleroderma Study Group has pointed out a role of the adjusted mean European Scleroderma Study Group Activity Index (EScSG-AI)10 in predicting internal organ involvement and disease progression in an early scleroderma cohort.11 Because of the limitation of the EScSG-AI (ie, high number of missing values and a cohort with a long-standing disease), in 2017, a European Scleroderma Trial and Research (EUSTAR) group task force succeeded in constructing a revised AI that performed better than the EScSG-AI in identifying patients with active disease.12

This study aimed to test the performance of the adjusted mean European Scleroderma Trial and Research Activity Index (EUSTAR-AI) in predicting patient disease course as compared with the EScSG-AI and to investigate the role on short-term disease progression of other prognostic factors known to affect survival.

Patients and methods

Study design

The study was based on the analysis of the EUSTAR database in which clinical information on patient visits are recorded prospectively using standardised data collection forms. The database structure has been described previously.13 The whole EUSTAR data set, consisting of 14 755 patients at the time of the data export (30 October 2017), was considered. Predictors with ≥50% missing values were not considered for inclusion (online supplementary table S1).

Patients classified with SSc according to American College of Rheumatology/European League Against Rheumatism classification criteria,14 with a disease duration from the onset of the first non-Raynaud sign/symptom ≤5 years at first visit recorded and a baseline visit between 2003 and 2014 were first extracted. Patients were considered for the study if they presented the following predefined features: (1) availability of all the items included in the EScSG-AI and in the EUSTAR-AI at baseline and yearly for at least two consecutive years (within the first 2 years of observation and with a time frame between consecutive visits not exceeding 18 months); (2) availability of items included in the Medsger’s severity scale15 at entry and after 2 years of observation and (3) availability of vital status at the last observation.

Potentially predictive features

Disease activity

Disease activity was measured by EUSTAR-AI and EScSG-AI. To capture the disease activity variations over time, we calculated the EUSTAR-AI and EScSG-AI adjusted mean (see online supplementary text).

Features predictive of shortened survival

We also investigated the predictive role in the short term of variables detectable at admission and reported to be predictive of the subsequent 5-year mortality4–9: age at disease onset, male sex, erythrocyte sedimentation rate (ESR) >25 mm/hour, haemoglobin <12 g/L, anti-RNA polymerase III antibody positivity, tendon friction rubs, the presence of proteinuria (positive level of urine protein more than trace), baseline severity in any major organ/system.

Primary and secondary outcomes

Given the current lack of a validated SSc damage index,16 we selected as primary outcome the disease severity progression using the Medsger’s severity scale.15 In particular, disease progression was defined as accrual of a new (Δ≥1) severity score at the 2-year follow-up visit compared with the initial visit. The secondary outcome was the progression in any organ/system domains of the Medsger’s severity scale analysed separately, defined as an increase of at least one point in severity grade (Δ≥1).

Statistical analysis

Continuous variables are presented as the mean±SD if normally distributed or as median and quartiles if distribution was skewed. Comparisons were performed using the χ2 or Fisher’s test for categorical variables and using the Student’s test for continuous variables, as appropriate. To explore specific determinants of disease progression, logistic regression analysis was carried out. Analyses were performed with Medcalc software, V.15.4.



A total of 549 patients with SSc were included in the analysis. The main epidemiological, serological and clinical features of the cohort at baseline are listed in table 1. There were 445 (81%) women; mean age (SD) at entry was 51.9 (±13.6). One hundred and seventy-nine (32.6%) patients were classified as having diffuse SSc. During the observation period, most patients (55.2%) developed a progression of organ involvement, that is, Δ≥1 in any of the evaluated organ systems according to Medsger’s severity scale, along the 2-year follow-up visit.

Table 1

Epidemiological, serological and clinical features at baseline (n=549)

Univariate and multivariate logistic regression

At univariate analysis (online supplementary table S2), the adjusted mean EUSTAR-AI (OR 1.43, p<0.0001), the adjusted mean EScSG-AI (OR 1.41, p<0.0001), diffuse subset (OR 1.46, p=0.040), anti-Scl-70 antibodies positivity (OR 1.72, p=0.003), ESR >25 mm/hour at baseline (OR 1.58, p=0.04), age at disease onset (OR 1.01, p=0.01) predicted any increase in severity progression. No predictive role emerged for other baseline variables, that is, male gender, tendon friction rubs, anti-RNA polymerase III antibodies positivity, the presence of urine proteins, haemoglobin <12 g/L and general, gut, peripheral vascular, muscle, joint/tendon, skin, lung, heart and kidney involvement. At multivariate analysis (table 2), the adjusted mean EUSTAR-AI (OR 1.43; 95% CI 1.23 to 1.66) was the only covariate retained in the model for the prediction of disease progression. Moreover, the adjusted mean EUSTAR-AI predicted any increase ≥1 in the severity score of skin, heart, lung and peripheral vascular system. However, activity indices were not able to predict general, kidney, muscle, gastrointestinal tract, joint/tendon severity accrual (table 2 and online supplementary table S2).

Table 2

Multivariate logistic regression analysis for organ severity accrual

A subanalysis confirmed that the adjusted mean EUSTAR-AI was the best predictor of severity progression at 2-year follow-up visit in both diffuse and limited subsets (OR 1.28; 95% CI 1.05 to 1,57, p=0.01 and OR 1.62; 95% CI 1.30 to 2.01, p<0.0001, respectively).


SSc is a challenging disease to manage with significant damage accrual that occurs early in the disease course and results in end-organ dysfunction and high mortality.17 18

A previous study has demonstrated that disease activity quantified by the adjusted mean EScSG-AI predicted the risk of disease progression in an early diffuse cutaneous SSc cohort over 3 years.11 In particular, in multivariate analysis, the adjusted mean EScSG-AI was the best predictor of progression of lung disease but did not play a significant role in the prediction of heart and renal disease severity. In the current study, we tried to assess the predictive validity of the 2017 EUSTAR-AI and to compare it with EScSG-AI. We demonstrated that the adjusted mean EUSTAR-AI had better predictive value for damage accrual and development of severe internal organ involvement over 2 years as compared with EScSG-AI. In particular, the adjusted mean EUSTAR-AI predicted the development of a higher total severity score and in the following distinct severity domains: heart, peripheral vascular, skin and lung. A protective role of baseline skin severity grade ≥1 was pointed out but is likely to depend on the natural disease course characterised by skin sclerosis reaching its maximal grade in the early 2–3 years.19

Nevskaya et al 11 did not investigate the role on short-time severity accrual of baseline features demonstrated to predict mortality in SSc, as ESR >25 mm/hour, tendon friction rubs, anti-RNA polymerase III antibodies positivity, the presence of urine proteins, haemoglobin <12 g/L, diffuse subset and internal organ involvement.4–9 We failed to point out any role of these features. These data suggest that variables predicting survival in the medium - long term differ from those associated with disease deterioration in the short period.

Our study has some limitations. First, we were not able to assess damage accrual and we measured disease severity as primary outcome, which might reflect both activity and damage. Second, data were obtained from scleroderma tertiary centres, meaning that we might fail to include patients with milder disease who are not referred. Nevertheless, a EUSTAR-AI predictive role of organ/system severity accrual in the short term has emerged, indicating that measuring this parameter can help the clinician in adjusting treatment in such time frame.


EUSTAR collaborators: Marco Matucci-Cerinic and Silvia Bellando Randone, University of Florence, Italy; Veronika Jaeger and Bettina Bannert, Department of Rheumatology, University Hospital Basel, Basel, Switzerland; Fabio Cacciapaglia, Rheumatology Unit-DiMIMP School of Medicine, University of Bari, Italy; Suzana Jordan, Rucsandra Dobrota and Mike Becker, Department of Rheumatology, University Hospital Zürich, Switzerland; Radim Becvarare and Michal Tomčík, 1st Medical School, Charles University, Prague, Czech Republic; Ewa Gindzienska-Sieskiewicz and Katarzyna Karaszewska, Department of Rheumatology and Internal Diseases, Medical University of Bialystok, Poland; Maurizio Cutolo, Carmen Pizzorni, Sabrina Paolino, Alberto Sulli, Barbara Ruaro and Elisa Alessandri, University of Genova, Italy; Veronica Giacco and Rosaria Irace, Rheumatology Section, Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy; Claudia Kedor, Vincent Casteleyn, Julia Hilger and Jakob Hoeppner, Department of Rheumatology, Charité University Hospital, Berlin, Germany; Simona Rednic, Iulia Szabo and Ana Petcu, University of Medicine and Pharmacy, ’iuliu Hatieganu’ Cluj, Cluj-napoca, Romania; Frantz Camelia and Carole Desbas, Rheumatology, University Cochin Hospital, Paris, France; P Vlachoyiannopoulos, Department of Pathophysiology Medical School, National University of Athens, Athens, Greece; C Montecucco, Roberto Caporali and Lorenzo Cavagna, iRCCs Policlinico s Matteo, Pavia, Italy; Jiri Stork, Department of Dermatology, the First Faculty of Medicine, Charles University, Prague, Czech Republic; Murat Inanc, Division of Rheumatology, Department of Internal Medicine, Istanbul Medical Faculty, Istanbul, Turkey; Patricia e Carreira and Beatriz E Joven, Hospital 12 de Octubre, Madrid, Spain; Srdan Novak and Felina Anic, KBC Rijeka, Croatia; lászló Czirják, Cecilia Varju and Tunde Minier, University of Pécs, Hungary; Carlo Chizzolini and Daniela Allai, University Hospital Geneva, Switzerland; Eugene J Kucharz, Anna Kotulska, Magdalena Kopec-Medrek and Malgorzata Widuchowska, Medical University of Silesia, Katowice, Poland; Andrea Doria, Rheumatology Unit, Department of Medicine, Padova University Hospital, Padova, Italy; Alenka Sipek Dolnicar, Department of Rheumatology, University Medical Center Ljublijana, Slovenia; Bernard Coleiro, ’Stella Maris’, Balzan, Malta; Armando Gabrielli, Lucia Manfredi, Devis Benfaremo and Alessia Ferrarini, Istituto Di Clinica Medica Generale, Ematologia Ed Immunologia Clinica, Università Politecnica Delle Marche Polo Didattico, University of Ancona, Italy; Dominique Farge Bancel, Adrian Hij and Pauline Lansiaux, Hôpital Saint-Louis, Paris, France; Maria Grazia Lazzaroni, Spedali Civili di Brescia, Servizio di Reumatologia Allergologia e Immunologia Clinica, Brescia, Italy; Roger Hesselstrand, Dirk Wuttge and Kristofer Andréasson, Lund University Hospital, Sweden; Duska Martinovic, Ivona Bozic, Mislav Radic, Clinical Hospital of Split, Croatia; Alexandra Balbir-Gurman and Yolanda Braun-Moscovici, B. Shine Rheumatology Institute, Rambam Health Care Campus, Haifa, Israel; Andrea Lo Monaco and Federica Furini, Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Ferrara, Italy; Nicolas Hunzelmann and Pia Moinzadeh, Universitätshautklinik Köln, Germany; Raffaele Pellerito, Ospedale Mauriziano, Torino, Italy; Dr Cristian Caimm and Eugenia Bertoldo, Reumatologia-Medicina Interna Università degli Studi di Verona, Italy; Dr Jadranka Morovic-Vergle and Ivana Melanie Culo, Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Dubrava University Hospital, Zagreb, Croatia; Christopher Denton, Royal Free And University College London Medical School, London, UK; Nemanja Damjanov, Institute Of Rheumatology Belgrade, Serbia and Montenegro; Jörg Henes and Ann-Christian Pecher, Medizinische Universitätsklinik Abt. Ii, Tübingen, Germany; Vera Ortiz Santamaria, Rheumatology Granollers General Hospital, Barcelona, Spain; Stefan Heitmann, Medeleine Codagnone and Johannes Pflugfelder, Marienhospital Stuttgart, Germany; Dorota Krasowska and Malgorzata Michalska-Jakubus, Department of Dermatology, Venereology and Pediatric Dermatology, Medical University of Lublin, Poland; Paul Hasler and Samuel Kretzschmar, Kantonsspital Aarau, Rheumaklinik und Institut für Physikalische Medizin und Rehabilitation Kantonsspital Aarau, Switzerland; Michaela Kohm, Klinikum der Johann Wolfgang Goethe Universität Medizinische Klinik III, Frankfurt am Main, Germany; Ivan Foeldvari Matthias Seidel and Nicola Helmus, Medizinische Universitäts-Poliklinik, Bonn, Germany; Gianluigi Bajocchi, Arcispedale Santa Maria Nuova Dipartimento Area Medica I, U.O. di Reumatologia, Reggio Emilia, Italy; Dr Maria João Salvador and José Antonio Pereira Da Silva, Da Universidade, Coimbra, Portugal; Bojana Stamenkovic and Aleksandra Stankovic, Institute For Prevention, Treatment and Rehabilitation Rheumatic and Cardiovascular Disease niska Banja, Serbia and Montenegro; Carlo Francesco Selmi, Maria De Santis and Angela Ceribelli, University of Milan, Italy; Mohammed Tikly, Chris Hani Baragwanath Hospital and University of the Witwatersrand, Johannesburg, South Africa; Lidia P Ananieva, Ludmila Garzanova, Olga Koneva and Maya Starovoytova, Vanasonova Institute of Rheumatology, Moscow, Russia; Ariane Herrick, Hope/Hospital University of Manchester, Rheumatic Diseases Centre, Clinical Sciences Building, Scott Lane, Salford, UK; Ulf Müller-ladner, Kerckhoff Clinic Bad nauheim, Germany; Francesco Puppo, Simone Negrini and Giuseppe Murdaca, Università di Genova, Italy; Merete Engelhart, University Hospital of Gentofte, Hellerup, Denmark; Gabriela Szücs and Szilvia Szamosi, University of Debrecen, Hungary; Carlos de la Puente, Cristina Sobrino Grande and Maria Jesus Garcia Villanueva, Hospital Ramon Y Cajal, Madrid, Spain; Øyvind Midtvedt and Anna-Maria Hoffmann-Vold, Rikshospitalet University Hospital, Oslo, Norway; Eric Hachulla, David Launay and Vincent Sobanski, Hôpital Claude Huriez, lille, France; Massimiliano Vasile and Katia Stefantoni, ’sapienza’ Università di Roma, Italy; Ruxandra Maria ionescu, Daniela Opris and Laura Groseanu, St. Maria Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Ami Sha and Adrianne Woods, Johns Hopkins School of Medicine, Baltimore, USA; Ana Maria Gheorghiu and Mihai Bojinca, Ion Cantacuzino Clinical Hospital, Bucharest, Romania; Cord sunderkötter and Jan Ehrchen, University of Münster, Germany; Francesca Ingegnoli, Istituto Gaetano Pini, University of Milano, Italy; luc Mouthon, Bertrand Dunogue, Benjamin Chaigne and Paul Legendre, Hôpital Cochin, Paris, France; 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, University Hospital of Copenhagen, Denmark; Carlos Alberto von Mühlen Rheuma Clinic, Porto Alegre, Brazil; Maria Rosa Pozzi, Ospedale san Gerardo, Monza, Italy; Kilian Eyerich and Felix Lauffer, TU Munich, Germany; Piotr Wiland, Magdalena szmyrka-Kaczmarek, Renata sokolik, Ewa Morgiel and Marta Madej, Wroclaw University of Medicine, Poland; Marie Vanthuyne and Houssiau Frédéric, Université Catholique de Louvain Bruxelles, Belgium; Juan Jose Alegre-sancho, Hospital Universitario Dr Peset, Valencia, Spain; Martin Aringer and Claudia Günther, University Medical Center, Carl Gustav Carus, Technical University of Dresden, Germany; Rene Westhovens and Jan lenaerts, University Hospital Leuven, Skeletal Biology and Engineering Research Center, Leuven, Belgium; Branimir Anic, Marko Baresic and Miroslav Mayer, University Hospital Center Zagreb, Crotia; Maria Üprus and Kati Otsa, East-Tallin Central Hospital, Tallin, Estonia; Sule Yavuz, University of Marmara, Altunizade, Istanbul, Turkey; Brigitte Granel, Hôpital Nord de Marseille, France; Carolina de souza Müller, Sebastião Cezar Radominski and Valderílio Feijó Azevedo, Hospital de Clinicas da Universidade Federal do Parana, Curitiba, Brazil; Fabian Mendoza and Joanna Busquets, Thomas Jefferson Scleroderma Center, Philadelphia, USA; Svetlana Agachi, Sergei Popa, Svetlana Agachi, Liliana Groppa, Lealea Chiaburu and Eugen Russu, Republican Clinical Hospital, Chisinau, Republic of Moldova; Thierry Zenone, Unit of Internal Medicine, Valence, France; Margarita Pileckyte, Kaunas University of Medicine Hospital Kaunas, Lithuania; Simon Stebbings, Sarah Jordan, Dunedin school of Medicine, New Zealand; Alessandro Mathieu, II Chair of Rheumatology, University of Cagliari-Policlinico Universitario, Cagliari, Italy; lisa Stamp, University of Otago, Christchurch, New Zealand; Kamal Solanki, Cherumi Silva, Joanne Schollum and Helen Barns-Graham, Waikato University Hospital, Hamilton, New Zealand; Douglas Veale, St. Vincent’s University Hospital, Dublin, Ireland; Esthela Loyo, Carmen Tineo Glenny Paulino, Hospital Regional Universitario Jose Ma Cabral y Baez, Clinica Corominas, Santiago, Dominican Republic; Sergio Toloza, Hospital San Juan Batista, Catamarca, Argentina; Mengtao Li, Peking Union Medical College Hospital (West Campus), Beijing, China; Antonietta Gigante, Sapienza Università di Roma, Università la sapienza, Policlinico Umberto i, Roma, Italy; Fahrettin Oksel and Figen Yargucu, Ege University, Bornova, Izmir, Turkey; Cristina-Mihaela Tanaseanu, Monica Popescu, Alina Dumitrascu and Isabela Tiglea, Clinical Emergency Hospital, St. Pantelimon, Bucharest, Romania; Rosario Foti, Elisa Visalli, Alessia Benenati and 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 and Rodica Chirieac, GRT Popa Center for Biomedical Research, European Center for Translational Research, University of Medicine and Pharmacy, Rehabilitation Hospital, Iasi, Romania; Peter Villiger, Sabine Adler and Johannes Fröhlich, University of Bern, Switzerland; Cristiane Kayser and Andrade Luis Eduardo C, Universidade Federal de São Paulo, Brazil; Dr Nihal Fathi, Safa Alii, Marrow Ahmed, Samar Hasaneen and Eman El Hakeem, Rheumatology Department Assiut University Hospital, Egypt; Jorge Juan Gonzalez Martin, Hospital Universitario Sanchinarro, Madrid, Spain; Patrick Carpentier and Bernard Imbert, Centre Hospitalier Universitaire de Grenoble, France; Camille Francès and Patricia Senet, Hôpital Tenon, Paris, France; Jean Sibilia, Emmanuel Chatelus, Jacques Eric Gottenberg and Hélène Chifflot, University Hospital of strasbourg, Hôpital de Hautepierre, strasbourg, France; Ira litinsky, Tel Aviv Sourasky Medical Center, Israel; Jean Luc Senécal, Martial Koenig, France Joval and Grodzicky Tamara, University of Montréal, Canada; Francesco Del Galdo, Giuseppina Abignano and Sookhoe Eng, University of Leeds, Chapel Allerton Hospital, Leeds, UK; Goda Seskute, Irena Butrimiene, Rita Rugiene and Diana Karpec, State Research Institute for Innovative Medicine, Vilnius University, Lithuania; Lesley Ann Saketkoo, Melanie Pascal and Joseph Alasky, Tulane/University Medical Center, Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, Louisiana, USA; Eduardo Kerzberg, Osteoarticular Diseases and Osteoporosis Centre, Pharmacology and Clinical Pharmacological Research Centre, School of Medicine, University of Buenos Aires, Ramos Mejía Hospital, Buenos Aires, Argentina; Washington Bianchi, Breno Valdetaro Bianchi, Dante Valdetaro Bianchi and Yeda Barcellos, Department of Rheumatology-Santa Casa da Misericórdia do Rio de Janeiro, Brasil; Ivan Castellví and Milena Millan, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Jasminka Milas-Ahic, Roberta Visevic Clinical Hospital Center Osijek, Croatia; Massimiliano limonta, USSD Reumatologia, Ospedali Riuniti di Bergamo, Italy; Doron Rimar, Itzhak Rosner and Gleb Slobodin, Rheumatology Unit Bnai Zion Medical Center, Haifa, Israel; Maura Couto Unidade de Reumatologia de Viseu, Portugal; François Spertini, Camillo Ribi and Guillaume Buss, Department of Rheumatology, Clinical Immunology and Allergy, Lausanne, Switzerland; Antonella Marcoccia, Francesco Bondanini, Aldo Ciani and Sandro Pertini, Hospital Roma, Italy; Sarah Kahl, Universitätsklinikum Schleswig-Holstein, Bad Bramstedt, Germany; Ivien M Hsu, Clinical Research Center, Robert Wood Johnson Medical School, New Brunswick, USA; Thierry Martin, Vincent Poindron and Kilifa Meghit, Nouvel Hôpital Civil, Strasbourg, France; Sergey Moiseev and Pavel Novikov, Clinic of Nephrology, Internal and Occupational Diseases, Moscow, Russia; Lorinda Chung, Kathleen Kolstad and Marianna Stark, Stanford University, School of Medicine, California, USA; Tim Schmeiser, Astrid Tiele, Krankenhaus St. Josef, Wuppertal-elberfeld, Germany; Dominik Majewski Poznan, University of Medical Sciences, Poland; Zbigniew Zdrojewski, Smolenska Zaneta and Karol Wierzba, University Clinical Centre, Medical University of Gdansk. Dębinki 7, Gdansk, Poland; Julia Martínez-Barrio, Francisco Javier López-Longo, Department of Rheumatology, Gregorio Marañón Univeristy Hospital Madrid, Spain; Dinesh Khanna, Elena Schiopu and April Marquardt, University of Michigan Scleroderma Program, Academic Offices, USA; Vera Bernardino, Maria Francisca Moraes-Fontes and Ana Catarina Rodrigues, Unidade de Doencas Autoimunes-Hospital Curry Cabral, Centro Hospitalar lisboa Central, Lisbon, Portugal; Gabriela Riemekasten, Sabine Sommerlatte, Sebastian Jendreck and Sabrina Arnold, Universitätsklinik lübeck, Germany; Lelita Santo, Manuel Gomes and Catarina Canha, Serviço de Medicina Interna, Centro Hospitalar e Universitário de Coimbra, Portugal; Yair Levy, Meir Medical Centre, Kfar-saba, Israel; Elena Rezus, Anca Cardoneanu, Alexandra Maria Burlui, University of Medicine and Pharmacy 'GR.T.Popa’ iasi, Rehabilitation Hospital, Iasi, Romania; Dr Omer Nuri Pamuk, Rakya University Medical Faculty, Department of Internal Medicine, Division of Rheumatology, Edirne, Turkey; Dr Daniel Brito de Araujo Universidade Federal de Pelotas, Brazil; Piercarlo Sarzi Puttini, Rossella Talotta and Sara Bongiovanni, University Hospital Luigi Sacco, Milan, Italy; Marek Brzosko, Beata Trzcinska-Butkiewicz and Marcin Milchert, University in Szczecin, Poland; Hadi Poormoghim, Elham Andalib and Simin Almasi, Firoozgar Hospital Tehran, Iran; Marta Maman and Priscilla Marcaida Fernando Melo, Department of Rheumatology, Buenos Aires, Argentina; Ina Kötter and Martin Krusche, Asklepios Clinic Altona, Medical Department 4, Rheumatology, Immunology, Nephrology, Hamburg, Germany; Giovanna Cuomo, Fiammetta Danzo and Francesco Masini, UOC Medicina Interna, Università della Campania, Napoli, Italy; Francis Gaches, Martin Michaud and Florian Cartos, Hôpital Joseph Ducuing Toulouse, France; Laura Belloli, Cinzia Casu, Ospedale Niguarda, Milano, Italy; Petros Sfikakis and Maria Tektonidou, Athens University Medical School, Greece; Juliana Markus and Roberto Ranza, Universidade Federal de Uberlândia, Brazil; Daniel Furst and Gary R Feldman, Arthritis Association of Southern California, Los Angeles, USA; Ana-Maria Ramazan, Emel Nurmambet, Amalia Miroto and Cristina Suta, Lulia Andronache Constanta City, Romania; Tom WJ Huizinga, Jeska de Vries-Bouwstra and H U Scherer, Department of Rheumatology, Leiden University Medical Center, The Netherlands; Marie-Elise Truchetet, Rheumatology Department, Bordeaux, France; Patrick Jego and A Lescoat, Service de Médecine Interne Hôpital Sud, Rennes, France; Lorenzo Dagna, Giacomo De Luca and Corrado Campochiaro, Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), San Raffaele Hospital, Milan, Italy; J M van Laar, Julia Spierings, Evelien Ton and Tim Radstake, University Medical Center, Utrecht, The Netherlands; Lidia Rudnicka, Malgorzata Olszewska and Anna Stochmal, Department of Dermatology, Medical University of Warsaw, Poland; Susana Oliveira, Joana Caetano and Marta Amaral, Systemic Immunomediated Diseases Unit, Department of Medicine IV, Fernando Fonseca Hospital Amadora, Portugal; Fabiola Atzeni and Donatella Sangari, Francesca Marino Rheumatology Unit, University of Messina, Italy; Masataka Kuwana and Yuichiro Shirai, Nippon Medical School Hospital Sendagi, Tokyo, Japan; Arsene Mekinian, Sebastien Riviere Internal Medicine Saint Antoine, Paris, France.



  • Handling editor Josef S Smolen

  • Contributors GV contributed to the study conception and design, acquisition of data, analysis and design of the study. SF and GV contributed to the data interpretation and analysis. All authors contributed to the acquisition of data; drafting and revising the manuscript and have critically reviewed and approved the final submitted version to be published.

  • Funding This study was funded by European Scleroderma Trials and Research group (EUSTAR).

  • Competing interests None declared.

  • 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.