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Extended report
Mapping and predicting mortality from systemic sclerosis
  1. Muriel Elhai1,
  2. Christophe Meune2,
  3. Marouane Boubaya3,
  4. Jérôme Avouac1,
  5. Eric Hachulla4,
  6. Alexandra Balbir-Gurman5,
  7. Gabriela Riemekasten6,
  8. Paolo Airò7,
  9. Beatriz Joven8,
  10. Serena Vettori9,
  11. Franco Cozzi10,
  12. Susanne Ullman11,
  13. László Czirják12,
  14. Mohammed Tikly13,
  15. Ulf Müller-Ladner14,
  16. Paola Caramaschi15,
  17. Oliver Distler16,
  18. Florenzo Iannone17,
  19. Lidia P Ananieva18,
  20. Roger Hesselstrand19,
  21. Radim Becvar20,
  22. Armando Gabrielli21,
  23. Nemanja Damjanov22,
  24. Maria J Salvador23,
  25. Valeria Riccieri24,
  26. Carina Mihai25,
  27. Gabriella Szücs26,
  28. Ulrich A Walker27,
  29. Nicolas Hunzelmann28,
  30. Duska Martinovic29,
  31. Vanessa Smith30,
  32. Carolina de Souza Müller31,
  33. Carlo Maurizio Montecucco32,
  34. Daniela Opris33,
  35. Francesca Ingegnoli34,
  36. Panayiotis G Vlachoyiannopoulos35,
  37. Bojana Stamenkovic36,
  38. Edoardo Rosato37,
  39. Stefan Heitmann38,
  40. Jörg H W Distler39,
  41. Thierry Zenone40,
  42. Matthias Seidel41,
  43. Alessandra Vacca42,
  44. Ellen De Langhe43,
  45. Srdan Novak44,
  46. Maurizio Cutolo45,
  47. Luc Mouthon46,
  48. Jörg Henes47,
  49. Carlo Chizzolini48,
  50. Carlos Alberto von Mühlen49,
  51. Kamal Solanki50,
  52. Simona Rednic51,
  53. Lisa Stamp52,
  54. Branimir Anic53,
  55. Vera Ortiz Santamaria54,
  56. Maria De Santis55,
  57. Sule Yavuz56,
  58. Walter Alberto Sifuentes-Giraldo57,
  59. Emmanuel Chatelus58,
  60. Jiri Stork59,
  61. Jacob van Laar60,
  62. Esthela Loyo61,
  63. Paloma García de la Peña Lefebvre62,
  64. Kilian Eyerich63,
  65. Vanesa Cosentino64,
  66. Juan Jose Alegre-Sancho65,
  67. Otylia Kowal-Bielecka66,
  68. Grégoire Rey67,
  69. Marco Matucci-Cerinic68,
  70. Yannick Allanore1
  71. on behalf of EUSTAR group
  1. 1Rheumatology A department, Paris Descartes University, INSERM U1016, Sorbonne Paris Cité, Cochin Hospital, Paris, France
  2. 2Department of Cardiology, Paris XIII University, INSERM UMR S-942, Bobigny Hospital, Paris, France
  3. 3Unit of Clinical Research, Paris Seine Saint Denis University, Bobigny, France
  4. 4Department of Internal Medicine, Hôpital Claude Huriez, University Lille Nord-de-France, Lille Cedex, Lille, France
  5. 5B Shine Rheumatology Unit, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion—Institute of Technology, Haifa, Israel
  6. 6Department of Rheumatology, University of Lübeck, Lübeck, Germany
  7. 7UO Reumatologia ed Immunologia Clinica Spedali Civili Brescia, Brescia, Italy
  8. 8Servicio de Reumatologia, Hospital Universitario 12 de Octubre, Madrid, Spain
  9. 9Department of Clinical and Experimental Medicine, ’F-Magrassi' II, Naples, Italy
  10. 10Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy
  11. 11Department of Dermatology, University Hospital of Copenhagen, Hospital Bispebjerg, Copenhagen, Denmark
  12. 12Department of Immunology and Rheumatology, University of Pécs, Pécs, Hungary
  13. 13Chris Hani Baragwanath Academic Hospital University of the Witwatersrand, Johannesburg, South Africa
  14. 14Department of Rheumatology and Clinical Immunology, Justus-Liebig University Giessen, Kerckhoff Clinic, Bad Nauheim, Germany
  15. 15Rheumatology Unit, Department of Medicine, University of Verona, Verona, Italy
  16. 16Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  17. 17Interdisciplinary Department of Medicine-Rheumatology Unit, Policlinico, University of Bari, Bari, Italy
  18. 18VA Nasonova Institute of Rheumatology, Moscow, Russian Federation
  19. 19Department of Clinical Sciences Lund, Section of Rheumatology, Lund University, Skåne University Hospital, Lund, Sweden
  20. 20Institute of Rheumatology, 1st Medical School, Charles University, Praha, Czech Republic
  21. 21Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
  22. 22Institute of Rheumatology, University of Belgrade Medical School, Belgrade, Serbia
  23. 23Rheumatology Department, Hospitais da Universidade, Coimbra, Portugal
  24. 24Department of Internal Medicine and Medical Specialities, ’Sapienza', University of Rome, Italy, Rome, Italy
  25. 25Department of Internal Medicine and Rheumatology Clinic, Ion Cantacuzino Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
  26. 26Department of Internal Medicine, Division of Rheumatology, University of Debrecen, Debrecen, Hungary
  27. 27Department of Rheumatology, Basel University, Unispital Basel, Basel, Switzerland
  28. 28Department of Dermatology, University Hospital Cologne, Cologne, Germany
  29. 29Department of Internal Medicine, Clinical Hospital of Split, Split, Croatia
  30. 30Department of Rheumatology, University of Ghent, Ghent, Belgium
  31. 31Rheumatology Division, Clinics Hospital, Federal University of Paraná, Curitiba, Brazil
  32. 32Unita Operativa e Cattedra di Reumatologia, IRCCS Policlinico S Matteo, Pavia, Italy
  33. 33Department of Rheumatology, St Maria Hospital, Carol Davila, University of Medicine and Pharmacy, Bucharest, Romania
  34. 34Dipartimento e Cattedra di Reumatologia, Università degli Studi di Milano, Istituto Ortopedico ’Gaetano Pini', Milano, Italy
  35. 35Department of Pathophysiology, Medical School, National University and Kapodistrian of Athens, Athens, Greece
  36. 36Institute for Prevention, Treatment and Rehabilitation of Rheumatic and Cardiovascular Diseases, Niska Banja, Serbia and Montenegro
  37. 37Dipartimento di Medicina Clinica, Centro per la Sclerosi Sistemica, Università La Sapienza, Policlinico Umberto I, Roma, Italy
  38. 38Department of Rheumatology, Marienhospital Stuttgart, Stuttgart, Germany
  39. 39Department of Internal Medicine 3, University Hospital Erlangen, Erlangen, Germany
  40. 40Department of Medicine, Unit of Internal Medicine, Valence cedex, France
  41. 41Medizinische Klinik III, University Hospital of Bonn, Bonn, Germany
  42. 42Rheumatology Unit, University Hospital of Cagliari, Monserrato, Italy
  43. 43Division of Rheumatology and Department of Development and Regeneration, University Hospital Leuven and Laboratory Tissue Homeostasis and Disease, Leuven, Belgium
  44. 44Department of Rheumatology and Clinical Immunology, Internal Medicine, KBC Rijeka, Rijeka, Croatia
  45. 45Research Laboratory and Division of Rheumatology Department of Internal Medicine, University of Genova, Genova, Italy
  46. 46Department of Internal Medicine, Hôpital Cochin, Paris, France
  47. 47Medizinische Universitätsklinik, Abt II (Onkologie, Hämatologie, Rheumatologie, Immunologie, Pulmonologie), Tübingen, Germany
  48. 48Department of Immunology and Allergy, University Hospital, Geneva, Switzerland
  49. 49Rheuma Clinic Av Carlos Gomes Porto Alegre, Porto Alegre, Brazil
  50. 50Rheumatology Unit, Waikato University Hospital, Hamilton City, Hamilton, New Zealand
  51. 51Department of Rheumatology, University of Medicine and Pharmacy ’Iuliu Hatieganu' Cluj, Cluj-Napoca, Romania
  52. 52Department of Medicine, University of Otago, Christchurch, New Zealand
  53. 53Division of Clinical Immunology and Rheumatology, Department of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
  54. 54Rheumatology Granollers General Hospital, Barcelona, Spain
  55. 55Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Rozzano, Italy
  56. 56Department of Rheumatology, University of Marmara, Istanbul, Turkey
  57. 57Servicio de Reumatología, Hospital Ramon Y Cajal, Madrid, Spain
  58. 58Department of Rheumatology, University Hospital of Strasbourg-, Hôpital de Hautepierre, Service de Rhumatologie, Strasbourg, France
  59. 59Department of Dermatology, Charles University and General University Hospital in Prague, Prague, Czech Republic
  60. 60Department of Rheumatology and Clinical Immunology, James Cook University Hospital, Middlesbrough, UK
  61. 61Reumatologia e Inmunologia Clinica, Hospital Regional Universitario Jose Ma Cabral y Baez, Clinica Corominas, Santiago, Dominican Republic
  62. 62Rheumatology Department, Hospital Universitario Madrid Norte Sanchinarro, Madrid, Spain
  63. 63Department of Dermatology and Allergy of the TU Munich, Munich, Germany
  64. 64Department of Rheumatology and Collagenopathies, Osteoarticular Diseases and Osteoporosis Centre, Pharmacology and Clinical Pharmacological Research Centre, School of Medicine-University of Buenos Aires, Ramos Mejía Hospital, Buenos Aires, Argentina
  65. 65Department of Rheumatology, Hospital Universitario Dr Peset, Valencia, Spain
  66. 66Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
  67. 67INSERM, CépiDc, Le Kremlin- Bicêtre, Le Kremlin-Bicêtre, France
  68. 68Department of Experimental and Clinical Medicine, Section of Internal Medicine and Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), University of Florence, Florence, Italy
  1. Correspondence to Professor Yannick Allanore, Paris Descartes University Cochin Hospital, Rheumatology A department, 27 rue du Faubourg Saint Jacques 75014 Paris, France; yannick.allanore{at}cch.aphp.fr

Abstract

Objectives To determine the causes of death and risk factors in systemic sclerosis (SSc).

Methods Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.

Results We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.

Conclusion Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

  • systemic sclerosis
  • epidemiology
  • cardiovascular disease
  • pulmonary fibrosis

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Footnotes

  • Handling editor Tore K Kvien

  • Contributors ME, CM and YA formulated the study hypotheses and contributed to its design and analysis of the data, literature search, composition of the tables and figures, and redaction of the first draft and subsequent iterations of the manuscript. ME, MB and CM performed the statistical analyses. JA, EH, ABG, GR, PA, BJ, SV, FC, SU, LC, MT, UML, PC, OD, FI, LPA, RH, RB, AG, ND, MJS, VR, CM, GS, UAW, NH, DM, VS, CDSM, CMM, DO, FI, PGV, BS, ER, SH, JHWD, TZ, MS, AV, EDL, SN, MC, LM, JH, CC, CAVM, KS, SR, LS, BA, VOS, MDS, SY, WASG, EC, JS, JVL, EL, PGDPL, KE, VC, JJAS, OKB, MMC and YA conceived and launched the EUSTAR database, collected data in their respective countries and offered critical comments regarding the manuscript. GR retrieved the death certificates of patients and of the general population and offered critical comments regarding the manuscript.

  • Funding This study was funded by the “Institut national de la santé et de la recherche médicale (INSERM)” (French National Health and Medical Research Institute).

  • Competing interests OD reports personal fees from 4D Science, grants and personal fees from Actelion, personal fees from Active Biotech, grants and personal fees from Bayer, personal fees from Biogen Idec, personal fees from BMS, grants and personal fees from Boehringer Ingelheim, personal fees from ChemomAb, personal fees from EpiPharm, personal fees from EspeRare Foundation, personal fees from Genentech/Roche, personal fees from GSK, personal fees from Inventiva, personal fees from Lilly, personal fees from Medac, personal fees from Mepha, personal fees from MedImmune, personal fees from Pharmacyclics, grants and personal fees from Pfizer, grants and personal fees from Sanofi, personal fees from Serodapharm, personal fees from Sinoxa, personal fees from AbbVie, personal fees from iQone Healthcare, outside the submitted work. In addition, OD has a patent mir-29 for the treatment of systemic sclerosis licensed. FI reports personal fees from AbbVie, personal fees from BMS, personal fees from MSD, personal fees from Novartis, outside the submitted work. JHWD reports personal fees from Actelion, grants and personal fees from Anamar, grants and personal fees from Bayer Pharma, grants and personal fees from Boehringer Ingelheim, grants from Celgene, personal fees from Galapagos, grants from GSK, grants and personal fees from Inventiva, personal fees from Pfizer, grants and personal fees from UCB, grants from Novartis, other from 4D Science, outside the submitted work. JvL reports personal fees from Pfizer, grants and personal fees from MSD, personal fees from Eli Lilly, personal fees from BMS, personal fees from Roche, outside the submitted work. Other coauthors have nothing to disclose.

  • Patient consent Obtained.

  • Ethics approval Local ethics committee.

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

  • Data sharing statement Data may be available from EUSTAR upon separate scientific request.

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