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Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial
  1. Renaud Felten1,
  2. Valérie Devauchelle-Pensec2,
  3. Raphaèle Seror3,
  4. Pierre Duffau4,
  5. David Saadoun5,
  6. Eric Hachulla6,
  7. Hatron Pierre Yves6,
  8. Carine Salliot7,
  9. Aleth Perdriger8,
  10. Jacques Morel9,
  11. Arsène Mékinian10,
  12. Olivier Vittecoq11,
  13. Jean-Marie Berthelot12,
  14. Emanuelle Dernis13,
  15. Veronique Le Guern14,
  16. Philippe Dieudé15,
  17. Claire Larroche16,
  18. Christophe Richez17,
  19. Thierry Martin18,
  20. Charles Zarnitsky19,
  21. Gilles Blaison20,
  22. Pierre Kieffer21,
  23. François Maurier22,
  24. Azeddine Dellal23,
  25. Stephanie Rist7,
  26. Emmanuel Andres18,
  27. Anne Contis4,
  28. Emmanuel Chatelus1,
  29. Christelle Sordet1,
  30. Jean Sibilia1,
  31. Cécile Arnold24,
  32. Mira Y Tawk24,
  33. Ouafaa Aberkane24,
  34. Lise Holterbach25,
  35. Patrice Cacoub5,
  36. Alain Saraux2,
  37. Xavier Mariette3,
  38. Nicolas Meyer25,
  39. Jacques-Eric Gottenberg1
  1. 1 Rheumatology, CHU Strasbourg, Centre National de Référence des maladies auto-immunes et systémiques rares Est/Sud-Ouest (RESO), Strasbourg, Alsace, France
  2. 2 Rheumatology, Hospital Cavale-Blanche, Brest, Bretagne, France
  3. 3 Rheumatology, Université Paris-Sud BU Kremlin-Bicêtre, Le Kremlin-Bicetre, Île-de-France, France
  4. 4 Internal Medicine, CHU de Bordeaux, Bordeaux, Aquitaine, France
  5. 5 University Hospital Pitié Salpêtrière, Paris, Île-de-France, France
  6. 6 Internal Medicine, Regional and University Hospital Centre Lille Internal Medicine Service, Lille, Hauts-de-France, France
  7. 7 Rheumatology, Regional Hospital Centre Orleans La Source Hospital, Orleans, Centre, France
  8. 8 Rheumatology, University Hospital Centre Rennes, Rennes, Bretagne, France
  9. 9 CHU Lapeyronie, Montpellier, Languedoc-Roussillon, France
  10. 10 Internal Medicine, Hospital Saint-Antoine, Paris, Île-de-France, France
  11. 11 Rheumatology, University Hospital Centre Rouen, Rouen, Normandie, France
  12. 12 Rheumatology, Hotel Dieu, Nantes, Pays de la Loire, France
  13. 13 Rheumatology, CH Le Mans, Le Mans, Pays de la Loire, France
  14. 14 Internal Médicine, Hôpital Cochin, Paris, Île-de-France, France
  15. 15 Rheumatology, Hôpital Bichat Claude-Bernard, Paris, Île-de-France, France
  16. 16 Internal Medicine, Hospital Avicenne, Bobigny, Île-de-France, France
  17. 17 Rheumatology, CHU Bordeaux GH Pellegrin, Bordeaux, Aquitaine, France
  18. 18 Internal Medicine, CHU Strasbourg, Strasbourg, Alsace, France
  19. 19 Rheumatology, Hôpital Jacques Monod, Montivilliers, Normandy, France
  20. 20 Internal Medicine, CH Colmar, Colmar, Alsace, France
  21. 21 Internal Medicine, CH Mulhouse, Mulhouse, Grand Est, France
  22. 22 Internal Medicine, Sainte Blandine Hospital, Metz, Lorraine, France
  23. 23 Rheumatology, GHI Le Raincy-Montfermeil, Montfermeil, Île-de-France, France
  24. 24 DRCI, CHU Strasbourg, Strasbourg, Alsace, France
  25. 25 Public Health, Methods in Clinical Research Team, Hopitaux universitaires de Strasbourg, Strasbourg, Alsace, France
  1. Correspondence to Dr Jacques-Eric Gottenberg, Hopital de Hautepierre, Strasbourg 67000, France; jacques-eric.gottenberg{at}chru-strasbourg.fr

Abstract

Objectives No immunomodulatory drug has been approved for primary Sjögren’s syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren’s syndrome-related systemic complications.

Methods Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren’s syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren’s Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician’s global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment.

Results 110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of −11.4% (95% credible interval −30.6 to 9.0) (Pr[Toc >Pla]=0.14).

Conclusion Among patients with primary Sjögren’s syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo.

Trial registration number NCT01782235.

  • Sjogren's syndrome
  • biological therapy
  • cytokines

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors All authors contributed to the study by their substantial contribution to the design of the study, acquisition of data and data interpretation. J-EG, LH and NM had access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors read the manuscript. All individuals included in the Acknowledgements section gave their permission to the corresponding author, who confirms that such permission has been obtained in the Authorship Form.

  • Funding The study was sponsored by Hôpitaux Universitaires de Strasbourg. Roche Chugai provided tocilizumab and the placebo and a grant to fund the study but had no role in the study design, data collection, analysis, interpretation or manuscript preparation, revision or approval of the manuscript. The French patient’s association (Association Française du Gougerot-Sjögren et des Syndromes Secs, AFGS) gave a grant to fund the study.

  • Competing interests J-EG received honoraries and research grants from BMS and Pfizer, and honoraries from CSL Behring, Lilly, Janssen, UCB, Roche. All other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years, no other relationships or activities that could appear to have influenced the submitted work.

  • Patient consent for publication Not required.

  • Ethics approval The protocol was reviewed and approved by the local institutional review board (Comité de Protection des Personnes Est IV; number: 12/30b). The study was conducted according to the current regulations of the International Conference on Harmonisation guidelines and the principles of the Declaration of Helsinki. Informed consent was obtained from all patients.

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

  • Data availability statement Data are available upon reasonable request. Data can be requested from the scientific committee of the trial.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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