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Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2)
  1. Pierre Charles1,2,
  2. Benjamin Terrier1,
  3. Élodie Perrodeau3,
  4. Pascal Cohen1,
  5. Stanislas Faguer4,
  6. Antoine Huart4,
  7. Mohamed Hamidou5,
  8. Christian Agard5,
  9. Bernard Bonnotte6,
  10. Maxime Samson6,
  11. Alexandre Karras7,
  12. Noémie Jourde-Chiche8,
  13. François Lifermann9,
  14. Pierre Gobert10,
  15. Catherine Hanrotel-Saliou11,
  16. Pascal Godmer12,
  17. Nicolas Martin-Silva13,
  18. Grégory Pugnet14,
  19. Marie Matignon15,
  20. Olivier Aumaitre16,
  21. Jean-François Viallard17,
  22. François Maurier18,
  23. Nadine Meaux-Ruault19,
  24. Sophie Rivière20,
  25. Jean Sibilia21,
  26. Xavier Puéchal1,
  27. Philippe Ravaud3,
  28. Luc Mouthon1,
  29. Loïc Guillevin1
  30. for the French Vasculitis Study Group
  1. 1Internal Medicine, Referral Center for Rare Systemic and Autoimmune Diseases: Vasculitis and Scleroderma, Cochin Hospital, Paris Descartes University, Paris, France
  2. 2Department of Internal Medicine, Institut Mutualiste Montsouris, Paris, France
  3. 3Centre d’Epidémiologie Clinique, Hôpital Hôtel-Dieu, Université Paris Descartes, Sorbonne Paris Cité, INSERM Unité 1153, Paris, France
  4. 4Département de Néphrologie et Transplantation d’Organes, CHU de Toulouse, Toulouse, France
  5. 5Service de Médecine Interne, Hôtel-Dieu, Centre Hospitalier Universitaire, Nantes, France
  6. 6Service de Médecine Interne et Immunologie Clinique, Centre Hospitalier Universitaire de Dijon, INSERM, UMR 1098, University of Bourgogne Franche-Comté, FHU INCREASE, Dijon, France
  7. 7Unité de Néphrologie, Hôpital Européen Georges-Pompidou, Université Paris Descartes, Paris, France
  8. 8Aix Marseille Univ, Centre de Néphrologie et de Transplantation Rénale, AP-HM, Hôpital de la Conception, Marseille, France
  9. 9Service de Médecine Interne Hématologie, Centre Hospitalier de Dax, Dax, France
  10. 10Pôle médecine, Hôpital Général Henri-Duffaut, Avignon, France
  11. 11Service de Néphrologie, Dialyse et Transplantation Rénale, Hôpital la Cavale Blanche, CHRU Brest, Brest, France
  12. 12Département de Médecine Interne, Centre Hospitalier Bretagne Atlantique de Vannes, Vannes, France
  13. 13Unité de Médecine Interne, CHU de Caen, Caen, France
  14. 14Service de Médecine Interne, CHU de Toulouse, Toulouse, France
  15. 15Service de Néphrologie, Hôpital Henri-Mondor, Créteil, France
  16. 16Service de Médecine Interne, Centre Hospitalier Universitaire, Hôpital Gabriel-Montpied, Clermont-Ferrand, France
  17. 17Service de Médecine Interne et Maladies Infectieuses, CHU de Bordeaux, Pessac, France
  18. 18Service de Médecine Interne, Hôpitaux privés de Metz, Metz, France
  19. 19Service de Médecine Interne, Centre Hospitalier Universitaire Jean-Minjoz, Besançon, France
  20. 20Service de Médecine Interne, CHU de Montpellier, Montpellier, France
  21. 21Service de Rhumatologie, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France
  1. Correspondence to Professor Loïc Guillevin, Department of Internal Medicine, Hôpital Cochin, Paris 75679, France; loic.guillevin{at}orange.fr

Abstract

Objective To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs).

Methods Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group.

Results Among the 162 patients (mean age: 60 years; 42% women) included, 117 (72.2%) had GPA and 45 (27.8%) had MPA. Preinclusion induction therapy included cyclophosphamide for 100 (61.7%), rituximab for 61 (37.6%) and methotrexate for 1 (0.6%). At month 28, 21 patients had suffered 22 relapses: 14/81 (17.3%) in 13 tailored-infusion recipients and 8/81 (9.9%) in 8 fixed-schedule patients (p=0.22). The tailored-infusion versus fixed-schedule group, respectively, received 248 vs 381 infusions, with medians (IQR) of 3 (2–4) vs 5 (5–5) administrations.

Conclusion AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions.

Trial registration number NCT01731561; Results.

  • ANCA vasculitis
  • ANCA
  • CD19+ B lymphocytes
  • granulomatosis with polyangiitis
  • microscopic polyangiitis

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors PCh and LG conceived and planned the study. ÉP and PR designed and carried out the statistical analyses. PCh wrote the first draft of the manuscript and all authors contributed to subsequent revisions. All other authors entered data, participated in devising the protocol and reviewed all versions of the manuscript.

  • Funding This study was funded by a research grant from the French Ministry of Health (PHRC National 2011 AOM11145) and sponsored by the Assistance Publique–Hôpitaux de Paris. Hoffmann-La Roche provided rituximab for the study.

  • Competing interests BT has received consulting and speaking fees (Roche, LFB, Grifols, GSK). MH has received personal fees from Roche. AK has received personal fees and non-financial support from Roche. XP has received speaking fees and honoraria (Pfizer, LFB, Roche) and a research grant (Pfizer).

  • Patient consent Obtained.

  • Ethics approval The Ethics Committee (Comité de Protection des Personnes Île-de-France 1 (Paris)) approved the study.

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

  • Collaborators Other investigators and members of the French Vasculitis Study Group who participated in the study are listed in the online supplementary.

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