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Extended report
Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides
  1. Benjamin Terrier1,
  2. Christian Pagnoux1,2,
  3. Élodie Perrodeau3,
  4. Adexandre Karras4,
  5. Chahera Khouatra5,
  6. Olivier Aumaître6,
  7. Pascal Cohen1,
  8. Olivier Decaux7,
  9. Hélène Desmurs-Clavel8,
  10. François Maurier9,
  11. Pierre Gobert10,
  12. Thomas Quémeneur11,
  13. Claire Blanchard-Delaunay12,
  14. Bernard Bonnotte13,
  15. Pierre-Louis Carron14,
  16. Eric Daugas15,
  17. Marize Ducret16,
  18. Pascal Godmer17,
  19. Mohamed Hamidou18,
  20. Olivier Lidove19,
  21. Nicolas Limal20,
  22. Xavier Puéchal1,
  23. Luc Mouthon1,
  24. Philippe Ravaud3,
  25. Loïc Guillevin1,21
  26. on behalf of the French Vasculitis Study Group
    1. 1Department of Internal Medicine, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, INSERM Unité 1016, Centre de Référence pour les Maladies Auto-immunes Rares, Paris, France
    2. 2Department of Rheumatology, Mount Sinai Hospital, Toronto, Ontario, Canada
    3. 3Centre d’Epidémiologie Clinique, Hôpital Hôtel-Dieu, Université Paris Descartes, INSERM Unité 738, Paris, France
    4. 4Unité de Néphrologie, Hôpital Européen Georges-Pompidou, Université Paris Descartea, Paris, France
    5. 5Service de Pneumologie, Centre de Référence pour Maladies Pulmonaires Rares, Hôpital Universitaire Louis Pradel, Lyon, France
    6. 6Service de Médecine Interne, Centre Hospitalier Universitaire, Hôpital Gabriel Montpied, Clermont-Ferrand, France
    7. 7Département de Médecine Interne, Hôpitaux Universitaires de Rennes, Hôpital Sud, Université Rennes I, IGDR–UMR 6290, Rennes, France
    8. 8Service de Médecine Interne, Hôpital Edouard Herriot, Lyon, France
    9. 9Service de Médecine Interne et d’Immunologie Clinique, Site Belle Isle, HPM, Metz, France
    10. 10Département de Médecine Interne, Centre Hospitalier Bretagne Atlantique de Vannes, Vannes, France
    11. 11Département de Néphrologie and Département de Médecine Interne, Centre Hospitalier de Valenciennes, Valenciennes, France
    12. 12Service de Médecine Interne, Centre Hospitalier Général de Niort, Niort, France
    13. 13Service de Médecine Interne et d’Immunologie Clinique, Centre Hospitalier Universitaire de Dijon, Université de Bourgogne, IFR100, Dijon, France
    14. 14Service de Néphrologie, Dialyse et Transplantation, Centre Hospitalier Universitaire de Grenoble, Grenoble, France
    15. 15Service de Néphrologie, INSERM Unité 699, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université Paris Diderot, Paris, France
    16. 16Département de Néphrologie, Hôpital d’Annecy, Annecy, France
    17. 17Service de Médecine Interne, Clinique Rhône Durance, Avignon, France
    18. 18Département de Médecine Interne, Centre Hospitalier Universitaire Hôtel-Dieu, Nantes, France
    19. 19Département de Médecine Interne, Hôpital La Croix Saint-Simon, Paris, France
    20. 20Service de Médecine Interne, Centre de Référence Labellisé pour la Prise en Charge des Cytopénies Auto-immunes de l’Adulte, Hôpital Henri Mondor, Assistance Publique–Hôpitaux de Paris, Vasculitis Clinic, Créteil, France
    21. 21Hôpital Cochin, Centre de Référence Maladies Systémiques et Autoimmunes Rares, AP HP, Université Paris Descartes, Service de Médecine Interne, Paris, France
    1. Correspondence to Dr Benjamin Terrier, Department of Internal Medicine, Hôpital Cochin, 75014 Paris, France; benjamin.terrier{at}aphp.fr

    Abstract

    Objective To compare long-term efficacy of remission-maintenance regimens in patients with newly diagnosed or relapsing antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides.

    Methods The 28-month Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis trial compared rituximab with azathioprine to maintain remission in patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis or renal-limited ANCA-associated vasculitis. Thereafter, prospective patient follow-up lasted until month 60. The primary endpoint was the major-relapse rate at month 60. Relapse and serious adverse event-free survival were also assessed.

    Results Among the 115 enrolled patients, only one was lost to follow-up at month 60. For the azathioprine and rituximab groups, respectively, at month 60, the major relapse-free survival rates were 49.4% (95% CI 38.0% to 64.3%) and 71.9% (95% CI 61.2% to 84.6%) (p=0.003); minor and major relapse-free survival rates were 37.2% (95% CI 26.5% to 52.2%) and 57.9% (95% CI 46.4% to 72.2%) (p=0.012); overall survival rates were 93.0% (95% CI 86.7% to 99.9%) and 100% (p=0.045) and cumulative glucocorticoid use was comparable. Quality-adjusted time without symptoms and toxicity analysis showed that rituximab-treated patients had 12.6 months more without relapse or toxicity than those given azathioprine (p<0.001). Antiproteinase-3-ANCA positivity and azathioprine arm were independently associated with higher risk of relapse. HRs of positive ANCA to predict relapse increased over time.

    Conclusion The rate of sustained remission for ANCA-associated vasculitis patients, following rituximab-based or azathioprine-based maintenance regimens, remained superior over 60 months with rituximab, with better overall survival.

    Trial registration number NCT00748644.

    • systemic vasculitis
    • granulomatosis with polyangiitis
    • treatment

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors BT, CP and LG contributed to data collection, data analysis and interpretation, manuscript preparation and review. EP and PR contributed to data analysis and interpretation, manuscript preparation and review. AK, CK, OA, PC, OD, HD-C, FM, PG, TQ, CB-D, BB, P-LC, ED, MD, PG, MH, OL, NL, XP and LM contributed to data generation, analysis and interpretation and manuscript preparation.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests BT has received lecture fees from Roche/Genentech and advisory board fees from ChemoCentryx. CP has received research grants and lecture fees from Roche/Genentech and advisory board fees from ChemoCentryx and Sano.

    • Patient consent Obtained

    • Ethics approval Local Institutional Review Board, CPP Paris Ile de France 3.

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

    • Data sharing statement All study data are included in this manuscript.

    • Collaborators A complete list of additional investigators and members of the French Vasculitis Study Group. The authors’ full names and academic degrees are as follows: Florence Vendé, MD, Maxime Samson, MD, PhD, Pierre‑Yves Hatron, MD, PhD, Abdeldjallil Koreichi, MD, Alain Ramassamy, MD, Hélène Francois, MD, PhD, Ali Boumallassa, MD, Anne-Bérangère Beucher, MD, Aurélien Delluc, MD, PhD, Bruno Graffin, MD, Catherine Hanrotel-Saliou, MD, Claire Grange, MD, David Launay, MD, PhD, Denis Bagnères, MD, Edouard Begon, MD, Frédéric Grassin, MD, Frédérique Bocquentin, MD, Guillaume Gondran, MD, Isabelle Delacroix, MD, Isabelle Guichard, MD, Isabelle Marie, MD, PhD, Jaques Pourrat, MD, PhD, Jean-François Viallard, MD, PhD, Benoit Wallaert, MD, PhD, Laure Lahaxe, MD, Laurence Vrigneaud, MD, Marc Fabre, MD, Marie Frimat, MD, Marie Lino, MD, Martine Gayraud, MD, Matthias Buchler, MD, PhD, Myriam Niel-Duriez, MD, Nolwenn Rabot, MD, Raphaèle Seror, MD, Ph.D., Roderich Meckenstock, MD, Serge Perrot, MD, PhD, Serge Seiberras, MD, Robin Dhote, MD, PhD, Vincent Poindron, MD, Virginie Rieu, MD, Xavier Delbrel, MD, Xavier Kyndt, MD, Yann Ollivier, MD.

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