Comparison Between Long-Term and Conventional Rituximab-Maintenance Treatments: Results of a Placebo-Controlled Randomized Trial

Pierre Charles¹, Elodie Perrodeau ², Maxime Samson ³, Bernard Bonnotte ⁴, Mohamed Hamidou ⁵, Christian Agard ⁵, Antoine Huart ⁶, Alexandre Karras ⁷, François Lifermann ⁸, Pascal Godmer ⁹, Pascal Cohen ¹⁰, Catherine Hanrotel-Saliou ¹¹, Nicolas Martin-Silva ¹², Grégory Pugnet ¹³, François Maurier ¹⁴, Jean Sibilia ¹⁵, Pierre-Louis Carron ¹⁶, Pierre Gobert ¹⁷, Nadine Meaux Ruault ¹⁸, Thomas Le Gallou ¹⁹, Stéphane Vinzio ²⁰, Jean-François Viallard ²¹, Eric Hachulla ²², Christine Vinter ², Xavier Puéchal for the French Vasculitis Study Group ¹⁰, Benjamin Terrier ¹⁰, Philippe Ravaud ², Luc Mouthon ¹⁰ and Loic Guillevin ¹⁰, ¹Institut Mutualiste Montsouris, Paris, France, ²APHP, Paris, France, ³CHU Dijon, Dijon, France, ⁴Service de Médecine Interne et Immunologie Clinique, CHU Dijon Bourgogne, Hôpital François Mitterrand, Dijon ; Université Bourgogne-Franche Comté, INSERM, EFS BFC, UMR1098, F-21000 Dijon, Dijon, France, ⁵CHU Nantes, Nantes, France, ⁶CHU Toulouse, Toulouse, France, ⁷Paris HEGP, Paris, France, ⁸CH Dax, Dax, France, ⁹CH Bretagne-Atlantique, Vannes, France, ¹⁰National Referral Center for Rare Systemic Autoimmune Diseases Paris Cochin, Paris, France, ¹¹CHU Brest, Brest, France, ¹²CHU Caen, Caen, France, ¹³CHU de Toulouse, Hôpital Purpan, Service de Médecine Interne, Toulouse, France, ¹⁴Service de Médecine Interne, Hôpital Belle Isle, Metz, Metz, France, ¹⁵CHU Strasbourg, Strasbourg, France, ¹⁶Grenoble, Grenoble, France, ¹⁷CH Avignon, Avignon, France, ¹⁸CHU Besançon, Besançon, France, ¹⁹CHU Rennes, Rennes, France, ²⁰GHM Grenoble, Grenoble, France, ²¹CHU Bordeaux, Bordeaux, France, ²²Dept. of Internal Medicine and Clinical Immunology, Hôpital Claude Huriez, University of Lille, Lille, France, Lille, France

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: ANCA and systemic vasculitides

Session Information

Date: Tuesday, November 12, 2019

Title: Vasculitis – ANCA-Associated Poster I

Session Type: Poster Session (Tuesday)

Session Time: 9:00AM-11:00AM

Background/Purpose: MAINRITSAN-trial results¹ demonstrated rituximab superiority (500 mg on days 0 and 14, then at months 6, 12 and 18) to azathioprine to maintain remission of ANCA-associated vasculitides (AAVs). In that trial, at month 28, 5% of rituximab-treated patients had experienced a major relapse but, at month 60 of follow-up, major relapse-free survival was 49.4%.²

The MAINRITSAN3 trial (NCT02433522) aimed to evaluate the efficacy of long-term rituximab administration to prevent AAV relapses in patients in remission after a first phase of rituximab-maintenance therapy.

Methods: To be included, patients had to have been enrolled in the MAINRITSAN2 trial³(randomized–controlled trial comparing 2 rituximab-infusion strategies for patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy: tailored-arm patients received a 500-mg rituximab infusion at randomization, with rituximab reinfusion only when CD19+ B lymphocytes or ANCA had reappeared or ANCA titer rose markedly; controls received a fixed 500-mg rituximab infusion on days 0 and 14 postrandomization, then at months 6, 12 and 18) and be in complete remission at the end of MAINRITSAN2 at month 28. At that time, patients were enrolled in MAINRITSAN3 and re-randomized to receive 4 more rituximab infusions, at inclusion and months 34, 40 and 46, or a placebo. Premedication for all patients comprised acetaminophen (1000 mg), methylprednisolone (100 mg) and dexchlorpheniramine (5 mg).

The primary endpoint was relapse-free survival at 56 months. Relapse was defined as new or reappearing symptom(s) or worsening disease with BVAS >0 and was evaluated by an independent Adjudication Committee.

Results: Between March 2015 and April 2016, 97 patients were enrolled in MAINRITSAN3 in 45 centers in France: 50 to receive rituximab and 47 placebo-group controls. Their mean age was 63.9 years, 35.1% were women, 68 (70.1%) had GPA and 29 (29.9%) had MPA, and 50% were ANCA-positive at enrollment. Comparing rituximab vs placebo groups, respectively: relapse-free survival rates were 96% [95% confidence interval (CI), 90.7–100%] vs 74.3% [62.8–88%], hazard ratio: 7.5 [1.67–33.6%] (p=0.008); major relapse-free survival rates were 100% [100–100%] vs 87.1% [78–97.3%] (p=0.009). Twelve (24%) rituximab recipients vs 14 (29.8%) controls had at least 1 severe adverse event (SAE) (p=0.65). No patient died. Six (12%) rituximab recipients had 9 infectious SAEs (septic shock or urinary, 2 each; Lyme disease, acute cholangitis, neutropenia, bronchitis or pneumonia, 1 each) vs 4 (8.5%) controls with 6 (4 pneumonia, 1 flu or 1 Pneumocystis jiroveci infection in a patient receiving methotrexate and glucocorticoids postrelapse after study discontinuation).

Conclusion: Long-term rituximab maintenance achieved significantly lower AAV relapse rates. SAEs were not more frequent in rituximab recipients.

1 Guillevin L et al. N Engl J Med 2014;371:1771–80

2 Terrier B et al. Ann Rheum Dis 2018;77:1150–6

3 Charles P et al. Ann Rheum Dis 2018;77:1143–9

Disclosure: P. Charles, None; E. Perrodeau, None; M. Samson, None; B. Bonnotte, None; M. Hamidou, Roche, 8; C. Agard, None; A. Huart, None; A. Karras, Roche, 8; F. Lifermann, None; P. Godmer, None; P. Cohen, None; C. Hanrotel-Saliou, None; N. Martin-Silva, None; G. Pugnet, None; F. Maurier, None; J. Sibilia, None; P. Carron, None; P. Gobert, None; N. Meaux Ruault, None; T. Le Gallou, None; S. Vinzio, None; J. Viallard, None; E. Hachulla, Actelion, 2, 5, Bayer, 2, 5, Chugai Pharma France, 8, GSK, 2, 5, Pfizer, 2, 5, Roche SAS, 5; C. Vinter, None; X. Puéchal for the French Vasculitis Study Group, LFB, 8, Pfizer, 2, 8, Roche, 8; B. Terrier, Grifols, 8, GSK, 8, LFB, 8, Roche, 8; P. Ravaud, None; L. Mouthon, None; L. Guillevin, None.

To cite this abstract in AMA style:

Charles P, Perrodeau E, Samson M, Bonnotte B, Hamidou M, Agard C, Huart A, Karras A, Lifermann F, Godmer P, Cohen P, Hanrotel-Saliou C, Martin-Silva N, Pugnet G, Maurier F, Sibilia J, Carron P, Gobert P, Meaux Ruault N, Le Gallou T, Vinzio S, Viallard J, Hachulla E, Vinter C, Puéchal for the French Vasculitis Study Group X, Terrier B, Ravaud P, Mouthon L, Guillevin L. Comparison Between Long-Term and Conventional Rituximab-Maintenance Treatments: Results of a Placebo-Controlled Randomized Trial [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/comparison-between-long-term-and-conventional-rituximab-maintenance-treatments-results-of-a-placebo-controlled-randomized-trial/. Accessed .

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