Article Text

Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials
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  1. Florence Delestre1,2,
  2. Pierre Charles2,3,
  3. Alexandre Karras2,4,
  4. Christian Pagnoux5,6,
  5. Antoine Néel7,
  6. Pascal Cohen1,
  7. Olivier Aumaître8,
  8. Stanislas Faguer9,
  9. Pierre Gobert10,
  10. François Maurier11,
  11. Maxime Samson12,
  12. Pascal Godmer13,
  13. Bernard Bonnotte12,
  14. Vincent Cottin14,
  15. Catherine Hanrotel-Saliou15,
  16. Thomas Le Gallou16,
  17. Pierre-Louis Carron17,
  18. Hélène Desmurs-Clavel18,
  19. Guillaume Direz19,
  20. Noémie Jourde-Chiche20,
  21. Francois Lifermann21,
  22. Nicolas Martin-Silva22,
  23. Grégory Pugnet23,
  24. Thomas Quéméneur24,
  25. Marie Matignon25,
  26. Ygal Benhamou26,
  27. Eric Daugas27,
  28. Estibaliz Lazaro28,
  29. Nicolas Limal29,
  30. Maïzé Ducret30,
  31. Antoine Huart31,
  32. Jean-François Viallard28,
  33. Eric Hachulla32,
  34. Elodie Perrodeau33,
  35. Xavier Puechal1,2,
  36. Loïc Guillevin1,2,
  37. Raphaël Porcher2,33,
  38. Benjamin Terrier1,2
  39. for the French Vasculitis Study Group (FVSG)
    1. 1 Department of Internal Medicine, National Reference Center for Rare Systemic Autoimmune Diseases, AP-HP.Centre, Hospital Cochin, Paris, France
    2. 2 Université Paris Cité, Paris, France
    3. 3 Department of Internal Medicine, Institut Mutualiste Montsouris, Paris, France
    4. 4 Department of Nephrology, Hôpital Européen Georges Pompidou, APHP, Paris, France
    5. 5 University of Toronto, Toronto, Ontario, Canada
    6. 6 Vasculitis clinic, Mount Sinai Hospital, Toronto, Ontario, Canada
    7. 7 Department of Internal Medicine, Centre Hospitalier Universitaire de Nantes, Nantes, France
    8. 8 Department of Internal Medicine, Hôpital Gabriel Montpied, Clermont-Ferrand, France
    9. 9 Département de Néphrologie et Transplantation d’Organes, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
    10. 10 Département de médecine, Hopital Général Henri-Duffaut, Avignon, France
    11. 11 Department of Internal Medicine, Hôpitaux Privés de Metz, Metz, France
    12. 12 Département de Médecine Interne et Immunologie Clinique, Centre Hospitalier Universitaire de Dijon, Dijon, France
    13. 13 Département de Hématologie Immunologie, Centre Hospitalier Bretagne Atlantique de Vannes, Vannes, France
    14. 14 Department of Respiratory Medicine, National Coordinating Reference Center for Rare Pulmonary Diseases, Louis Pradel Hospital, Lyon, France
    15. 15 Department of Nephrology, Centre Hospitalier Universitaire de Brest, Hôpital la Cavale Blanche, Brest, France
    16. 16 Department of Internal Medicine, Centre Hospitalier Universitaire de Rennes, Rennes, France
    17. 17 Département de néphrologie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
    18. 18 Department of Internal Medicine, Hôpital Edouard Herriot, Lyon, France
    19. 19 Rheumatology Department, Le Mans General Hospital, Le Mans, France
    20. 20 Centre de Néphrologie et Transplantation Rénale, Hôpital de La Conception, Aix-Marseille Université, Marseille, France
    21. 21 Department of Internal Medicine, Centre Hospitalier de Dax, Dax, France
    22. 22 Department of Internal Medicine, Centre Hospitalier Universitaire de Caen, Caen, France
    23. 23 Department of Internal Medicine, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
    24. 24 Département de Néphrologie et de Médecine Interne, Centre Hospitalier de Valenciennes, Valenciennes, France
    25. 25 Nephrology and Renal Transplantation Department, Hopitaux Universitaires Henri Mondor, Créteil, France
    26. 26 Department of Internal Medicine, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France
    27. 27 Department of Nephrology, Hopital Bichat - Claude-Bernard, Paris, France
    28. 28 Department of Internal Medicine, Bordeaux University Hospital, Pessac, France
    29. 29 Department of Internal Medicine, Hôpitaux Universitaires Henri Mondor, Créteil, France
    30. 30 Department of Nephrology, Annecy Hospital, Annecy, France
    31. 31 Department of Nephrology, Hospital Rangueil, Toulouse, France
    32. 32 Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Systémiques et Auto-Immunes Rares du Nord-Ouest (CERAINO), Centre Hospitalier Universitaire de Lille, Lille, France
    33. 33 Center of Research in Epidemiology and Statistics Sorbonne Paris Cité, Paris, France
    1. Correspondence to Dr Benjamin Terrier, Department of Internal Medicine, Hôpital Cochin, Paris, 75679, France; benjamin.terrier{at}aphp.fr

    Abstract

    Objective To compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively).

    Methods The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84.

    Results 277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25).

    Conclusions According to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.

    • Rituximab
    • Systemic vasculitis
    • Autoimmune Diseases

    Data availability statement

    Data are available upon reasonable request.

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Over the past decade, randomised controlled trials have progressively established rituximab (RTX) as the gold standard for maintenance therapy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), starting with the Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trial, which showed that RTX was superior to azathioprine (AZA) for maintaining remission at 28 months. MAINRITSAN2 and MAINRITSAN3 then compared 18 months of fixed-schedule RTX with an individually tailored regimen (MAINRITSAN2), and four additional 500 mg RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). However, the optimal RTX schedule and duration remain unknown, and long-term follow-up of these trials is needed to clarify the long-term risk of relapse, the long-term safety of RTX and thus, the most accurate maintenance strategy.

    WHAT THIS STUDY ADDS

    • In this long-term follow-up and pooled analysis of the 277 patients enrolled in the three MAINRITSAN trials, the largest cohort of patients prospectively followed in randomised controlled trials to date, the 84-month sustained remission rate in patients with AAV was higher with the 18-month fixed RTX regimen compared with AZA, and to the 18-month tailored RTX regimen. Extending RTX to 36 months did not appear to reduce the relapse rate compared with 18-month of fixed RTX.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • In light of these results, AZA and 18-month tailored RTX regimens should no longer be recommended for the majority of patients, and a fixed RTX regimen of at least 18 months should be considered the gold standard. With the longer follow-up of MAINRITSAN3, extending RTX from 18 to 36 months should probably only be considered in patients at high risk of relapse, as it does not appear to prevent long-term relapses.

    Introduction

    Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic inflammatory disease characterised by necrotising inflammation of the vessels wall, primarily affecting small to medium-sized vessels. AAVs include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis. The prognosis of patients with GPA and MPA has dramatically improved over the past decades with the use of glucocorticoids and immunosuppressive regimens. Since 2010, rituximab (RTX) has progressively emerged as a cornerstone treatment for both induction1–3 and maintenance therapy.4–7 The prospective, open-label, randomised, controlled Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trial showed that 500 mg fixed-schedule RTX infusions over 18 months was superior to azathioprine (AZA) for maintaining remission at 28 months,7 which was confirmed over 60 months of follow-up.8 The MAINRITSAN2 trial compared individually-tailored regimen (ie, with RTX reinfusion when CD19+ B cells or ANCA had reappeared or when ANCA titre rose) to fixed-schedule as maintenance therapy, and showed that the relapse rate at month 28 did not differ significantly between the two arms,4 despite a trend towards more relapses in patients receiving the individually-tailored regimen (17% vs 10%). Finally, the MAINRITSAN3 trial, which included patients in remission at the end of MAINRITSAN2 trial, showed that four additional RTX infusions compared with placebo was associated with lower rates of relapses (9 vs 26%),5 supporting the idea that prolonging RTX infusions could benefit in patients at increased risk of relapse. We hereby describe the pooled and long-term analysis for efficacy and safety of the three randomised controlled MAINRITSAN trials, which constitutes the largest cohort of AAV patients treated with RTX and prospectively followed to date.

    Methods

    Design

    The present study is a nationwide, prospective cohort study conducted in 39 centres in France between October 2008 and December 2020. Details on the design of the MAINRITSAN trials were reported previously4 5 7 and summarised in online supplemental figure 1. Long-term outcome data from the MAINRITSAN, MAINRITSAN2 and MAINRITSAN3 randomised controlled trials were collected by the site investigators, analysed by the Data Analysis Committee (FD, BT) and pooled.

    Supplemental material

    Briefly, patients with newly diagnosed or relapsing GPA, MPA or renal limited vasculitis in complete remission after induction therapy were included. Patients in MAINRITSAN were randomly assigned to receive either 500 mg of RTX on days 0 and 14 and at months 6, 12 and 18 after study entry (18-month fixed RTX regimen), or daily AZA until month 22. Five patients included in MAINRITSAN were second randomised in MAINRITSAN2 and their follow-up from MAINRITSAN was consequently censored at time of randomisation in MAINRITSAN2; also their follow-up in MAINRITSAN2 began at time of randomisation in MAINRITSAN2. Patients in MAINRITSAN2 received either 18 months of fixed-schedule RTX as in MAINRITSAN or 500 mg RTX infusion at randomisation with 500 mg RTX reinfusion only if peripheral CD19+B cells or ANCA reappeared or if ANCA titres increased based on trimestral testing by month 18 (18-month tailored RTX regimen). Patients who had successfully completed the MAINRITSAN2 trial without any major relapses and were in complete remission at month 28 could be enrolled and reassigned to a treatment group in the MAINRITSAN3 trial. Participants included in MAINRITSAN3 received an extended administration of four additional 500 mg RTX infusions or placebo given biannually over 18 more months, thus after either 18-month fixed schedule (36-month fixed/fixed RTX) or 18-month tailored RTX (36-month tailored/fixed RTX) according to their randomisation group in MAINRITSAN2. Patients were followed every 3 months after randomisation during 28 months in each MAINRITSAN trial; then patients were prospectively followed every 3–6 months according to their clinical status until month 84.

    Study assessments

    At each follow-up visit, data on disease activity, medications and adverse events (AEs) were collected. According to clinical status, patients’ sera were tested in each study centre for ANCA by indirect immunofluorescence, proteinase 3 (PR3) and myeloperoxidase (MPO) ANCA, CD19+ B cells, gammaglobulin and serum creatinine levels.

    Outcomes

    The primary endpoint was the time to first major relapse (reappearance or worsening of disease with Birmingham Vasculitis Activity Score (BVAS)>0 and involvement of at least one major organ or life-threatening manifestation, or both). Secondary endpoints included time to first relapse, either major or minor (reappearance or worsening of disease with BVAS>0, not corresponding to a major relapse but requiring mild treatment intensification), AEs and their severity and mortality. Follow-up was censored at time of first relapse and relapses were treated according to the site investigator’s decision. Severe adverse events (SAEs) were defined as follows: grade 3 and 4 AEs (ie, severe or medically significant requiring hospitalisation or prolongation of hospitalisation, disabling, life threatening or with urgent intervention indicated), death from any cause, cancers, cardiovascular events or infusion reactions that contraindicated further infusions.

    Statistical analyses

    Patients from the MAINRITSAN trial were assigned to their randomisation group, that is, maintenance with AZA or 18-month fixed RTX. For participants in MAINRITSAN2 trial, in order to control the immortality bias engendered by rerandomisation of non-relapsing patients in MAINRITSAN3, we used a cloning-weighting strategy by emulating what would have happened if randomisation to either 18 months or 36 months of RTX maintenance therapy had occurred immediately on enrolment in MAINRITSAN2. Accordingly, patients who were subsequently included in the MAINRITSAN3 trial in the placebo arm were assigned to either 18-month fixed-schedule RTX or 18-month individually-tailored RTX, and those included in the RTX arm of MAINRITSAN3 were assigned to either 36-month tailored/fixed RTX or 36-month fixed/fixed RTX groups, according to their randomisation arm in MAINRITSAN2. Participants to the MAINRITSAN2 trial who did not participate to the MAINRITSAN3 trial were then considered as having 50% chance to having been (virtually) assigned to either 18-month or 36-month maintenance, through cloning and weighting.9 10 Details are given in the online supplemental material.

    Supplemental material

    After pooling the data, patients were thus divided into five groups depending on the allocated maintenance regimen in the trials they had been enrolled to, and arms they had been randomised to: AZA, 18-month individually tailored RTX, 18-month fixed RTX, 36-month tailored/fixed RTX and 36-month fixed/fixed RTX. Details on participants in each group are given in the online supplemental material.

    Given the differential follow-up among the trials, participants to MAINRITSAN having longer follow-up, data were cut at relapse, death, last follow-up or month 84 from randomisation to MAINRITSAN or MAINRITSAN2, whichever occurred first. The comparison of treatment groups was performed in a one-stage individual participants data network meta-analysis model, based on a Cox model with baseline hazard stratified on the trial and adjusted for prognostic factors. Missing baseline data were handled through multiple imputations. Details on those analyses are given in the online supplemental material. By construction, differences between 18-month and 36-month RTX treatment strategies should not occur before 18 months so that non-proportional hazards are expected. Accordingly, we also quantified the treatment effect in terms of 84-month restricted mean survival difference. Analyses were performed using R V.4.0.5.

    Role of funding source

    The primary funding source was French Ministry of Health. It had no role in collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

    Patient and public involvement statement

    Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

    Results

    Patients’ characteristics

    Figure 1 illustrates the flow chart of the 277 patients enrolled in the MAINRITSAN trials. One hundred and fifteen patients were enrolled in MAINRITSAN (58 randomised to AZA, 57 to RTX). One hundred and sixty-two patients were randomised in MAINRITSAN2 (81 to 18-month fixed-RTX and 81 to 18-month tailored-RTX), of which 97 were second randomised in MAINRITSAN3 (50 to RTX and 47 to placebo). Five patients died during the trials, 6 were lost of follow-up at 28 months, and one patient withdrew consent. Overall, 265 remaining patients were followed prospectively until 31 December 2020, every 3–6 months according to their clinical status. All 277 patients were included for analysis.

    Figure 1

    Study flow chart. MAINRITSAN, Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis; RTX, rituximab.

    After pooling the data, patients were divided into five groups depending on the received maintenance regimen: (1) AZA group (n=58); (2) 18-month individually-tailored RTX group (n=40); (3) 18-month fixed RTX group (n=97); (4) 36-month tailored/fixed RTX group (n=42); (5) 36-month fixed/fixed RTX group (n=41).

    Baseline characteristics were well balanced across the MAINRITSAN cohorts (table 1). Two hundred and four patients (73.6%) had GPA, 68 (24.5%) had MPA and 5 (1.8%) had renal-limited vasculitis. One hundred and ninety-six (70.8%) had newly diagnosed disease, and 227 (81.9%) were ANCA-positive, mostly PR3-ANCA (n=152, 54.9 %). The median long-term follow-up time was 73 (51–115) (median (IQR)) months.

    Table 1

    Baseline characteristics

    Relapses

    Pooled analysis

    One hundred and thirty-four patients experienced at least one relapse, for a total of 195 relapses (major or minor) and 102 major relapses. Median time to major relapse was 25 (10–38) months after randomisation in the AZA group, and 36 (22–48) months in RTX-treated patients whatever the RTX regimens. Relapsing disease and ENT involvement were associated with an increased risk of major relapses (HR 1.92, 95% CI 1.21 to 3.05 and HR 1.71, 95% CI 1.05 to 2.79, respectively). ENT involvement and better renal function were associated with an increased risk of overall relapses (HR 1.68, 95% CI 1.12 to 2.52 and HR 1.13, 95% CI 1.06 to 1.21, respectively) (table 2). PR3-ANCA was not associated with an increased risk of relapse (HR 1.25, 95% CI 0.70 to 2.23), but MPO-ANCA negativation during induction was associated with a lower risk of major relapse (HR 0.27, 95% CI 0.10 to 0.72) and overall relapse (HR 0.21, 95% CI 0.086 to 0.51).

    Table 2

    Multivariable models for relapse

    Comparison of treatment strategies

    The 84-month major relapse-free survival was 49% (95% CI 38% to 64%) for AZA, 70% (95% CI 62% to 80%) for 18-month fixed RTX, 49% (95% CI 36% to 67%) for 18-month tailored RTX, 74% (95% CI 63% to 88%) for 36-month tailored/fixed RTX and 83% (95% CI 74% to 93%) for 36-month fixed/fixed RTX (figure 2). The 18-month fixed RTX was associated with lower risk of major relapse than AZA (HR 0.38, 95% CI 0.20 to 0.71) and 18-month tailored RTX (HR 0.34, 95% CI 0.17 to 0.70), resulting in a difference in restricted mean major relapse-free survival at 84 months of −17.5 (95% CI −27.5 to −7.5) months and −8.0 (95% CI −16.4 to 0.3) months, respectively (table 3). At month 84, 36-month fixed/fixed RTX was not associated with a lower risk of major relapse than 18-month fixed-schedule (HR 0.88, 95% CI 0.47 to 1.66) or overall relapse (HR 0.69, 95% CI 0.38 to 1.25). 84-month major relapse free survival was also similar between 36-month tailored/fixed RTX and 18-month fixed RTX (HR 1.37, 95% CI 0.61 to 3.06).

    The long-term follow-up of MAINRITSAN3, taking into account previous arm of MAINRITSAN2, showed that patients treated with individually-tailored RTX in MAINRITSAN2 followed by placebo in MAINRITSAN3 had a poorer major-relapse free survival compared to patients receiving at least 18-month of fixed-schedule RTX, either in MAINRITSAN2 or MAINRITSAN3 (figure 3).

    Figure 3

    Kaplan-Meier curve of major relapses in MAINRITSAN3 patients according to sequential treatment regimen during MAINRITSAN2 and MAINRITSAN3 (ie, individually tailored RTX then placebo, individually tailored RTX then RTX, fixed schedule RTX then placebo, and fixed schedule RTX then RTX). AZA, azathioprine; MAINRITSAN, Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis; RTX, rituximab.

    Figure 2

    Kaplan-Meier curves of major relapses (A) and overall relapses (B) according to maintenance treatment strategy (ie, AZA, 18-month fixed RTX, 18-month individually tailored RTX, 36-month tailored/fixed RTX, 36-month fixed/fixed RTX). AZA, azathioprine; RTX, rituximab.

    Table 3

    Comparison of treatment strategies

    Cumulative prednisone dose was higher for patients treated with AZA than patients treated with RTX (p=0.020) (online supplemental figure 2), but there was no significant statistical difference in cumulative prednisone dose between the four RTX groups. Relapses occurred earlier after last RTX injection in patients treated with individually-tailored RTX than in those treated with fixed-schedule RTX (p=0.020) (online supplemental figure 3).

    Supplemental material

    Supplemental material

    Adverse events

    At month 84, SAE-free survival in AZA, 18-month fixed RTX, 18-month tailored RTX, 36-month tailored/fixed RTX and 36-month fixed/fixed RTX groups were 42% (95% CI 31% to 57%), 48% (95% CI 39% to 59%), 44% (95% CI 32% to 62%), 58% (95% CI 44% to 77%) and 51% (95% CI 35% to 74%), respectively. Infections were the most frequent SAE with 75 (27%) patients presenting at least one serious infectious event (SIE). At month 84, SIE-free survival in AZA, 18-month fixed RTX, 18-month tailored RTX, 36-month tailored/fixed RTX and 36-month fixed/fixed RTX were 67% (95% CI 55% to 80%), 71% (95% CI 55% to 82%), 67% (95% CI 55% to 82%), 72% (95% CI 59% to 88%) and 74% (95% CI 62% to 88%), respectively. Nine opportunistic infections occurred (four Pneumocystis jirovecii pneumonia, one invasive aspergillosis, four mycobacterial infections), equally distributed between the groups.

    Deaths

    Five (2%) patients died during the trials (2 patients during MAINRITSAN and 3 during MAINRITSAN2) and 23 (8%) supplementary deaths occurred during follow-up. Deaths were related to infections in seven cases, cardiovascular events in six cases, cancer in five cases, uncontrolled vasculitis in one case, and to unknown causes in nine cases. At month 84, overall survival in AZA, 18-month fixed RTX, 18-month tailored RTX, 36-month tailored/fixed RTX and 36-month fixed/fixed RTX groups were 93% (95% CI 86% to 100%), 94% (95% CI 90% to 99%), 85% (95% CI 76% to 95%), 85% (95% CI 73% to 99%) and 92% (95% CI 85% to 99%), respectively.

    Discussion

    We describe here the long-term outcome of 277 patients enrolled in the three MAINRITSAN trials, which represent the largest cohort of AAV patients treated with RTX maintenance therapy in prospective randomised controlled trials to date.

    First, this long-term analysis confirms the superiority of RTX when administered every 6 months for 18 months over AZA for maintaining remission in AAV. This is consistent with the recently published RITuximab versus AZathioprine After induction of REMission (RITAZAREM) study, in which RTX given every 4 months up to month 20 was superior to AZA in preventing relapse in patients with a history of relapse.11 The relapse rate with RTX was also consistent with previously published data.12

    In the previous study reporting the 60-month follow-up of patients enrolled in the MAINRITSAN trial,8 relapses occurred rapidly after discontinuation of AZA. In contrast, relapses in the RTX arm occurred later, with only 3 patients (5%) relapsing within the first 28 months and 13 patients (23%) relapsing within 60 months, suggesting that the efficacy of RTX could be only suspensive. However, in this extended follow-up, the median time to major relapse in the RTX arm remains higher than in the AZA arm and stable over time, supporting a prolonged efficacy of RTX.

    A key issue raised by this study relates to the results of the MAINRITSAN2 trial and the apparent non-inferiority of the individually tailored RTX regimen compared with the fixed-schedule RTX regimen. The MAINRITSAN2 trial concluded that there was no significant difference in relapse rates between the 18-month individually-tailored RTX regimen and the 18-month fixed-schedule RTX regimen.4 However, as previously highlighted, MAINRITSAN2 was not a non-inferiority trial and equivalence between the two treatment arms could not be stated. In addition, the relapse rate was still numerically higher in the individually-tailored arm than in the fixed-schedule arm (17% vs 10%). Finally, as previously reported, after a 28-months follow-up, no firm conclusion could be drawn regarding the sustained efficacy of RTX, as most relapses in RTX-treated patients in MAINRITSAN occurred 18–24 months after the last RTX infusion,5 whereas follow-up duration in MAINRITSAN2 was stopped 10 months after the last infusion. After a longer follow-up and by pooling the three MAINRITSAN trials, the rate of major relapse in the 18-month individually-tailored RTX group was significantly higher than the 18-month fixed RTX group. Moreover, the long-term analysis of MAINRITSAN3 showed a significantly poorer relapse-free survival in patients successively treated with the individually-tailored regimen during MAINRITSAN2 followed by placebo during MAINRITSAN3. The difference between individually-tailored and fixed-schedule regimen, which was not significant after MAINRITSAN2, became apparent in the pooled and long-term analysis. Also, a difference in baseline characteristics between the two MAINRITSAN2 groups (more GPA patients with PR3-ANCA, and higher baseline eGFR in the fixed-RTX arm) possibly penalised the fixed-RTX arm short term, and allowed the benefit of fixed-RTX to be detected only on the longer term. In the light of these long-term results, the 18-month individually-tailored regimen should no longer be prescribed except in rare situations.

    The optimal duration of RTX maintenance treatment is still controversial. Indeed, prior to the widespread use of RTX to maintain remission, the randomised trial of prolonged REMission-MAINtenance therapy in systemic vasculitis (REMAIN) trial demonstrated the superiority of prolonging maintenance therapy with AZA and low-dose prednisone for 48 months versus 24 months on relapse prevention and renal survival.13 The MAINRITSAN3 trial suggested that 36 months of RTX was superior to 18 months of RTX, with relapse rates of 4% versus 26% for all relapses, and 0% versus 13% for major relapses at month 48, respectively. However, we now show that both overall and major relapse-free survival were not improved in the 36-month RTX groups when compared with the 18-month fixed-RTX group. This apparent discrepancy may be explained by the fact that the placebo arm in MAINRITSAN3 was disadvantaged by the previous individually-tailored regimen, as it was the only arm that included some patients who never received 18-month fixed-schedule RTX in the MAINRITSAN trials. However, in this new and long-term analysis, patients treated with 36-month fixed/fixed RTX had not an improved relapse-free survival compared with patients treated with 18-month fixed regimen, and 36-month regimen should probably only be considered in patients at high risk of relapse.

    The identification of predictive factors of relapse remains an important issue to refine the therapeutic strategy. Our study confirms that the presence of ENT involvement, better renal function or the occurrence of previous relapses are factors associated with a higher risk of subsequent relapse. Furthermore, patients with negativation of MPO-ANCA after induction had lower overall relapse than those with persistent ANCA. Of note, some factors previously known to be associated with an increased risk of relapse, especially PR3-ANCA or GPA phenotype, were not associated with the risk of major relapse in the population of RTX-treated patients, which is consistent with the recent RITAZAREM study in which PR3-ANCA also did not seem to influence major relapse risk in RTX treated patients.11 Of note, a post-hoc analysis of the RAVE study showed that patients with PR3-ANCA might benefit more from RTX induction therapy compared with CYC,14 suggesting that the predictive factors for relapse might be modified in the RTX era.

    An attractive approach might be to consider the 18-month fixed-schedule RTX regimen as the first-line maintenance regimen for all patients, and then to improve the identification of patients who would benefit from additional RTX infusions up to 36 months. The French Vasculitis Study Group (FVSG) recently identified variables that could more accurately assess the likelihood of relapse in GPA and MPA, based on PR3-ANCA positivity status, eGFR and age at diagnosis.15 McClure et al have also recently developed a relapse risk prediction model, applied at the time of the last RTX infusion, to help guide decision-making regarding extended RTX maintenance therapy, including male gender, age>60 years, positive ANCA test, relapsing disease, ENT involvement, prednisone dose and concomitant immunosuppressant as predictive factors for relapse.16 Prolonged therapy to 36-month should thus be evaluated in patients at high risk of relapse with those scores, either at diagnosis or at the last RTX infusion. Gamerith et al recently published that higher levels of three soluble immune checkpoints (sTim-3, sCD27 and sBTLA) at baseline predicted relapse in PR3-ANCA patients treated with RTX and are also an interesting avenue to explore.17

    Discussion regarding the optimal duration of RTX maintenance therapy should also include the long-term safety profile of RTX. This one appeared reassuring in a large cohort of patients with rheumatoid arthritis, with a stable excess risk of infection over time and with the number of RTX courses received, between 3 and 4 SAEs per 100 patient years.18 In our study, 27% of patients developed a serious infection during follow-up, but the rate of serious infection was higher in the AZA group than in the RTX-treated group, and the extension of RTX treatment from 18 to 36 months did not increase the rate of serious infection. However, recent COVID-19 pandemic highlighted the increased risk of a worse infection outcome in patients treated with RTX,19 as well as an impaired humoral response to vaccines on treatment.20 21 Therefore, weighing the benefits and risks of prolonged treatment with RTX is essential, and a personalised strategy based on factors predictive of relapse should be considered to alleviate treatment in low-risk patients. In any case, as recommended by recent European League Against Rheumatism guidelines, patients treated with RTX should be regularly monitored for treatment-related AEs and receive appropriate infectious prophylaxis, including trimethoprim-sulfamethoxazole.22

    One of the main strengths of this study is that it provides a pooled analysis of all FVSG randomised controlled trials on RTX maintenance therapy in AAV, having access to the complete initial and follow-up data of the patients. This study also increases the representativeness of the study population and gains in power compared with each of the individual trials. Another strength is the long-term follow-up of these studies, especially given the high risk of late relapses in RTX-treated patients. The study also has some limitations. First, given this is a retrospective analysis of prospectively collected data, the initial trials were not powered for those comparisons and some of them may be underpowered. Then, the comparison of different study populations could have biased analysis but this was controlled by adjustment for identified prognostic factors. In addition, the immortality bias introduced by including in MAINRITSAN3 only non-relapsing patients from MAINRITSAN2 was controlled by cloning MAINRITSAN2 patients who were not included in MAINRITSAN3 and assigning them a probability factor for virtual allocation to either arm of MAINRITSAN3.

    In conclusion, this pooled and long-term analysis of the 277 patients enrolled in the three MAINRITSAN trials shows that the 84-month sustained remission rate in patients with AAV is higher with the 18-month fixed RTX regimen compared with AZA and to the 18-month tailored RTX regimen. Extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with 18 months of fixed-dose RTX and should probably only be considered in patients at high risk of relapse.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants but was not approved by pooled analysis of previously ethically approved randomised controlled trials NCT00748644, NCT01731561 and NCT02433522. Participants gave informed consent to participate in the study before taking part.

    References

    Supplementary materials

    Footnotes

    • Handling editor Josef S Smolen

    • Twitter @Delestreflo, @Maxime_Samson21, @#OrphaLung, @NJourde

    • Collaborators French Vasculitis Study Group (FVSG)Collaborators of the French Vasculitis Study GroupChristian Agard, Julien Allard, Jean-Benoit Arlet, Denis Bagneres, Edouard Begon, Anne-Bérangère Beucher, Claire Blanchard-Delaunay, Frédéric Bocquentin, Anthony Bonnin, Ali Boumallassa, Benoit Brihaye, Mathias Buchler, Sébastien Canet, Richard Damade, Isabelle de Lacroix-Szmania, Christian Delafosse, Sébastien Delbes, Xavier Delbrel, Mathilde de Menthon, Claire de Moreuil, Robin Dhote, Bertrand Dunogué, Cécile-Audrey Durel, Marc Fabre, Olivier Fain, Hélène Francois, Marie Frimat, Jean-Michel Galempoix, Helder Gil, Bernard Gilson, Guillaume Gondran, Fréderic Grassin, Isabelle Guichard, Constance Guillaud, Hassan Kassem, Abdeldjallil Koreichi, Xavier Kyndt, Laure Lahaxe, Nathalie Lerolle, Guillaume Leveiller, Olivier Lidove, Marie Lino-Daniel, Nadine Meaux-Ruault, Roderich Meckenstock, Stéphanie Mestrallet, Luc Mouthon, Thomas Papo, Romain Paule, Simona Pavel, Laurent Perard, Serge Perrot, Vincent Poindron, Mathieu Puyade, Nolwenn Rabot, Alain Ramassamy, Alexis Régent, Claire Rigothier, Sophie Rivière, Raphaèle Seror, Aurélie Schiffman, Nicolas Schleinitz, Damien Sene, Audrey Sultan, Nathalie Tieulie, Christine Vinter, Stéphane Vinzio, Ursula Warzocha, Lidwine Wemeau.

    • Contributors BT designed the study. FD collected data. RP performed statistical analysis. BT and FD provided analysis and interpretation of data. BT, FD and RP drafted the article. PC, AK, CP, AN, PC, OA, SF, PG, FM, MS, PG, BB, VC, CH-S, TLG, P-LC, HD-C, GD, NJ-C, FL, NM-S, GP, TQ, MM, YB, ED, EL, NL, MD, AH, J-FV, EH, EP, XP, LG and BT prospectively followed patients included in the study and contributed to data collection. PC, AK, CP, NJ-C, XP, ED and OA provided critical revision for important intellectual content. All authors had full access to all the data, reviewed the results, approved the final version of the manuscript and accept responsibility to submit for publication. FD is responsible for the overall content as the guarantor, accepts full responsibility for the finished work and controlled the decision to publish.

    • Funding The primary funding source was French Ministry of Health. It had no role in collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

    • Competing interests All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare compting interest as follows: Dr BT reports receiving consulting and speaking fees (Roche, LFB, Grifols, GSK). Dr XP reports receiving speaking fees and honoraria (Pfizer, LFB, Roche) and a research grant (Pfizer). Dr. LG reports receiving fees for serving on an advisory board from GlaxoSmithKline and lecture fees from Roche, Actelion, Pfizer, CSL Behring, LFB Pharma, and Octapharma. Dr. CP reports receiving fees for serving on advisory boards from Roche, Genzyme, and GlaxoSmithKline, lecture fees from Roche, Bristol-Myers Squibb, and EuroImmune, and grant support from Roche. Dr. AK reports receiving lecture fees from Roche and travel support from Roche and Amgen. Dr. FM reports receiving personal fees from Actelion and travel support from Sobi and LFB Pharma. Dr. PG reports receiving personal fees from Gambro and LEO Pharma. Dr. TQ reports receiving travel support from Merck Sharp & Dohme, Alexion, and Actelion. Dr. Blanchard-Delaunay reports receiving personal fees from CSL Behring. Dr. PG reports receiving travel support from Octapharma, LFB Pharma, Roche, and Novartis. Dr. P-LC reports receiving travel support from Gambro, Bellco, Roche, Hemotech, and Sanofi. Dr. NL reports receiving travel support from GlaxoSmithKline. Dr. Hamidou reports receiving lecture fees from Roche and LFB Pharma, personal fees from Actelion, and travel support from Roche, Actelion, LFB Pharma, and GlaxoSmithKline. Dr. MD reports receiving personal fees from Fresenius Medical Care. Dr. ED reports receiving lecture fees and travel support from Shire, Amgen, and Genzyme, and grant support from Roche. Dr. BB reports receiving grant support from Roche/Chugai. No other potential conflict of interest relevant to this article was reported.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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

    • 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.