Rituximab for maintenance of remission in ANCA-associated vasculitis: expert consensus guidelines

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Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Considerable improvements in therapy mean induction of remission occurs in most patients with AAV [1–4]. However, disease relapse continues to pose a burden to patients. Morbidity accrues with relapses through disease-related damage and adverse effects of therapies to manage these relapses, negatively impacting on quality of life [5]. Rituximab (RTX), a monoclonal antibody targeting CD20, leads to peripheral B cell depletion. This has been successfully trialled, and is licensed, for the induction and maintenance of remission in AAV [2, 3]. RTX is increasingly being used for the maintenance of remission in patients with AAV, to reduce the risk of relapse and its consequences [6]. Other commonly used agents that have been trialled for the maintenance of remission in AAV include azathioprine, methotrexate and mycophenolate [7–9]. The decision to select RTX for the maintenance of remission is multifactorial, including but not limited to, patient-related factors and preferences, previous treatment and response, consideration of the overall risk of relapse, and access to therapy. These guidelines have been developed by a group of physicians practising in the UK. While guidelines on the management of AAV have proposed RTX as a treatment option in remission maintenance, there has been limited guidance on how this should be used [10, 11]. We present guidelines developed through a modified Delphi exercise on the use of RTX in the maintenance of remission in adult AAV patients, with additional focus on adjunct therapies, adverse effects and use of prophylaxis. These guidelines can be used to assist specialty physicians making treatment decisions in patients with AAV when RTX has been chosen for remission maintenance. This modified Delphi exercise invited experts in the management of AAV practising in the UK to participate. The group of clinicians included 11 nephrologists, eight rheumatologists and one paediatric rheumatologist. The modified Delphi exercise was planned with four rounds, including a face-to-face meeting. The first round sought to identify key areas for the scope of these guidelines and systematic literature review. These key areas form the basis for each statement and sub-statement. The literature search was conducted using key search strings of systemic vasculitis, GPA, MPA and EGPA, including eponymous names where applicable, combined with RTX, CD20 and/or B lymphocytes as appropriate for each database (full search string in supplementary material, available at Rheumatology online). Studies including at least 20 patients receiving at least two infusions of RTX were included. The literature review addressing the key issues identified from the first round was presented to each participant with a summary of responses. Following a third round, an expanded literature review was produced to address important issues with limited evidence in AAV. An expanded literature search of studies on Pneumocystis jirovecii pneumonia prophylaxis, vaccination, late onset neutropenia and hypogammaglobulinaemia in autoimmune disease was conducted (full search strategy provided in supplementary material, available at Rheumatology online). A final vote determined the level of agreement; a level of 80% was prespecified for inclusion in these guidelines. No statement was excluded for this reason. Prior to the final voting round, the guidelines were distributed to clinicians not involved in guideline development and patient participants in order to assess their face validity and clinical utility. The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence were used to grade the level of evidence and recommendation for each statement [12]. The BVAS or GPA specific measure BVAS/WG are used for assessment of disease activity [13, 14]. In these guidelines, the disease states used are: active disease, disease remission, refractory disease and relapse. Active disease: manifestations attributable to AAV, and not due to disease-related damage. Disease remission: disease control (BVAS or BVAS/WG ≤1); glucocorticoid free remission refers to disease control (BVAS or BVAS/WG ≤ 1) off glucocorticoid therapy. Refractory disease: despite treatment of disease, remission has not been established, with persistent or progressive disease activity. Disease relapse: where disease activity has previously been controlled, and has become active, defined by at least 1 unit increase in BVAS or BVAS/WG. Major relapse: relapse with 1 new, recurrent or worsening major item on BVAS or BVAS/WG; minor relapse: relapse without a major item on BVAS or BVAS/WG We recommend the use of RTX for the maintenance of remission in patients with GPA and MPA following RTX induction. RTX maintenance can also be considered after cyclophosphamide induction. Level of evidence: 1b (following cyclophosphamide induction), 2b (following RTX induction). Grade of recommendation: A (following cyclophosphamide induction), B (following RTX induction). Vote: 18/18 (100%). Two randomized controlled trials (RCT) have evaluated the efficacy of RTX for the maintenance of remission in AAV [15, 16]. The MAINRITSAN trial randomized 115 patients with newly diagnosed (80%) or relapsing (20%) AAV (excluding EGPA) to receive a RTX or azathioprine based maintenance regimen following remission induction with cyclophosphamide [15]. The RTX regimen was two 500 mg doses of RTX a fortnight apart after remission induction followed by 500 mg every 6 months until month 18 (i.e. three further doses). After 28 months, fewer major relapses occurred in patients who received RTX compared with azathioprine (5% vs 29%, hazard ratio 6.61; 95% CI: 1.56, 27.96; P = 0.002), resulting in a number needed to treat of four patients to prevent one major relapse [15]. The superiority of RTX over azathioprine in relapse prevention persisted at 60 months’ follow-up [17]. MAINRITSAN2 compared the fixed-schedule RTX dosing from the MAINRITSAN trial with an individually tailored RTX maintenance regimen, where after an initial maintenance infusion of 500 mg RTX ×2, further 500 mg doses were administered based on 3-monthly measures of ANCA and B cells [16]. In this trial, RTX induction was used in 37% of patients. At 28 months after the first maintenance RTX infusion, eight (9.9%) patients receiving fixed-schedule RTX had relapsed (three major) compared with 13 (16.0%) patients experiencing 14 relapses (six major) in the tailored infusion arm. One ongoing RCT, RITAZAREM (NCT01697267), compares 4-monthly 1000 mg RTX dosing with azathioprine for the maintenance of remission following RTX induction in patients with a relapse of AAV [18]. Several observational studies, with follow-up to 7.6 years, provide further evidence on the safety and efficacy of RTX for the maintenance of remission in patients with new, relapsing and refractory AAV [19–26]. Reflecting current practice patterns, these studies have largely used RTX to maintain remission after successful RTX induction. Despite limited evidence regarding the use of RTX for the maintenance of remission in EGPA, we advise a similar approach to use in GPA and MPA. Overall treatment responses to RTX may differ from GPA and MPA, and steroid withdrawal may be more challenging. Level of evidence: 4. Grade of recommendation: C. Vote: 15/18 (83%). EGPA is a relatively understudied subgroup of AAV, owing to phenotypic differences from GPA and MPA, and relative rarity of disease. Published trials of RTX for induction and maintenance of remission in AAV have not included patients with EGPA. One multicentre retrospective case series of 41 patients with predominantly refractory or relapsing EGPA reported a clinical improvement in 83% by 6 months, with 34% achieving complete remission [27]. Pred

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