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

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[This is the executive summary of Rituximab for maintenance of remission in ANCA-associated vasculitis: expert consensus guidelines: full guideline, doi: 10.1093/rheumatology/kez640] 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. Whilst 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 (see full guideline). 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 (see full guidelines). 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 was used to grade the level of evidence and recommendation for each statement [12]. The BVAS or GPA specific measure BVAS/WG is 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%). 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%). We recommend fixed interval dosing with RTX, either 500 mg or 1000 mg administered every 6 months for a period of 2 years. There is ongoing relapse risk after RTX withdrawal and patients should be monitored accordingly. Level of evidence: 1b. Grade of recommendation: B. Vote: 18/18 (100%). Changes to treatment in refractory disease or relapse despite induction and RTX maintenance therapy should be determined according to severity of disease activity and organ involvement. A guide to treatment decisions is presented (Fig. 1). Level of evidence: 4. Grade of recommendation: C. Vote: 18/18 (100%). RTX for the maintenance of remission in ANCA-associated vasculitis: guide to treatment decisions RTX for the maintenance of remission in ANCA-associated vasculitis: guide to treatment decisions In selected patients, relapse risk remains high after 2 years of maintenance therapy, and extended duration therapy could be considered. This includes patients who relapse after a prior course of RTX maintenance, with persistent elevation or return of ANCA, or where the consequence of relapse would be organ or life threatening. Optimal treatment approaches beyond 2 years are yet to be determined in these patients. RTX 500-1000 mg every 6-12 months for up to 5 years could be considered. In patients with prior relapse after maintenance RTX cessation, this could be adjusted based on time from treatment cessation to disease relapse. Level of evidence: 5. Grade of recommendation: D. Vote: 17/18 (94.4%). Further research is needed to consider the role of biomarkers (e.g. ANCA and B cell return) in guiding RTX maintenance therapy in AAV. Level of evidence: 2a. Grade of recommendation: B. Vote: 18/18 (100%). Where RTX is commenced in a patient already receiving a DMARD for remission maintenance (e.g. azathioprine, methotrexate or mycophenolate), we suggest that the existing DMARD(s) be withdrawn. Level of evidence: 4. Grade of recommendation: C. Vote: 15/18 (83.3%). Glucocorticoid tapering strategies should aim for complete cessation 6–12 months after RTX commencement. Level of evidence: 5. Strength of recommendation: D. Vote: 17/18 (94.4%). Pneumocystis jirovecii prophylaxis is suggested in all patients receiving RTX maintenance therapy. Level of evidence: 4. Grade of recommendation: C. Vote: 16/18 (88.9%). Influenza and pneumococcal vaccinations should be recommended to al

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