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

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]. Prednisolone cessation was possible in only two patients at 12 months. In a single centre study including 69 patients with EGPA, similar remission rates were identified (34% at 6 months and 49% at 12 months) [28]. Median prednisolone doses were 7.25 mg/day at 12 months and 5 mg/day at 24 months. Relapse was common, with 54% of patients relapsing, predominantly due to uncontrolled asthma or other respiratory manifestations. In both studies, patients who were ANCA positive were more likely to achieve remission. An ongoing RCT, MAINRITSEG (NCT02807103), is evaluating RTX in patients with EGPA for maintenance of remission [29]. 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%). This regimen is recommended following the completion of induction therapy. The treatment regimen should be individualized, particularly in post-pubertal adolescents and older individuals with comorbidities where concerns regarding adverse effects exist. There are limited data for the use of RTX in children. No direct comparisons have been made between the two most commonly used doses of RTX—500 and 1000 mg. Both published RCTs have used 500 mg doses of RTX while observational studies have largely used 1000 mg doses and this dose is being used in the ongoing RITAZAREM trial [15, 16, 19, 21–23]. While observational cohorts include a greater proportion of patients with relapsing or refractory disease than RCTs, it is unknown if the dose of RTX influences clinical outcomes in these patients. There are two main approaches to RTX dosing intervals: fixed interval dosing and biomarker guided dosing. As detailed above, the MAINRITSAN2 trial compared fixed 6-monthly RTX infusions with dosing based on 3-monthly assessments for ANCA return or increase and B cell return [16]. At 28 months’ follow-up, no difference in relapse rate was identified between the two groups (P = 0.22); 8/81 (9.9%) patients receiving fixed interval dosing had experienced eight relapses including three major relapses, whereas 13/81 (16.0%) patients with repeat dosing determined by biomarker changes had experienced 14 relapses including six major. No difference in serious adverse events related to infection was identified, with 16 individuals receiving fixed interval RTX having 18 infections and nine individuals with tailored dosing having 18 infections. The role of biomarker guided RTX dosing has not been proven and requires further study, including the evaluation of long-term outcomes. Relapses in spite of ANCA negativity and B cell depletion have been observed in both RCTs and observational studies [15–17, 21–23, 26, 30]. Fixed interval dosing has therefore been recommended. As discussed below, in selected patients, biomarker fluctuations, comorbidities and adverse effects may necessitate a more individualized approach to RTX dose and dosing intervals. 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%). A guide to treatment decisions In view of the rarity of refractory disease or relapse on RTX maintenance therapy, there are no studies specifically evaluating treatment approaches. Various strategies have been adopted in specialized centres and described in RCTs and observational studies [15, 16, 19, 21, 22]. Referral to a specialized centre is advised. Assessment requires careful consideration of the relative contribution of disease damage and activity to patient symptoms, alternative diagnoses, and potential disease drivers including infection, nasal carriage of Staphylococcus aureus and cocaine use. Treatment of disease activity should depend on its severity, including consideration of major organ involvement and whether any benefit from RTX has been derived. For example, major organ involvement typically necessitates re-induction therapy. Shortened interval dosing is considered where disease activity emerges shortly prior to scheduled infusions, and the addition of concomitant immunosuppression could be considered where, despite a response to RTX, there is mild persistent disease activity without major organ manifestations. Concomitant therapy includes traditional maintenance agents (e.g. azathioprine, methotrexate or mycophenolate), or low dose glucocorticoids (≤5 mg/day prednisolone, or equivalent). In the event of RTX failure, alternative maintenance strategies should be considered. 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%). Long term follow-up data from the MAINRITSAN trial highlight the risk of relapse after RTX cessation [17]. Until 28 months’ follow-up, 10 months after the last RTX infusion, only three (5%) patients experienced a major relapse. Over the subsequent 22 months, without further scheduled RTX infusions, an additional 13 (23%) patients experienced a major relapse. Consistent with this, RTX maintenance cohorts demonstrate a progressive reduction in relapse-free survival after RTX cessation [22, 23]. An ongoing RCT (MAINRITSAN3) compares the effects of extended RTX maintenance with standard duration therapy (NCT02433522) [31]. Optimal regimens for extended RTX maintenance require further study. Extended treatment to 5 years is proposed in patients at high risk of relapse or its consequences. The dosing strategy presented (Fig. 1) is a guide, derived by expert consensus. Individualization of any extended treatment regimen is emphasized, based on the patient’s wishes, comorbidities, age, and the history of their AAV. Identifying patients at greatest risk of relapse after RTX treatment remains challenging. Patients who have relapsed after a previous course of RTX are considered empirically to be at greater risk of further relapse. Patients who are ANCA positive, either through persistent positivity or return, are likely to have a greater risk of relapse. Notably, in the MAINRITSAN trial, the risk of relapse for patients who were ANCA positive at each follow-up visit increased over time [17]. Following RTX cessation, one cohort reported that switching from negative to positive ANCA status was predictive of subsequent relapse [22]. This is with from the trial, randomized patients who had months of treatment to or maintenance azathioprine and glucocorticoid The withdrawal of azathioprine maintenance therapy and ANCA positivity at (i.e. months after of increased the risk of relapse. The factors should be considered in each patient’s and the risk of relapse be potential adverse effects of ongoing risk factors for relapse as disease, GPA and the of involvement should also be considered in the overall risk of relapse [15, cohorts of patients with AAV have not identified a between RTX dose and infection or hypogammaglobulinaemia Long term data are and ongoing is recommended. is needed to the role of (e.g. ANCA and B cell in RTX maintenance therapy in AAV. Level of evidence: Grade of recommendation: B. Vote: 18/18 (100%). The use of as B cell and ANCA, in therapy in AAV is As discussed above, relapses to in the of 22]. treatment regimens have not measures of treatment related to including infection rates and in further therapy. While these should not treatment decisions in the of long-term studies and the MAINRITSAN2 trial that the use of ANCA and B cell return can be considered in treatment decisions in with other patient and disease-related factors 22]. The of alternative for disease disease-related damage and adverse effects of therapy is RTX is in a patient receiving a for remission maintenance (e.g. azathioprine, methotrexate or mycophenolate), we that the be Level of evidence: 4. Grade of recommendation: C. Vote: 15/18 Concomitant therapy refers to use of or with In clinical trials of RTX for the maintenance of remission in AAV, concomitant therapy has not been In observational in patients are receiving a as maintenance therapy and RTX has been there has been withdrawal of this to the potential for increased adverse the use of concomitant therapy has not been recommended. There is limited evidence from of patients receiving RTX maintenance treatment with refractory or relapsing disease described in observational studies, concomitant therapy may be in this 22]. of persistent disease activity despite ongoing RTX maintenance therapy may benefit from the addition of a concomitant strategies should for complete cessation months after RTX Level of evidence: 5. of recommendation: D. Vote: 17/18 (94.4%). remission remains in view of adverse In term follow-up of patients in RCTs, glucocorticoid use was with greater disease after for number of relapses follow-up, age, disease activity and involvement glucocorticoid strategies are possible in patients with AAV. One RCT that randomized patients to RTX induction or cyclophosphamide followed by azathioprine maintenance provided a glucocorticoid to cessation at 6 months to patients in both remission was in of the RTX patients and of who received RCTs of RTX for the maintenance of remission have used glucocorticoid for glucocorticoid reduction in the first months, but typically at low dose until at least 18 months following induction therapy [15, 16]. In uncontrolled prednisolone dose reduction and cessation is with RTX maintenance therapy In patients with EGPA have greater with glucocorticoid resulting in control of asthma [27]. may also complete cessation of glucocorticoids Pneumocystis jirovecii is in patients receiving RTX maintenance therapy. Level of evidence: 4. Grade of recommendation: C. Vote: is for at least 6 months from of induction therapy for AAV. In RCTs of RTX maintenance, two of were identified in patients on RTX, of were on therapy at the time of [17]. There is a of strategies in patients for autoimmune disease including AAV. In trials of RTX in AAV, strategies have most commonly using and [2, 16]. for the use of alternative including and are limited owing to the rarity of use. Extended duration of is recommended in patients considered to be at high The following factors the of low cell increased age, use of glucocorticoid or other and disease including disease. to organ of patients with have been identified in patients for autoimmune disease, including AAV of in individuals with ongoing immunosuppression should be considered when a of is and should be recommended to patients. should be are provided at least 1 month prior to RTX infusion, should not Level of evidence: 5. Grade of recommendation: D. Vote: 18/18 (100%). a of and in patients with AAV, with a of respiratory infections The benefit of in the is Despite previous on disease activity in patients with AAV, a RCT and observational cohort the safety of in patients with AAV In patients receiving RTX maintenance therapy, remains a particularly where B cell depletion The efficacy of in patients receiving RTX maintenance has not been evaluated for AAV. response has been in patients with 6 months despite B cell in most patients with patients receiving methotrexate the response was and occurred in a proportion of at least 1 month prior to RTX is recommended to However, the of treatment and of of the in spite of potential remains In the of RTX maintenance should be monitored in patients is recommended if recurrent or infections or paediatric than appropriate of should be Level of evidence: 5 Grade of recommendation: B Vote: 18/18 (100%). Despite reported by RCTs of RTX maintenance therapy, hypogammaglobulinaemia has been observed in observational cohorts of patients receiving RTX [15, 16, are likely a of observational cohorts include a greater proportion of patients with a burden of prior immunosuppression for refractory or relapsing disease, and hypogammaglobulinaemia is is in and can be a late While term data are the with persistent hypogammaglobulinaemia is and/or infections. is not whether RTX should be for low or and in clinical trials a of has been used [18]. The that RTX hypogammaglobulinaemia should be considered. Patients with an of recurrent or infections and hypogammaglobulinaemia may benefit from including therapy and/or This should be considered in these of patients in with guidelines. Consistent with other published guidelines, while patients with persistent without infections may not require further their infection and responses should be in with For patients in paediatric the long-term of hypogammaglobulinaemia are of greater and review should be sought when of RTX and could be considered in patients with hypogammaglobulinaemia and a important response to RTX is Level of evidence: 5. Grade of recommendation: C. Vote: 18/18 (100%). In relapse of AAV occurs in patients receiving therapy for disease typically necessitates further immunosuppression despite an The of RTX hypogammaglobulinaemia with other targeting is on of RTX and and the of these agents should be in with and patients should be of the of late onset neutropenia with RTX use. A history of late onset neutropenia not RTX use. Level of evidence: 4. Grade of recommendation: C. Vote: In patients with a history of late onset there should be greater and patient of after RTX onset neutropenia is but to from of in of B cell onset neutropenia has been identified in patients in RTX maintenance cohorts and RCTs 19, to the of late onset evaluation for neutropenia is not The neutropenia is typically in the of therefore likely onset neutropenia without therapy, with used in patients with or with in with therapy. of in patients for autoimmune disease, including AAV, are In patients with a history of neutropenia by infection, there is limited in repeat RTX In addition to the areas discussed the following issues were identified as areas further and of maintenance therapy on quality of The effects of extended RTX maintenance therapy. effects of treatment including progressive and long-term outcomes of term of patients with RTX maintenance therapy including disease-related damage and of RTX maintenance therapy and extended RTX maintenance therapy. of relapse including the role of (e.g. ANCA, for risk of relapse. of RTX for the maintenance of remission in and paediatric patients, and treatment for AAV is increasingly successful at achieving remission, and maintenance of remission has become a key in the long-term management of these patients. The clinical efficacy of RTX in both the induction and the maintenance of remission has been in clinical trials [2, through a modified Delphi exercise an expert we present guidelines that both the RCT and of in the use of RTX for the maintenance of remission in AAV. We and for the guidelines. We the of the for has been by an by the Rheumatology and has received from and and from and has received from and and from and has received from and and is a of for and has received from from and from for has received from and is on a clinical trial for has been provided by has received or from and has received from and and is an on a clinical trial by has received from and is an on a clinical trial by has received from and from for is an in clinical trials by and has received or from and and received from and The in Rheumatology are of the and and not of the for the the Oxford or the to the are

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