Rituximab, a CD20-directed cytolytic antibody, is indicated for both induction and maintenance therapy in two subtypes (granulomatosis with polyangiitis, GPA; microscopic polyangiitis, MPA) of ANCA-associated vasculitis (AAV). The 2020 expert consensus guidelines from the British Society for Rheumatology were developed in order to provide in-depth clinical guidance for rituximab’s use as a remission maintenance therapy. The guidelines suggest that for new and relapsing patients with GPA/MPA, rituximab is recommended for the maintenance of remission following successful rituximab or cyclophosphamide induction. The same recommendation applies for eosinophilic granulomatosis with polyangiitis (EGPA), the third subtype of AAV, despite limited evidence related to this relatively understudied phenotype of AAV. The guidelines state that the treatment response to rituximab in EGPA patients may differ, and steroidal cessation may present more challenges. [1]
The expert panel recommends fixed interval dosing for the rituximab maintenance regimen (either 500 mg or 1000 mg administered intravenously every 6 months for 2 years) over biomarker-guided dosing due to a lack of proven efficacy of biomarker-guided dosing, including the evaluation of long-term outcomes. Currently, there have been no direct studies comparing those two dosages in terms of efficacy and safety. Despite the paucity of data on rituximab maintenance therapy extending beyond two years, the panel suggests that the rituximab therapy may continue up to 5 years in select patients with high relapse risk. However, the optimal treatment approaches beyond 2 years are yet to be determined in these patients. Overall, the guidelines emphasize the importance of individualized rituximab maintenance therapy based on age, comorbidities, and history of AAV. [1]
Given the possible risk of side effects, the guidelines recommend the withdrawal of disease-modifying antirheumatic drugs (DMARDs) (e.g., azathioprine, methotrexate, mycophenolate) once initiation of rituximab maintenance therapy. Glucocorticoids are recommended to be weaned off over the course of six to 12 months or over shorter tapering strategies if tolerated. Patients with the EGPA phenotype may have a harder time with steroid withdrawal and may experience inadequate symptom improvements. [1]
A 2023 evidence-based guideline on eosinophilic granulomatosis with polyangiitis (EGPA) developed by a panel of European experts emphasized a multidisciplinary approach for diagnosis and treatment. ANCA testing was advised for all patients suspected of EGPA, with MPO-ANCA positivity correlating with vasculitis features such as glomerulonephritis and neuropathy. For remission induction in patients with new-onset, active eosinophilic granulomatosis with polyangiitis (EGPA), the treatment approach is stratified based on disease severity. For severe disease, indicated by unfavorable prognostic factors like peripheral neuropathy or alveolar hemorrhage, glucocorticoids should be administered initially, optionally followed by cyclophosphamide or rituximab. Pulsed intravenous glucocorticoids, typically methylprednisolone, are advised for severe cases, transitioning to high-dose oral glucocorticoids. Cyclophosphamide is beneficial for longer relapse-free survival, yet the optimal duration of therapy remains unclear; usually, therapy continues until remission, potentially extending to 9-12 months for slowly improving patients. Rituximab has shown comparable efficacy to cyclophosphamide for remission induction, independent of ANCA status or disease onset and relapse. For maintenance therapy, the focus remains on minimizing glucocorticoid toxicity. In severe EGPA, rituximab, mepolizumab, or traditional DMARDs combined with glucocorticoids are recommended, with an emphasis on tapering glucocorticoids to the minimum effective dose. Rituximab has shown efficacy in maintaining remission and reducing glucocorticoid dependency, especially in those achieving remission on rituximab. Mepolizumab is predominantly used for chronic asthma control but could also benefit major organ involvement, suggesting its potential broader application in severe manifestations. For non-severe EGPA, glucocorticoids combined with mepolizumab are effective in maintaining remission, as observed in clinical trials and studies. This approach underscores a strategic shift towards reducing glucocorticoid exposure while maintaining therapeutic effectiveness. [2]
A 2021 multicenter, randomized, phase 3, controlled trial (REOVAS), published as a two poster abstracts, evaluated the long-term efficacy of rituximab (RTX) compared with conventional immunosuppressive therapy (glucocorticoids, alone or in combination with cyclophosphamide ) for remission induction in 105 patients with newly diagnosed or relapsing EGPA. Rituximab was given as the experimental intervention, while the comparator group received glucocorticoids alone or with cyclophosphamide, depending on disease severity. At day 180, 63.5% of patients in the rituximab arm achieved the primary endpoint of remission compared with 60.4% in the conventional strategy group (relative risk [RR] 1.05; 95% CI, 0.78 to 1.42; p=0.75). By day 360, remission rates were 59.6% and 64.2%, respectively (relative risk 1.08; 95% CI, 0.80 to 1.45; p=0.63). Mean remission duration was comparable between groups (16.4 vs 16.2 weeks). Daily glucocorticoid exposure remained similar, with cumulative doses of 4591 mg and 4453 mg, respectively. No significant differences in relapse rates or SF-36 scores were observed; however, numerical trends favoring rituximab were noted in the HAQ and Vasculitis Damage Index (VDI) at days 180 and 360, though these did not reach statistical significance. The findings suggest that rituximab was not superior to conventional therapy in inducing remission among patients with EGPA at both 180 and 360 days. [3]
Following the 12-month core REOVAS trial, in which RTX did not demonstrate superiority over conventional strategies for remission induction at 180 days, patients underwent extended follow-up with disease activity, medication use, and adverse events collected semiannually. The primary endpoint of the extended analysis was minor and major relapse-free survival, while major relapse incidence and asthma or ENT exacerbation-free survival were assessed as secondary endpoints. Of the 105 patients enrolled, 104 (99%) were successfully followed over a median of 45 months. Minor and major relapse-free survival was non-significantly higher in the RTX group than the conventional treatment group (63.5% vs. 50.9%; p=0.24). In contrast, major relapse-free survival favored RTX (90.4% vs. 79.2%; p=0.17). Subgroup analyses revealed notably higher efficacy of RTX in MPO-ANCA-positive patients, with relapse-free survival of 92.3% (95% CI, 66.7% to 99.6%) compared to 50% (95% CI, 58% to 72%) in the conventional treatment arm (p=0.02). Among patients who were not co-enrolled in the MAINRITSEG maintenance trial (n=66), the relapse-free survival also numerically favored RTX over conventional therapy, especially in ANCA-positive patients, where relapse-free survival reached 78.6% versus 35.7% (p=0.054). Notably, in MPO-ANCA-positive individuals within this subset, relapse-free survival was 100% in the RTX group compared to 22.2% in the conventional group (p=0.007), indicating a significant treatment benefit. These findings suggest that while long-term outcomes between RTX and conventional therapy are generally comparable in the overall EGPA population, RTX confers superior relapse prevention in ANCA-positive subgroups. [4]
Regarding data specific to central nervous system (CNS) vasculitis, rituximab is generally considered an effective alternative treatment option. However, the evidence appears primarily based on case reports of individual patients reporting a positive clinical response. A 2022 review recommends rituximab for either the induction, maintenance, or severe/refractory cases of CNS vasculitis, with evidence supported by individual cases. Various combination regimens with rituximab are also being evaluated. [5], [6], [7]
A 2024 systematic review evaluated rituximab in CNS vasculitis. A total of 27 studies were included for analysis. These comprised four case series, 15 non-randomized cohorts, and eight RCTs examining both the efficacy and safety of rituximab for CNS vasculitis and related conditions such as ANCA-associated vasculitis. However, all the included RCTs focused on ANCA-associated vasculitis. One retrospective study of primary CNS vasculitis involved 8.5% of their cohort population receiving a combination steroid plus rituximab regimen. Rituximab was administered as a 375 mg/m2 intravenous infusion once a week for four weeks, followed by a repeat infusion at six months, if required. Overall, the authors found that treatment with steroids and another immunosuppression led to potential improvements in CNS vasculitis. Despite these favorable results, the review acknowledges the varying relapse rates and the need to weigh rituximab’s use against potential adverse effects such as infections. [8], [9]