Efficacy and safety of rituximab versus cyclophosphamide in primary membranous nephropathy: A systematic review and meta-analysis

Background PMN is a leading cause of nephrotic syndrome in adults. In some patients, PMN can be severe or continue to worsen even after 6 months of supportive treatment. Rituximab and cyclophosphamide are used to treat moderate-risk or high-risk PMNs, but the efficacy and safety of rituximab and cyclophosphamide in patients with PMN are still unclear. Methods We searched PubMed, Embase and the Cochrane Library for the time period through November 2025 to identify randomized controlled trials and cohort studies that evaluated rituximab compared with cyclophosphamide for the treatment of PMN. The primary outcomes were complete remission (CR), partial remission (PR), and total remission (TR = PR + CR). The secondary outcomes included the relapse rate, adverse events, and serious adverse events. The random effects model was used to estimate relative risks (RRs) with 95% confidence intervals (CIs). Results Thirteen studies (N = 1228) were eligible for final inclusion. Rituximab demonstrated similar efficacy to cyclophosphamide in inducing complete or partial remission at 18 months (RR, 0.98; 95% CI, 0.86–1.10; p = 0.70) and 24 months (RR, 1.01; 95% CI, 0.91–1.13; p = 0.82). Similarly, rates of complete remission were comparable between the two treatment groups at 18 months (RR, 0.83; 95% CI, 0.62–1.11; p = 0.21) and 24 months (RR, 0.93; 95% CI, 0.76–1.15; p = 0.51). There were significant differences in the incidence of AEs or SAEs between RTX and cyclophosphamide. The RRs were 0.77 (95% CI, 0.68–0.87; p < 0.0001) and 0.60 (95% CI, 0.42–0.86; p = 0.005), respectively. Conclusions The current limited evidence suggests that RTX treatment has comparable long-term efficacy to cyclophosphamide in PMN patients at moderate risk or high risk. Compared with cyclophosphamide treatment, rituximab treatment was associated with significantly fewer adverse events and serious adverse events. Further large-scale, longer follow-up, well-designed RCTs on head-to-head comparisons of the safety and efficacy of rituximab versus cyclophosphamide are urgently needed.