Comparative Evaluation of Rituximab Versus Approved Therapies in Aquaporin-4-IgG-Positive Neuromyelitis Optica Spectrum Disorder: A Systematic Review and Network Meta-analysis

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a rare antibody-mediated neuro-autoimmune disease. Monoclonal antibodies targeting B cell antigens CD19 and CD20, the interleukin-6 receptor, or the complement cascade are used as preventive therapies to reduce relapse rates. We conducted a network meta-analysis (NMA) to compare the effect of rituximab on time to first relapse with ravulizumab, eculizumab, inebilizumab, and satralizumab in patients with NMOSD who are aquaporin-4 (AQP4)-IgG-positive. Methods: A systematic search was conducted in PubMed, Scopus, CINAHL, EMBASE, Web of Science, the Cochrane Library, and gray literature sources up to October 31, 2024, and updated on November 1, 2025, following PRISMA guidelines. A network meta-analysis of randomized and open-label trials was conducted to compare time to first relapse between rituximab and other monoclonal antibody therapies. Results: From 6337 records, 3825 duplicates were removed; 2512 were screened, 2327 excluded, leaving eight trials. The prior treatment, relapse history, and definitions and adjudication of relapse varied across studies. Rituximab showed higher hazard ratio (HR) point estimates for time to first relapse compared with ravulizumab with or without immunosuppressive therapies (IST) (HR 5.00, 95% CI 0.25, 101.01) and eculizumab ± IST (HR 1.17, 95% CI 0.12, 10.89), but were lower compared with satralizumab ± IST (HR 0.29, 95% CI 0.04, 2.23). In patients not receiving IST, rituximab showed numerically higher HR compared with ravulizumab (HR 3.33, 95% CI 0.13, 83.16) and eculizumab (HR 1.59, 95% CI 0.05, 50.17), but lower point estimates compared with inebilizumab (HR 0.31, 95% CI 0.04, 2.31) and satralizumab (HR 0.27, 95% CI 0.03, 2.21). Conclusion: This NMA showed hazard ratio point estimates favoring eculizumab and ravulizumab over rituximab. However, wide, overlapping confidence intervals and between-study heterogeneity indicate substantial uncertainty. Head-to-head trials or registry-based studies are needed to determine the most effective treatment for AQP4-IgG-positive NMOSD.