One target, two evidence streams: Rituximab versus ocrelizumab in relapsing multiple sclerosis: A design-stratified systematic review, meta-analysis, and concordance assessment

Rituximab is widely used off-label as a lower-cost alternative to ocrelizumab for relapsing multiple sclerosis (MS), but comparative effectiveness and safety remain uncertain. We assessed direct head-to-head evidence and concordance between randomized and real-world findings.

PubMed/MEDLINE, Cochrane Library, Scopus, and Web of Science were searched through July 9, 2026. Randomized and longitudinal nonrandomized studies directly comparing rituximab with ocrelizumab in adults with relapsing MS were included. Evidence was synthesized separately using random-effects meta-analysis. Risk of bias was assessed with RoB 2 and ROBINS-I, and certainty with GRADE.

Thirteen studies were included: one randomized trial (216 participants) and 12 observational studies (14,753 treatment observations). Rituximab was noninferior to ocrelizumab for freedom from new or enlarging T2 lesions from months 6 to 24 (risk difference, -2.6 percentage points; 95% CI, -9.4 to 4.3; high certainty). Observational evidence suggested higher relapse activity with rituximab for time to first relapse (HR, 1.92) and annualized relapse rate (IRR, 1.80), but certainty was very low. MRI and disability outcomes were similar. Rituximab was associated with earlier discontinuation, while serious-infection estimates were inconsistent.

Standardized rituximab achieved comparable MRI lesion suppression, but comparative clinical efficacy and serious-infection risk remain uncertain.