Anti-CD20 monoclonal antibody therapies in relapsing multiple sclerosis: A systematic review and meta-analysis of randomised controlled trials

Background: Anti-CD20 monoclonal antibodies (mAbs) selectively deplete B lymphocytes and have demonstrated efficacy in relapsing forms of multiple sclerosis (MS). This meta-analysis synthesises evidence from all available randomised controlled trials (RCTs) comparing anti-CD20 agents with active or placebo comparators. Methods: We searched MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov from inception to 10 August 2026. RCTs of rituximab, ocrelizumab, ofatumumab, ublituximab, or divozilimab in relapsing MS were eligible, including head-to-head comparisons of two anti-CD20 agents. Primary outcome was the clinical relapse risk ratio (RR). Secondary outcomes included Gd-enhancing lesion count, new T2 lesion count, EDSS worsening, and serious adverse events (SAEs). Pooled estimates used inverse-variance fixed-effects and DerSimonian–Laird random-effects models (R metafor package). Heterogeneity was quantified with I² and Cochran Q and investigated with stratified analyses. Publication bias was assessed with Egger's regression test and funnel plots. The review is registered in PROSPERO (CRD420261364004; retrospectively registered). Results: Eleven RCTs (N = 5911) were included, comprising ten trials of anti-CD20 therapy against placebo or a non-anti-CD20 active comparator and the first head-to-head trial of two anti-CD20 agents (OVERLORD-MS, rituximab vs ocrelizumab). Anti-CD20 agents reduced clinical relapses (RR 0.48, 95% CI 0.43–0.52; I² = 24%; p < 0.001; I² = 0% when the head-to-head trial was excluded), Gd+ lesions (RR 0.07, 95% CI 0.03–0.18; I² = 95%; p < 0.001), new T2 lesions (RR 0.24, 95% CI 0.17–0.34; I² = 78%; p < 0.001), and EDSS worsening (RR 0.71, 95% CI 0.62–0.82; I² = 0%; p < 0.001). SAE rates were similar (RR 1.06, 95% CI 0.89–1.25; I² = 0%; p = 0.52). Egger's test showed no significant funnel-plot asymmetry for the primary outcome (p = 0.66). Leave-one-out analysis confirmed robustness of primary outcome estimates. Stratified analyses associated the MRI-outcome heterogeneity with trial programme design and comparator differences rather than with inconsistent drug performance. Conclusion: Anti-CD20 mAbs confer consistent, clinically meaningful reductions in relapse rate and MRI disease activity. In the only direct head-to-head RCT, rituximab was non-inferior to ocrelizumab for MRI disease activity in newly diagnosed relapsing MS. Heterogeneity for MRI outcomes is strongly associated with trial design and warrants cautious interpretation; with few trials per stratum this attribution is associative rather than definitive. These agents represent a high-efficacy treatment class for relapsing MS. © 2026 Elsevier B.V.