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.