Comparative Safety Profiles of Ocrelizumab and Rituximab in Multiple Sclerosis Treatment Using Real‐World Evidence

Objective The objective of this study was to compare the long‐term safety profiles of ocrelizumab and rituximab in persons with multiple sclerosis (MS). Methods Using retrospective data from the University of California (UC) Health System, we simulated a target clinical trial. The primary cohort from UC San Francisco (UCSF) and a validation cohort from 5 other UC Medical Centers were analyzed. After applying exclusion criteria and propensity score matching based on disease characteristics, demographics, and socioeconomic factors, we compared UCSF patients receiving ocrelizumab (n = 542) and rituximab (n = 271)and validated in the UC‐wide MS population (n = 486 and n = 162 patients, respectively). The primary outcome was an all‐cause hospitalization rate; secondary outcomes included hypogammaglobulinemia development and infection incidence. Results Rituximab showed higher all‐cause hospitalization rates compared to ocrelizumab in both UCSF (incidence rate ratio IRR = 2.29, 95% confidence interval CI = 1.37–3.82, p = 0.001) and UC‐wide cohorts (IRR = 4.54, 95% CI = 4.30–7.61, p < 0.001). Cumulative hazard ratios (HRs) were similarly elevated with rituximab at UCSF (HR = 2.27, 95% CI = 1.37–3.75, p = 0.001) and UC‐wide (HR = 4.01, 95% CI = 2.25–6.32, p < 0.001). The risk of developing hypogammaglobulinemia was higher with rituximab at both UCSF (HR = 2.72, 95% CI = 1.18–6.29, p = 0.003) and UC‐wide (HR = 4.79, 95% CI = 2.04–11.25, p < 0.001). Interpretation A more favorable safety profile was observed for ocrelizumab, with lower rates of hospitalization and hypogammaglobulinemia across 2 independent cohorts. These findings may help guide treatment strategies in persons with MS. ANN NEUROL 2025