By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Rituximab is an anti-CD20 chimeric monoclonal antibody used off-label to treat multiple sclerosis (MS). Ocrelizumab is a humanized monoclonal anti-CD20 monoclonal antibody that is Food and Drug Administration-approved for the treatment of MS. In this observational cohort study, the authors were not able to demonstrate noninferiority of rituximab compared to ocrelizumab because of a significantly lower relapse rate in the ocrelizumab-treated group.
Roos I, Hughes S, McDonnell G, et al. Rituximab vs ocrelizumab in relapsing-remitting multiple sclerosis. JAMA Neurol 2023;80:789-797.
This was an observational cohort study of patients in the international MSBase registry and the Danish MS Registry between January 2015 and March 2021. Patients with relapsing-remitting multiple sclerosis (MS) treated with rituximab or ocrelizumab and who had six months of pre-treatment data and at least six months of post-treatment follow-up were included in the study.
The primary endpoint was noninferiority of annualized relapse rate (ARR) in rituximab when compared to ocrelizumab. Secondary endpoints were cumulative hazard of relapse and six-month confirmed disability accumulation or improvement and treatment discontinuation.
A total of 1,613 patients with a mean age of 42 years were included in the analyses. A total of 710 patients treated with ocrelizumab were matched with 186 patients treated with rituximab. The pairwise mean follow-up was 1.4 years. The authors reported that the primary endpoint, ARR, was higher in patients treated with rituximab than in those treated with ocrelizumab (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.4-2.4; ARR of 0.20 vs. 0.09; P < 0.001).
On the secondary endpoints, the cumulative hazard of relapses was higher among patients treated with rituximab than ocrelizumab (HR, 2.1; 95% CI, 1.5-3.0). There was no difference in the risk of disability accumulation.
The authors concluded that ocrelizumab appeared to be more effective than rituximab in their cohort study. When they examined the third secondary endpoint of treatment persistence, patients treated with rituximab were more likely to discontinue.
However, most patients who stopped rituximab were switched to ocrelizumab; this was not because of perceived failure. A limitation of the study included relatively short follow-up (the mean follow-up of 1.4 years).
COMMENTARY
Although both rituximab and ocrelizumab are anti-CD20 B-cell targeted therapies, there are differences in their effect on the immune system, including ocrelizumab having an increased antibody-dependent cell-mediated cytotoxic effect and reduced complement-dependent cytotoxic effects, as compared to rituximab.
Because ocrelizumab is a humanized monoclonal antibody, it may be less immunogenic and elicit less anti-drug antibodies than rituximab. Hence, it is imperative that we investigate any potential differences between these agents in terms of efficacy as well as adverse events.
In this study, the authors reported that ocrelizumab appears to be superior to rituximab in reducing the frequency of relapses. There are some potential confounders. Compared with patients treated with ocrelizumab, patients treated with rituximab had higher disability scores (mean [standard deviation; SD] Expanded Disability Status Scale [EDSS] score, 3.5 [1.9] vs. 3.0 [1.8]), more relapses (mean [SD] relapses, 0.7 [1.0] vs. 0.5 [0.7]), higher magnetic resonance imaging activity in the prior 12 months (mean [SD] gadolinium-enhancing lesions in 385 of 950 [41%] vs. 56 of 173 [32%]),and received more prior MS therapies.
Also, this was an observational cohort study, not a randomized controlled trial. But despite these concerns, this study raises important questions about assumptions on comparable efficacy between these medications, given their similar mechanism of action.
Potential differences in the efficacy and side effects of these medications need to be investigated further with randomized controlled trials.
