Hypogammaglobulinemia and infections in patients with multiple sclerosis treated with anti-CD20 monoclonal antibodies: a systematic review and meta-analysis of observational studies

Monoclonal antibodies targeting CD20 (anti-CD20 mAbs) used in patients with multiple sclerosis (MS) can cause hypogammaglobulinemia and increase the risk of infections. We aim to identify the proportion of individuals developing hypogammaglobulinemia and/or infections during the treatment with an anti-CD20 mAb. A systematic review of observational studies was conducted in PubMed, Embase and Web of Science from 2014 to 2024. Studies involvingindividuals diagnosed with MS, treated with an anti-CD20 mAb, evaluating outcomes related to hypogammaglobulinemia and/or infections were included. A random effect meta-analysis approach was used. 55 articles were selected for meta-analysis, of which 27 related to rituximab, 25 related to ocrelizumab, 1 related to ofatumumab and 2 related to rituximab vs. ocrelizumab and ocrelizumab vs. ofatumumab, covering a population of 14,548 MS patients. Overall, rituximab exhibited a higher prevalence of hypogammaglobulinemia [11%; 95% Confidence Interval (CI): 0.08 to 0.15], infections of any grade (25%; 95%CI: 0.18 to 0.32), genito-urinary infections (9%;95%CI: 0.05 to 0.12), while ocrelizumab exhibited a higher prevalence of serious infections (6%; 95%CI: 0.03 to 0.09) and respiratory infections (12%; 95%CI: 0.07 to 0.17). The paucity of data for ofatumumab and ublituximab highlights a research gap. The subgroup analyses by follow-up revealed that the proportion of these AEs increase with treatment duration. Substantial heterogeneity was identified in all analyses [I2 > 82%)]. The quality of included studies was mainly classified as poor. Monitoring and educating patients on anti-CD20 mAb is fundamental to quickly identifying adverse events and minimizing clinical risks.PROTOCOL REGISTRATION: www.crd.york.ac.uk/prospero identifier is CRD42024617575.