SARS-CoV-2 management strategies in B-Cell-depleted people with multiple sclerosis: from prevention to antiviral treatment.

INTRODUCTION: Multiple sclerosis (MS) is a leading cause of neurological disability in young adults, necessitating early high-efficacy disease-modifying therapies (DMTs). Monoclonal antibodies targeting the CD20 antigen are a cornerstone of effective disease control, but depletion of peripheral B-cells blunts the humoral immune response. This review synthesizes current evidence on COVID-19 risk, prevention and treatment in anti-CD20-treated people with multiple sclerosis (pwMS). AREAS COVERED: A PubMed literature search through June 2026 identified relevant studies on anti-CD20 therapies and COVID-19 in pwMS. While MS itself does not increase COVID-19 susceptibility, anti-CD20-induced immunosuppression predisposes patients to severe COVID-19 outcomes and protracted or relapsing infections. Furthermore, B-cell depletion severely impairs vaccine efficacy, leaving patients with markedly diminished or absent neutralizing antibody responses. EXPERT OPINION: To mitigate COVID-19 risks, future strategies should focus on three pillars. First, strategic switching among anti-CD20 antibodies to improve vaccine efficacy. Second, variant-targeted monoclonal antibodies for pre- and post-exposure prophylaxis in patients lacking robust humoral responses. Finally, early administration of direct-acting small-molecule antivirals to halt viral replication before hyperinflammation. Moving forward, integrating real-world data, identifying immunogenetic risk biomarkers, and evaluating long-term combinations of vaccine-passive immunizations will help safely sustain high-efficacy MS treatments.