Optimizing the Use of Anti-CD20 Agents in Multiple Sclerosis and Other Autoimmune Central Nervous System Disorders: A Narrative Review.

Anti-CD20 monoclonal antibodies have become central therapies for multiple sclerosis (MS) and other autoimmune disorders of the central nervous system, including neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and autoimmune encephalitis. These agents robustly suppress inflammatory disease activity through prolonged B-cell depletion; however, cumulative exposure is associated with increased infection risk, hypogammaglobulinemia, and impaired vaccine-induced humoral responses. In recent years, extended interval dosing (EID) and dose-reduction strategies have emerged as potential approaches to mitigate long-term safety concerns while preserving therapeutic efficacy. This review, a joint effort of the Steering Committees of the Italian Neuroimmunology Association and of the Neuroimmunology Study Group of the Italian Society of Neurology, summarizes current evidence on long-term anti-CD20 treatment optimization across autoimmune central nervous system (CNS) disorders, with particular focus on cumulative exposure, extended-interval dosing, dose reduction, B-cell-guided retreatment, treatment discontinuation, and safety monitoring. This review does not provide formal consensus recommendations but highlights disease-specific considerations that may help clinicians balance sustained disease control against cumulative treatment-related risks. Observational studies in MS suggest that EID of ocrelizumab and rituximab may maintain short-term clinical and radiological disease control in selected stable patients while potentially reducing immunoglobulin decline and improving vaccine responsiveness. However, the available evidence remains heterogeneous and largely based on retrospective real-world cohorts. In NMOSD, rituximab remains widely used despite the availability of newer targeted therapies, and individualized reinfusion strategies based on B-cell monitoring may help balance efficacy and safety. By contrast, anti-CD20 efficacy in MOGAD appears less consistent, whereas in autoimmune encephalitis rituximab is particularly effective in antibody-mediated disease associated with neuronal surface antigens. Overall, strategies to reduce cumulative anti-CD20 exposure represent a promising direction for long-term treatment optimization, although prospective randomized studies are still needed to define the safest and most effective dosing approaches.