Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating and neurodegenerative disease affecting the central nervous system (CNS) that is classically thought to be driven by CD4+ T-cell subset imbalance between effector Th1/Th17 cells and regulatory T-cells (Tregs) [1]. However, experimental studies and the success of B-cell-depleting therapies have promoted the role of B cells in driving the clinical course in MS [2], [3], [4], [5], [6], [7], [8]. Indeed, anti-CD20 monoclonal antibodies are high-efficacy disease-modifying therapies (DMT) that have been approved as first-line treatments for treating all active adult patients on the MS disease spectrum [from relapsing remitting (RRMS) to secondary and primary progressive (SPMS)].

Much has been posited on the potential immunological action of anti-CD20 therapies in MS, from targeting CNS memory B cells that are highly efficient antigen-presenting cells, to reducing cytokine secretion leading to decreases in inflammatory responses of T cells and myeloid cells, or even resetting the B/T cells repertoire after B-cell depletion [9], [10], [11]. Taken together, these treatments have pleotropic modes of action that have proven beneficial in quiescing inflammatory activity in MS. Yet, these treatments come at the price of immunosuppression, which may lead to increased risk of infection and secondary treatment-related hypogammaglobulinemia [12], [13], [14], [15], [16]. Given the importance of these treatments in the armamentarium of MS DMTs, neurologists need to weigh the risks and benefits of long-term immunosuppression with B-cell depleting therapies.

This review aims to provide insight into the available anti-CD20 therapies with respect to MS by detailing their short- and long-term efficacy from randomized controlled trials, and the available safety data from post-marketing and real-world studies. Finally, we will also detail future perspectives in tailoring anti-CD20 therapies given the risk of long-term immunosuppression with these treatments.