B‐cell Therapy for Multiple Sclerosis: Entering an era

Abstract

Monoclonal antibodies that target CD20 expressing B cells represent an important new treatment option for patients with multiple sclerosis (MS). B-cell-depleting therapy is highly effective against relapsing forms of the disease and is also the first treatment approach proven to protect against disability worsening in primary progressive MS. Moreover, evolving clinical experience with B-cell therapy, combined with a more sophisticated understanding of humoral immunity in preclinical models and in patients with MS, has led to major progress in deciphering the immune pathogenesis of MS. Here, we review the nuanced roles of B cells in MS autoimmunity, the clinical data supporting use of ocrelizumab and other anti-CD20 therapies in the treatment of MS, as well as safety and practical considerations for prescribing. Last, we summarize remaining unanswered questions regarding the proper role of anti-CD20 therapy in MS, its limitations, and the future landscape of B-cell-based approaches to treatment. Ann Neurol 2018;83:13-26.

Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis

“…Proposed mechanisms for PPMS pathogenesis include compartmentalized leptomeningeal inflammation behind a relatively intact blood–brain barrier, oxidative stress driving mitochondrial injury, chronic microglial activation causing oligodendrocyte dysfunction and axonal injury, and age‐related iron accumulation . By examining MS phenocopy mutations, this study identified genes encoding neuroaxonal proteins ( KIF5A ), mitochondrial function ( REEP1, SPG7 ), and astrocyte osmoregulation ( MLC1 ), supporting the hypothesis that genetic variation contributes to progressive neuronal and glial dysfunction in PPMS.…”

Longitudinally persistent cerebrospinal fluid B-cells resist treatment in multiple sclerosis

“…The efficacy of anti-CD20 B-cell depleting therapy in autoimmune disease is linked to depletion of memory B-cell subsets rather than naïve and transitional subsets (36,37). We previously proposed that USM B-cells may play a role in MS due to their appearance in MS CSF during periods of active CNS inflammation (8).…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Basic and clinical research demonstrates that suppressing the immune response by depleting autoreactive immune cells may re‐establish the immune balance (Wraith, ). Taking MS for example, monoclonal antibodies (including Rituximab and Ocrelizumab) that selectively target and deplete CD20 + B cells have been approved for the treatment of MS (Greenfield & Hauser, ; Hauser et al, ; Sabatino, Zamvil, & Hauser, ; Salzer et al, ). Our colleagues have demonstrated that relapsing–remitting MS patients with Rituximab as the initial treatment have better relapse control and tolerability in comparison with other disease‐modifying drugs (Granqvist et al, ; Spelman, Frisell, Piehl, & Hillert, ).…”