Journal
THERAPEUTIC ADVANCES IN NEUROLOGICAL DISORDERS
Volume 5, Issue 6, Pages 311-319Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1756285612461165
Keywords
B cells; chemokines; CXCL13; gadolinium-enhanced magnetic resonance imaging; multiple sclerosis; rituximab; T cells
Categories
Funding
- National MS Society (NMSS), USA [RG 3292]
- NIH [K24RR017100, PO1NS059560-01, 5UL1 RR024992]
- NMSS [RG80186, RG80588]
- National MS Society (NMSS) [JF 2144A2/1]
- Manny and Rosalyn Rosenthal-Dr John L. Trotter MS Center Chair in Neuroimmunology
- Barnes-Jewish Hospital Foundation
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In multiple sclerosis (MS), the presence of B cells, plasma cells and excess immunoglobulins in central nervous system lesions and in the cerebrospinal fluid implicate the humoral immune system in disease pathogenesis. However, until the advent of specific B-cell-depleting therapies, the critical role of B cells and their products in MS was unproven. Rituximab, a monoclonal antibody that depletes B cells by targeting the CD20 molecule, has been shown to effectively reduce disease activity in patients with relapsing MS as a single agent. Our investigator-initiated phase II study is the only published clinical trial in which rituximab was used as an add-on therapy in patients with relapsing MS who had an inadequate response to standard injectable disease-modifying therapies (DMTs). The primary endpoint, magnetic resonance imaging (MRI) gadolinium-enhanced (GdE) lesion number before versus after rituximab, showed significant benefit of rituximab (74% of post-treatment MRI scans being free of GdE lesions compared with 26% free of GdE lesions at baseline; p < 0.0001). No differences were noted comparing patients on different DMTs. Several secondary clinical endpoints, safety and laboratory measurements (including B- and T-cell numbers in the blood and cerebrospinal fluid (CSF), serum and CSF chemokine levels, antibodies to myelin proteins) were assessed. Surprisingly, the decline in B-cell number was accompanied by a significant reduction in the number of T cells in both the peripheral blood and CSF. Rituximab therapy was associated with a significant decline of two lymphoid chemokines, CXCL13 and CCL19. No significant changes were observed in serum antibody levels against myelin proteins [myelin basic protein (MBP) and myelin/oligodendrocyte glycoprotein (MOG)] after treatment. These results suggest that B cells play a role in MS independent from antibody production and possibly related to their role in antigen presentation to T cells or to their chemokine/cytokine production.
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