Ocrelizumab associates with reduced cerebrospinal fluid B and CD20^dim CD4⁺ T cells in primary progressive multiple sclerosis

The anti-CD20 monoclonal antibody ocrelizumab reduces disability progression in primary progressive multiple sclerosis. CD20 is a prototypical B-cell marker; however, subpopulations of CD4(+) and CD8(+) T cells in peripheral blood and cerebrospinal fluid also express low levels of CD20 (CD20(dim)). Therefore, direct targeting and depletion of these CD20(dim) T-cell subpopulations may contribute to the therapeutic effect of ocrelizumab. The aim of this observational cohort study was to compare CD20(+) B-cell and CD20(dim) T-cell distributions between peripheral blood and cerebrospinal fluid of ocrelizumab-treated or ocrelizumab-untreated people with primary progressive multiple sclerosis. Ocrelizumab treatment was associated with depletion of circulating B cells and CD20(dim) CD4(+) and CD20(dim) CD8(+) T cells (P < 0.0001, P = 0.0016 and P = 0.0008, respectively) but, in cerebrospinal fluid, only with lower proportions of B cells and CD20(dim) memory CD4(+) T cells (P < 0.0001 and P = 0.0043, respectively). The proportional prevalence of cerebrospinal fluid CD20(dim) memory CD8(+) T cells was not significantly reduced (P = 0.1333). Only in cerebrospinal fluid, the proportions of CD20(dim) cells within CD4(+) and not CD8(+) T cells positive for CCR5, CCR6 and CXCR3 were reduced in ocrelizumab-treated participants. The proportion of CD20(dim) CD4(+) T cells and abundance of CD4(+) relative to CD8(+) T cells in cerebrospinal fluid correlated positively with age (R = 0.6799, P = 0.0150) and Age-Related Multiple Sclerosis Severity score (R = 0.8087, P = 0.0014), respectively. We conclude that, in contrast to cerebrospinal fluid CD20(dim) CD8(+) T cells, B cells and CD20(dim) CD4(+) T cells are reduced in cerebrospinal fluid of people with primary progressive multiple sclerosis with an ocrelizumab-associated depletion of circulating B cells and CD20(dim) T cells. Therefore, these cells are likely to contribute to the therapeutic effects of ocrelizumab in people with primary progressive multiple sclerosis.