Dimethyl fumarate as a first- vs second-line therapy in MS: Focus on B cells

OBJECTIVE: To elucidate the immunomodulatory effects of dimethyl fumarate (DMF) on B cells in patients with relapsing MS receiving DMF as a “1st-line” vs “2nd-line” therapy. METHODS: B cells were isolated from 43 patients with MS at baseline and after 15-week DMF therapy. Phenotype and functional markers and cytokine profile were assessed by flow cytometry. Analysis included clinical and MRI parameters recorded during a 1-year follow-up. RESULTS: 1st-line and 2nd-line patients presented several differences in their baseline immune profile, which corresponded with differences in their immunologic response to DMF treatment. DMF reduced the proportions of B cells and CD8 T cells whereas increased monocytes. DMF reduced memory B cells, including plasma cells in 2nd-line patients only, whereas strongly increased transitional B cells. Several IL10(+) B-cell subsets and TGFβ(+) B cells were increased. Proinflammatory LTα(+) and TNFα(+) B cells were reduced, while IL4(+) B cells elevated, whereas IFNγ(+) B cells showed opposite effects in 1st-line and 2nd-line patients. HLA and ICAM-1 expression was increased, but % CD86(+) B cells reduced. The expression of B-cell activating factor receptor and the proportion of activated CD69 B cells were increased. CONCLUSIONS: DMF is associated with increased transitional and IL10(+) and TGFβ(+) regulatory B cells and a shift toward a more anti-inflammatory immune profile. Cell activation with reduced costimulatory capacity may induce immune hyporesponsiveness. Carryover effects of preceding therapies in 2nd-line patients and the stage of disease influence the immune profile of the patients and the immunomodulatory effects of DMF.