Distinct disease-modifying therapies are associated with different blood immune cell profiles in people with relapsing-remitting multiple sclerosis

Relapsing-remitting multiple sclerosis (RRMS) is a chronic inflammatory neurodegenerative disease of the central nervous system. Several disease-modifying therapies (DMTs) are approved for RRMS, all of which target the immune system, although having different mechanisms of action. DMTs have been shown to reduce disease activity and disability progression in people with RRMS (pwRRMS). However, comprehensive comparisons of their effects on the immune system are scarce. We assessed circulating numbers of B cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs), natural killer (NK) cells and NKT cells, and their subsets, in treatment-naïve pwRRMS or treated with different DMTs. All evaluated DMTs induced diverse effects and no common signature was observed on any of the several cell populations analysed. Cluster analysis was performed and two clusters of pwRRMS were identified. Cluster 1 includes pwRRMS on fingolimod, alemtuzumab and dimethyl fumarate (DMF); and cluster 2 includes pwRRMS on teriflunomide, natalizumab or interferon (IFN)β. The T cell subsets were the ones that contributed the most to cluster discrimination with no clear pattern on the other cell populations. Compared to treatment-naïve pwRRMS, DMTs in cluster 1 lead to lower numbers of CD4+ and CD8+ T cells, and Treg subsets, being fingolimod the therapy causing the strongest effect. For the DMTs in cluster 2, no pattern of changes was seen in the number of any of the immune cell populations analysed. The effect of the DMTs on B cell numbers is extremely diverse, with natalizumab causing a great increase and fingolimod, on the contrary, a pronounced decrease. The effect of DMTs on NKT and NK cell subsets is highly variable. This study emphasises that, despite all being efficient in treating multiple sclerosis, the impact of different DMTs on the numbers of different immune cell populations differs strongly on the cell populations affected, as well as on the magnitude and direction of the effect. ### Competing Interest Statement The authors have declared no competing interest.