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Aim: Dimethyl fumarate (DMF) is one of the most promising therapies for relapsing‐remitting multiple sclerosis (RRMS) patients since it has shown immunomodulatory and neuroprotective effects. However, a percentage of RRMS patients do not exhibit an optimal response to DMF. The objective of this study was to identify early biomarkers of treatment response by analyzing changes in peripheral leukocyte subpopulations directly in whole blood samples. Methods: A longitudinal and prospective study analyzing peripheral blood leukocyte subpopulations in 22 RRMS patients before initiating DMF treatment (baseline) and at 1, 3, 6, and 12 months of follow‐up was performed. Differences between no evidence of disease activity (NEDA) and ongoing disease activity (ODA) patients were analyzed. Results: The beneficial effect of DMF was associated with a specific depletion of memory CD4+ and CD8+ T lymphocytes and B cells. Importantly, only NEDA patients showed (a) a shift from a pro‐ to an antiinflammatory profile, with an increase of Th2 cells and a decrease of Th1‐like Th17 lymphocytes; and (b) an increase of regulatory CD56bright NK cells. Conclusion: The optimal response to DMF is mediated by a shift to antiinflammatory and immunoregulatory profile, which puts forward Th1‐like Th17 lymphocytes as a potential early biomarker of treatment response. [ABSTRACT FROM AUTHOR]

Summary: Aims: Fingolimod, an orally active immunomodulatory drug for relapsing‐remitting multiple sclerosis (RRMS), sequesters T cells in lymph nodes through functional antagonism of the sphingosine‐1‐phosphate receptor, reducing the number of potential autoreactive cells that migrate to the central nervous system. However, not all RRMS patients respond to this therapy. Our aim was to test the hypothesis that by immune‐monitoring RRMS patient's leukocyte subpopulations it is possible to find biomarkers associated with clinical response to fingolimod. Methods: Prospective study. Analysis of peripheral blood mononuclear cell subpopulations by multiparametric flow cytometry, at baseline and +1, +3, +6, +12 months of follow‐up in 40 RRMS patients starting fingolimod therapy. Results: Fingolimod treatment induced a severe lymphopenia affecting mainly T and B cells. A relative increase in Treg (memory Treg: 3.8 ± 1.0% baseline vs 8.8 ± 4.4% month +1; activated Treg: 1.5 ± 0.7% baseline vs 3.7 ± 2.1% month +1, P < 0.001) as well as transitional B cells (10.5 ± 12.3% baseline vs 18.7 ± 14.6% month +1, P < 0.001) was observed. Interestingly, lymphocyte subpopulations were already at baseline significantly different in responder patients. The percentage of recent thymic emigrants (RTE) used to stratify fingolimod responder, and no responder patients was the best biomarker (4.0 ± 1.4% vs 7.4 ± 1.9%, respectively [P < 0.001]). Conclusion: The results support that immune‐monitoring of lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment. [ABSTRACT FROM AUTHOR]