Dimethyl fumarate (DMF) and ocrelizumab are two effective immunomodulators for multiple sclerosis (MS) with distinct mechanisms of action. Identifying overlapping therapeutic effects between both agents may elucidate common pathways in preventing disease activity. Objectives: In this study we analyzed cytokine and immune-profiling data to evaluate the similarities and differences between the two disease-modifying therapies for MS. Methods: Plasma and PBMCs from MS patients were collected at

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... line, 3 months and 6 months after treatment with DMF (n=16) and ocrelizumab (n=13). Immunophenotyping was performed with mass cytometry (CyTOF) and analyzed with gating based on cell surface markers. Cytokine analysis from plasma was performed with Olink assays and analyzed with linear mixed effects models. Results: DMF reduced both effector T and memory B cell populations while increasing CD56bright natural killer (NK) cells. Ocrelizumab exerted its main immunomodulatory effect by reducing the frequency of all B cells and increasing frequency of NK cells. At 6 months, naive B-cells began to reconstitute; however, memory B cells remain depleted. DMF treatment was associated with a significant reduction of plasma cytokines involved in inflammatory pathways, such as IL-6, IL-12, and Dectin-1 signaling. In addition, DMF lowered plasma cytokines that are dysregulated in psoriasis and involved in allograft rejection pathways. Ocrelizumab treatment led to the upregulation of neurotropic proteins in the plasma of MS patients, including proteins involved in NAD+ biosynthesis and tryptophan catabolism. Conclusion: Our high-dimensional immunophenotyping results suggest that to exert their effects on MS patients, DMF and ocrelizumab both increase NK cells in addition to affecting different immune cell populations and cytokine pathways. Detecting similarities between the mechanisms of the two drugs may contribute to identifying more specific therapeutic targets.