Dimethyl fumarate (DMF; trade name Tecfidera™) is an oral formulation of the fumaric acid ester that is FDA approved for treatment of relapsing-remitting multiple sclerosis (RRMS). To better understand the therapeutic effects of Tecfidera and its rare side-effect of progressive multifocal leukoencephalopathy (PML), we conducted cross-sectional and longitudinal studies by immunophenotyping cells from peripheral blood (particularly T lymphocytes) derived from untreated, 4-6 month and 18-26 month Tecfidera-treated stable RRMS patients using multi-parametric flow cytometry. The absolute numbers of CD4 and CD8 T cells were significantly decreased and the CD4/CD8 ratio was increased with DMF treatment. The proportion of both effector memory (Tem) and central memory T cells (Tcm) were reduced while naïve T cells (Tn) increased in treated patients. T cell activation was reduced with DMF treatment especially among Tem and effector memory RA (Temra) T cells. T helper subsets Th1 (CXCR3+), Th17 (CCR6+), and particularly those expressing both CXCR3 and CD161 were reduced most significantly, while the anti-inflammatory Th2 subset (CCR3+) was increased after DMF treatment. A corresponding increase in IL-4, and decrease in IFNγ and IL-17-expressing CD4+ T cells was observed in DMF-treated patients. DMF in vitro treatment also led to increased T cell apoptosis and decreased activation, proliferation, reactive oxygen species, and CCR7 expression. Our results suggest that DMF acts on specific memory and effector T cell subsets by limiting their survival, proliferation, activation, and cytokine production. Monitoring these subsets could help to evaluate the efficacy and safety of DMF treatment.

Microbial metabolites, produced in the intestine, have significant effects on inflammatory diseases throughout the body. Short-chain fatty acids (SCFAs) have protective effects on experimental autoimmune encephalitis (EAE) responses but the detailed roles of SCFAs and their receptors in regulating autoimmune CNS inflammation have been unclear. SCFAs metabolically regulate T cells and change the phenotype of antigen presenting cells to efficiently induce IL-10 + regulatory T cells. In line with the overall protective effect, blood levels of major SCFAs, such as acetate, propionate and butyrate, are significantly decreased in long-term active progressive multiple sclerosis (MS) patients. Importantly, SCFAs can induce CD4 + effector T cells, which are highly inflammatory when transferred into mice, suggesting that the direct effect of SCFAs on T cells can even be pro-inflammatory in the CNS. In contrast to the moderate protective effect of SCFAs, mice deficient in GPR41 or GPR43 are more resistant to EAE pathogenesis. Thus, despite the overall protective function of SCFAs, SCFAs and their receptors have the potential to regulate autoimmune CNS inflammation both positively and negatively.

The clinical success of anti-CD20 monoclonal antibody (mAb)-mediated B cell depletion therapy has contributed to the understanding of B cells as major players in several autoimmune diseases. The first therapeutic anti-CD20 mAb, rituximab, is a murine–human chimera to which many patients develop antibodies and/or experience infusion-related reactions. A second generation of anti-CD20 mAbs has been designed to be more effective, better tolerated, and of lower immunogenicity. These include the humanized versions: ocrelizumab, obinutuzumab, and veltuzumab, and the fully human, ofatumumab. We conducted a literature search of relevant randomized clinical trials in the PubMed database and ongoing trials in Clinicaltrials.gov. Most of these trials have evaluated intravenous ocrelizumab or subcutaneous ofatumumab in rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus. Understanding how newer anti-CD20 mAbs compare with rituximab in terms of efficacy, safety, convenience, and cost is important for guiding future management of anti-CD20 mAb therapy in autoimmune diseases.

Dimethyl fumarate (DMF) is an effective treatment option for relapsing–remitting multiple sclerosis (MS), but its therapeutic mechanism of action has not been fully elucidated. A better understanding of its mechanism will allow for the development of assays to monitor its clinical efficacy and safety in patients, as well as guide the development of the next generation of therapies for MS. In order to build the foundation for determining its mechanism, we reviewed the manner in which DMF alters lymphocyte subsets in MS patients, its impact on clinical efficacy and safety, as well as its molecular effects in cellular and animal models. DMF decreases absolute lymphocyte counts, but does not affect all subsets uniformly. CD8+ T-cells are the most profoundly affected, but reduction also occurs in the CD4+ population, particularly within the pro-inflammatory T-helper Th1 and Th17 subsets, creating a bias toward more anti-inflammatory Th2 and regulatory subsets. Similarly, B-lymphocyte, myeloid, and natural killer populations are also shifted toward a more anti-inflammatory state. In vitro and animal models demonstrate a role for DMF within the central nervous system (CNS) in promoting neuronal survival in an Nrf2 pathway-dependent manner. However, the impact of DMF directly within the CNS of MS patients remains largely unknown.

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