Dimethyl fumarate induced lymphopenia in multiple sclerosis: A review of the literature

Dimethyl fumarate (DMF) is a first line medication for multiple sclerosis. It has a favourable safety profile, however, there is concern regarding the occurrence of moderate-severe and sustained lymphopenia and the associated risk of progressive multifocal leukoencephalopathy. We carried out an extensive literature review to understand the molecular mechanisms underlying this adverse reaction. Dynamic changes in certain components of the immune system are likely to be important for the therapeutic effects of DMF, including depletion of memory T cells and decrease in activated T cells together with expansion of naïve T cells. Similar modifications were reported for the B cell components. CD8⁺ T cells are particularly susceptible to DMF-induced cell death, with marked reductions observed in lymphopenic subjects. The reasons underlying such increased sensitivity are not known, nor it is known how expansion of other lymphocyte subsets occurs. Understanding the molecular mechanisms underlying DMF action is challenging: in vivo DMF is rapidly metabolized to monomethyl fumarate (MMF), a less potent immunomodulator in vitro. Pharmacokinetics indicate that MMF is the main active species in vivo. However, the relative importance of DMF and MMF in toxicity remains unclear, with evidence presented in favour of either of the compounds as toxic species. Pharmacogenetic studies to identify genetic predictors of DMF-induced lymphopenia are limited, with inconclusive results. A role of the gut microbiome in the pharmacological effects of DMF is emerging. It is clear that further investigations are necessary to understand the mechanisms of DMF-induced lymphopenia and devise preventive strategies. Periodic monitoring of absolute lymphocyte counts, currently performed in clinical practise, allows for the early detection of lymphopenia as a risk-minimization strategy.