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.

富马酸二甲酯 (DMF) 是多发性硬化症的一线药物。它具有良好的安全性，但是，存在中重度和持续淋巴细胞减少的发生以及进行性多灶性白质脑病的相关风险的担忧。我们进行了广泛的文献回顾，以了解这种不良反应的分子机制。免疫系统某些成分的动态变化可能对 DMF 的治疗效果很重要，包括记忆 T 细胞的消耗和活化 T 细胞的减少以及幼稚 T 细胞的扩增。对 B 细胞成分报告了类似的修改。CD8 ⁺T 细胞特别容易受到 DMF 诱导的细胞死亡的影响，在淋巴细胞减少的受试者中观察到显着减少。这种敏感性增加的原因尚不清楚，也不知道其他淋巴细胞亚群的扩增是如何发生的。了解 DMF 作用背后的分子机制具有挑战性：体内DMF 会迅速代谢为富马酸单甲酯 (MMF)，这是一种效力较低的体外免疫调节剂。药代动力学表明MMF是体内主要的活性物质. 然而，DMF 和 MMF 在毒性方面的相对重要性仍不清楚，有证据表明这两种化合物中的任何一种都是有毒物质。用于确定 DMF 诱导的淋巴细胞减少症的遗传预测因子的药物遗传学研究有限，结果尚无定论。肠道微生物组在 DMF 药理作用中的作用正在显现。很明显，需要进一步研究以了解 DMF 诱导的淋巴细胞减少的机制并制定预防策略。目前在临床实践中进行的绝对淋巴细胞计数的定期监测允许早期检测淋巴细胞减少症作为风险最小化策略。