From Biogen, Inc (B.T.W., A.M.T., D.G., S.S., M.S.B., R.H.S.), Cambridge, MA; Department of Neurology (R.H., M.P., A.C.), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology (K.S.-K., R.G.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.
Neurol Neuroimmunol Neuroinflamm. 2021 Jan 19;8(2). doi: 10.1212/NXI.0000000000000950. Print 2021 Mar.
To test the hypothesis that dimethyl fumarate (DMF, Tecfidera) elicits different biological changes from DMF combined with monoethyl fumarate (MEF) (Fumaderm, a psoriasis therapy), we investigated DMF and MEF in rodents and cynomolgus monkeys. Possible translatability of findings was explored with lymphocyte counts from a retrospective cohort of patients with MS.
In rodents, we evaluated pharmacokinetic and pharmacodynamic effects induced by DMF and MEF monotherapies or in combination (DMF/MEF). Clinical implications were investigated in a retrospective, observational analysis of patients with MS treated with DMF/MEF (n = 36).
In rodents and cynomolgus monkeys, monomethyl fumarate (MMF, the primary metabolite of DMF) exhibited higher brain penetration, whereas MEF was preferentially partitioned into the kidney. In mice, transcriptional profiling for DMF and MEF alone identified both common and distinct pharmacodynamic responses, with almost no overlap between DMF- and MEF-induced differentially expressed gene profiles in immune tissues. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated oxidative stress response pathway was exclusively regulated by DMF, whereas apoptosis pathways were activated by MEF. DMF/MEF treatment demonstrated that DMF and MEF functionally interact to modify DMF- and MEF-specific responses in unpredictable ways. In patients with MS, DMF/MEF treatment led to early and pronounced suppression of lymphocytes, predominantly CD8 T cells. In a multivariate regression analysis, the absolute lymphocyte count (ALC) was associated with age at therapy start, baseline ALC, and DMF/MEF dosage but not with previous immunosuppressive medication and sex. Furthermore, the ALC increased in a small cohort of patients with MS (n = 6/7) after switching from DMF/MEF to DMF monotherapy.
Fumaric acid esters exhibit different biodistribution and may elicit different biological responses; furthermore, pharmacodynamic effects of combinations differ unpredictably from monotherapy. The strong potential to induce lymphopenia in patients with MS may be a result of activation of apoptosis pathways by MEF compared with DMF.
为了验证丁二酸二甲酯（DMF，特立氟胺）与单乙基丁二酸酯（MEF，一种银屑病治疗药物，Fumaderm）联合使用时会产生不同于 DMF 的生物学变化这一假说，我们在啮齿动物和食蟹猴中研究了 DMF 和 MEF。通过对特立氟胺/ MEF（n = 36）治疗多发性硬化症（MS）患者的回顾性队列研究，探讨了淋巴细胞计数的潜在可转化性。
在啮齿动物中，我们评估了 DMF 和 MEF 单药治疗或联合治疗（DMF/ MEF）引起的药代动力学和药效学效应。在特立氟胺/ MEF 治疗的 MS 患者的回顾性观察性分析（n = 36）中，研究了临床意义。
在啮齿动物和食蟹猴中，单甲基富马酸（MMF，DMF 的主要代谢物）显示出更高的脑穿透性，而 MEF 则优先分布在肾脏中。在小鼠中，单独使用 DMF 和 MEF 的转录谱分析确定了共同和独特的药效反应，免疫组织中 DMF 和 MEF 诱导的差异表达基因谱几乎没有重叠。核因子（红系衍生 2）样 2（Nrf2）介导的氧化应激反应途径仅受 DMF 调节，而凋亡途径则受 MEF 激活。DMF/ MEF 治疗表明，DMF 和 MEF 以不可预测的方式相互作用，从而改变 DMF 和 MEF 的特异性反应。在 MS 患者中，DMF/ MEF 治疗导致淋巴细胞，主要是 CD8 T 细胞的早期和显著抑制。在多变量回归分析中，绝对淋巴细胞计数（ALC）与治疗开始时的年龄、基线 ALC 和 DMF/ MEF 剂量相关，但与以前的免疫抑制药物和性别无关。此外，在接受 DMF/ MEF 转换为 DMF 单药治疗的 MS 小患者队列（n = 6/7）中，ALC 增加。
富马酸酯具有不同的分布，并可能引起不同的生物学反应；此外，组合的药效反应不可预测地不同于单药治疗。与 DMF 相比，MEF 可能通过激活凋亡途径，在 MS 患者中产生强烈的潜在致淋巴细胞减少作用。
