5'-DMT-G(dmf)-Suc-CPG; 1000 Å (RNA)

Dimethyl fumarate (DMF), a fumaric acid with antioxidant and immunomodulatory properties, is among the most commonly used oral therapies for relapsing multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) has been associated with several disease-modifying therapies (DMTs), including DMF in treating MS. We present detailed clinical characteristics of nine PML cases and show that the PML incidence in DMF-treated patients is 0.02 per 1000 patients. In addition to persistent severe lymphopenia, older age appears to be a potential risk for PML. However, younger patients without lymphopenia were also observed to develop PML. DMF-associated PML has occurred in patients with absolute lymphocyte counts (ALCs) above the guideline threshold, suggesting that changes in specific subsets might be more important than total ALC. Furthermore, since DMF has been found to decrease immune cell migration by decreasing the expression of adhesive molecules, the cerebrospinal fluid (CSF) immune profile may also be useful for assessing PML risk in DMF-treated patients. This review provides an up-to-date assessment of PML cases occurring in DMF-treated patients and discusses other potential considerations in light of our current understanding of DMF's mechanism of action on the immune system in the periphery and in the central nervous system (CNS).

Cerebrovascular disease and its risk factors cause persistent decrease of cerebral blood flow, chronic cerebral hypoperfusion (CCH) is the major foundation of vascular cognitive impairment (VCI). The hippocampus is extremely vulnerable to cerebral ischemia and hypoxia. Oxidative stress and neuroinflammation injury are important pathophysiological mechanisms of this process, which is closely related to hippocampal neurons damage and loss. Dimethyl fumarate (DMF), an FDA-approved therapeutic for multiple sclerosis (MS), plays a protective role in multiple neurological disorders. Studies have shown that DMF exerts anti-inflammatory and antioxidant effects via the NRF2/ARE/NF-κB signaling pathway. Thus, this study aimed to evaluate the neuroprotective effect of DMF in the CCH rat model. Ferroptosis, a novel defined iron-dependent cell death form, were found to be strongly associated with the pathophysiology of CCH. Emerging evidences have shown that inhibition of ferroptosis by targeting NRF2 exerted neuroprotective effect in neurodegeneration diseases. We also investigated whether DMF can alleviate cognitive deficits through inhibition of ferroptosis by the NRF2 signaling pathway in this study. DMF was intragastric for consecutive five weeks (100 mg/kg/day). Then behavior test and histological, molecular, and biochemical analysis were performed. We found that DMF treatment significantly improved cognitive deficits and partially reversed hippocampus neuronal damage and loss caused by CCH. And DMF treatment decreased hippocampus IL-1β, TNF-α, and IL-6 pro-inflammatory cytokines concentration, and mediated the NF-κB signaling pathway. And DMF also alleviated hippocampus oxidative stress through reducing MDA, and increasing GSH and SOD levels, which are also closely associated with ferroptosis. Besides, DMF treatment reduced the expression of PTGS2, and increased the expression of FTH1 and xCT, and the iron content is also reduced, which were the important features related to ferroptosis. Furthermore, DMF activated the NRF2/ARE signaling pathway and upregulated the expression of HO-1, NQO1 and GPX4. These outcomes indicated that DMF can improve cognitive impairment in rats with CCH, possibly through alleviating neuroinflammation, oxidative stress damage and inhibiting ferroptosis of hippocampal neurons. Overall, our results provide new evidence for the neuroprotective role of DMF.

Dimethyl fumarate (DMF) demonstrated favorable benefit-risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension. The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE. Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0-2), then DMF (Years 3-10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years. By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04-10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF (n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120-0.169)), while for PBO/DMF (n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0-2 years, 0.330 (95% CI, 0.266-0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118-0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening. Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF's positive benefit/risk profile for long-term RRMS treatment.