Progressive multifocal leukoencephalopathy in dimethyl fumarate-treated multiple sclerosis patients

Abstract

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).

Early High Efficacy Treatment in Multiple Sclerosis Is the Best Predictor of Future Disease Activity Over 1 and 2 Years in a Norwegian Population-Based Registry

“…The injectables have poorer acceptability profiles than other DMTs, and the high efficacy drugs have lower dropout rates than moderate efficacy drugs (47). Although side effects from moderate efficacy therapies are rarely life threatening, there are several reported cases of PML in Tecfidera treated patients (48). In the end, higher disability at a younger age seems a more significant risk than most of the adverse effects associated with established high efficacy DMTs.…”

Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy

“…Older age may have also played a role in the development of PML in the patient, as it has emerged as a risk factor for immunotherapy-related PML, although the risk varies widely with different disease-modifying therapies. [6][7][8] Furthermore, there exist reports of PML in otherwise immunocompetent elderly individuals, although this remains exceedingly rare. 9 While the precise mechanism that brings about PML is not entirely understood, it is likely facilitated by the decrease in lymphocyte production and potency associated with age-related immunosenescence.…”

Progressive multifocal leukoencephalopathy and sphingosine 1-phosphate receptor modulators used in multiple sclerosis: an updated review of literature

“…PML, a central nervous disease caused by the John Cunningham polyomavirus (JCV), virtually always affects individuals who are immuno-deficient, including patients with human immunodeficiency virus (HIV) infection, patients receiving immunosuppressive therapy for lymphoproliferative or rheumatologic diseases, and MS patients receiving immunomodulatory medications [13]. So far, PML has been reported in MS patients treated with natalizumab, dimethyl fumarate, fingolimod, and, most recently, ocrelizumab and alemtuzumab [14][15][16][17][18][19][20]. Of the four S1PR modulators, almost all cases of PML have been reported in MS patients treated with fingolimod, the drug that has been marketed for the longest period of time.…”