Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned

Abstract

Progressive multifocal leukoencephalopathy (PML) is a rare, devastating demyelinating disease of the CNS caused by the JC virus (JCV) that occurs in patients with compromised immune systems. Detection of PML in systemically immunocompetent patients with multiple sclerosis treated with natalizumab points to a role for this drug in the pathophysiology of PML. Emerging knowledge of the cellular and molecular biology of JCV infection and the pathogenesis of PML-including interplay of this common virus with the human immune system and features of natalizumab that might contribute to PML pathogenesis-provides new opportunities to monitor viral status and predict risk of JCV-associated disease. In the absence of an effective treatment for PML, early detection of the disease in patients with multiple sclerosis who are receiving natalizumab or other immunomodulatory treatments is vital to minimize CNS injury and avoid severe disability. Frequent MRI, stratified along a clinical and virus-specific immune risk profile, can be used to detect presymptomatic PML. Improved approaches to PML risk stratification are needed to guide treatment choices and surveillance of patients with multiple sclerosis.

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

“…Association of PML with natalizumab therapy is wellestablished, most notably in MS patients for which the drug was originally approved (3,16,19,68). In MS patients (Figure 1B), an appreciable number of PML cases were reported for fingolimod and dimethyl fumarate, but natalizumab accounts for 91% of FAERS-reported PML patients (1,576 cases).…”

“…Progressive multifocal leukoencephalopathy (PML) is a rare CNS disorder that typically occurs in the context of immunosuppression. Examples include HIV infection, hematological malignancies, or following immunosuppressive treatments for autoimmune diseases such as multiple sclerosis (MS) or transplantation (1)(2)(3). Infection with JC virus (JCV), a polyomavirus that is common in the general population, is a prerequisite (4).…”

“…Increased risk of PML in patients on immunosuppressant therapies is well-documented, with the MS/Crohn's disease drug natalizumab carrying the highest risk (3,9). Other MS drugs with PML risk are fingolimod and dimethyl fumarate (9,10).…”

Preventing infectious complications when treating non‐malignant immune‐mediated hematologic disorders

“…Progressive multifocal leukoencephalopathy (PML) is a devastating, opportunistic demyelinating disease caused by the John Cunningham (JC) virus, an ubiquitous polyomavirus that is estimated to latently infect the kidneys in more than 50% of healthy adults . In the context of immunodeficiency, JC virus can undergo genetic rearrangements in noncoding regions and can transform to a neurotropic virus that is able to infect glial cells and cause PML . The incidence of PML varies depending on the degree of immunosuppression and the underlying disease.…”

Disease-modifying therapies for multiple sclerosis

“…• MRI monitoring is mandatory in patients treated with natalizumab, fingolimod, dimethyl fumarate, on at least an annual basis, and every 3-6 months in natalizumab-treated patients at high risk of PML38…”