Understanding Progressive Multifocal Leukoencephalopathy Risk in Multiple Sclerosis Patients Treated with Immunomodulatory Therapies: A Bird’s Eye View

Abstract

The increased use of newer potent immunomodulatory therapies for multiple sclerosis (MS), including natalizumab, fingolimod, and dimethyl fumarate, has expanded the patient population at risk for developing progressive multifocal leukoencephalopathy (PML). These MS therapies shift the profile of lymphocytes within the central nervous system (CNS) leading to increased anti-inflammatory subsets and decreased immunosurveillance. Similar to MS, PML is a demyelinating disease of the CNS, but it is caused by the JC virus. The manifestation of PML requires the presence of an active, genetically rearranged form of the JC virus within CNS glial cells, coupled with the loss of appropriate JC virus-specific immune responses. The reliability of metrics used to predict risk for PML could be improved if all three components, i.e., viral genetic strain, localization, and host immune function, were taken into account. Advances in our understanding of the critical lymphocyte subpopulation changes induced by these MS therapies and ability to detect viral mutation and reactivation will facilitate efforts to develop these metrics.

JCPyV NCCR analysis in PML patients with different risk factors: exploring common rearrangements as essential changes for neuropathogenesis

“…To date, several DMTs used in multiple sclerosis (MS) have been associated with PML. Natalizumab, fingolimod and dimethyl fumarate have been associated with an increased risk of developing PML in the MS population [6]. The risk of developing natalizumab-associated PML depends on three factors: the presence of anti-JC antibodies, a long treatment duration (particularly longer than 24 months) and prior immunosuppressive drugs [7].…”

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

“…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). Rituximab, which is used to treat a variety of conditions such as hematological malignancies, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), has been implicated as a cause of PML for several years but it has been difficult to establish its level of risk (11)(12)(13)(14).…”

Progressive multifocal leukoencephalopathy and granule cell neuronopathy with novel mutation flanking VP1 C-terminus in natalizumab-extended interval dosing

“…Concomitant cerebellar/pontine white matter changes have been observed in GCN, and it has been postulated that this could be because of a coinfection with 2 different JCV strains. 6 While the NCRR variant is responsible for the PML-typical white matter changes, a different JCV strain with a VP1 C-terminus mutation leads to JCV-GCN with its characteristic cerebellar atrophy. 7 The current case demonstrates an association between the concurrence of PML-lesions and JCV-GCN and the coinfection with the virulent NCRR variant and a novel mutation in the noncoding region flanking the VP1 C-terminus.…”