Diagnosis and Treatment of Progressive Multifocal Leukoencephalopathy Associated with Multiple Sclerosis Therapies

Abstract

Progressive multifocal leukoencephalopathy (PML) is a rare, but serious, complication encountered in patients treated with a select number of disease-modifying therapies (DMTs) utilized in treating multiple sclerosis (MS). PML results from a viral infection in the brain for which the only demonstrated effective therapy is restoring the perturbed immune system-typically achieved in the patient with MS by removing the offending therapeutic agent or, in the case of HIV-associated PML, treatment with highly active antiretroviral therapies. Other therapies for PML remain either ineffective or experimental. Significant work to understand the virus and host interaction has been undertaken, but lack of an animal model for the disorder has significantly hindered progress, especially with respect to development of treatments. Strategies to limit risk of PML with natalizumab, a drug that carries a uniquely high risk for the development of the disorder, have been developed. Identifying factors such as positive JC virus antibody status that increase PML risk, at least in theory, should decrease the incidence rate of the disease. Whether other risk factors for PML can be identified and validated or unique strategies should be employed in association with other DMTs that predispose to PML and whether this has a salutary effect on outcome remains to be demonstrated. Identifying PML early, then promptly eliminating drug in the case of natalizumab-associated PML has demonstrated better outcomes, but the complication of PML continues to carry significant morbidity and mortality. While the scientific community has yet to identify targeted therapy with proven efficacy against JCV or PML there are several candidates being studied.

Cost Assessment Modelling of Treatments for Highly Active Relapsing Multiple Sclerosis

“…As in all health economic modelling, the results of the present study are subject to uncertainty. Although progressive multifocal leukoencephalopathy (PML) is a severe adverse event associated with natalizumab, and to a lesser extent also with other MS drugs [48], the treatment-related risk of PML in MS is still very low [49]. Due to the high uncertainty in the PML incidence data in clinical trials, it was not considered in our analyses.…”

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).…”

“…The only therapeutic approaches that showed some efficacy in the control of JCV replication in the CNS are based on immune restoration. Depending on the underlying disease before onset of PML, ∼20-90% of patients die and survivors develop severe physical and cognitive disabilities (15,16). Due to the severity of PML as a serious adverse event (SAE) linked to several immunosuppressant drugs, an ideal scenario would be to administer a PML risk test and exclude high risk patients from a therapy in order to prevent PML cases.…”

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

“…The anti‐TNFα monoclonal antibody–based therapies are linked to the reactivation of a latent infection with Mycobacterium tuberculosis . The treatment of multiple sclerosis with the monoclonal antibody natalizumab carries the risk of JC virus–associated progressive multifocal leukoencephalopathy that contributes to significant morbidity and mortality . Again, the suppression of autoimmune inflammation may reignite microbial inflammation.…”