Genetic risk test may identify drugs that adversely affect patients with MS

Key takeaways:

• Researchers performed genetic analyses of 336 cases of those with PML, 94 of whom were patients with MS.
• Four genetic risk variants were found with a nine-fold increased risk in carriers of at least one variant.

PHILADELPHIA — A genetic risk test for patients with multiple sclerosis can identify drugs that may lead to development of progressive multifocal leukoencephalopathy, per data presented at the American Neurological Association annual meeting.

[Progressive multifocal leukoencephalopathy] is a debilitating and potentially fatal neurological disorder,” Peggy S. Eis, PhD, of Population Bio Inc., in New York, and colleagues wrote. “Immunosuppressed patients who are positive for JC virus are at risk but typically do not develop PML. A growing number of drug-induced PML cases have been reported in the literature and/or to the FDA for patients on immunosuppressant therapies.”

More than 30 drugs list warnings for the condition, eight of which come with a Boxed Warning and with the highest incidence rate for drug-induced PML recorded in patients with MS who have been prescribed natalizumab.

Researchers sought to identify genetic risk variants in PML patient genomes to create a specific risk test, as it is a debilitating and potentially fatal neurological disorder, and to test a hypothesis that certain individuals have a preexisting genetic risk for developing PML.

Eis and colleagues conducted a genetic analysis of candidate PML risk variants among 336 PML cases, of which 94 individuals were diagnosed with MS and exposed to PML-linked drugs before developing the condition. Analysis focused on immune-modulating genes. Both the affected study population and matched controls (JCV-positive patients with MS on a PML-linked drug 2 years) were included within association and pharmacogenetic analyses.

According to results, researchers validated four candidate PML risk genetic variants in the largest genetic study to date of PML (Hatchwell E. et al. Frontiers in Neurology, 2022), which were associated with PML in both analysis groups.

In drug-exposed PML cases, a nine-fold increased risk of PML in carriers of at least one variant was found, with all four risk variants likely to be harmful and located in two immune pathways involved in viral defense: complement system (C8B, in the terminal pathway, causes C8 deficiency; FCN2 is part of the lectin pathway) and genes causing or linked to hemophagocytic lymphohistiocytosis (HLH) disorders.

“The increased risk of drug-induced PML in patients testing positive is higher than already-known genetic associations that are used to guide treatments ... yet many neurologists and oncologists may have limited awareness of how many drugs have been linked to PML,” Eis said in a related release. “Clearly, warning labels on some of these drugs need to be updated and can now include a requirement for genetic testing before these drugs are prescribed.”