Four genetic mutations have been linked to progressive multifocal leukoencephalopathy (PML), a rare but sometimes fatal brain infection that can be provoked by dozens of FDA-approved drugs.
Image Credit: Orawan Pattarawimonchai/Shutterstock.com
The study, which was published in Frontiers in Neurology on December 14th, 2022, will allow clinicians to filter out people who are at high risk of developing PML.
The study discovered that possessing one of four genetic variations increased the incidence of PML 8.7 times in those taking PML-inducing drugs. The risk was 33-fold higher due to one of the variants.
Eight medications bear a Black Box Warning for PML, the FDA’s severe warning. Other PML warnings are included on over 30 other drugs. Patients taking more than 75 different medications have collectively reported incidences of PML to the FDA. Many of the most successful treatments for multiple sclerosis (MS), blood cancers, rheumatoid arthritis, Crohn’s disease, and organ transplant rejection are included on the list.
PML is caused by the JC virus (JCV), a virus that affects up to 80% of the population. PML develops when the virus reactivates and targets the brain, resulting in potentially fatal consequences. Scientists have long sought to understand why the virus causes PML in some individuals but not others.
The researchers initially established that four genetic variants were considerably more common in drug-induced PML patients than in the general population. They next sought these variants in the ideal control group, which included MS patients who carried JCV and had been using a high-risk medication for years but had not developed PML. When compared to these matched controls, the results were even more impressive.
Almost 11% of PML patients tested positive for at least one of the four variants. To put this finding in focus, these variants account for a greater proportion of PML instances than the well-known BRCA mutations account for in breast cancer cases. Furthermore, their predictive value exceeds levels that have prompted the FDA to mandate genetic screening for other potentially dangerous medicines.
As more immunosuppressive therapies are developed, the incidence of drug-induced PML is increasing. More than 500 instances were reported to the FDA’s adverse event reporting system in 2021. These drugs are widely prescribed: almost 1 million people in the United States have MS, another 1.5 million have blood malignancies that are regularly treated with PML-inducing treatments, and 850,000 Americans have received organ transplants.
It’s critical to be able to identify genetic mutations that greatly increase a person’s risk of this devastating infection. Preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.”
Dr Lawrence Steinman, Professor, Neurology and Neurological Sciences, Pediatrics, and Genetics, Stanford University
Tysabri, a strong MS treatment developed in his lab, was temporarily pulled from the market due to PML and currently carries a Black Box Warning. Dr Steinman is not affiliated with this study.
Determining genetic susceptibility to PML is an extremely promising method of reducing disease risk. A simple inexpensive test may prove revolutionary in this regard.”
Dr Joseph Berger, Chief, Multiple Sclerosis, University of Pennsylvania Perelman School of Medicine
Dr Joseph Berger is also an independent PML expert and lead author for the American Academy of Neurology’s PML Guidelines Committee.
Hatchwell, E., et al. (2022) Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies. Frontiers in Neurology. doi.org/10.3389/fneur.2022.1016377.