A new study has shown a clear association between four genetic abnormalities and progressive multifocal leukoencephalopathy (PML), a rare but sometimes deadly brain disease that may be induced by dozens of FDA-approved medicines.
The study, which was published today in Frontiers in Neurology, will enable medical professionals to filter out those who are most at risk for PML.
The study found that people who took drugs that caused PML were 8.7 times more likely to get PML if they had one of four genetic variations. One of the variations was responsible for a 33-fold increase in risk.
The FDA’s strictest warning, the Black Box Warning for PML, is present on eight drugs. More than 30 other medications come with different PML alerts. In all, individuals using more than 75 different medications have reported PML episodes to the FDA. Many of the top therapies for multiple sclerosis (MS), blood malignancies, rheumatoid arthritis, Crohn’s disease, and organ transplant rejection are included on the list.
The JC virus (JCV), a typically benign virus that affects up to 80% of people, is what causes PML. PML is caused when the virus reactivates and launches an assault on the brain, which may have potentially fatal effects. For a very long time, scientists have been trying to figure out why the virus causes PML in some individuals but not in others.
In this study, researchers first showed that four genetic variations were much more common in people who got drug-induced PML than in the general population. Then, they looked for these changes in the best control group, which was made up of MS patients who had JCV and had been taking a high-risk drug for years, but who had not developed PML. When these matched controls were used, the results were even stronger.
Nearly 11% of PML patients tested positive for at least one of the four variants. To give you an idea of how important this finding is, these variants explain more PML cases than the well-known BRCA mutations do breast cancer cases. Also, their ability to predict the future is better than what led the FDA to require genetic testing for other risky drugs.
As more immunosuppressant medications are developed, the incidence of drug-induced PML has been rising. More than 500 incidents were reported to the FDA’s adverse event reporting system in 2021. In the U.S., nearly 1 million people have Multiple Sclerosis (MS), another 1.5 million have blood cancers that are often treated with PML-inducing drugs, and 850,000 Americans have had organ transplants.
“It’s critical to be able to identify genetic mutations that greatly increase a person’s risk of this devastating infection,” remarks Dr. Lawrence Steinman, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford University, who was not involved in the study.
His lab made Tysabri, a strong drug for MS that was taken off the market for a while because of PML and now has a Black Box Warning.
“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,” he adds.
Identifying genetic susceptibility to PML is an incredibly promising method of lowering disease risk, according to Dr. Joseph Berger, chief of multiple sclerosis at the University of Pennsylvania Perelman School of Medicine and lead author for the American Academy of Neurology’s PML Guidelines Committee.
“A simple inexpensive test may prove revolutionary in this regard.”
Source: 10.3389/fneur.2022.1016377
Image Credit: Getty