• Posted December 12, 2022

Patients' Genes Raise Odds for Rare Brain Infection When Using Certain Meds

For some people, dozens of U.S.-approved drugs can lead to a rare but often fatal brain infection.

Researchers have now confirmed a strong link between four genetic mutations and this illness, called progressive multifocal leukoencephalopathy (PML).

A new study found that in people taking PML-inducing drugs, having one of four genetic variants increased the odds of developing PML 8.7 times on average.

One of the variants increased risk 33-fold.

The findings give doctors the insight to screen out patients with the highest risk for the condition before prescribing these drugs.

The U.S. Food and Drug Administration has put its most serious warning -- called a Black Box Warning -- for PML on eight approved medications.

More than 30 drugs carry other PML warnings, and cases have been reported in connection with more than 75 drugs treating everything from multiple sclerosis (MS) to blood cancer, rheumatoid arthritis, Crohn's disease and organ transplant rejection.

This has the potential to affect a lot of people.

Nearly 1 million Americans have MS, for example. Another 1.5 million have blood cancers commonly treated with PML-inducing drugs. About 850,000 Americans have received organ transplants, the study authors noted.

As more immunosuppressant medications are developed, drug-induced PML is on the rise, with more than 500 cases listed in the FDA's adverse event reporting system in 2021.

"It's critical to be able to identify genetic mutations that greatly increase a person's risk of this devastating infection,"Dr. Lawrence Steinman said in a news release from Emerald Lake Safety.

Steinman, a professor of neurology and neurological sciences, pediatrics and genetics at Stanford University in California, was not involved in this study.

His lab developed a multiple sclerosis medication known as Tysabri. It has a Black Box Warning after temporarily being removed from the market because of PML.

"Preventative screening for these variants should become part of the standard of care," Steinman said. "I wish we had more powerful tools like this for other therapies."

A typically harmless virus known as JC virus causes PML. Though up to 80% of people carry it, PML occurs when the virus reactivates and attacks the brain.

In the new study, the researchers found that four genetic variants were far more common in patients who developed drug-induced PML than in the general population. They then looked for these variants in a control group of MS patients who did not develop PML even though they carried the virus and were taking a high-risk drug for years.

The investigators found that their results were even stronger when compared to these matched controls.

Nearly 11% of patients who had PML tested positive for at least one of the four gene variants. That's higher than levels that have led the FDA to require genetic screening for other risky medications, the study authors noted.

"Determining genetic susceptibility to PML is an extremely promising method of reducing disease risk. A simple inexpensive test may prove revolutionary in this regard,"said 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.

Berger was not involved in this study.

The findings were published Dec. 14 in Frontiers in Neurology. Dr. Eli Hatchwell of Population Bio UK, in the United Kingdom, led the international research team that conducted the study.

More information

The U.S. National Institute of Neurological Disorders and Stroke has more on PML.

SOURCE: Emerald Lake Safety, news release, Dec. 14, 2022