Scientists Find Clue to Dangerous Side Effect of MS Drug

WEDNESDAY Sept. 9, 2009 -- Scientists may have discovered part of the reason why Tysabri, a drug used to treat multiple sclerosis, may lead to the development of a rare but potentially deadly brain disease in some patients.

The drug seems to rouse the typically dormant JC virus from its slumber, allowing it to cross into the brain.

Although this finding may lead to a way of predicting who is at risk for the brain infection -- called progressive multifocal leukoencephalopathy (PML) -- at this point, the implications are still unclear.

"We don't know what this means until we find out over time whether or not people actually do get PML," said Patricia O'Looney, vice president of biomedical research at the National Multiple Sclerosis Society in New York City. "But it certainly is exploring a key question."

The study authors also warned against coming to premature conclusions.

"We don't advocate a change in management [of the disease] at this point because the clinical relevance of these findings is still unknown," said Dr. Igor J. Koralnik, senior author of a paper appearing in the Sept. 10 issue of the New England Journal of Medicine. "But it should spur further research."

Natalizumab (Tysabri) first received U.S. Food and Drug Administration approval in November 2004, only to be pulled from the market three months later after several patients in clinical trials developed the rare but deadly viral infection.

According to the study authors, as of July 24, 2009, 13 patients with multiple sclerosis taking Tysabri are known to have developed PML, along with one patient with Crohn's disease (Tysabri was approved to treat Crohn's in early 2008).

The JC virus is present yet dormant in about 90 percent of people. It can reactivate in people with AIDS or otherwise compromised immune systems.

"We don't have a very good handle right now on how to determine who's at higher risk for PML," O'Looney stated. "There's no way to monitor patients and no way to predict who will be susceptible. It's important to find some marker or indication of the presence of these viruses either in the urine or the blood."

In this latest study, 19 patients with relapsing-remitting multiple sclerosis who were taking Tysabri underwent lab work at three, six, 12 and 18 months after starting treatment.

After 12 months, measurements of JC virus in the urine rose from 19 percent (about normal) of samples to 63 percent. At this time, only one patient showed JC virus in their blood.

By 18 months, the virus had infiltrated plasma samples in 20 percent of patients and blood cells in 60 percent of patients. And the virus type in question here had undergone a rearrangement that made it more adept at crossing into the brain.

Immune system responses associated with higher levels of JC virus dropped after six and 12 months of treatment. "This was unexpected," said Koralnik, who is director of the HIV/Neurology Center at Beth Israel Deaconess Medical Center in Boston. "It dampened the immune response as measured in blood samples and that was associated with the appearance of the virus in the urine."

None of the patients developed PML or any indication that they might develop the infection.

"The next question is: does that mean that all those who have virus in the blood or rearrangement in the urine will develop PML?" Koralnik said. "This is something that obviously we can't answer with this pilot study. The epidemiology indicates that the development of PML is still a rare event in Tysabri-treated patients, but we hope that if we follow the appearance of the virus in the blood or urine and follow changes [in the actual virus], in the future we will be able to detect better those at risk of developing PML while in treatment."

Two other papers in the same issue of the journal described case studies of patients with multiple sclerosis who developed PML after using Tysabri. One was a 52-year-old man who became critically ill but eventually recovered.

The second was a 35-year-old man, who also recovered. The authors of this paper stressed that the risk of PML in patients being treated with Tysabri is still low, about one in 1,000 and possibly even lower.

Until there is a good way to predict who is at risk for PML, experts urged doctors to be alert for early signs of this brain infection.

"Patients and physicians still need to have tight vigilance for any new symptoms that can occur while a patient is on Tysabri," O'Looney said.

More information

The National Multiple Sclerosis Society has more on living with MS.

Posted: September 2009


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