A cautious approach to skin disease
On April 9, the biotech company Genentech announced that it was withdrawing its psoriasis medicine Raptiva from the market because it can cause a rare but often fatal brain infection called progressive multifocal leukoencephalopathy, or PML. Four cases of the disease have been reported in patients taking Raptiva; all had been on the drug for at least three years.
Raptiva is used to control moderate to severe cases of plaque psoriasis, the most common form of the autoimmune disease, which causes red scaly patches on the skin that can itch and hurt. Raptiva, approved in the U.S. in 2003, works by inhibiting the overactive immune cells that give rise to the condition.
What is PML?
PML is a devastating infection of the nervous system caused by a virus. Known as JC virus, it attacks the white matter of the brain and disrupts nervous system activity. Symptoms depend on where in the brain the virus hits and can include deficits in speech, vision, movement and thought processes. The disease progresses rapidly and inexorably toward serious disability and death. “The average survival is generally no more than three months,” says Dr. Joseph Berger, a neurologist at the University of Kentucky who has studied and written about the disease.
PML was an extremely rare disease until the 1980s, when it started showing up in AIDS patients. Worldwide, only 230 cases were documented between 1958 -- when the disease was first described -- and 1984. “Then it became explosive,” Berger says, with about 1 in 20 AIDS deaths showing signs of PML upon autopsy.
PML does not occur without some underlying risk, and to date the highest risk comes from HIV infection. But it also can arise in people who have certain cancers, as well as transplant patients and those taking a small number of medicines, Berger says. The common thread in all these conditions is immunosuppression, either caused by a virus, cancer or drugs.
What is JC virus?
JC virus has infected an estimated 80% of the world’s adult population and often remains latent in the body. For the disease to arise, a series of things -- some with very low probability -- must happen. A mutation must occur that makes the virus capable of attacking brain cells. The transformed virus must be activated and gain entry to the brain. And the brain’s immune surveillance must be deficient.
Certain immunosuppressed states -- such as AIDS -- create that perfect storm of events allowing the virus to run rampant in the brain in a small percentage of people. More recently, certain drugs -- including Raptiva, the multiple sclerosis drug Tysabri and the rheumatoid arthritis drug Rituxan -- have been linked with PML. It’s still a very rare occurrence, but the seriousness of PML has cast a huge risk shadow over the benefits these drugs provide.
It’s not entirely clear how these medicines allow JC virus to ramp up. Tysabri has been the most studied. Researchers speculate that the drug helps JC virus mutate into a brain-attacking virus, while compromising the brain’s normal immune surveillance. At present, there is no way to predict which patients might be at risk of developing the infection.
Why is Tysabri still on the market?
Tysabri was pulled from the market in 2005 after three patients taking it for their multiple sclerosis developed PML. This was a big blow, because clinical trials had demonstrated the drug cut MS relapse rates -- bouts of worsening neurologic function -- by more than half. In June 2006, the Food and Drug Administration approved Tysabri’s return to the market with a carefully crafted set of safety checks. Patients see their physicians monthly to be checked for features suggestive of PML -- basically, “anything new that can’t be explained by the multiple sclerosis,” Berger says. These include neurological symptoms, loss of white matter (which can be detected with MRI) and the presence of JC virus in spinal fluid.
Dr. Melvin Chiu, a dermatologist at the UCLA David Geffen School of Medicine who directs UCLA’s Psoriasis and Phototherapy Center, says the situation with Tysabri differs from Raptiva when you consider the severity of the disease each drug is meant to treat. “That’s not to say psoriasis is not disabling, but it doesn’t have the life-threatening connotations that multiple sclerosis has,” he says. “So from a risk-benefit analysis, it might not be worth the risk to be on Raptiva, especially given that there are several other therapies available for psoriasis patients that don’t carry that risk.”
What other psoriasis therapies are there?
“The immune response in psoriasis is abnormal, leading to a lot of inflammation in the skin -- and therefore these scaly plaques,” Chiu says. “The treatment of psoriasis is aimed at decreasing that inflammatory response by decreasing the immune response a bit.”
In addition to Raptiva, other injectable therapies for psoriasis include Enbrel, Humira and Remicade. None has been linked to PML and all three act in a way different from Raptiva: Raptiva inhibits the activation and transport of T cells; the other three drugs inhibit a chemical messenger released by immune cells, called TNF.
Other drugs available in pill form include methotrexate, cyclosporine and Soriatane. UV phototherapy is yet another treatment for psoriasis.
What should patients who are taking Raptiva do?
Patients should not stop taking the drug immediately, because their psoriasis can flare up upon withdrawal. Instead, in consultation with their physician, patients should taper off slowly and maybe transition to some other therapy when they’re tapering off, Chiu says.
You can read more about psoriasis and its treatment at the National Psoriasis Foundation website, www.psoriasis.org.