The Risk of Progressive Multifocal Leukoencephalopathy in Patients Prescribed Biologic Therapies

The risks and benefits associated with the use of natalizumab must be carefully considered.

Progressive multifocal leukoencephalopathy (PML) was once a very rare disease. Until 1981, only 3 cases had been described in medical literature. By 1984, physicians reported an increase in the incidence of PML in association with HIV infection.

With approval of biologic agents such as natalizumab and efalizumab, PML incidence has been rising. The manufacturer of efalizumab voluntarily withdrew its product in 2009, and the FDA placed restrictions on use of natalizumab in 2006. Despite the risk-reduction strategies, between 2005 and 2013, agencies received reports of 400 cases of PML associated with natalizumab use.

PML typically presents with changes in cognition and behavior. These outward manifestations of the disease often occur before brain lesions appear on radiographic imaging. In addition to radiographic changes, PML may cause histologic changes in brain tissue.

Initially, studies employing electron microscopy led investigators to believe that a virus was the underlying cause of PML. Less than a decade later, researchers isolated a polyomavirus known as John Cunningham virus (JC virus or JCV) in brain tissue of a patient with PML.

JCV is nearly ubiquitous. Scientists estimate that JC virus has infected half of the general adult population and 90% adults in some urban populations. Fortunately, JCV does not harm the vast majority of people with the virus. Scientists believe JCV only causes PML in patients with compromised immunity.

In JCV-free patients receiving natalizumab, about 1 in 10,000 patients develop PML. The risk is higher in patients infected with JCV. Even so, fewer than 1 in 1000 JCV-infected patients with no prior immunosuppressive use develop PML after 1 to 24 months of natalizumab therapy. That number increases to about 6 in 1000 patients after 2 to 3 years of use. Prescribing natalizumab requires careful consideration of the risks and benefits of treatment.