Rare Neurological Condition Linked to Newer Monoclonal Antibody Biologics

Reports of a rare and deadly neurological condition called progressive multifocal leukoencephalopathy (PML) in patients taking certain biologic immunosuppressants for autoimmune or inflammatory conditions are raising concerns about the safety of these drugs.

In February, the US Food and Drug Administration (FDA) issued a public health advisory alerting physicians and patients to 1 possible and 3 confirmed cases of PML in patients taking efalizumab, a once-weekly injection approved for the treatment of severe plaque psoriasis in adults. The label of this drug had been changed to reflect the risk of serious infections, including PML, in October 2008.

Previously, the agency and/or drugmakers had warned of cases of PML in patients taking 2 other drugs: mycophenolate mofetil, which is approved for the prevention of organ rejection in transplant recipients but has also been used off-label in patients with autoimmune disorders such as systemic lupus erythematosus, and rituximab, which is approved for the treatment of non-Hodgkin lymphoma and for moderate to severe rheumatoid arthritis. Also, after 3 PML cases were identified in clinical trials of natalizumab, which is approved for the treatment of multiple sclerosis and moderate to severe Crohn disease, the agency has established a restricted distribution program for the drug in order to track cases of PML in patients taking it. The European Medicines Agency, the FDA's counterpart in the European Union, suspended the marketing of efalizumab and has declined to allow marketing of natalizumab for Crohn disease, although it remains available for multiple sclerosis.

The emergence of this cluster of PML cases in patients taking these biologics, which target specific components of the immune system, is forcing physicians and patients to reassess these therapies' risks and benefits.

PML, a rapidly degenerative neurological condition, is most commonly seen in patients with AIDS; in rare cases, it also occurs in other immunosuppressed individuals such as organ transplant patients, patients with cancer, and persons undergoing long-term corticosteroid or immunosuppressive therapies, according to the National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/disorders/pml/pml.htm). Its cause, polyomavirus JC, or the JC virus, is common in the US population and is usually harmless. But for reasons that are not entirely clear, the virus can become reactivated in immunocompromised individuals, leading to demyelination, severe neurological problems, and often death within months.

Little is known about how individuals become infected with the virus or why such infections usually remain latent, explained Margo Smith, MD, director of infectious disease at Washington Hospital Center and a member of an FDA panel that assessed in 2007 whether to allow the marketing of natalizumab for Crohn disease. Smith explained that even among patients with AIDS, the condition is typically seen only in those who have CD4 T-cell counts below 100/μL.

Clinical trials of natalizumab identified 2 cases of PML among 1869 patients treated with the drug for multiple sclerosis and 1 case in a trial involving 1043 patients with Crohn disease. Such data suggest the incidence of PML among patients treated with this product may be as high as 1 in 1000. “That's a pretty high risk,” she said.

Smith said that it appears there may be something about natalizumab, at least in patients with multiple sclerosis or Crohn disease, that allows the JC virus to proliferate in oligodendrocytes.

“These later [generation] monoclonal drugs are changing something about our T-cell immunity that we don't understand,” she said.

Leonard H. Calabrese, DO, head of the Cleveland Clinic's section of clinical immunology, who along with his colleagues has recently published a pair of reviews of PML in rheumatic patients (Calabrese LH and Molloy ES. Ann Rheum Dis. 2008;67[suppl III]:iii64-iii65 and Calabrese LH et al. Arthritis Rheum. 2007;56[7]:2116-2128), said the cause of these infections is probably a combination of immune suppression and specific drug effects. Some of the drugs might “induce highly specific breaches of the integrated immune response,” added Calabrese, who has received speaking and consulting fees from Genentech, the maker of rituximab and efalizumab, and Élan, which, along with Biogen, makes natalizumab.

For physicians using these biologics to treat patients with autoimmune or rheumatic disorders, this emerging evidence creates new challenges. Calabrese noted that many physicians are not familiar with PML and how to identify it and that those who do choose to use these drugs must learn how to monitor their patients for signs of PML. According to the NINDS, such symptoms may include clumsiness and progressive weakness, as well as changes in vision, speech, and, sometimes, personality.

In addition, Smith noted that PML can be particularly difficult to diagnose in patients with multiple sclerosis or some other neurological diseases because physicians may attribute the symptoms to a worsening of the patient's existing illness.

The potential risk of PML also profoundly changes the risk-benefit analysis for these drugs, Calabrese said.

But it can be difficult for severely ill patients to objectively weigh the risks of a treatment that they hope will help them, noted Smith, who dissented with the FDA panel's decision to allow marketing of natalizumab for Crohn disease. She explained that even though these disorders may be devastating to the individuals affected by them, it is important to question whether the benefit that a patient might derive from the drug is worth the risk of PML, which results in death for the majority of patients, often within months.

It is not yet clear which patients may be at greater risk of developing PML when taking these drugs, although Calabrese and colleagues suspect patients with systemic lupus erythematosus may be particularly vulnerable. Treatment primarily involves immune-boosting therapies. In patients with HIV, such treatment consists of highly active antiretroviral therapies; however, only about 50% survive. The prognosis for patients without HIV is even worse: 80% die within 6 months, while survivors may have severe neurological problems.