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PML in Patients Receiving Natalizumab

Natalizumab, which offered promise to some patients with autoimmune diseases, has been linked to three cases of progressive multifocal leukoencephalopathy.

The ability to inhibit specific immune system components has been a major advance in treating autoimmune diseases. Natalizumab, a humanized IgG4 antibody that binds to ₄ integrins on leukocytes and inhibits their interaction with vascular-cell adhesion molecule 1 on vascular epithelium and mucosal addressin-cell adhesion molecule 1 on endothelial cells, has been found to block lymphocyte and macrophage trafficking to inflammation sites, particularly in the central nervous system (CNS) and the gut mucosa. It has shown efficacy in treating Crohn disease and multiple sclerosis. Unfortunately, progressive multifocal leukoencephalopathy (PML) has been reported in three patients receiving this agent.

Kleinschmidt-DeMasters and Tyler describe a 46-year-old woman with relapsing-remitting multiple sclerosis who received natalizumab and interferon beta-1a from April 2002 through January 2005, first in a clinical trial and then in an extension study. In November 2004, she developed new neurologic symptoms that progressively increased until her death in February 2005. A premortem PCR assay of cerebrospinal fluid for JC virus was positive, and postmortem examination showed PML involvement of the left and right cerebral hemispheres and the brainstem.

Langer-Gould and colleagues describe a 45-year-old man with relapsing-remitting multiple sclerosis who received natalizumab plus interferon beta-1a in a clinical trial from October 2002 through mid-December 2004. In October 2004, MRI revealed a new CNS lesion; the next month, the patient developed additional neurologic symptoms, and a repeat MRI showed multiple lesions consistent with PML. A brain biopsy in February 2005 confirmed PML. The patient was treated with cidofovir and intravenous immune globulin without effect but has shown some improvement on cytarabine.

Following the recognition of these cases, the manufacturer of natalizumab initiated a comprehensive review of all adverse events in patients receiving the drug. Consequently, Van Assche and colleagues reevaluated serum and tissue samples from a 60-year-old man who had died of an apparent astrocytoma in December 2003 after receiving natalizumab for Crohn disease beginning in March 2002 and, following a 9-month hiatus, again in February 2003. They found that the patient had had unrecognized PML. Frozen serum samples from this patient dating back to 1999 were assayed for JC virus. JC virus DNA, undetectable in samples through February 2003 (even during periods when the patient received infliximab and azathioprine), was found in samples taken in May 2003, 2 months before the onset of neurologic symptoms.

Comment: These reports raise more questions than they answer. PML, a rare CNS infection with the ubiquitous JC polyoma virus, has been seen only in severely immunocompromised individuals. Natalizumab has not previously been associated with other serious infectious complications, although the number of individuals who received this agent in clinical trials was relatively small. The selective effect of natalizumab on lymphocyte trafficking is probably a major factor in the development of PML and now raises concern regarding the development of other opportunistic infections involving the CNS and the gastrointestinal tract. Natalizumab’s manufacturer has voluntarily suspended all marketing and distribution of the agent, despite its significant benefit to some individuals with otherwise untreatable conditions. A more detailed risk-benefit analysis is needed to determine whether natalizumab can be reintroduced for such patients, perhaps in conjunction with active monitoring for JC virus infection or reactivation.

— Richard T. Ellison III, MD

Published in Journal Watch Infectious Diseases September 9, 2005

Citation(s):

Kleinschmidt-DeMasters BK and Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005 Jul 28; 353:369-74.

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Langer-Gould A et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005 Jul 28; 353:375-81.

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Van Assche G et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005 Jul 28; 353:362-8.

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Adelman B et al. Natalizumab and progressive multifocal leukoencephalopathy. N Engl J Med 2005 Jul 28; 353:432-3.

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• Medline abstract (Free)