- CME Teaching Brief - MedPage Today- LINKThe multiple sclerosis drug Tysabri (natalizumab), withdrawn from the market following reports linking it to two cases of a rare fatal opportunistic infection, appears to work with other drugs to allow reactivation of an otherwise innocuous latent virus.

That's the consensus of investigators in a special early release of information scheduled for publication in the July 28 New England Journal of Medicine. The drug, launched with great promise for MS patients, was withdrawn on Feb. 28.

That NEJM issue will contain details of three separate case reports of patients who developed progressive multifocal leukoencephalopathy, or PML, during treatment with Tysabri. Two patients were treated for MS and one for Crohn's disease.

One of the patients with MS and the patient with Crohn's died from PML. The other MS patient became quadriplegic and lost the ability to speak. This patient improved after discontinuation of Tysabri, followed by further therapy with Ara-C (cytarabine), which has been shown to be effective in the laboratory against the suspected viral infection.

Last week, the Boston Globe reported that Tysabri's maker, Biogen Idec, had informed the FDA of a possible fourth case of PML, in a woman with MS who had taken it along with the company's other MS drug, Avonex (interferon beta-1a). Her case was not reported in the journal, and her condition could not be ascertained immediately. However, the NEJM said it was the Globe report that triggered the early release of its data.

Although PML was diagnosed in only three (now possibly four) of the 3,000 or so patients who took Tysabri in clinical trials, drug safety monitors were alarmed because the infection is almost always seen only in severely immunocompromised patients. These include AIDS patients or organ transplant recipients who are taking immunosuppressants. Until these case reports, there were no known cases of PML in patients with MS.

PML is caused by reactivation of a clinically latent infection with the JC polyomavirus. These often-fatal opportunistic infections of the central nervous system destroy oligodendrocytes in the brain, resulting in demyelination of multifocal areas and deterioration of various neurologic functions.

The JC virus is acquired by most people during childhood and antibodies against the virus are present in 50% to 86% of adults. The virus remains dormant in the bone marrow, kidney, and spleen, and infection is usually asymptomatic unless the person is immunocompromised.

Tysabri is a humanized monoclonal antibody against α4-integrins, receptor proteins involved in cellular binding and response to extracellular matrix. When used in conjunction or in sequence with other drugs that affect immune function, Tysabri appears to interrupt normal lymphocyte function, allowing the JC virus to grow unchecked, said Igor J. Kralnick, M.D., of Harvard Medical School in an interview.

"In the patients who received natalizumab and also had other medications such as Avonex, it's likely that the prevention of normal migration of the lymphocytes in the tissue allows the virus to replicate without being contained, and finds its way to the brain and causes the disease," said Dr. Kralnick, who co-authored an editorial accompanying the NEJM case reports.

"It is also not entirely ruled out that some people have the virus latent in the brain and in certain circumstances need to have the trafficking of the lymphocytes to prevent the virus from reactivating within the brain."


One patient, a 46-year-old woman who had received 37 monthly doses of Tysabri, plus weekly Avonex injections for relapsing-remitting MS, died about three years after starting on Tysabri. At autopsy, she was found to have multiple large and small PML lesions in tissue sections taken from most areas of both cerebral hemispheres, according to a NEJM report by B.K. Kleinschmidt-DeMasters, M.D., and colleagues at the University of Colorado Health Sciences Center.

The second fatal PML case reported in the NEJM occurred in a 60-year-old Belgian man who had received five doses of Tysabri for Crohn's disease as part of a clinical trial, wrote Paul Rutgeerts, M.D., Ph.D., and colleagues at the University of Leuven Hospitals in Leuven, Belgium.


The patient died five months after reporting to the emergency room with severe confusion and disorientation. Although he was originally thought to have died from an astrocytoma, the investigators took another look at the serum samples and brain lesion tissues taken at biopsy after hearing about two other cases of PML in patients on Tysabri.

The investigators found evidence of the JC polyomavirus in blood samples taken three months after the patient had started on an open-label trial of Tysabri, but before he had exhibited symptoms. The patient had previously taken the immunosuppressant Imuran (azathioprine), but had discontinued it eight months before admission to the hospital.

In the third case reported in the NEJM, researchers reported on a 23-year-old man who had received 28 infusions of Tysabri, in addition to weekly injections of Avonex. He developed a rapidly progressive case of PML that did not respond to treatment with corticosteroids, Vistide (cidofovir) and IV immune globulin. The infection left the patient "quadriplegic, globally aphasic, and minimally responsive."

Three months after stopping Tysabri, his physicians detected widespread inflammation of the CNS, which they attributed to immune-reconstitution inflammatory syndrome. Following a course of Ara-C, the patient had improvement of symptoms, including return of speech and ability to walk, although he still had cognitive and neurologic impairment. The authors reported that the reasons for improvement were unclear as Ara-C has been shown to be effective in vitro, but it failed to show efficacy in a randomized control trial in HIV patients with PML.


"Our case report suggests that some degree of recovery from natalizumab-associated PML is possible," wrote Annette Langer-Gould, M.D., of Stanford and colleagues there and at the University of California San Francisco.

Biogen Idec, the drug-maker, noting the recovery, commented in a letter to the NEJM that accompanied the research papers, “It is possible that testing for the appearance of JC virus in plasma, along with a high degree of clinical suspicion, will permit early diagnosis and discontinuation of natalizumab therapy and allow patients to recover. Similar findings have been reported for BK virus, a related polyomavirus that infects transplant recipients.”