Tysabri in the news
MS drug Tysabri reawakens brain virus -study
09.09.09, 09:06 PM EDT
WASHINGTON, Sept 9 (Reuters) - The multiple sclerosis drug Tysabri awakens a virus that causes a rare brain disease, not only suppressing the body's ability to fight it but making the virus stronger, U.S. researchers reported on Wednesday.
But these changes take place even in patients who show no symptoms of the infection -- a finding that suggests scientists still do not fully understand why 13 patients taking Tysabri have developed the potentially fatal brain infection.
Tysabri, known generically as natalizumab, is designed the suppress the immune system which mistakenly attacks nerves in MS patients.
Made by Biogen Idec Inc ( BIIB - news - people ) and marketed with Irish drugmaker Elan Corp Plc ( ELN - news - people ), Tysabri was temporarily withdrawn from the market in 2005 after it was linked with progressive multifocal leukoencephalopathy or PML. It was brought back in 2006 with stricter safety warnings.
Dr. Igor Koralnik of Harvard Medical School and Beth Israel Deaconess Medical Center and colleagues studied 19 multiple sclerosis patients just starting Tysabri.
They were looking for a virus called JC virus.
'This virus, the JC virus named for the initials of a patient, is found in about 90 percent of the population,' Koralnik said in a statement.
'But in healthy individuals the virus lies dormant in the kidneys and causes no problems.'
Urine samples from the 19 patients showed levels of the JC virus shot up after a year of taking Tysabri, Koralnik and colleagues reported in the New England Journal of Medicine.
The virus infected the blood cells of 60 percent of the patients after 18 months, they found.
They confirmed that Tysabri was affecting immune cells called T cells. 'It further tells us that reactivation and transformation of the virus may first occur in the kidney and that once the activated virus spills into the blood it can easily spread to the brain,' Koralnik said.
None of the 19 patients developed any symptoms or brain lesions suggestive of PML, so the researchers do not suggest that patients should stop taking Tysabri.
Tysabri is one of several immune system suppressing therapies that have been linked to PML, including Rituxan, sold by Biogen with Roche Holding ( RHHBY.PK - news - people ) AG unit Genentech ( DNA - news - people ), and Raptiva, a psoriasis drug Genentech pulled from the market.
More than 40,000 MS patients take Tysabri.
(Reporting by Maggie Fox; Editing by Cynthia Osterman)
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NEJM...
Volume 361:1067-1074 September 10, 2009 Number 11
Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab
Yiping Chen, M.D., Ph.D., Evelyn Bord, B.S., Troy Tompkins, B.S., Janice Miller, B.S., Chen S. Tan, M.D., R. Philip Kinkel, M.D., Marion C. Stein, M.D., Raphael P. Viscidi, M.D., Long H. Ngo, Ph.D., and Igor J. Koralnik, M.D.
ABSTRACT
Background Progressive multifocal leukoencephalopathy (PML) occurs in a fraction of patients with multiple sclerosis who were treated with natalizumab. Most adults who are infected with the JC virus, the etiologic agent in PML, do not have symptoms. We sought to determine whether exposure to natalizumab causes subclinical reactivation and neurotropic transformation of JC virus.
Methods We followed 19 consecutive patients with multiple sclerosis who were treated with natalizumab over an 18-month period, performing quantitative polymerase-chain-reaction assays in blood and urine for JC virus reactivation; BK virus, a JC virus–related polyomavirus, was used as a control. We determined JC virus–specific T-cell responses by means of an enzyme-linked immunospot assay and antibody responses by means of an enzyme-linked immunosorbent assay and analyzed JC virus regulatory-region sequences.
Results After 12 months of natalizumab therapy, the prevalence of JC virus in the urine of the 19 patients increased from a baseline value of 19% to 63% (P=0.02). After 18 months of treatment, JC virus was detectable in 3 of 15 available plasma samples (20%) and in 9 of 15 available samples of peripheral-blood mononuclear cells (60%) (P=0.02). JC virus regulatory-region sequences in blood samples and in most of the urine samples were similar to those usually found in PML. Conversely, BK virus remained stable in urine and was undetectable in blood. The JC virus–specific cellular immune response dropped significantly between 6 and 12 months of treatment, and variations in the cellular immune response over time tended to be greater in patients in whom JC viremia developed. None of the patients had clinical or radiologic signs of PML.
Conclusions Subclinical reactivation of JC virus occurs frequently in natalizumab-treated patients with multiple sclerosis. Viral shedding is associated with a transient drop in the JC virus–specific cellular immune response.
Source Information
From the Divisions of Viral Pathogenesis (Y.C., E.B., T.T., J.M., C.S.T., I.J.K.) and Infectious Diseases (C.S.T.) and the Departments of Neurology (R.P.K., M.C.S., I.J.K.) and Medicine (L.H.N.), Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston; and the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore (R.P.V.).
Address reprint requests to Dr. Koralnik at the Beth Israel Deaconess Medical Center, E/CLS 1005, 330 Brookline Ave., Boston, MA 02215, or at ikoralni@bidmc.harvard.edu.
content.nejm.org
FOCUS ON RESEARCH
Volume 361:1041-1043 September 10, 2009 Number 11
Reemergence of PML in Natalizumab-Treated Patients — New Cases, Same Concerns
Eugene O. Major, Ph.D.
When progressive multifocal leukoencephalopathy (PML), a rare demyelinating disease induced by JC virus, appeared in 2004 as a complication of natalizumab treatment for multiple sclerosis, a more common demyelinating disease, it seemed an odd twist of nature. PML had never been reported in patients with multiple sclerosis, and to find patients who simultaneously had two demyelinating diseases with very different origins and pathologic characteristics was a dramatic surprise.
Natalizumab, a humanized monoclonal antibody that binds to the {alpha}4 integrin molecule at the ß1 and ß7 epitopes, is an adhesion-molecule inhibitor that prevents extravasation of T and B cells into the brain . . . [Full Text of this Article]
Source Information
From the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, Bethesda, .......
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