Evaluation of Patients Treated with Natalizumab for Progressive Multifocal Leukoencephalopathy
Tarek A. Yousry, Dr.Med.Habil., Eugene O. Major, Ph.D., Caroline Ryschkewitsch, B.S., Gary Fahle, B.S., Steven Fischer, M.D., Ph.D., Jean Hou, B.S., Blanche Curfman, B.S., Katherine Miszkiel, M.D., Nicole Mueller-Lenke, M.D., Esther Sanchez, M.D., Frederik Barkhof, M.D., Ph.D., Ernst-Wilhelm Radue, M.D., Hans R. Jäger, M.D., and David B. Clifford, M.D.
Background Progressive multifocal leukoencephalopathy (PML)was reported to have developed in three patients treated withnatalizumab. We conducted an evaluation to determine whetherPML had developed in any other treated patients.
Methods We invited patients who had participated in clinicaltrials in which they received recent or long-term treatmentwith natalizumab for multiple sclerosis, Crohn's disease, orrheumatoid arthritis to participate. The clinical history, physicalexamination, brain magnetic resonance imaging (MRI), and testingof cerebrospinal fluid for JC virus DNA were used by an expertpanel to evaluate patients for PML. We estimated the risk ofPML in patients who completed at least a clinical examinationfor PML or had an MRI.
Results Of 3417 patients who had recently received natalizumabwhile participating in clinical trials, 3116 (91 percent) whowere exposed to a mean of 17.9 monthly doses underwent evaluationfor PML. Of these, 44 patients were referred to the expert panelbecause of clinical findings of possible PML, abnormalitieson MRI, or a high plasma viral load of JC virus. No patienthad detectable JC virus DNA in the cerebrospinal fluid. PMLwas ruled out in 43 of the 44 patients, but it could not beruled out in one patient who had multiple sclerosis and progressionof neurologic disease because data on cerebrospinal fluid testingand follow-up MRI were not available. Only the three previouslyreported cases of PML were confirmed (1.0 per 1000 treated patients;95 percent confidence interval, 0.2 to 2.8 per 1000).
Conclusions A detailed review of possible cases of PML in patientsexposed to natalizumab found no new cases and suggested a riskof PML of roughly 1 in 1000 patients treated with natalizumabfor a mean of 17.9 months. The risk associated with longer treatmentis not known.
Source Information
From the Institute of Neurology, Queen Square, London (T.A.Y., K.M., H.R.J.); the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, Md. (E.O.M., C.R., J.H., B.C.); the Department of Laboratory Medicine, NIH Clinical Center, Bethesda, Md. (G.F., S.F.); the Department of Neuroradiology, University of Basel, Basel, Switzerland (N.M.-L., E.-W.R.); the Department of Radiology, Vrije Universiteit Medical Centre, Amsterdam (E.S., F.B.); and the Departments of Neurology and Medicine, School of Medicine, Washington University, St. Louis (D.B.C.). Drs. Yousry, Major, and Clifford contributed equally to this article.
Address reprint requests to Dr. Major at the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, NIH, 10 Center Dr., Bldg. 10, Rm. 3B14, Bethesda, MD 20892-1296, or at majorg{at}ninds.nih.gov.
Natalizumab for Relapsing Multiple Sclerosis
Tenser R. B., Jeffery D. R., Meyer M. A., Polman C. H., Rudick R. A., Major E. O., Yousry T. A., Clifford D. B., Ropper A. H.
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N Engl J Med 2006;
354:2387-2389, Jun 1, 2006.
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