Monday, May 12

Risk factors for rare diseases can be risky to define: PML and TYSABRI (natalizumab)

Abstract: When rare neurologic diseases become topics of editorials in journals such as Nature Neuroscience,1 the New England Journal of Medicine,2 and Neurology®, 3 there is usually something more of general interest than the rare disease itself. Such is the case for progressive multifocal leukoencephalopathy (PML), the JC virus-induced demyelinating disease that was once relegated for discussion to the back of the textbook, whether in microbiology or neurology. Not any longer. Incidence and publication of cases of PML have risen more than 50-fold within the last decade. Renewed recognition of PML started in
the mid-1980s, when it was recognized as an AIDS-defining illness in 1%-3% of all HIV-1-infected persons, still true in the era of combined antiretroviral therapy.4 PML is reported in patients with underlying neoplastic diseases, organ transplants, and rheumatic diseases, but by 2004, PML dramatically entered the mainstream as a serious adverse event associated with a promising monoclonal antibody therapy, natalizumab, for treatment of relapsing-remitting multiple sclerosis (MS). Nature itself showed that demyelinating diseases of substantially different etiologies and pathologies can occur in the same brain, and remarkably enough in some cases, not with a fatal outcome. In 2006, the estimated occurrence of PML in natalizumab-treated patients with MS, with an average treatment of 17 months, was 1 per 1,000.5 With more than 115,000 patients globally treated with natalizumab for longer periods of time, that estimate is 1 per 330.6 In patients who test positive for antibodies to JCV, have a clinical history of immune suppressive treatment before natalizumab, and have received more than 24 doses, the number of PML cases is 1 per 90. CLICK: