Iatrogenic immunosuppression with biologics in MS

Abstract

Natalizumab (Tysabri®, Biogen Idec Inc., Cambridge, MA) is a recombinant humanized monoclonal antibody that binds to the α4 chain of the integrin very late activation antigen (VLA)-4 and to α4β7 integrin. It was designed to diminish the adherence of activated leukocytes to biologic membranes and their subsequent migration into peripheral tissues, including the brain and the spinal cord. The clinical effectiveness of natalizumab in patients with relapsing-remitting multiple sclerosis (MS) was evaluated in 2 phase 3 clinical trials (the AFFIRM monotherapy trial1 and the SENTINEL add-on trial with interferon beta-1a [Avonex®, Biogen Idec Inc.]2). In the United States, the Food and Drug Administration first approved natalizumab on November 24, 2004, for the treatment of relapsing forms of MS. Only 3 months later, the manufacturers of natalizumab announced its voluntary withdrawal after 2 patients with MS and 1 patient with Crohn disease who had received natalizumab in clinical trials were diagnosed with progressive multifocal leukoencephalopathy (PML).3–5 PML, a brain demyelinating disorder caused by the human polyomavirus JC, is almost exclusively diagnosed in individuals who experience severe and prolonged immunosuppression. The occurrence of PML in patients with MS treated with natalizumab was unexpected to many because there …