Autopsy-proven demyelination associated with infliximab treatment

Tumor necrosis factor–a (TNF-a) is a well-studied proinflammatory cytokine that contributes to the pathogenesis of immune and infectious diseases. TNF-a effects are mediated by signaling through TNF-a receptors, which are present ubiquitously. Limiting the actions of TNF-a, either by blocking the receptor or inhibiting circulating (free) TNF-a, is a useful treatment strategy in autoimmune disorders with prominent inflammation, such as inflammatory bowel disease and rheumatoid arthritis (RA). However, when treatment with agents that inhibit TNF-a function was applied to multiple sclerosis (MS), an unanticipated worsening was observed. The clinical trial of lenercept (a recombinant TNF-a receptor–immunoglobulin 1g fusion protein that protected against experimental autoimmune encephalitis) for the treatment of relapsingremitting multiple sclerosis was stopped prematurely when the treatment arm was noted to have earlier and more frequent exacerbations. TNF-a antagonists are therefore contraindicated in patients with MS. In patients with no history of demyelinating disease, TNF-a antagonism has led to unmasking of demyelinating events with a clinical pattern typical of that seen in MS. All CNS cases of demyelinating disease to date have been based on clinical, laboratory, and radiographic findings. Herein we present a unique case of histologically confirmed demyelination following treatment with TNFa inhibitors.