Emerging Mechanisms of Action and Loss of Response to Infliximab in Ibd: A Broader Picture

Abstract

Biologic drugs, as Infliximab (IFX), are widely used in inflammatory bowel disease (IBD). IFX is a chimeric monoclonal immunoglobulin directed against TNF-α and acting in IBD through several mechanisms of action. We divide these mechanisms into central and peripheral. Central mechanisms are considered effective at systemic level, like the reduction of plasmatic pro-inflammatory cytokines (TNF-α, IFN-γ), the promotion of apoptosis of inflammatory cells, the induction of T regulatory cells (FOXP3CD4+) and the modulation of cellular inflammatory pathways. Peripheral mechanisms could be considered acting at mucosal levels like normalization of endothelial functions, blockade of angiogenesis, restoring balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matalloproteases (TIMPs). This classification could serve as solid guide to better categorize mechanisms of lack of response to IFX, which account for up to 30% of patients per year. Central mechanism of loss of response proposed are the formation of antiinfliximab antibodies (ATI), trough serum levels, metabolic factors and pharmacogenomics; peripheral mechanisms of loss of response could be the degradation of IFX by MMPs at mucosal level and the loss of IFX trough inflamed mucosa. In the present review, we analyze mechanisms of action and loss of response to IFX in course of IBD known until today.