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.

Formyl Peptide Receptors and Annexin A1: Complementary Mechanisms to Infliximab in Murine Experimental Colitis and Crohn’s Disease

“…By binding soluble and transmembrane tumor necrosis factor alpha (TNF-a), IFX attenuates inflammation and decreases the need for surgery (2,4,5). However, side effects and nonresponsiveness illuminate the relevance of validating biomarkers to assess therapeutic efficacy (6,7).…”

Body mass index influences infliximab post-infusion levels and correlates with prospective loss of response to the drug in a cohort of inflammatory bowel disease patients under maintenance therapy with Infliximab

“…There have been several studies which have identified elevated BMI and body fat as risk factors for both disease severity and a poorer response to anti-TNF-α treatment, however, the pharmacokinetic mechanisms by which this occurs remain unclear [ 12 , 15 , 22 , 25 ]. This study has confirmed this association by showing a high rate of LOR, of 20% in patients, with a higher BMI and body fat level, and is the is the first to measure the role of post-infusion levels of drug, cytokine or antibodies rather than solely depending on trough levels.…”

“…Higher post-infusion IFX levels could be a result of reduced clearance of the drug, caused by a reduced formation of ATIs due to the additional immunosuppressant effect. In addition, Azathioprine is known to cause a reduction in other signalling factors which consume anti-TNF-α, for example other antibodies (anti-nuclear antibodies (ANA) and anti-double stranded DNA (dsDNA), along with other pro-inflammatory cytokines [ 24 , 25 ]. The probability of LOR to the following infusion was shown to be reduced by an increase in post-infusion IFX levels.…”

The Innate and Adaptive Immune System as Targets for Biologic Therapies in Inflammatory Bowel Disease

“…Infliximab, the first anti-TNF-α antibody to be FDA (Food and Drugs administration) approved, is a chimeric monoclonal antibody directed against TNF-α, composed of a variable region of murine origin comprising 25%, and a constant region of human origin comprising the remaining 75%, joined through disulfide bonds. Infliximab binds to both soluble and transmembrane forms of TNF-α with high affinity [ 72 ]. It is administered via intravenous infusions at a weight-based dose, and is approved for both induction and maintenance of remission in both CD and UC as published in both the ACCENT I and ACT I trials [ 73 , 74 ].…”