Inflammatory pathways of importance for management of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a group of chronic disorders of the gastrointestinal tract comprising Crohn’s disease (CD) and ulcerative colitis (UC). Their etiologies are unknown, but they are characterised by an imbalanced production of pro-inflammatory mediators, e.g., tumor necrosis factor (TNF)-α, as well as increased recruitment of leukocytes to the site of inflammation. Advantages in understanding the role of the inflammatory pathways in IBD and an inadequate response to conventional therapy in a large portion of patients, has over the last two decades lead to new therapies which includes the TNF inhibitors (TNFi), designed to target and neutralise the effect of TNF-α. TNFi have shown to be efficient in treating moderate to severe CD and UC. However, convenient alternative therapeutics targeting other immune pathways are needed for patients with IBD refractory to conventional therapy including TNFi. Indeed, several therapeutics are currently under development, and have shown success in clinical trials. These include antibodies targeting and neutralising interleukin-12/23, small pharmacologic Janus kinase inhibitors designed to block intracellular signaling of several pro-inflammatory cytokines, antibodies targeting integrins, and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium, reducing their infiltration into the inflamed mucosa. In this review we have elucidated the major signaling pathways of clinical importance for IBD therapy and highlighted the new promising therapies available. As stated in this paper several new treatment options are under development for the treatment of CD and UC, however, no drug fits all patients. Hence, optimisations of treatment regimens are warranted for the benefit of the patients either through biomarker establishment or other rationales to maximise the effect of the broad range of mode-of-actions of the present and future drugs in IBD.

Keywords: Anti-tumor necrosis factor, Biologics, Crohn’s disease, Pro-inflammatory cytokines, Signaling pathways, Treatment, Ulcerative colitis

Core tip: Crohn’s disease and ulcerative colitis are the two prevailing forms of inflammatory bowel disease (IBD). Both diseases are associated with an increased expression of pro-inflammatory cytokines and immune cell infiltration of the inflamed tissue. Current treatment options with tumor necrosis factor-α inhibitors are discussed. Additionally, new therapeutic strategies showing promising results, e.g., small pharmacologic inhibitors aimed at inhibiting Janus kinase pathway and antibodies blocking recruitment of immune cells to the site of inflammation are also discussed. In this review we have elucidated the major signaling pathways of clinical importance for new therapeutic strategies of IBD.