Beyond the Gut: The Importance of Controlling Systemic Inflammation in Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) management goals have recently focussed on gastrointestinal symptom resolution and mucosal healing. IBD causes systemic disorder, with inflammation occuring both within and outside the gut, with associated morbidity, disability, and quality of life (QoL) impairment. Thus, there is a need to reduce the overall burden of chronic inflammation in IBD. Environmental factors, genetics, gut microbiota, and the immune system significantly impact IBD and its extraintestinal manifestations (EIMs). T cells play a crucial role in immunity, and certain subsets are associated with several chronic inflammatory disorders, including IBD. Targeting such cells and/or key inflammatory cytokines (e.g. interleukins [IL], and tumour necrosis factor [TNF]) provides a basis for several IBD therapies. Systemic inflammation in IBD can involve the development of fistulae and/or EIMs. Common EIMs include musculoskeletal pain, dermatological and ocular lesions, and primary sclerosing cholangitis (PSC). Early diagnosis of fistulae and EIMs should help guide IBD therapy and reduce overall morbidity. Many EIM treatment options are currently available with varying degrees of efficacy e.g. sulfasalazine, COX-2 inhibitors, certain antibiotics, immunomodulators, anti-TNFs, corticosteroids, and ursodeoxycholic acid. However, fistulae and most EIMs respond well to anti-TNFs, such as adalimumab and infliximab. Prognostic markers aid disease treatment. C-reactive protein (CRP) is a valuable marker of systemic inflammation in IBD (particularly Crohn’s disease [CD]). Current anti-TNF agents (e.g. adalimumab) markedly reduce CRP levels in IBD and have a significant effect on IBD and various EIMs. Numerous novel agents for IBD are under development; examples include Janus kinase (JAK) inhibitors, IL inhibitors, SMAD-7 blockers, sphingosine 1-phosphate receptor 1 (S1P1) inhibitors, and anti-adhesion molecules.