Inflammatory bowel disease: from pathophysiology to clinical aspects

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic relapsing-remitting inflammatory disease of the gastrointestinal tract. Treatment is aimed at achieving remission, for which a growing number of treatment options is available. However, there appears to be a therapeutic ceiling, since only a certain proportion of patients responds to any given therapy. Moreover, patients can lose response to therapy over time. The pathogenesis of IBD is insufficiently understood. A better insight into the pathophysiology could aid in optimizing treatment and, in the long term, might even lead to the development of preventive strategies.

To gain more insight into the pathophysiology of IBD, we have set up “the twin cohort for the study of (pre)clinical IBD in the Netherlands” (the TWIN-IBD study). In this study twin pairs concordant and discordant for IBD are longitudinally followed. This study offers the opportunity to study individuals at risk of developing IBD, of which some might ultimately develop IBD. Furthermore, twin pairs share their genetic and (childhood) environmental background.

We found within the TWIN-IBD study that the gut microbiome of healthy cotwins (i.e. individuals at risk of developing IBD) displays an IBD-like signature. This suggests that these microbiome changes might precede disease development or reflect a shared genetic and environmental background. We also observed a greater overlap in the T-cell receptor repertoire in Crohn’s disease concordant twin pairs, suggesting a potential role for (antigen-driven) T-cell skewing in the pathophysiology of Crohn’s disease. From these data, we additionally identified potential Crohn’s disease-related T-cell receptor clusters.

Beyond the twin cohort, this PhD thesis examines several other aspects of IBD pathophysiology and clinical management. Mucosal kinase activity profiles were associated with inflammation and differed between ulcerative colitis and Crohn’s disease; kinase activity profiles were also associated with response to tofacitinib (a Janus kinase inhibitor that is used in the treatment of ulcerative colitis). In a separate study, we found that female IBD patients more frequently discontinue anti-tumor necrosis factor-alpha therapy, mainly because of side-effects. Finally, we systematically reviewed and subsequently externally validated published prediction models for disease activity in Crohn's disease. These published prediction models were found to be insufficiently accurate to avoid endoscopic evaluation.

IBD poses a challenge for clinicians and patients alike, as therapies are often ineffective and clinical monitoring remains cumbersome. In this PhD thesis we studied both pathophysiological (i.e. the microbiome, T-cell receptor repertoire, and mucosal kinase activity) and clinical aspects (i.e. response to and discontinuation of treatment, and prediction of disease activity) of IBD. Enhanced understanding of the IBD pathophysiology has the potential to optimize treatment efficacy and clinical management and might ultimately inform strategies aimed at disease prevention.