New insights into inflammatory bowel disease and colitis-associated neoplasia

Abstract

This thesis describes new insights into the development of inflammatory bowel disease (IBD: ulcerative colitis (UC) or Crohn’s disease (CD)) and IBD-associated neoplasia. In the first part, the value of serological markers as predictors of IBD was investigated in a large European cohort of individuals.A combination of serological markers was found to predict the development of IBD in individuals from a low-risk population. Furthermore, the role of pharmacological activation of the nuclear farnesoid X receptor (FXR) was investigated in patients with Crohn’s colitis, using a synthetic FXR agonist. FXR is a nuclear receptor that exerts anti-inflammatory effects when stimulated by a FXR agonist. Under unstimulated conditions, expression of ileal FXR target genes was previously found to be lower in patients with Crohn’s colitis. This thesis shows that activation of FXR by the FXR ligand chenodeoxycholic acid is feasible in patients with Crohn’s colitis, which provides a rationale to further explore the potential therapeutic role of FXR agonists in these patients. In the second part of this thesis new insights into the development of IBD-associated neoplasia are addressed. Progression rates of flat low-grade dysplasia (LGD) and indefinite dysplasia (IND) to advanced neoplasia (high-grade dysplasia (HGD) and colorectal cancer (CRC)) were investigated before and after review of the histological diagnosis by a panel of three expert gastrointestinal pathologists. The 5-year progression rate to advanced neoplasia increased in patients with a LGD diagnosis confirmed by the panel, whereas it decreased in patients with IND. The results demonstrate that a diagnosis of LGD or IND in patients with IBD, and therefore the associated prognosis with regard to progression to advanced neoplasia, largely depends on the interpretation ofthe consulting pathologist. In addition to this study, the value of a series of immunohistochemical markers in UC patients were investigated with regard to the prediction of neoplastic progression. Co-expression of p53 and AMACR was found to be the best in this respect, and might be useful as a potential marker of neoplastic progression in patients with UC and flat LGD or IND. The risk of subsequent colorectal neoplasia was also investigated in a large cohort of IBD patients with an adenoma and compared to that in IBD subjects without adenomas as well as non-IBD patients with adenomas. IBD patients with an adenoma were found to have an increased risk of developing advanced neoplasia compared to adenoma patients without IBD and IBD patients without an adenoma. In the last two chapters the effects of thiopurines were investigated. Thiopurines are immunomodulators commonly used for maintenance of remission in both UC and CD. In a large Dutch cohort of IBD patients thiopurine use was found to be associated with a significantly decreased risk of developing advanced neoplasia. Since thiopurine use has often been associated with an increased risk of extra-intestinal malignancies, the risk of non-melanoma skin cancer (NMSC) in IBD patients using thiopurines was evaluated as well. In contrast to previous studies, thiopurine use was not found to be associated with an increased risk of NMSC.