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Markers in monitoring disease activity and colorectal cancer development in Inflammatory Bowel Disease

par Cremer, Anneline
Président du jury Langer, Ingrid
Promoteur Franchimont, Denis
Co-Promoteur Trepo, Eric
Publication Non publié, 2023-11-23

Thèse de doctorat

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Résumé :

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) with a remitting and relapsing course. The treat-to-target approach with the tight monitoring of disease activity plays an important role in the management of IBD patients, aimed at modifying the course of the disease. IBD patients can be composed of heterogeneous subpopulations with different evolution of the disease and risk profiles of complications. Colorectal cancer (CRC) is one of the most feared complications.We have been interested in the monitoring of IBD with faecal calprotectin (FC) as a surrogate non-invasive marker of gut inflammation. FC is nowadays commonly used for the daily management of IBD patients and the variability of its measurement is a significant concern in daily routine. We conducted an observational case‐control study enrolling patients with either IBD or irritable bowel syndrome (IBS). We were able to show that a single stool punch is reliable and representative of the entire stool sample for FC measurement. We also demonstrated that variability of FC concentrations between two bowel movements a few days apart is significantly high, with FC variations being more pronounced in patients with high levels of FC, although not clinically relevant in our study. In addition, we provided practical guidance for clinicians for the use of FC in the daily detection and management of IBD patients. Our study indicates that the FC variability rarely affects therapeutic decisions: A minimum optimal variation must be achieved in decision-making strategies, rather than a cut-off, especially in patients with high FC levels. The therapeutic armamentarium has expanded considerably in recent years in IBD, in particular with the arrival of Janus kinase (JAK) inhibitors that may complement or substitute the use of monoclonal antibodies. We conducted an observational multicentre Belgian phase IV cohort study and were able to report on the efficacy and safety of tofacitinib in a real-world multi-refractory population of UC patients. Real-world efficacy and safety data is paramount to translate evidence from randomised controlled trials into clinical practice and to raise possible safety concerns. The balance between efficacy and safety is an ongoing challenge in the treatment of IBD.Carcinogenesis in IBD follows the inflammation-dysplasia-cancer (IDC) sequence from inflammation, to indefinite, low-grade (LGD), high-grade dysplasia (HGD), with some progressing to cancer. The natural history of dysplasia is relatively unknown and the biological changes that underlie the development of colitis-associated colorectal cancer (CAC) are not fully understood. We performed a unique multicentric translational research project within the Belgian Inflammatory Bowel Disease Research and Development group, gathering 1183 dysplasia and CAC lesions in 541 IBD patients, and were able to report on novel data on the natural history of inside and outside diseased area lesions. We showed that IBD patients have a low risk of development of more-advanced lesion after resection of dysplastic lesions. A large proportion of IBD patients with CAC were diagnosed without prior detected dysplasia and often outside screening/surveillance program. Our findings provide clinicians and patients with relevant findings and observations that inform shared-decision making in the context of diagnosis of dysplasia and may help increase awareness and adherence of clinicians to the management of dysplasia according international recommendations.The IDC progression results from the transformation and progressive accumulation of chromosomal abnormalities, somatic mutations, copy number variations, and epigenetic modifications (i.e. methylation), related to inflammation. Transcriptional rewiring, through non-genetic events, such as epigenetic changes, early in tumorigenesis seems to play an important role in the IDC progression. We identified a transcriptomic signature of 27 genes related to the IDC sequence, and generated a score which makes it possible to correctly reclassify dysplasia and CAC in IBD patients. Our study may not only shed light on some of the relevant genes involved in the IDC sequence, but also uncover some key signalling pathways in the progression of chronic inflammation to CAC. Our score could be used in future prospective cohorts in order to use it not as a simple classifier but as a prognostic marker for dysplasia and cancer. A signature of the IDC sequence could potentially help stratify patients at risk for CAC and adapt follow-up and treatment decisions accordingly.