19 Assessment of disease behaviour and disease complications Long-lasting disease activity of IBD may progress to the development of disease complications, such as stricturing (e.g. intestinal stenosis) or penetrating disease (e.g. intestinal fistulae, perforations or formation of abscesses). In patients with CD, these complications eventually occur in up to 70% of patients.45,46 In terms of pathophysiology, fibrosis is considered as the primary driver of these disease complications, which is defined as excessive deposition of extracellular matrix (ECM), mainly collagens, together with aberrant remodelling of ECM as a result of chronic intestinal inflammation and impaired wound healing.47 Fibrosis is a process regulated by mucosaresiding (myo)fibroblasts, which proliferate and differentiate in the development (or progression) of intestinal stricture formation.48 Abnormal ECM remodelling is the result of an impaired balance between the production of structural ECM proteins (e.g., collagen) and turnover (e.g. proteasemediated breakdown of the ECM). For instance, matrix metalloproteinases (MMPs), which are collagenases able to break down constituents of the ECM, are produced by immune cells like T-lymphocytes and granulocytes and contribute to mucosal damage, disruption of epithelial barrier integrity, and eventually the formation of intestinal fistulae.49,50 Formation of fistulae may occur when healing of chronic ulcerations is hampered by increased activity of immune cells that exhibit high protease activity, leading to chronic tracts of granulation tissue between two epithelial-lined surfaces after re-epithelialization of penetrating ulcers.51,52 Cross-sectional imaging techniques such as intestinal ultrasound, computed tomography (CT) or magnetic resonance (MR) enterography are clinically used to detect intestinal stricture formation, internal penetrating disease and intra-abdominal abscess formation with varying accuracy, where MRI is the preferred technique for evaluation of deep internal or pelvic fistulae/ abscesses.53-55 However, the diagnostic accuracy of these modalities for the detection of disease complications is limited. Since there are few studies available demonstrating their diagnostic accuracy in varying clinical contexts, their performance methods remain unstandardised and insufficiently validated. As such, these methods are considered suboptimal in determining the degree of intestinal fibrosis in clinical practice.56 In addition, none of these techniques have proven to be helpful in precisely assessing the degree of inflammatory versus fibrotic tissue in a stenosis in order to guide disease management.7 Taken together, there is yet no consistent approach for monitoring intestinal stricture and/or fistulae formation over time. Currently, no biomarkers exist that are able to assess the degree of fibrosis in a given patient, which complicates the early detection of these disease complications. The identification of adequate biomarkers could aid in prompt initiation of therapeutic intervention, selection of alternative treatments, and ultimately the prevention of more severe disease. General introduction and outline of the thesis
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