17 biochemical assessment that comprises a full blood count, inflammatory biomarkers such as C-reactive protein (CRP), platelets, electrolytes, liver- and kidney function tests, albumin, and provides a stool sample for microbiological culture (e.g. for ruling out bacterial, viral or parasitic infection) and for measurement of fecal calprotectin (FCal) levels.7 FCal is a neutrophil protein that can be detected in stool upon intestinal inflammation. It is highly sensitive in detecting IBDassociated intestinal inflammation, since it associates well with disease activity as established by endoscopy.11,12 In addition to biochemical measures that aid in the diagnosis, there are also several serological biomarkers that may support diagnosis of IBD. Well-known examples of these markers include anti-Saccharomyces cerevisiae antibodies (ASCA, most specific to CD) and perinuclear antineutrophil cytoplasmic antibodies (pANCA, most specific to UC). However, their diagnostic accuracy is often limited.13 Hence, serological testing is clinically not recommended for the routine diagnostic make-up of CD or UC. Likewise, antimicrobial antibodies such as anti-CBir1 or anti-OmpC are currently not being used as their additional diagnostic value is considered only marginal.14 Although their exact clinical value remains elusive, these markers are still included in serum biomarker panels that are used to detect IBD15,16, and have previously been tested for their predictive ability with regard to the development of IBD.17-20 Similarly, recent efforts have shown that selected serum antimicrobial antibodies could be used to predict the future development of IBD.21 Based on the notion that specific antibody responses may constitute one of the earliest pathogenic events in IBD, the characterisation of immune-based biomarker signatures may facilitate the early detection of IBD development and improve the initial disease diagnosis. Assessment and monitoring of intestinal inflammatory disease activity Patients with IBD often suffer from long-lasting mucosal disease activity that is difficult to detect, to monitor and to promptly treat. Other means are required to allow accurate disease activity monitoring and early therapeutic intervention, since ongoing disease activity negatively affects the disease course by increasing the risk of hospitalization and the need for surgery.22 Importantly, this also negatively impacts patient-reported quality of life as well as rates of socioeconomic participation.23 Endoscopy is still the ‘gold standard’ diagnostic procedure to assess the presence and severity of intestinal inflammatory disease activity in patients with IBD.24 However, endoscopic procedures entail a high patient burden, are time-consuming and very expensive. In light of these considerations, there is an urgent need for alternatives, i.e. biomarkers that accurately reflect endoscopic disease activity in IBD. Clinical symptoms are usually non-specific for disease activity, and non-endoscopic clinical scoring systems, such as the Harvey-Bradshaw Index (HBI) for CD and the Simple Clinical Colitis Activity Index (SCCAI) for UC, usually do not correlate well with endoscopically active disease.25,26 Blood C-reactive protein (CRP) and fecal calprotectin (FCal) levels are currently the most widely used disease activity biomarkers in IBD, but they still demonstrate inconsistent associations with mucosal inflammation as evaluated by endoscopy and have limited specificity.27-29 For example, FCal lacks the specificity to distinguish between IBD and other types or causes of intestinal inflammation.30 Thus, additional, preferably minimally invasive biomarkers are needed that are capable of reflecting intestinal inflammation.31,32 Inflammation is a key pathophysiological process in IBD, which may range from local mucosal inflammation to widespread systemic inflammation. Blood CRP and FCal levels are General introduction and outline of the thesis
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