258 cytokine may be considered as a representative marker of endoscopic disease activity driven by Th1-cell cytokine production (IL-6, IL-12, TNF-α and IFN-γ).15,31 Given these findings, follow-up studies are warranted to determine whether therapeutic interference in patients with increased fecal calprotectin levels accompanied by high IFN-γ and CRP levels results in improved patient outcomes. Finally, we observed a positive correlation between fecal calprotectin levels and serum amyloid A (SAA), an acute-phase protein implicated in multiple chronic inflammatory diseases and commonly found to be elevated in CD patients.32 SAA is an apolipoprotein of high-density lipoproteins (HDL) and plays a role in cholesterol transport to and from sites of inflammation.33 It has previously been demonstrated that SAA correlates well with other acute-phase reactants, such as CRP and alpha-1-antichymotrypsin (alpha-1-ACT) and is suggested to be helpful in monitoring CD disease activity.24,34 In the present study, the concentrations of a large number of biomarkers have been assessed using a highly-sensitive electrochemiluminescence (ECL) assay and were directly correlated to the fecal calprotectin level. To our best knowledge, no studies have focused on the direct correlations between fecal calprotectin levels and serum biomarker levels with such a wide dynamic range of detection, providing us with high sensitivity measurements of cytokines, chemokines and markers for angiogenesis and vascular injury. However, a limitation of this study is that no endoscopic results were available for this patient cohort, which is generally considered as gold standard for demonstrating disease activity in CD.35,36 In clinical practice, it is challenging to identify an acute disease exacerbation, since its clinical presentation is often highly non-specific. Regularly, CD patients have concomitant symptoms that might be attributed to functional bowel syndromes, stricturing CD or gastro-intestinal infections. In contrast, other patients that do not present with any disease symptoms, may still show an active intestinal inflammation as determined by endoscopic investigation. In this study, we have identified multiple candidate serum biomarkers to quantify the severity of a flare in patients with confirmed CD. This could also lead to means to distinguish inflammatory from non-inflammatory disease flares. Future prospective studies are warranted in which CD patients undergoing an endoscopic disease evaluation will be included in order to confirm that indeed only in patients with elevated Th1- and Th17-associated cytokines, inflammatory flares have occurred. Altogether, this may lead to an advanced prediction model for detecting disease exacerbations, based on a combined array of currently identified Th1- and Th17-associated cytokines. Subsequently, the predictive accuracy of this model could be compared with the distinctive power of currently used disease activity parameters. In conclusion, we show that a positive correlation exists between multiple Th1- and Th17associated cytokines and fecal calprotectin levels, presenting additional non-invasive candidate biomarkers for clinical use in CD patients. Moreover, these candidate biomarkers could be of value in monitoring and treating disease activity in CD. Future studies should aim to further assess the diagnostic potential of a distinct biomarker profile in relation to endoscopic activity measures. Chapter 7
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