279 T-cell subsets. It is produced by innate immune cells, such as macrophages, neutrophils and mast cells, and forms a bridge between the innate and the adaptive immune system. Upon acute inflammatory events, IL-6 is recognized as important stimulator of acute-phase reactant production in the liver, including CRP. In IBD, the importance of IL-6 is highlighted by the fact that serum concentrations rise concurrently with increasing inflammatory disease activity, as well as elevated soluble receptor complexes (sIL-6R/IL-6) that can bind to and activate IL-6R-lacking immune cells (trans signaling), contributing to chronic mucosal inflammation.47 Pro-inflammatory actions of IL-6 have been demonstrated to predominantly occur via trans signaling, which is strongly associated with the development of and sustained intestinal inflammation in IBD.48-50 Here, IL-6 levels fairly accurately differentiated between high and low endoscopic disease activity. As a result, serum IL-6 levels made a substantial contribution to the predictive power of the final biomarker combination. IL-8 is known as an important neutrophil chemoattractant, modulating recruitment and degranulation of neutrophils located in the intestinal mucosa.51 Previously, it was demonstrated that serum IL-8 levels are elevated in active IBD, most prominently in UC, as compared to healthy subjects.52 In line, we found significantly elevated serum concentrations of IL-8 in UC compared to CD and healthy controls. Therefore, IL-8 is suggested to be a key factor in the process of neutrophil-mediated intestinal inflammation in active UC. Previously, it was shown that mucosal IL-8 levels can predict future disease relapse in patients with quiescent UC.53 Moreover, serum IL-8 levels present high accuracy in differentiating IBD from irritable bowel syndrome (IBS) patients. 54 In this respect, IL-8 might be particularly helpful in identifying an acute disease exacerbation, irrespective of the often non-specific clinical presentation. Currently, disease activity in IBD is clinically assessed by evaluating a combination of symptoms (quantified with clinical risk scoring methods), biochemical measures such as serum CRP and fecal calprotectin, and ultimately endoscopic evaluation. However, the clinical scoring methods, such as the Harvey Bradshaw Index (HBI) or the Simple Clinical Colitis Activity Index (SCCAI) correlate poorly with endoscopic disease activity.24,25, 55-57 Our results are in line with these studies, since only serum IL-6 levels correlated significantly with the clinical disease indices in our cohort. Moreover, associations between serumCRP and fecal calprotectin and endoscopic disease activity in IBD appear inconsistent.58 Despite this, these parameters are the most frequently-used non-invasive biomarkers analyzed to monitor disease activity in IBD.14,23,59 However, several studies have shown that one single biomarker is unlikely to accurately predict the mucosal status in IBD, given its complex immunological pathogenesis.10,11,14,17,60 Endoscopic remission is the ultimate goal and measure of therapeutic efficacy in IBD. Additional non-invasive markers are needed to be able to accurately represent endoscopic remission.61,62 Previous studies have developed disease activity indices reflecting mucosal status, based on clinical characteristics and standard laboratory measurements, but few included inflammatory biomarkers as we investigated in this study.63 Incorporation of such inflammatory biomarkers in existing prediction models or disease indices may contribute to establishing an immunology-based prediction model for endoscopic mucosal status in IBD. An important strength of the present study is the comprehensive analysis of a selected panel of serum inflammatory biomarkers using an electrochemiluminescence (ECL) assay. Using Predicting endoscopic disease activity in IBD
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