278 Discussion In this study, we demonstrate that serum Eotaxin-1, SAA, IL-6, IL-8, IL-17A and TNF-α are better predictors of endoscopic disease activity in IBD than the routinely applied serum CRP, fecal calprotectin levels and HBI or SCCAI scores. A combined panel of Eotaxin-1, SAA, IL-6 and IL-8 showed the best prediction of the actual mucosal status in IBD with a sensitivity of 90.7% and specificity of 68.4%. Furthermore, only a fewpatients weremisclassified as having high endoscopic disease activity, yielding a positive predictive value of 86.7%. The combination of these four inflammatory biomarkers demonstrated higher discriminative value regarding endoscopic disease activity in IBD than routinely applied measures of disease activity (i.e. serum CRP, fecal calprotectin levels and clinical disease indices [HBI/SCCAI]). All biomarkers that were found to be predictive for endoscopically confirmed disease activity are involved in the pathogenesis of IBD. Eotaxin-1 (CCL11) is a selective chemoattractant and important in the activation and recruitment of eosinophils to the lamina propria of the gut. 29 Eotaxin-1 levels have been shown to be elevated in the serum of patients with (active) IBD.30-33 In our study, however, we found higher serum Eotaxin-1 concentrations in UC as compared to CD. Remarkably, serum levels were generally reduced in CD as compared to healthy controls, though there was a large variation in Eotaxin-1 levels in this patient group (Figure 1). Despite this, we observed a clear positive correlation between inflammatory activity in the composite IBD endoscopy score and serum levels of Eotaxin-1 (Supplementary Figure S1). Moreover, serum Eotaxin-1 showed discriminative value for differentiating IBD patients having either remissive or mild disease from patients with moderate or severe endoscopic disease activity (Figure 3). These findings of correlations between serum Eotaxin-1 levels and disease activity corroborate previous observations in human IBD and experimental colitis models that suggested that the eosinophilselective chemokine Eotaxin-1 associates with disease pathogenesis.34, 35 Eotaxin-1 is produced by intestinal epithelial cells, endothelial cells and macrophages under the influence of several other cytokines that are involved in IBD disease activity, such as IL-17A.36-39 Serum amyloid A (SAA) was also predictive for IBD disease activity. SAA is an apolipoprotein of high-density lipoproteins (HDL) and belongs to the family of acute-phase reactants. It is produced by the liver upon enhanced serum levels of pro-inflammatory cytokines, such as TNF-α and IL-6, and is enhanced in several chronic inflammatory diseases.40, 41 Previously, it was demonstrated that circulating IL-6 and SAA are useful indicators of disease activity in IBD.42 In contrast to the pro-inflammatory nature of most of the studied cytokines, it is unknown whether SAA contributes to inflammation. The positive correlation with disease activity suggests a pro- inflammatory function, but recently it was also shown that SAA may protect the epithelial barrier by stimulating protective and anti-inflammatory IL-22-producing neutrophils.43 Irrespective of its role in disease development, SAA has been shown to be the most sensitive acute-phase protein in IBD (when compared to other acute phase proteins, such as alpha-1-antichymotrypsin (alpha1-ACT) and alpha-1-acid glycoprotein (alpha-1-AGP), or even CRP).44 Therefore, SAA may be of added value as inflammatory biomarker in monitoring the acute-phase reaction, besides CRP.45 IL-6 was also part of the selected combination of predictive inflammatory biomarkers. IL-6 is one of the most ubiquitously present and pleiotropic cytokines that is involved in most (chronic) inflammatory diseases, including IBD.46 IL-6 can change the balance of effector CD4+ Chapter 8
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