280 this highly-sensitive, validated detection method of serum inflammatory biomarkers, we were able to establish serum biomarker concentrations with a broad dynamic range of detection. However, biomarker concentrations were not within the detection range in a small number of samples (6.0%) and were excluded from the analyses. In order to determine whether this may skew the interpretation of our results, we performed a full statistical analysis on a dataset where missing values were replaced by the lower limit of detection (LLoD) or upper limit of detection (ULoD) as indicated by the signals obtained in the ECL assay. Importantly, these analyses further confirmed the final prediction model. In an earlier study, we found correlations between several serum inflammatory cytokines in CD and fecal calprotectin levels, where we observed positive correlations for Th1- and Th17- associated serum cytokines (including CRP, SAA and IL-6) and fecal calprotectin levels.22 However, that study was limited by a relatively small cohort of CD patients and the absence of endoscopic results, which prevented us from establishing correlations with IBD disease activity. Likewise, the current study has also some limitations. For instance, a larger cohort would have allowed us to predict endoscopic disease activity using the pre-defined categories as outcome parameter with values ranging from 0 to 3. In this respect, the inclusion of more IBD patients with endoscopic remissioncouldhaveenabledus toassess thepredictiveaccuracyof acombinationof inflammatory biomarkers between the quiescent and active state of the disease and establish clinically useful cut-offs. Similarly, a greater sample size would have resulted in more reliable subgroup analyses for CD and UC. Moreover, this would have provided us with the ability to adjust for confounding variables (e.g. medication use, co-morbidity or acute inflammatory events). Lastly, shortening of the time interval between endoscopy and serum sample collection would have improved the reliability of our results. Our results demonstrate that a combination of serum inflammatory biomarkers has the potential to differentiate between IBD patients with varying degrees of endoscopic disease activity in a minimally invasive manner. The panel of four biomarkers described in this study has a high accuracy, and it is important now to externally validate this combined array of biomarkers in another IBD cohort. As such, the development of a minimally invasive multi-marker serum test may be particularly clinically relevant as the discrimination between varying degrees of endoscopically active disease may help in guiding therapeutic decision making and adjusting medical therapy.61 Furthermore, endoscopic remission or ‘mucosal healing’ is increasingly recognized as important therapeutic endpoint in clinical trials.64 Since prediction of endoscopic disease activity may be found in a combined set of serum biomarkers, this study is also aimed to trigger avenues for future research that further evaluate the potential of a serum biomarker panel to represent disease activity in IBD. Additionally, since cytokines play a pivotal role in the immunopathogenesis of IBD, it is interesting to analyze the effect of induction therapy on serum inflammatory status in relation to endoscopic remission in IBD. Future studies are warranted that focus on the diagnostic potential of this distinct inflammatory biomarker profile in predicting response to (biological) therapy in IBD. In conclusion, the panel of four serum inflammatory biomarkers identified in this study shows a predictive value of endoscopic disease activity in IBD that is much better than current routine laboratory tests. SAA, Eotaxin-1, IL-6, IL-8, IL-17A and TNF-α all individually showed better Chapter 8
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