Maarten Cozijnsen

155 Addenda Summary Summary The primary aim of this thesis was to compare the efficacy and safety of the experimental top-down treatment strategy with the conventional step-up treatment strategy in children and adolescents with Crohn’s disease (CD). In the top down infliximab treatment strategy, patients start with infliximab – a highly effective treatment option – instead of reserving it for those that don’t respond to other treatment options, which is the conventional step- up treatment strategy. Additional aims were to develop a novel index that correlates with mucosal CD inflammation, to study differences in the immune responses upon infliximab or prednisolone treatment, to evaluate the real-world efficacy of adalimumab and to compare the benefits and risks of combining anti-tumor necrosis factor (TNF) and immunomodulator therapy with treating only with anti-TNF. In Chapter 2 , we report the accuracy of a novel mucosal inflammation, non-invasive (MINI) index that strongly correlates with mucosal inflammation and that can accurately assess endoscopic remission. The MINI index was generated on a large prospective cohort of pediatric Crohn’s disease (CD) patients and was validated on three independent prospective cohorts. A cutoff of <8 best balanced sensitivity and specificity in reflecting endoscopic remission. A cutoff of <6 had a higher positive predictive value (PPV) to reflect endoscopic remission (86%) and ≥8 was most accurate to diagnose mucosal inflammation (PPV 90%). The added benefit of the MINI index over measurement of fecal calprotectin alone was small but significant, especially for patients with concentrations of fecal calprotectin from 100 to 599mg/g. The MINI index can be used both in clinical practice for tight monitoring of mucosal inflammation and facilitating appropriate selection of children for ileocolonoscopy, and serve as an outcome measure in clinical trials instead of, or in addition to ileocolonoscopy to increase feasibility and enrollment rates. Chapter 3 describes the study protocol of the international multicenter open-label randomized controlled trial (RCT) – Top-down Infliximab Study in Kids with CD (TISKids) – we set up to compare the efficacy and safety of two treatment strategies: the top-down infliximab treatment strategy and the conventional step-up treatment strategy. The chapter describes the study design and the outcome parameters that are measured. While writing this thesis, the study is ongoing. In November 2018 we’ve included the last patient and after an initial follow-up of 1 year, we’ll be able to assess and report on the primary and secondary study outcomes. Currently, the manuscript with the results at one year follow-up is submitted for publication. The study will continue for a total follow-up duration of 5 years.