Maarten Cozijnsen

156 Chapter 4 describes the results of the analyses of the immune responses of patients treated in the international multicenter open-label RCT Infliximab Top-down Study in Kids with CD (ITSKids). We aimed to study the differences in the immune responses of newly diagnosed pediatric CD patients to infliximab and prednisolone treatment, as the underlying immune mechanisms by which infliximab treatment restores homeostasis are largely unknown. We demonstrated that infliximab treatment reduces systemic and intestinal CD inflammation more effectively than prednisolone treatment does. We identified three dominant pathways that associate with infliximab treatment and with endoscopic remission: Firstly, infliximab treatment homogeneously reduces the expression and concentration of Th1 related genes and proteins. Secondly, infliximab treatment reduces the expression of S100 calcium binding proteins and the concentrations of several neutrophil chemo attractants. Thirdly, infliximab treatment reduces the transcription and concentration of proteins involved in tissue remodeling. Furthermore, we identified these pathways in analyses of patient blood rather than in analyses of mucosal biopsies, thereby proving it possible to use patients’ blood to monitor immune responses to infliximab treatment. Chapter 5 describes the results of a nationwide, observational case series in which we assessed the safety and effectiveness of adalimumab therapy in pediatric CD patients that previously failed infliximab treatment in a real-world setting. Adalimumab induced remission in two-thirds of the infliximab refractory patients, of whom 50% maintained remission up to two years. Adalimumab failure occurred in 24% within 1 year and in 42% within two years. Only one serious adverse event occurred. The results corresponded well with literature. Additionally, within our cohort, we demonstrated that primary non-responders to infliximab had a higher risk for adalimumab failure than those who had lost response to infliximab. Furthermore, we found a trend for a relatively higher remission rate and lower failure rate in patients who had developed antibodies toward infliximab, compared to those without. Chapter 6 is a review of scientific literature in which we compare the benefits and risks of combining anti-TNF treatment with immunomodulator therapy based on published evidence. Although almost all studies in pediatric patients with inflammatory bowel disease did not find increased benefit for combination versus monotherapy, the available evidence in children is scarce. Several adult trials have shown higher treatment efficacy in patients receiving infliximab combination therapy, especially for induction of remission. However, the treatment benefit is modest and might be overcome by optimization of infliximab therapy dosing. Moreover, combination therapy does seem to increase the risk of malignancy. Thus, we concluded that, although evidence of increased effectiveness is lacking in pediatric CD, based on adult CD literature, it is likely that combination therapy is more effective at the cost of increased risk of adverse effects.