Maarten Cozijnsen

141 Chapter 7 General discussion Current scientific data suggest superiority of top-down infliximab treatment While writing this discussion, the Top-down Infliximab Study in Kids with Crohn’s disease (TISKids) study is ongoing ( Chapter 3 ) and results at one year follow-up are submitted to a medical scientific journal undergoing peer review. At 52 weeks, the sustained clinical remission rate was higher in the top-down group (19/46 [41%]) than in the step-up group (6/48 [12%], p=0.002). We thus concluded, based on one year follow-up, that top-down infliximab treatment is superior to step-up treatment in inducing and maintaining clinical remission in children with moderate-to-severe CD. In addition, the results from the analysis of patients treated in the Infliximab Top-down Study in Kids with Crohn’s diseases (ITSKids) – the randomized controlled trial (RCT) that preceded TISKids, but was stopped prematurely because of a low inclusion rate - suggest a superior short-term effectiveness of top- down treatment: at week 10, patients treated top-down had better clinical outcomes and inflammatory proteins were lower in RNA of blood leukocytes and in serum (Th1 related, neutrophil related, and tissue remodeling proteins – see Chapter 4 ). Besides TISKids and ITSKids, the other available evidence on the relative effectiveness of top-down infliximab treatment (as compared to step-up treatment) also suggests higher effectiveness of top- down treatment: two prospective studies revealed higher clinical and endoscopic remission rates 1,2 and retrospective studies in pediatric CD patients revealed lower relapse rates 3–6 and higher remission rates. 7 We conclude that the results of the TISKids study advocate change of treatment guidelines and to make top-down infliximab treatment the standard treatment strategy in children with moderate-to-severe CD. Besides short-term effectiveness, it is speculated that starting CD treatment with infliximab from diagnosis may result in better long-term treatment outcomes. Firstly, it may prevent disease complications (e.g. strictures, fistulas, extra intestinal manifestations) and need for surgery. We designed TISKids with a follow-up of 5 years in order to also assess long-term outcomes such as complication rates and need for surgery. Secondly, starting with infliximab from diagnosis may reduce a subsequent need for infliximab maintenance treatment and risk of disease relapses. We test this hypothesis in TISKids by stopping infliximab after the 5 th infusion in patients that achieved clinical disease remission –the down part of the top- down strategy. Results at the longer term (up to 5 years) will follow after study completion. Besides effectiveness, treatment choices should be based on the safety of the available treatment options. As stated in the General Introduction, step-up treatment has several disadvantages: prednisolone treatment has considerable side effects and only rarely induces endoscopic remission 8–10 and EEN necessitates a complete refrain from normal food for a 6-8 weeks which is unpleasant and hard to comply with. Moreover, even after