Maarten Cozijnsen

16 Thus, a large proportion of pediatric patients require more intensive treatment in the first year after diagnosis. For these patients, the step-up strategy delays the initiation of effective treatment and increases the risk of CD progression and complications. In Chapter 3 of this thesis we describe the international multicenter randomized controlled trial (RCT) we set up to compare the efficacy and safety of top-down treatment (starting with IFX from diagnosis) with the conventional step-up treatment strategy in newly diagnosed pediatric CD patients. Mechanism of action of anti-TNF treatment in CD Multiple mechanisms of action may contribute to the beneficial effect of anti-TNF antibody therapy in CD (Figure 2). Both the antibody’s binding fragment (FAB) region and the fragment crystallizable (FC) region exert immunomodulatory properties. The FAB regions of IFX and adalimumab (ADA) specifically bind to TNF-alpha molecules. Upon binding with its FAB region, anti-TNF antibodies block and neutralize the signaling potential of TNF. Additionally, anti- TNF antibodies bound to a tmTNF-expressing target cell suppress pro-inflammatory cytokine production or induce apoptosis in the target cell, a process denoted as reverse signalling. 24–26 Although it was anticipated that anti-TNF antibodies would primarily exert their beneficial function in CD by neutralizing TNF function through its FAB regions, it is now recognized that the FC tail of the antibody is important for effectiveness. Etanercept—a TNF receptor/ immunoglobulin G fusion protein, capable of neutralizing sTNF—has been shown to be ineffective in CD. 27 Secondly, certolizumab pegol—a PEGylated FAB fragment of an anti-TNF antibody that lacks an FC region—had only low efficacy in CD. 28 The poor efficacy of these biologicals that are effective for the treatment of other chronic inflammatory diseases— rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis among others—may suggest that the FC region has a crucial role in inducing immunomodulation in CD. The FC region enables bound antibodies to elicit complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). 29 Secondly, it enables an antibody- antigen complex to bind with cells presenting an FC receptor, such as macrophages. Based on in vitro experiments it is suggested that TNF-anti-TNF immune complexes may lead to the induction of immunosuppressive macrophages, able to produce anti-inflammatory proteins, inhibit T-cell proliferation and promote wound healing. 30,31 The induction of these immunosuppressive macrophages may partly explain the higher effectiveness of anti-TNF antibodies that possess an FC region, but this hypothesis still needs to be proven. In a pilot analysis of the Infliximab Top-down Study in Kids with Crohn’s disease (ITSKids) multicenter randomized trial in Chapter 4, we demonstrate that IFX treatment has a strong effect on blood leukocyte mRNA expression and protein concentrations by reducing Th1 and neutrophil signatures, and tissue remodeling proteins.