Maarten Cozijnsen

55 Chapter 3 TISKids: an international multicenter RCT Background Crohn’s disease (CD) is a chronic inflammatory disease predominantly affecting the gastrointestinal tract. The disease pathogenesis is not fully known, but involves an aberrant immune response to the patients’ intestinal microbiota. Because of the inflammation, patients may present with symptoms such as abdominal pain, diarrhea, fatigue and weight loss, and further investigation may reveal increased inflammatory products in the patients’ blood and feces. The diagnosis is based on the patients’ history, physical examination, endoscopic and radiologic imaging of the bowel as well as microscopic evaluation of mucosal biopsies.(1) Approximately 4 per 100.000 children develop CD during childhood or adolescence.(2) Compared with adult onset CD, patients with childhood onset may present with more extensive and progressive disease, and generally require more intensive treatment.(3, 4) Pediatric CD treatment focusses on relieving symptoms, restoring longitudinal growth and pubertal development, and on suppressing the inflammatory immune response leading to macroscopically detectable repair of the mucosal surface, also known as mucosal healing. (5) Acquiring mucosal healing is important since it predicts a favorable disease outcome, and reduces the need for steroids, the risk of complications, of hospitalization and need for surgery.(6) Current pediatric CD guidelines instruct physicians to start treatment with exclusive enteral nutrition (EEN) or prednisolone to induce disease remission, and at the same time start with a thiopurine, such as azathioprine (AZA), or methotrexate (MTX) to maintain remission.(5) Only patients refractory to these treatments can step-up to anti- tumor necrosis factor (TNF) antibody therapy. However, this so-called step-up treatment strategy has disadvantages. Although prednisolone and EEN both induce clinical remission effectively (in approximately 80% of patients), prednisolone has considerable side-effects, and EEN necessitates a complete refrain from normal food for a long period of time which is unpleasant and hard to comply to.(5) Furthermore, prednisolone only rarely induces mucosal healing.(5, 7, 8) Once in clinical remission, 60-70% of patients maintain remission during the first year of AZA treatment.(5) One registry showed that 54% (55/102) of pediatric CD patients had received either an additional corticosteroid course or had started IFX within the first year after diagnosis.(9) Thus a large proportion of pediatric patients requires 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. Since its introduction, infliximab (IFX) – the first anti-TNF antibody registered for CD – has shown to be very effective for treating refractory pediatric CD patients.(10) In the REACH trial – the pivotal IFX trial in pediatric CD patients refractory to azathioprine treatment – 88%