Maarten Cozijnsen

142 successful induction of remission, 28% of pediatric CD patients with moderate-to-severe disease activity have shown to require infliximab treatment in the first year after diagnosis. 11 For these patients, the step-up strategy delays the initiation of effective treatment at the cost of side effects while increasing the risk of CD progression and complications. Infliximab is well tolerated by most patients, but may contribute to serious adverse effects such as acute and delayed infusion reactions, serious infections and opportunistic infections. 8,12–15 In the TISKids study after 52 weeks of follow-up, the number of patients with an adverse event was not significantly different between both treatment groups: 95 adverse events were reported in 22/50 (44%) top-down treated patients and in 28/47 (60%) step-up treated patients (p=0.125). More uncertainty remains for the risks of malignancies and mortality, which are more rare but serious adverse events. Recent evidence of a large long-term observational registry (DEVELOP) found an increased risk of malignancy for past use of combination treatment with anti-TNF and a thiopurine, while there still is ongoing debate whether the use of a thiopurine alone induces increased risk in pediatric IBD patients. 16 By pooling patients with past use of a thiopurine alone and past use of both a thiopurine and anti-TNF treatment, the investigators found an increased risk for patients that had used a thiopurine (with or without anti-TNF). Authors concluded that infliximab treatment does not increase risk of malignancy while thiopurine treatment does. However, their conclusion is questionable, because in the originally defined patient groups – before pooling of the groups – only past use of both a thiopurine and anti-TNF treatment associated with risk of malignancy, and past use of a thiopurine alone did not. Furthermore the study was sponsored by a pharmaceutical company with a financial interest in infliximab. Findings of a recent prospective multinational observational study, indicate current thiopurine use may be a risk factor for development of lymphomas in pediatric-onset IBD patients, and not infliximab. 17 In summary, evidence suggests that the risk of malignancy seems most increased when using both infliximab and a thiopurine, less increased when using only a thiopurine, and not increased when using only infliximab treatment. TISKids is designed to also compare the safety of the top-down and step-up treatment strategies both at short term (one year follow-up) and at longer term (5 years of follow-up). TISKids does not have enough statistical power to compare the risk of rare adverse events between treating top-down and step-up.