Maarten Cozijnsen

132 Conclusions and future perspectives Although almost all studies in pediatric IBD patients did not find increased benefit for combination vs. monotherapy, the available evidence in children is scarce. Several adult trials have shown higher treatment efficacy in patients receiving IFX combination therapy, especially for induction of remission. However, the treatment benefit is at most modest, and might be overcome by optimization of IFX therapy dosing. Although IM naïve may benefit more than IM experienced patients, concomitant IMs have demonstrated to increase IFX levels and reduce immunogenicity rates regardless of past IM use. The reduction of immunogenicity rates may lead to a benefit in terms of increased durability of responsiveness to therapy , which is particularly important for young patients given their long lives ahead. Combination therapy does, however, seem to increase the risk of malignancy. Although no more safety issues were identified in the reviewed trials, the use of combination therapy will expose patients to the individual toxicities of both drugs, next to potential risks due to the combination of drugs. In a joint consensus guideline of the European Crohn’s and Colitis organization (ECCO) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) on the medical management of pediatric Crohn’s disease (3), the authors concluded that there is insufficient evidence to define the risk/benefit ratio for combining anti-TNF with IM therapy. The authors did note that combination therapy in the first six months of anti- TNF therapy may be associated with a lower rate of antibodies development and loss of response, but that this benefit should be weighed against the eventually increased lymphoma risk with thiopurines. The use of concomitant low dose MTX may be safer but it is much less evidence-based, and not supported by the COMMIT trial. In the pediatric UC guideline of the same organizations (4) the authors concluded that there is no good evidence to support combining IFX with thiopurines in children with thiopurines refractory UC and that the balance of safety vs. benefits of combination treatment needs to be fully explained. It is noteworthy that several newer studies have published on this topic after the UC guidelines. Although clearly more research is needed on this topic, the current evidence is sufficient to make some recommendations. The use of combination therapy in clinical practice may be indicated in patients having high risk of serious disease related complications, such as growth retardation, formation of strictures or fistulas, or need for surgery. For instance, significant pan enteric disease, which is not amenable to surgery and is associated with increased long term complications, might indicate combination therapy in the beginning. The timing of stepping down to monotherapy should be individualized. Using combination therapy for a short duration (e.g. 6 months) at the start of anti-TNF