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Infliximab at diagnosis: moving towards personalisation in paediatric inflammatory bowel disease

The optimal strategy for induction of remission in paediatric Crohn’s disease, and in particular the timing of introduction of monoclonal antibody therapy, remains controversial. This has longterm implications in a condition where shortterm benefit, including impact on growth, must be balanced against the potential need for treatment escalation and risks associated with therapy. This is not helped by the fact the condition is heterogeneous in type, distribution and severity. International guidance currently recommends that children presenting with moderate to severe luminal disease are commenced on exclusive enteral nutrition (EEN), oral corticosteroids, intravenous corticosteroids or antiTNF therapy, with widespread use of EEN as first line. In their groundbreaking article, Jongsma et al describe the use of antiTNF therapy for induction of remission, and compare this to ‘conventional’ therapy in an openlabel randomised control trial. All patients had moderate to severe disease. The data are novel and have the potential to inform practice. Rather than focusing on the continued debate between topdown versus stepup therapy, these data inform paediatric gastroenterologists on the utility of induction therapy with infliximab, with the protocol dictating patients who are able should stop the drug after the final infusion at 22 weeks. The results of the study, conducted on 100 patients, highlight the efficacy of infliximab (59%) to induce clinical remission at 10 weeks compared with ‘conventional’ therapy (34%), comprising 6 weeks of EEN or oral corticosteroids. Azathioprine was started early in both treatment arms and appears to have been well tolerated. At 52 weeks, the results were less clear; the firstline infliximab group achieved clinical remission in 70% of patients, compared with 56% of the conventional group, p=0.42. While remission without treatment escalation was observed in more firstline infliximab patients than in the conventional arm (41% vs 15%, respectively), this was somewhat confounded by the effect of the induction regimen of infliximab (with azathioprine) lasting beyond 30 weeks, compared with the conventional arm who were on azathioprine monotherapy from as early as 6 weeks. The difficulty is, if infliximab is safe and effective at diagnosis, should all cases be started on it? This is particularly important as in this study only 35/97 patients remained on monoclonal antibody treatment at 52 weeks, and as the authors discuss, in general, recent national and international guidance, suggests once treatment with monoclonal antibody therapy is started it is continued. at least medium term. It has long been established that many patients will achieve mediumterm remission without immunosuppression, with Markowitz et al, in a paediatric cohort, demonstrating that at 1year post induction therapy 43% of patients remained in remission without the need for corticosteroids or thiopurines. Therefore, there is potential for large numbers of patients being on longterm monoclonal antibody therapy who do not necessarily need it and so while Jongsma et al elegantly demonstrate the potential of infliximab to induce remission, further questions arise from this data set; which patients should have aggressive therapy at diagnosis? Who should continue on antiTNF treatment beyond induction? Who will develop fistulating or stricturing disease? Who will have longterm quiescent disease? Answering these questions necessitates consideration of the heterogeneity of inflammatory bowel disease (IBD), and the need to better inform this by developing predictors based on characteristics or biomarkers at diagnosis, and during early therapy. This strategy moves away from a one size fits all approach, recognising there are multiple different phenotypes within the wide spectrum of IBD. Although this ambition is clearly at the forefront of translational IBD research, this is confounded by realisation that genomic, transcriptional, microbial and clinical stratification tools, alongside genomic, transcriptomic and microbial biomarkers are difficult to identify, and even more problematic to implement. In paediatric Crohn’s disease, the landmark publication from Kugathasan et al, detailed risk models including clinical features, gene expression, microbial profiles that predicted the occurrence of disease complications, with a maximal area under the receiver operator curve of 0.72. Biasci et al have published data detailing a CD8 Tcell transcriptional signature that is reported to separate all IBD patients into high versus low longterm disease activity, although this has not been replicated in paediatric cohorts. 7 Similarly, our own group has identified a Th17 cell signature in ileal biopsies of newly diagnosed paediatric Crohn’s disease patients associated with prolonged time to relapse. However, despite increasing data, clinical application of these findings has lagged behind scientific reporting. Moving forward it appears likely that precisely phenotyped prospective cohorts treated according to standardised criteria, rather than randomised controlled trials, should be employed to develop stratification models which can then be updated by continued study and refinement. Moving from treating patients as homogeneous cohorts, to assessing them as individuals with their own specific cause of IBD, their own disease course and their own responses to treatment has the potential to improve outcomes. The evidence that topdown therapy promotes remission in cohorts of patients is not in question, however, the appropriateness of this approach is questioned by the potential to overtreat. For example, although the impact of antiTNF therapy on fistulating complications is demonstrable, the progression of fibrostenotic disease does not appear to be prevented by antiTNF therapy. Jongsma et al must be congratulated on their study, but we remain cautious that the findings should not be overinterpreted and longterm followup data on this cohort will be important. The future implementation of these data must be centred on accurate identification of the patients who will benefit from antiTNF induction therapy, sparing those not requiring it and using a better alternative Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK Human Genetics and Genomics, University of Southampton, Southampton, UK