Maarten Cozijnsen

21 Chapter 1 General introduction The second way is predicting who does not respond to anti-TNF antibodies and may better receive an alternative treatment option. Research on this topic is complicated by the low chance of primary non-response in pediatric CD, and demands a relatively large patient sample in order to be studied. As we discussed previously, some patient characteristics are known to impact anti-TNF treatment success, i.e. no previous anti-TNF exposure, younger age and shorter disease duration are associated with higher anti-TNF response rates. However, these features are currently not used to determine who should or should not receive anti-TNF treatment, since they cannot accurately predict anti-TNF primary non- response—one exception being IFX non responders, who are not switched to ADA but to a drug that does not target TNF). In adult CD, not in pediatric CD, several trials have sought for baseline biomarkers that can predict anti-TNF response. Response to anti-TNF antibodies has been associated with baseline RNA expression of several genes in mucosal biopsies 52 and peripheral blood 53 , and with the patients’ genetic make-up. 54–59 Arijs et al demonstrated that RNA expression profiles of mucosal biopsies from adult colonic CD patients were able to accurately distinguish all IFX responders from IFX non-responders—response was determined based on change in endoscopic disease severity at week 4-6.(42) The authors reported that the top 5 differentially expressed genes alone reached perfect accuracy, i.e. 100% (top 5 genes: TNF-a-induced protein 6 [TNFAIP6], S100 calcium-binding protein A8 [S100A8], interleukin-11, G0/G1switch 2 [G0S2], and S100 calcium-binding protein A9 [S100A9])—no such predictive gene set was identified in ileal CD patients. More recently, West et al reported high Oncostatin M expression in mucosal tissue to be associated with anti-TNF response, which may be a promising marker in the future. 60 These findings now require replication in a separate cohort of pediatric CD patients before they can be used in clinical practice to guide treatment choices. Thirdly, it would be beneficial to predict patients at risk of losing response to anti-TNF antibodies during treatment, since these patients may need intensified treatment and more frequent follow-up. There are multiple trials that addressed this topic. Typically, they have a follow-up period of 1 year and measure a certain marker after the induction period (roughly at 2-4 months from anti-TNF antibody initiation) and relate these results to their 1 year effectiveness outcomes. When measured after the induction period, lower clinical disease activity 12 , lower endoscopic disease activity 62 , lower calprotectin concentrations 63 , lower disease activity measured by sonography 64 or by magnetic resonance enterography 65,66 , and higher IFX trough levels 44,67 are associated with longer disease remission. In short, all available evidence indicates that more effective induction treatment results in more durable disease remission. Assessment of most of these factors are already part of routine clinical assessment and assist in timely discovery of treatment inefficacy.