Optimisation of long-term outcomes in paediatric inflammatory bowel disease patients: role of therapeutic drug monitoring and endoscopic remission.

Optimisation of long-term outcomes in paediatric inflammatory bowel disease patients: role of therapeutic drug monitoring and endoscopic remission. Despite the growing insights into the pathogenesis of inflammatory bowel disease (IBD) and recent therapeutic developments, IBD is still a life-long and incurable disease. Not only is IBD in children more aggressive, but it also has its own unique age-related problems such as the impact on growth, puberty, and bone health. Immunosuppressive and/or immune modulating treatments are often necessary to obtain remission, but also to overcome these unique age-related problems. Therefore, on one hand, children are likely to be exposed for many years to drugs not free of side effects, to achieve these goals, while on the other hand, uncontrolled inflammation puts them at risk for disease-associated complications, such as fibrosis, fistulas, repeated surgical resections, and cancer. It is, therefore, of even greater importance in children to reach treatment goals in a timely manner and individualise treatment to minimise toxicity. Several strategies have been proposed to achieve these goals. The general aim of this doctoral thesis was to improve the long-term outcome by further exploring and unravelling these strategies, specifically in paediatric IBD patients. In the chapter 3 of this doctoral thesis, we investigated the long-term outcome of paediatric IBD patients receiving conventional therapy in order to identify prognostic factors at diagnosis that correlated with treatment failure. Risk stratification algorithms can help physicians to guide their therapeutic actions more accurately by not postponing adequate therapy in high-risk patients and without the need to possibly over-treat patients causing unnecessary risks of immunosuppression. We found that especially a high disease burden at diagnosis predicted the need for step-up therapy with either biologics or surgery. Patients were more likely to fail conventional therapy in case of higher C-reactive protein (CRP), lower albumin, and growth impairment for Crohn's disease and higher Paediatric Ulcerative Colitis Activity Index (PUCAI) score and lower iron levels for ulcerative colitis. The need for step-up therapy significantly increased with the number of risk factors. Since this effect was already seen early during follow-up under conventional therapy, we probably can expect to catch the window of opportunity to modify the natural disease course when providing these high-risk patients an accelerated step-up therapy together with a tight control of inflammation. However, up to two-thirds of paediatric IBD patients will fail conventional therapy, and will require step-up treatment five years after diagnosis with either surgery or biologics. Since anti-tumour necrosis factor (TNF) therapy is the only class of biologics so far approved in paediatric IBD, further optimisation is necessary to improve outcome. Therapeutic drug monitoring (TDM) has been proposed as one of the ways to optimise both initial response and long-term continuation of anti-TNF therapy. Prevention of anti-drug antibody formation and loss of response remain the two most important challenges in the management of IBD with respect to biologics. Research in TDM is rapidly expanding, but the focus lies mainly on adults. TDM studies in children are still under investigated. The objective of the second part of this doctoral thesis was therefore to study that adequate drug exposure to infliximab (IFX) would lead to better long-term outcomes in paediatric IBD. The ideal drug exposure (or therapeutic window) might, however, be patient-specific, vary over time throughout the treatment course (during induction phase, at the end of induction, and during the maintenance phase), and might also depend on the treatment endpoint (such as clinical, biological or endoscopic remission). Therefore, our research has guided us through these three important phases of IFX therapy with respect to all different treatment endpoints. Specific attention went to endoscopic remission since this has emerged as the Holy Grail instead of focusing on relieving symptoms alone. However, data on this topic were lacking in children. In chapter 4, we demonstrated a strong exposure-response effect in children receiving maintenance IFX therapy. Not only, were higher IFX trough levels associated with a better outcome at that specific time, but also an adequate drug exposure throughout the whole maintenance phase was essential for a long and durable response and remission. In addition, we found, for the first time, a clear association between IFX exposure and endoscopic remission. The threshold was set at an IFX trough level of 5.4 µg/mL to achieve endoscopic remission during maintenance in children. In chapter 5, we showed that the IFX exposure at the end of induction therapy was also essential for a favourable long-term outcome. Patients achieving endoscopic remission at six months or clinical and/or biological remission at Week 52 had already significantly higher post-induction IFX trough levels. These trough levels were the only independent predictor for these different outcomes. An IFX trough level of 5.0 µg/mL was deemed necessary to reach endoscopic remission at six months. In chapter 6, we revealed that higher drug levels already during induction therapy, as early as Week 4, were associated with significantly better endoscopic and deep remission rates at six months. In fact, patients who were in endoscopic remission at six months also had a higher drug exposure leading up to Week 12. Confirming that the IFX exposure during the whole induction phase is essential for a favourable long-term outcome. Threshold levels for different timepoints, including intermediate and trough levels during induction, were determined in order to achieve the highest possible response. Our results make it more feasible to translate the findings to routine clinical practice where patients usually present at different timepoints. Finally, the hope it that TDM may improve outcome by maintaining appropriate trough concentrations at an individual level. The next step towards better management of patients with IBD is, therefore, to better understand the inter-individual pharmacokinetic variability. It has been known that IFX trough levels are greatly influenced by the degree of intestinal inflammation. Our research confirmed this association, as especially patients with a lower haemoglobin at IFX initiation had lower IFX exposure during induction. Thus, these patients could probably benefit from higher IFX doses already at the start, and doses could be adjusted afterwards by TDM to achieve remission. In addition, lower serum IFX levels were found in lower-weight and height classes. Therefore, probably a more intensive treatment schedule than prescribed in the label is warranted. Nonetheless, development of pharmacokinetic models and prospective trials is crucial to further elucidate the ultimate treatment regimen prior to routine implementation into clinical practice. Last, switching from the IFX originator to the biosimilar CT-P13 did not influence the pharmacokinetics or efficacy ans was presumed safe (chapter 7). To conclude, we discovered prognostic markers that could stratify at diagnosis which patients were more likely to require surgery or biologics and thus, could benefit from accelerated step-up therapy. In addition, we demonstrated the importance of an adequate IFX exposure during induction and maintenance therapy in paediatric IBD patients since higher IFX trough levels throughout the different phases of the treatment course (induction, at the end of induction, and maintenance phase) are significantly associated with better endoscopic outcome. IFX target concentrations are suggested for these different phases, specifically in children, what is necessary to implement TMD in clinical practice and to improve outcome.status: publishe