Anti-Tumour Necrosis Factor Therapy for Paediatric Crohn’s Disease: Improved Benefits Through Treatment Optimisation, Deeper Understanding of Its Risks, and Reduced Costs due to Biosimilar Availability

Antibodies directed to tumour necrosis factor-α (TNF-α) are very effective in treating paediatric Crohn’s disease (CD). Over the last few years, research has provided important new insights into how to optimise this treatment’s effectiveness. Research on predictors for anti-TNF treatment responsiveness has revealed potential markers, but data on their accuracy in paediatric CD patients are lagging behind. Also, new evidence has become available on the safety profile of anti-TNF antibodies that suggests the assumed increased malignancy risk seen in patients on anti-TNF and thiopurine combination treatment may be linked more to thiopurine use and not to anti-TNF treatment. In addition, the early results of CT-P13, an infliximab biosimilar, in CD patients confirm the expected similarity with its originator. Thus, the effectiveness of anti-TNF antibody treatment is slowly improving, its malignancy risk is lower than assumed, and its costs are reduced by the introduction of equally effective biosimilars. Together, these trends allow for a more prominent role for anti-TNF antibodies in future treatment of paediatric CD

Infliximab in young paediatric IBD patients : it is all about the dosing

Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients = 10 years). Median age was 8.3 years (IQR 6.9-8.9) in YP compared with 14.3 years (IQR 12.8-15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (<5.4 mu g/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0-12.9) vs. OP; 5.5 mg/kg (IQR 5.0-9.3);p <0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI - 1.2 to - 1.01);p <0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP;p = 0.56). Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged <10 years. What is Known?Peer reviewe

Top-down Infliximab Study in Kids with Crohn's disease (TISKids): an international multicentre randomised controlled trial

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Biomarkers predicting the effect of anti-TNF treatment in paediatric and adult inflammatory bowel disease

Objectives: Paediatric and adult inflammatory bowel disease (pIBD, aIBD) patients may lose response to anti-tumour necrosis factor (TNF) treatment within the first year. Adult-extrapolated weight-based dosing is incorrect in children, due to age-related pharmacokinetic differences. We investigated biomarkers for initial and maintenance of response to infliximab (IFX) or adalimumab (ADA), comparing pIBD and aIBD patients. Methods: In this prospective, observational study, pIBD (n = 24) and aIBD (n = 21) patients were included when initiating anti-TNF. Escalation from standard dosing and continued anti-TNF at 12 and 18 months were assessed. Biomarkers included clinical laboratory parameters, faecal calprotectin (FCP) and IFX trough levels (TLs). Plasma proteomics was performed in pIBD.Results: During our study, treatment escalation (in clinical loss of response) occurred more common in pIBD versus aIBD (p = 0.02). We established that IFX therapy escalation in pIBD patients was not due to low infliximab levels. We identified 9 pro-inflammatory proteins that were elevated in patients losing response. Conclusion: Anti-TNF exposure-response relationship may be different in pIBD versus aIBD. No biomarkers for maintained response were identified, but 9 inflammatory proteins were of interest as potential predictors for loss of response in pIBD.</p

Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Infliximab in Pediatric Inflammatory Bowel Disease: A Systematic Review and Revised Dosing Considerations

OBJECTIVES: Infliximab (IFX), a monoclonal antibody directed against tumor necrosis factor alpha is a potent treatment option for inflammatory bowel disease (IBD). Dosing regimens in children are extrapolated from adult data using a fixed, weight-based dose, which i

Vedolizumab Trough Levels in Children With Anti-Tumor Necrosis Factor Refractory Inflammatory Bowel Disease

Objectives: Inflammatory bowel disease (IBD) can be successfully treated with vedolizumab. Studies in adult IBD patients have shown that differences in response to vedolizumab may be related to variability in vedolizumab trough levels, but in children with pediatric-onset IBD data regarding vedolizumab trough levels are not available. Thus far, the role of trough levels in pediatriconset IBD treatment remains unclear. We aimed to investigate predictors of vedolizumab trough levels in pediatric-onset IBD patients. Methods: Data from anti-tumor necrosis factor refractory pediatric-onset IBD patients who received vedolizumab were collected retrospectively. Vedolizumab trough levels were measured in serum samples collected before each infusion. A linear mixed model was conductedto analyze factorsthatinfluencetroughlevels. Results: Twenty-six pediatric-onset IBD patients (14 ulcerative colitis [UC]), 9 Crohn Disease [CD], 3 IBD-unclassified [IBD-U]) received 258 vedolizumab infusions. Mean vedolizumab trough level at week 6 was 29.9mg/mL (SD 17.8), and 11.5 mg/mL (SD 4.9) during maintenance therapy. CD patients had significantly lower trough levels than IBD-U patients (b 15.2; 95% confidence interval [CI] 1.1 to 29.2; P¼ 0.036). Higher fecal calprotectin (b 0.009; 95% CI 0.02 to 0.003; P¼ 0.007) and C-reactive protein levels (b 0.4; 95% CI 0.72 to 0.04; P¼ 0.027) were associated with lower trough levels, whereas shortening of time between infusions led to higher trough levels (b 0.77; 95% CI 0.9 to 0.64; P< 0.001). Conclusions: In this group of pediatric-onset IBD patients, trough levels were significantly lower in CD patients compared with UC/IBD-

Self-efficacy did not predict the outcome of the transition to adult care in adolescents with inflammatory bowel disease

Aim: It can be difficult for adolescents with inflammatory bowel disease (IBD) to make the transition from paediatric to adult care. We studied the outcomes of this process and defined what constituted a successful transition. Methods: In 2008, 50 adolescents who attended our IBD transition clinic completed IBD-yourself, a self-efficacy questionnaire that we had previously developed and validated. We approached the subjects in 2014, two to six years after they transferred to adult care, and 35 agreed to take part in the current study. The outcome of transition was assessed by our newly developed Transition Yourself Score. In addition, the relationship between self-efficacy and the outcome of the transition was measured. Results: The mean age of the patients was 21.8 years, and 69% suffered from Crohn's disease. The transition process was successful in 63% of cases, moderately successful in 31% and failed in 6%. A successful transition was associated with effective use of medication and clinical remission at the time of transfer, but could not be predicted by self-efficacy. The Transition Yourself Score will be validated in future studies. Conclusion: Nearly two-thirds (63%) of the adolescents who attended the IBD transition clinic had a successful transition to adult care