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-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.

Randomised clinical trial: First-line infliximab biosimilar is cost-effective compared to conventional treatment in paediatric Crohn's disease.

BACKGROUND: Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed. AIM: To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease. METHODS: We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks. RESULTS: We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first-line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03-2.35, p = 0.036). CONCLUSIONS: First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease. TRIAL REGISTRATION NUMBER: NCT02517684.

De Novo Crohn's Disease in Children With Ulcerative Colitis Undergoing Ileal Pouch-Anal Anastomosis: A Multicenter, Retrospective Study From the Pediatric IBD Porto Group of the ESPGHAN.

BACKGROUND AND AIMS: We sought to define the prevalence and to characterize possible predictive factors of Crohn's disease (CD) occurring in children with ulcerative colitis (UC) after ileal pouch-anal anastomosis (IPAA). METHODS: This was a multicenter, retrospective study including 15 centers of the Porto IBD group of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition. Children with a confirmed diagnosis of UC undergoing colectomy with IPAA and a minimal follow up of 6 months were identified. The following data were collected: demographic data; endoscopic and histologic data; disease activity; laboratory exams; therapeutic history; indication for surgery, type, and timing; and IPAA functional outcomes and complications. In de novo CD cases, time of diagnosis, phenotype, location, and therapies were gathered. RESULTS: We identified 111 UC children undergoing IPAA from January 2008 to June 2018 (median age at colectomy: 13 years; age range: 1-18 years; female/male: 59/52). The median time from diagnosis to colectomy was 16 (range, 0-202) months. At the last follow-up, 40 (36%) of 111 children developed pouchitis. The criteria for de novo CD were met in 19(17.1%) of 111 children with a 25-month median (range, 3-61 months). At last follow-up, 12 (63.1%) of 19 were treated with biologics and in 5 (26.3%) of 19 children, the pouch was replaced with definitive ileostomy. In a multivariable logistic regression model, decreased preoperative body mass index z scores (odds ratio, 2.2; 95% confidence interval, 1.1-4.4; P = .01) resulted as the only variable associated with CD development. CONCLUSIONS: Children with UC undergoing IPAA carry a high risk of developing subsequent CD. De novo CD cases showed decreased preoperative body mass index z scores, identifying a poor nutritional status as a possible predictive factor.

This is the largest European study describing the prevalence of Crohn's disease (CD) development in children with ulcerative colitis undergoing subtotal colectomy with ileal pouch­anal anastomosis. Children affected by ulcerative colitis carry a higher risk when compared with adults to develop de novo CD after surgery. On the other hand, the multivariate analysis identified decreased values of preoperative body mass index z scores as a possible predictor of new-onset CD.

Validation and Reference Scores of the Transition Readiness Assessment Questionnaire in Adolescent and Young Adult IBD Patients.

OBJECTIVES: Transition readiness can predict a successful transition from pediatric to adult care. This study aimed to validate and develop age-dependent reference scores for the (Dutch version of) Transition Readiness Assessment Questionnaire (TRAQ), in adolescents and young adults (AYAs) with inflammatory bowel disease (IBD). METHODS: TRAQ has 20 items (score 1-5) distributed over 5 domains (total sum score 100) and is completed by AYAs. Following the COnsensus-based Standards for the selection of health Measurement INstruments methodology, we conducted the translation, back-to back translation, pretesting, and validation of the final Dutch version of TRAQ (TRAQ-NL) questionnaire. We used a Rasch model for structural validation, hypothesis testing for construct validity, and Cronbach alpha to demonstrate reliability. Reference scores were calculated using percentiles. RESULTS: Two hundred fifty TRAQ questionnaires were evaluated in 136 AYAs with IBD [56% Crohn disease, 58% male, median age 17.5 years (range 15.7-20.4)]. The overall mean item score was 3.87 (range 1.45-5). With good reliability (Cronbach alpha 0.87), TRAQ-NL discriminated well between knowledge levels, especially in the lower levels. Transition readiness was defined as low, moderate, adequate, or excellent in patients with TRAQ percentile scores (PC) <25th (<3.375 mean item score), 25th-50th (3.375-3.9), 50th-90th (3.91-4.7), or >90th (>4.7). Younger patients, concomitant illness, fewer visits to the transition clinic, and parental dependence were associated with significantly lower TRAQ scores. CONCLUSION: TRAQ(-NL) is reliable and valid, with age-dependent PC to identify (in)adequate transfer readiness. TRAQ can now be more easily used as a patient-reported outcome measure to monitor transition readiness longitudinally in routine care for AYAs IBD patients.

Serum Immune Profiling in Paediatric Crohn's Disease Demonstrates Stronger Immune Modulation With First-Line Infliximab Than Conventional Therapy and Pre-Treatment Profiles Predict Clinical Response to Both Treatments.

BACKGROUND: Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual paediatric Crohn's disease [CD] patients is needed. We assessed how serum immune profiles before and after first-line infliximab [FL-IFX] or conventional [CONV] induction therapy associate with disease remission at week 52. METHODS: Pre- [n = 86], and 10-14-week post-treatment [n = 84] sera were collected from patients with moderate-to-severe paediatric CD in the TISKids trial, randomized to FL-IFX [n = 48; five 5-mg/kg infusions over 22 weeks] or CONV [n = 43; exclusive enteral nutrition or oral prednisolone]; both groups received azathioprine maintenance. The relative concentrations of 92 inflammatory proteins were determined with Olink Proteomics; fold changes [FC] with |log2FC| > 0.5 after false discovery rate adjustment were considered significant. RESULTS: FL-IFX modulated a larger number of inflammatory proteins and induced stronger suppression than CONV; 18/30 proteins modulated by FL-IFX were not regulated by CONV. Hierarchical clustering based on IFX-modulated proteins at baseline revealed two clusters of patients: CD-hi patients had significantly higher concentrations of 23/30 IFX-modulated proteins [including oncostatin-M, TNFSF14, HGF and TGF-α], and higher clinical disease activity, C-reactive protein and blood neutrophils at baseline than CD-lo patients. Only 24% of CD-hi FL-IFX-treated patients maintained remission without escalation at week 52 vs 58% of CD-lo FL-IFX-treated patients. Similarly, 6% of CD-hi CONV-treated patients achieved remission vs 20% of CONV-treated CD-lo patients. Clustering based on immune profiles post-induction therapy did not relate to remission at week 52. CONCLUSION: FL-IFX leads to stronger reductions and modulates more immune proteins than CONV. Stratification on pre-treatment profiles of IFX-modulated proteins directly relates to maintenance of remission without treatment escalation. TRIAL REGISTRATION NUMBER: NCT02517684.

Prediction of thiopurine failure in pediatric Crohn's disease: pediatric IBD Porto group of ESPGHAN.

BACKGROUND: Maintaining of remission early in the disease course of Crohn's disease (CD) is essential and has major impact on the future prognosis. This study aimed to identify baseline predictors to develop model allowing stratification of patients who will not benefit from long-term azathioprine (AZA) treatment and will require more intensive therapy. METHODS: This study was designed to develop clinical prediction rule using retrospective data analysis of pediatric CD patients included in prospective inception cohort. Clinical relapse was defined as necessity of re-induction of remission. Sequence of Cox models was fitted to predict risk of relapse. RESULTS: Out of 1190 CD patients from 13 European centers, 441 were included, 50.3% patients did not experience clinical relapse within 2 years of AZA treatment initiation. Median time to relapse was 2.11 (CI 1.59-2.46) years. Of all the tested parameters available at diagnosis, six were significant in multivariate analyses: C-reactive protein (p = 0.038), body mass index Z-score >0.8 SD (p = 0.002), abnormal sigmoid imaging (p = 0.039), abnormal esophageal endoscopy (p = 0.005), ileocolonic localization (p = 0.023), AZA dose in specific age category (p = 0.031). CONCLUSIONS: Although the possibility of predicting relapse on AZA treatment appears limited, we developed predictive model based on six baseline parameters potentially helpful in clinical decision. IMPACT: The possibility of predicting relapse on AZA treatment appears to be possible but limited. We identified six independent predictors available at diagnosis of early AZA/6-MP treatment failure in pediatric CD patients. Using combination of these factors, a model applicable to clinical practice was created. A web-based tool, allowing estimation of individual relapse risk in pediatric CD patients on a particular therapeutic regimen, has been developed.

Identification of a Disease-Associated Network of Intestinal Immune Cells in Treatment-Naive Inflammatory Bowel Disease.

Chronic intestinal inflammation underlies inflammatory bowel disease (IBD). Previous studies indicated alterations in the cellular immune system; however, it has been challenging to interrogate the role of all immune cell subsets simultaneously. Therefore, we aimed to identify immune cell types associated with inflammation in IBD using high-dimensional mass cytometry. We analyzed 188 intestinal biopsies and paired blood samples of newly-diagnosed, treatment-naive patients (n=42) and controls (n=26) in two independent cohorts. We applied mass cytometry (36-antibody panel) to resolve single cells and analyzed the data with unbiased Hierarchical-SNE. In addition, imaging-mass cytometry (IMC) was performed to reveal the spatial distribution of the immune subsets in the tissue. We identified 44 distinct immune subsets. Correlation network analysis identified a network of inflammation-associated subsets, including HLA-DR+CD38+ EM CD4+ T cells, T regulatory-like cells, PD1+ EM CD8+ T cells, neutrophils, CD27+ TCRγδ cells and NK cells. All disease-associated subsets were validated in a second cohort. This network was abundant in a subset of patients, independent of IBD subtype, severity or intestinal location. Putative disease-associated CD4+ T cells were detectable in blood. Finally, imaging-mass cytometry revealed the spatial colocalization of neutrophils, memory CD4+ T cells and myeloid cells in the inflamed intestine. Our study indicates that a cellular network of both innate and adaptive immune cells colocalizes in inflamed biopsies from a subset of patients. These results contribute to dissecting disease heterogeneity and may guide the development of targeted therapeutics in IBD.

Evaluation of exclusive enteral nutrition and corticosteroid induction treatment in new-onset moderate-to-severe luminal paediatric Crohn's disease.

To induce remission in luminal paediatric Crohn's disease (CD), the ESPGHAN/ECCO guideline recommends treatment with exclusive enteral nutrition (EEN) or oral corticosteroids. In newly diagnosed moderate-to-severe paediatric CD patients, we determined the proportion of patients in which EEN or corticosteroids induced remission and maintained remission on azathioprine monotherapy. We included patients from the "TISKids" study assigned to the conventional treatment arm. Patients were aged 3-17 years and had new-onset, untreated luminal CD with weighted paediatric CD activity index (wPCDAI) > 40. Induction treatment consisted of EEN or oral corticosteroids; all received azathioprine maintenance treatment from start of treatment. The primary outcome of this study was endoscopic remission defined as a SES-CD score < 3 without treatment escalation at week 10. Secondary outcomes included proportion of patients without treatment escalation at week 52. In total, 27/47 patients received EEN and 20/47 corticosteroids. At baseline, patient demographics and several inflammation parameters were similar between the two treatment groups. At 10 weeks, clinical remission rates were 7/23 (30%) for EEN and 7/19 (37%) for corticosteroids (p = 0.661). Twenty-nine of 47 consented to endoscopy at 10 weeks, showing endoscopic remission rates without treatment escalation in 2/16 (13%) of EEN-treated patients and in 1/13 (8%) of corticosteroid-treated patients (p = 1.00). At week 52, 23/27 (85%) EEN-treated patients received treatment escalation (median 14 weeks) and 13/20 (65%) corticosteroid-treated patients (median 27 weeks), p = 0.070.Conclusion: In children with moderate-to-severe newly diagnosed CD, induction treatment with EEN or CS regularly is insufficient to achieve endoscopic remission without treatment escalation at week 10. Trial registration number: NCT02517684 What is Known: • Endoscopic remission is associated with a low risk of disease progression. • FL-IFX was superior to conventional treatment in achieving and maintaining remission in paediatric patients with moderate-to-severe CD the first year from diagnosis. What is New: • In children with newly diagnosed moderate-to-severe CD, clinical remission rates and endoscopic remission rates without treatment escalation at week 10 were 30% and 13% after EEN and 37% and 8% after corticosteroid induction treatment. • The current treatment target was often not achieved by either EEN or corticosteroid induction treatment after bridging to azathioprine.

Rotterdam Transition Test: A Valid Tool for Monitoring Disease Knowledge in Adolescents With Inflammatory Bowel Disease.

OBJECTIVES: Disease knowledge is important in adolescents with inflammatory bowel disease (IBD) transitioning to adult care. We developed an IBD-specific knowledge questionnaire, the Rotterdam Transition Test (RTT), and aimed to validate this tool. METHODS: This is a prospective longitudinal validation study. The RTT has 25 open questions on IBD, medication, lifestyle, and transition to adult care. A scoring model was developed, and inter-rater agreement was assessed. Using a Rasch model, we determined the difficulty and performance of the questions. Cronbach alpha was used to demonstrate reliability. Patient factors (age, disease, education, medication use, illness acceptance, and independence) were correlated to RTT score. RESULTS: A total of 207 RTTs were evaluated in 111 adolescent IBD patients. The scoring model showed a kappa score of >0.61 for all questions. Reliability with Cronbach alpha was good (0.81). Mean total result of the RTT was 58% (girls) and 55% (boys) of maximal score.The RTT discriminated well between the different levels of knowledge. Knowledge scores increased in patients who did repeated RTTs during the transition period. Male sex, low educational level, disease acceptance issues, and dependence on parents associated with a significantly lower total RTT score. Prednisone use within 3 months and treatment without biologics associated with significantly higher RTT scores. Disease activity was not a significant factor. CONCLUSIONS: The RTT is a reliable and valid tool to assess IBD knowledge. The RTT can be used to detect and discuss knowledge gaps in adolescents with IBD transitioning to adult healthcare.

First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: an open-label multicentre randomised controlled trial.

OBJECTIVE: In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment. DESIGN: In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis. RESULTS: 100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004). CONCLUSIONS: FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02517684).

Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis.

Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.

Study Protocol of the Exercise Study: Unraveling Limitations for Physical Activity in Children With Chronic Diseases in Order to Target Them With Tailored Interventions-A Randomized Cross Over Trial.

Introduction: Physical activity is associated with many physiological and psychological health benefits across the lifespan. Children with a chronic disease often have lower levels of daily physical activity, and a decreased exercise capacity compared to healthy peers. In order to learn more about limitations for physical activity, we investigate children with four different chronic diseases: children with a Fontan circulation, children with Broncho Pulmonary Dysplasia (BPD), Pompe disease and inflammatory bowel disease (IBD). Each of these diseases is likely to interfere with physical activity in a different way. Knowing the specific limitations for physical activity would make it possible to target these, and increase physical activity by a personalized intervention. The aim of this study is to first investigate limitations for physical activity in children with various chronic diseases. Secondly, to measure the effects of a tailored exercise intervention, possibly including a personalized dietary advice and/or psychological counseling, on exercise capacity, endurance, quality of life, fatigue, fear for exercise, safety, muscle strength, physical activity levels, energy balance, and body composition. Methods and Analysis: This randomized crossover trial will aim to include 72 children, aged 6-18 years, with one of the following diagnosis: a Fontan circulation, BPD, Pompe disease and IBD. Eligible patients will participate in the 12-week tailored exercise intervention and are either randomized to start with a control period or start with the intervention. The tailored 12-week exercise interventions, possibly including a personalized dietary advice and/or psychological counseling, will be designed based on the found limitations for physical activity in each disease group during baseline measurements by the Rotterdam Exercise Team. Effects of the tailored training interventions will be measured on the following endpoints: exercise capacity (measured by cardiopulmonary exercise test), endurance, physical activity levels, muscle strength, quality of life, fatigue, fear for exercise, disease activity, cardiac function (in children with a Fontan circulation), energy balance, and body composition. Ethics and Dissemination: Conducted according to the Declaration of Helsinki and Good Clinical Practice. Medical-ethical approval was obtained. Trial Registration Number: NL8181, https://www.trialregister.nl/trial/8181.

Health outcomes of 1000 children born to mothers with inflammatory bowel disease in their first 5 years of life.

OBJECTIVE: The aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes. DESIGN: We performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies. RESULTS: We included 1000 children born to 626 mothers (381 (61%) Crohn's disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population. CONCLUSION: In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies.

The Medical Management of Paediatric Crohn's Disease: an ECCO-ESPGHAN Guideline Update.

OBJECTIVE: We aimed to provide an evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn's disease [CD]. METHODS: We formed 10 working groups and formulated 17 PICO-structured clinical questions [Patients, Intervention, Comparator, and Outcome]. A systematic literature search from January 1, 1991 to March 19, 2019 was conducted by a medical librarian using MEDLINE, EMBASE, and Cochrane Central databases. A shortlist of 30 provisional statements were further refined during a consensus meeting in Barcelona in October 2019 and subjected to a vote. In total 22 statements reached ≥ 80% agreement and were retained. RESULTS: We established that it was key to identify patients at high risk of a complicated disease course at the earliest opportunity, to reduce bowel damage. Patients with perianal disease, stricturing or penetrating behaviour, or severe growth retardation should be considered for up-front anti-tumour necrosis factor [TNF] agents in combination with an immunomodulator. Therapeutic drug monitoring to guide treatment changes is recommended over empirically escalating anti-TNF dose or switching therapies. Patients with low-risk luminal CD should be induced with exclusive enteral nutrition [EEN], or with corticosteroids when EEN is not an option, and require immunomodulator-based maintenance therapy. Favourable outcomes rely on close monitoring of treatment response, with timely adjustments in therapy when treatment targets are not met. Serial faecal calprotectin measurements or small bowel imaging [ultrasound or magnetic resonance enterography] are more reliable markers of treatment response than clinical scores alone. CONCLUSIONS: We present state-of-the-art guidance on the medical treatment and long-term management of children and adolescents with CD.

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 pediatric-onset 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 conducted to analyze factors that influence trough levels. 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 29.9 µg/mL (SD 17.8), and 11.5 µg/mL (SD 4.9) during maintenance therapy. CD patients had significantly lower trough levels than IBD-U patients (ß 15.2; 95% confidence interval [CI] -1.1 to 29.2; P = 0.036). Higher fecal calprotectin (ß -0.009; 95% CI -0.02 to -0.003; P = 0.007) and C-reactive protein levels (ß -0.4; 95% CI -0.72 to -0.04; P = 0.027) were associated with lower trough levels, whereas shortening of time between infusions led to higher trough levels (ß -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-U patients. Higher levels of inflammatory markers were associated with lower vedolizumab trough levels.

Appraisal of the PIBD-classes Criteria: A Multicentre Validation.

INTRODUCTION: The PIBD-classes criteria were developed to standardise the classification of children with inflammatory bowel disease [IBD], from Crohn's disease [CD], through IBD-unclassified [IBD-U], to typical ulcerative colitis [UC]. We aimed to further validate the criteria and to explore possible modifications. METHODS: This was a multicentre retrospective cohort study of children diagnosed with IBD with at least 1 year of follow-up. Clinical, radiological, endoscopic, and histological data were recorded at diagnosis and latest follow-up, as well as the 23 items of the PIBD-classes criteria. The PIBD-classes criteria were assessed for redundant items, and a simplified algorithm was proposed and validated on the original derivation cohort from which the PIBD-classes algorithm was derived. RESULTS: Of the 184 included children [age at diagnosis 13 ± 3 years, 55% males], 122 [66%] were diagnosed by the physician with CD, 17 [9%] with IBD-U, and 45 [25%] with UC. There was high agreement between physician-assigned and PIBD-classes generated diagnosis for CD [93%; eight patients moved to IBD-U] and for UC [84%; six moved to IBD-U and one to CD]. A simplified version of the algorithm with only 19 items is suggested, with comparable performance to the original algorithm [81% sensitivity and 81% specificity vs 78% and 83% for UC; and 79% and 95% vs 80% and 95% for CD, respectively]. CONCLUSIONS: The PIBD-classes algorithm is a useful tool to facilitate standardised objective classification of IBD subtypes in children. A modified version of the PIBD-classes maintains accuracy of classification with a simplified algorithm.

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 is often not adequate. While clinical trials have focused on safety and efficacy, there is limited data on pharmacokinetic characteristics and immunogenicity of IFX in children. The objective was to provide a systematic overview of current literature on pharmacokinetic and immunogenicity of IFX in children with IBD, to assess the validity of current adult to pediatric dosing extrapolation. METHODS: A literature search identified publications up to October 2018. Eligibility criteria were study population consisting of children and/or adolescents with IBD, report of IFX trough levels and/or antibodies-to IFX, full text article or abstract, article in English, and original data. RESULTS: Initial electronic search yielded 2360 potentially relevant articles, with 1831 remaining after removal of duplicates. An additional search yielded another 202 potentially relevant articles. Of the 2033 retrieved articles, 2000 articles were excluded based on title, abstract, or eligibility criteria. Clearance of IFX was increased in young children and children with extensive disease, leading to lower trough levels after extrapolated dosing of 5 mg/kg, antibodies-to IFX emergence, and subsequent reduced efficacy. CONCLUSIONS: Adult to pediatric weight-based dosing extrapolation is often inadequate. We provide several considerations for optimal dosing of IFX in children and adolescents with IBD.

Value of an outpatient transition clinic for young people with inflammatory bowel disease: a mixed-methods evaluation.

OBJECTIVE: Developing and evaluating effective transition interventions for young people (16-25 years) with inflammatory bowel disease (IBD) is a high priority. While transition clinics (TCs) have been recommended, little is known about their operating structures and outcomes. This study aimed to gain insight into the value of a TC compared with direct handover care. DESIGN: Controlled mixed-methods evaluation of process outcomes, clinical outcomes and patient-reported outcomes. SETTING: Two outpatient IBD clinics in the Netherlands. PARTICIPANTS: Data collection included: semistructured interviews with professionals (n=8), observations during consultations with young people (5×4 hours), medical chart reviews of patients transferred 2 to 4 years prior to data collection (n=56 in TC group; n=54 in control group) and patient questionnaires (n=14 in TC group; n=19 in control group). OUTCOMES: Data were collected on service structures and daily routines of the TC, experienced barriers, facilitators and benefits, healthcare use, clinical outcomes, self-management outcomes and experiences and satisfaction of young people with IBD. RESULTS: At the TC, multidisciplinary team meetings and alignment of care between paediatric and adult care providers were standard practice. Non-medical topics received more attention during consultations with young people at the TC. Barriers experienced by professionals were time restrictions, planning difficulties, limited involvement of adult care providers and insufficient financial coverage. Facilitators experienced were high professional motivation and a high case load. Over the year before transfer, young people at the TC had more planned consultations (p=0.015, Cohen's d=0.47). They showed a positive trend in better transfer experiences and more satisfaction. Those in direct handover care more often experienced a relapse before transfer (p=0.003) and had more missed consultations (p=0.034, Cohen's d=-0.43) after transfer. CONCLUSION: A TC offer opportunities to improve transitional care, but organisational and financial barriers need to be addressed before guidelines and consensus statements in healthcare policy and daily practice can be effectively implemented.