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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.

ObjectiveIn 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.DesignIn 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 Results100 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).ConclusionsFL-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 numberClinicalTrials.gov Registry (NCT02517684).

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.

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's 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's alpha was good (0.81). Mean total result of the RTT was 58% (females) and 55% (males) 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 three months and treatment without biologics associated with significantly higher RTT scores. Disease activity was not a significant factor. CONCLUSION The Rotterdam Transition Test 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. An infographic is available for this article at:http://links.lww.com/MPG/C472.

Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic—intestinal and retinal—disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

ObjectiveWe aimed to provide an evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn’s disease [CD].MethodsWe 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.ResultsWe 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.ConclusionsWe present state-of-the-art guidance on the medical treatment and long-term management of children and adolescents with CD.

Contains fulltext : 220523.pdf (Publisher’s version ) (Closed access) 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.

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.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.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 (β 15.2; 95% confidence interval [CI] -1.1 to 29.2; P = 0.036). Higher fecal calprotectin (β -0.009; 95% CI -0.02 to -0.003; P = 0.007) and C-reactive protein levels (β -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 (β -0.77; 95% CI -0.9 to 0.64; P 0.001).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.

IntroductionThe 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.MethodsThis 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.ResultsOf 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].ConclusionsThe 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.

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.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.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-score0.8 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).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.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.

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.

This randomized trial studied the effect of cognitive behavioral therapy (CBT) for the treatment of subclinical anxiety and/or depression on disease course in young IBD patients. CBT did not influence time to relapse, clinical disease activity, C-reactive protein or calprotectin levels., Background Anxiety and depressive symptoms are prevalent in patients with inflammatory bowel disease (IBD) and may negatively influence disease course. Disease activity could be affected positively by treatment of psychological symptoms. We investigated the effect of cognitive behavioral therapy (CBT) on clinical disease course in 10–25-year-old IBD patients experiencing subclinical anxiety and/or depression. Methods In this multicenter parallel group randomized controlled trial, IBD patients were randomized to disease-specific CBT in addition to standard medical care (CBT + care us usual [CAU]) or CAU only. The primary outcome was time to first relapse in the first 12 months. Secondary outcomes were clinical disease activity, fecal calprotectin, and C-reactive protein (CRP). Survival analyses and linear mixed models were performed to compare groups. Results Seventy patients were randomized (CBT+CAU = 37, CAU = 33), with a mean age of 18.3 years (±50% < 18 y, 31.4% male, 51.4% Crohn’s disease, 93% in remission). Time to first relapse did not differ between patients in the CBT+CAU group vs the CAU group (n = 65, P = 0.915). Furthermore, clinical disease activity, fecal calprotectin, and CRP did not significantly change over time between/within both groups. Exploratory analyses in 10–18-year-old patients showed a 9% increase per month of fecal calprotectin and a 7% increase per month of serum CRP in the CAU group, which was not seen in the CAU+CBT group. Conclusions CBT did not influence time to relapse in young IBD patients with subclinical anxiety and/or depression. However, exploratory analyses may suggest a beneficial effect of CBT on inflammatory markers in children.

ObjectiveCrohn’s disease (CD) pathogenesis associated with dysbiosis and presence of pathobionts in the lumen, intracellular compartments and epithelial biofilms. Azithromycin is active in all three compartments. Our goal was to evaluate if azithromycin-based therapy can improve response and induce remission compared with metronidazole alone in paediatric CD.DesignThis blinded randomised controlled trial allocated children 5–18 years with 1012.5 or remission using intention to treat analysis.Results73 patients (mean age 13.8±3.1 years) were enrolled, 35 to group 1 and 38 to group 2. Response and remission rates at week 8 were identical 23/35 (66%) in group 1 and 17/38 (45%) and 15/38 (39%) in group 2 (P=0.07 and P=0.025, respectively). The needed to treat for remission was 3.7. Faecal calprotectin declined significantly in group 1 (P=0.003) but not in group 2 (p=0.33), and was lower at week 8 (P=0.052). Additional therapy was required in 6/35(17%) from group 1 versus 16/38(42%) in group 2 (P=0.027) by week 8. Among 12 failures in group 2, open-label azithromycin led to remission in 10/12 (83%).ConclusionsThe combination of azithromycin and metronidazole failed to improve response but was superior for induction of remission and reduction in calprotectin.Trial registration numberNCT01596894.

Uncontrolled interferon γ (IFNγ)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFNγ-secreting CD4+ T cells. Deficiency in IL-10 signaling dramatically increased IL-1β release by moDCs. IL-1β boosted IFNγ secretion by CD4+ T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1β expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFNγ-secreting CD4+ T cells in humans and identifies IL-1β as a potential classifier for a subgroup of IBD patients.

Background Transition programmes are designed to prepare adolescent inflammatory bowel disease [IBD] patients for transfer to adult care. It is still unclear which outcome parameters define ‘successful transition’. Therefore, this study aimed to identify outcomes important for success of transition in IBD. Methods A multinational Delphi study in patients, IBD nurses, and paediatric and adult gastroenterologists was conducted. In stage 1, panellists commented on an outcome list. In stage 2, the refined list was graded from 1 to 9 [least to very important], by an expert and a patient panel. In stage 3, the expert panel ranked important outcomes from 1 to 10 [least to most important]. Descriptive statistics and Mann–Whitney U-tests were performed. Results The final item list developed in stage 1 was tested by the expert [n = 74 participants, 52.7% paediatric] and patient panel [n = 61, aged 16–25 years, 49.2% male]. Respectively, ten and 11 items were found to be important by the expert and patient panel. Both panels agreed on eight of these items, of which six reflected self-management skills. In stage 3, the expert panel formed a top-ten list. The three most important items were: decision-making regarding IBD [mean score 6.7], independent communication [mean score 6.3] and patient satisfaction [mean score 5.8]. Conclusion This is the first study identifying outcomes that IBD healthcare providers and patients deem important factors for successful transition. Self-management skills were considered more important than IBD-specific items. This is a first step to further define success of transition in IBD and subsequently evaluate the efficacy of different transition models.

Breach of tolerance to gluten leads to the chronic small intestinal enteropathy celiac disease. A key event in celiac disease development is gluten-dependent infiltration of activated cytotoxic intraepithelial lymphocytes (IELs), which cytolyze epithelial cells causing crypt hyperplasia and villous atrophy. The mechanisms leading to gluten-dependent small intestinal IEL infiltration and activation remain elusive. We have demonstrated that under homeostatic conditions in mice, gluten drives the differentiation of anti-inflammatory T cells producing large amounts of the immunosuppressive cytokine interleukin-10 (IL-10). Here we addressed whether this dominant IL-10 axis prevents gluten-dependent infiltration of activated cytotoxic IEL and subsequent small intestinal enteropathy. We demonstrate that IL-10 regulation prevents gluten-induced cytotoxic inflammatory IEL infiltration. In particular, IL-10 suppresses gluten-induced accumulation of a specialized population of cytotoxic CD4+CD8αα+ IEL (CD4+ CTL) expressing Tbx21, Ifng, and Il21, and a disparate non-cytolytic CD4+CD8α− IEL population expressing Il17a, Il21, and Il10. Concomitantly, IL-10 suppresses gluten-dependent small intestinal epithelial hyperproliferation and upregulation of stress-induced molecules on epithelial cells. Remarkably, frequencies of granzyme B+CD4+CD8α+ IEL are increased in pediatric celiac disease patient biopsies. These findings demonstrate that IL-10 is pivotal to prevent gluten-induced small intestinal inflammation and epithelial damage, and imply that CD4+ CTL are potential new players into these processes.

IntroductionCoeliac disease (CD) occurs in 1% of the population, develops early in life and is severely underdiagnosed. Undiagnosed and untreated disease is associated with short- and long-term complications. Treatment with a gluten-free diet results in health improvement. The current health care approach is unable to solve the underdiagnosis of CD and timely diagnosis and treatment is only achieved by active case finding. Aim of this study is to perform a novel case-finding project to detect CD in 12 months-4 years old symptomatic children who visit the YHCCs in a well-described region in the Netherlands to show that it is feasible, cost-effective and well accepted by the population.Methods/analysisProspective intervention cohort study. Parents of all children aged 12 months-4 years attending the Youth Health Care Centres (YHCCs) for a regular visit are asked if their child has one or more CD-related symptoms from a standardized list. If so, they will be invited to participate in the case-finding study. After informed consent, a point of care test (POC) to assess CD-specific antibodies against tissue-transglutaminase (TG2A) from a droplet of blood, is performed onsite at the YHCCs. If the POC test is positive, CD is highly suspected and the child will be referred to hospital for definitive diagnosis according to the ESPGHAN guideline.Main outcomes: 1. incidence rate of new CD diagnoses in the study region Kennemerland in comparison to the rest of the Netherlands.2. Feasibility and cost-effectiveness of active case-finding for CD in the YHCCs. All costs of active case finding, diagnostics and treatment of CD and the potential short and long term consequences of the disease will be calculated for the setting with and without case finding.3. Ethical acceptability: by questionnaires on parental and health care professionals satisfaction. A statistical analysis plan (SAP) has been written and will be published on the GLUTENSCREEN website.Ethics and disseminationThe Medical Ethics Committee Leiden approved this study. If we prove that active case finding in the YHCC is feasible, efficient, cost-effective and well accepted by the population, implementation is recommended.Trial registration numberNL63291.058.17What is already known on this topic?Despite recommendation on ‘who should be tested for CD’ in guidelines, the diagnosis of CD remains severely underdiagnosed.Untreated CD has a considerable health burden for society.Studies have shown that an active case-finding strategy in adults is an effective means to improve the frequency of CD diagnosis.What this study hopes to add?Effectiveness and feasibility of active-case finding as secondary prevention strategy in the diagnosis of childhood CD in the primary care setting in the NetherlandsThis study will provide important information about the cost-effectiveness and acceptability of the general Dutch population concerning active case-finding

IntroductionCoeliac disease (CD) occurs in 1% of the population, develops early in life and is severely underdiagnosed. Undiagnosed and untreated disease is associated with short-term and long-term complications. The current healthcare approach is unable to solve the underdiagnosis of CD and timely diagnosis and treatment is only achieved by active case finding. Aim: to perform a case finding project to detect CD children who visit the Youth Health Care Centres (YHCCs) in a well-described region in the Netherlands to evaluate whether it is feasible, cost-effective and well accepted by the population.Methods/analysisProspective intervention cohort study. Parents of all children aged 12 months and 4 years attending the YHCCs for a regular visit are asked whether their child has one or more CD-related symptoms from a standardised list. If so, they will be invited to participate in the case finding study. After informed consent, a point of care test (POCT) to assess CD-specific antibodies against tissue transglutaminase (TG2A) is performed onsite the YHCCs. If the POCT is positive, CD is highly suspected and the child will be referred to hospital for definitive diagnosis according to the Guideline Coeliac Disease of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition guideline.Main outcomesIncidence rate of new CD diagnoses in the study region in comparison to the one in the same age diagnosed by standard of care in the rest of the Netherlands.Feasibility and cost-effectiveness of active CD case finding at the YHCCs. All costs of active case finding, diagnostics and treatment of CD and the potential short-term and long-term consequences of the disease will be calculated for the setting with and without case finding.Ethical acceptability: by questionnaires on parental and healthcare professionals’ satisfaction.A statistical analysis plan was prepared and is published on the GLUTENSCREEN website (Statistical-Analysis-Plan-11-5-2021_def.pdf (glutenscreen.nl) and added as annex 1).Ethics and disseminationThe Medical Ethics Committee Leiden approved this study. If we prove that case finding at the YHCC is feasible, cost-effective and well accepted by the population, implementation is recommended.Trial registration numberNL63291.058.17.

Youth with inflammatory bowel disease (IBD) often experience psychological difficulties, such as anxiety and depression. This randomized controlled study tested whether a 3-month disease-specific cognitive behavioral therapy (CBT) in addition to standard medical care versus standard medical care only was effective in improving these youth’s psychological outcomes. As this study was aimed at prevention, we included 70 youth (10–25 years) with IBD and symptoms of subclinical anxiety and/or depression, and measured psychological outcomes at 6- and 12-month follow-up. In general, participants in both groups showed improvements in anxiety, depression, health-related quality of life, social functioning, coping, and illness perceptions, sustained until 12 months follow-up. Overall, we found no differences between those receiving additional CBT and those receiving standard medical care only. We assume that this can be explained by the perceived low burden (both somatically and psychologically) or heightened awareness of psychological difficulties and IBD. ClinicalTrials.gov NCT02265588.

ObjectiveDeveloping 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.DesignControlled mixed-methods evaluation of process outcomes, clinical outcomes and patient-reported outcomes.SettingTwo outpatient IBD clinics in the Netherlands.ParticipantsData 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).OutcomesData 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.ResultsAt 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.ConclusionA 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.

We evaluated the effect of the 2012 The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guideline and the diagnostic algorithm on coeliac disease diagnosis in children in the South West region of the Netherlands. All children who were evaluated for coeliac disease between 1 January 2012 (implementation date of the guideline1) and 1 January 2014 were included in this retrospective evaluation. Patients were diagnostic tested in seven general hospitals and in one university hospital. A total of 253 …

Background Youths with inflammatory bowel disease (IBD) are at risk for developing anxiety and depressive symptoms with a reported 20%-50% prevalence rate. Aims This prospective study aimed to: (1) describe the prevalence and severity of anxiety and depressive symptoms in a large Dutch cohort of young IBD patients, and (2) identify demographic and clinical risk factors for anxiety and depression. Methods IBD patients (n = 374; 10-25 years) were screened for anxiety, depression and quality of life using validated age-specific questionnaires. Patients with elevated scores for anxiety and/or depressive symptoms received a diagnostic interview assessing psychiatric disorders. Demographic and clinical characteristics were retrieved from medical charts. Multiple logistic regression analysis was performed to identify risk factors for anxiety and/or depression. Results Patients (mean age 18.9 years, 44.1% male, Crohn's disease 60.4%) had disease in remission (75.4%), or mild, moderate and severe clinical disease activity in, respectively, 19.8%, 2.7% and 2.1%. Mild anxiety/depressive symptoms were present in 35.2% and severe symptoms in 12.4% of patients. Elevated symptoms of either anxiety (28.3%), depression (2.9%) or both (15.8%) were found and did not differ between adolescents (10-17 years) and young adults (18-25 years). Active disease significantly predicted depressive symptoms (odds ratio (OR): 4.6 [95% confidence interval [CI]: 2.4-8.8], P < 0.001). Female gender (OR: 1.7 [95% CI: 1.1-2.7]), active disease (OR: 1.9 [95% CI: 1.1-3.2]) and a shorter disease duration (OR: 1.3 [95% CI: 0.6-1.0) (all P < 0.025) significantly predicted anxiety and/or depressive symptoms. ConclusionsConsidering the high prevalence of anxiety and depressive symptoms, psychological screening is recommended in young IBD patients. Screening facilitates early recognition and psychological treatment. Female patients and patients with active disease are the most vulnerable.

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.

Supplemental Digital Content is available in the text., Objective— Endothelial cells store VWF (von Willebrand factor) in rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs). WPB exocytosis is coordinated by a complex network of Rab GTPases, Rab effectors, and SNARE (soluble NSF attachment protein receptor) proteins. We have previously identified STXBP1 as the link between the Rab27A-Slp4-a complex on WPBs and the SNARE proteins syntaxin-2 and -3. In this study, we investigate the function of syntaxin-3 in VWF secretion. Approach and Results— In human umbilical vein endothelial cells and in blood outgrowth endothelial cells (BOECs) from healthy controls, endogenous syntaxin-3 immunolocalized to WPBs. A detailed analysis of BOECs isolated from a patient with variant microvillus inclusion disease, carrying a homozygous mutation in STX3(STX3−/−), showed a loss of syntaxin-3 protein and absence of WPB-associated syntaxin-3 immunoreactivity. Ultrastructural analysis revealed no detectable differences in morphology or prevalence of immature or mature WPBs in control versus STX3−/− BOECs. VWF multimer analysis showed normal patterns in plasma of the microvillus inclusion disease patient, and media from STX3−/− BOECs, together indicating WPB formation and maturation are unaffected by absence of syntaxin-3. However, a defect in basal as well as Ca2+- and cAMP-mediated VWF secretion was found in the STX3−/− BOECs. We also show that syntaxin-3 interacts with the WPB-associated SNARE protein VAMP8 (vesicle-associated membrane protein-8). Conclusions— Our data reveal syntaxin-3 as a novel WPB-associated SNARE protein that controls WPB exocytosis.

textabstractBackground: Propofol is often used for procedural sedation in children undergoing gastrointestinal endoscopy. Reliable assessment of the depth of hypnosis during the endoscopic procedure is challenging. Processed electroencephalography using the Narcotrend Index can help titrating propofol to a predefined sedation level. Aims: The aim of this trial was to investigate the impact of Narcotrend Index-guided titration of propofol delivery on the speed of recovery. Methods: Children, aged 12-17 years, undergoing gastrointestinal endoscopy under procedural sedation, had propofol delivered via target controlled infusion either based on Narcotrend Index guidance (group NI) or standard clinical parameters (group C). Sedation was augmented with remifentanil in both study groups. The primary endpoint of this study was to compare the speed of fulfilling discharge criteria from the operating room between study groups. Major secondary endpoints were propofol consumption, discharge readiness from the recovery room, hypnotic depth as measured by the Narcotrend Index, and adverse events. Results: Of the 40 children included, data were obtainable from 37. The time until discharge readiness from the operating room was shorter in group NI than in group C, with a difference between medians of 4.76 minutes [95%CI 2.6 to 7.4 minutes]. The same accounts for recovery room discharge times; difference between medians 4.03 minutes [95%CI 0.81 to 7.61 minutes]. Propofol consumption and the percentage of EEG traces indicating oversedation were higher in group C than in group NI. There were no significant adverse events in either study group. Conclusion: Narcotrend Index guidance of propofol delivery for deep sedation in children aged 12-17 years, underdoing gastrointestinal endoscopy results in faster recovery, less drug consumption, and fewer episodes of oversedation than dosing propofol according to clinical surrogate parameters of depth of hypnosis. The results of this study provide additional evidence in favor of the safety profile of propofol/remifentanil for procedural sedation in adequately selected pediatric patients.

Introduction Neonates exposed to tumour necrosis factor [TNF] alpha inhibitors in utero are born with detectable drug levels which can still be detected throughout the first year of life. Since 2011, the hepatitis B virus [HBV] vaccine is routinely administered to all newborns in the Netherlands. Adults treated with anti-TNF have been reported to respond inadequately to the HBV vaccine. The aim of this study was to compare anti-HB levels in anti-TNF-exposed children with non-exposed children following routine Dutch HBV vaccination. Methods We performed a cross-sectional, controlled cohort study from 2014 to 2017 in a single, tertiary referral centre. Pregnant women treated with anti-TNF for inflammatory bowel disease [IBD] and their subsequent children were recruited from the IBD preconception outpatient clinic. Pregnant women not treated with anti-TNF for IBD and their subsequent children were eligible as controls. Adherence to the Dutch National Vaccination Programme was mandatory for participation in this study. A venous blood sample was obtained 1 month after final HBV vaccination. Anti-HB levels were measured by enzyme-linked immunosorbent assay. Results Anti-HB levels at 12 months did not differ between the anti-TNF-exposed [n = 15] and the control group [n = 12] [> 1000 IU/l vs > 1000 IU/l, p = 0.59]. All children were successfully immunized against HBV, defined as anti-HB > 10 IU/l. Median anti-TNF levels determined in cord blood at birth were 9.0 µg/ml [interquartile range: 3.0-15.0 µg/ml] for infliximab and 0.4. µg/ml [interquartile range: 0.3-0.6 µg/ml] for adalimumab. There were no differences in general birth and health outcomes. Conclusion Children born with detectable anti-TNF levels can be effectively vaccinated against HBV.

Background Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Recently, physical activity has been suggested to improve the quality of life and course of disease in adult IBD patients. The aim of this study was to investigate physical functioning in paediatric IBD patients and to determine the effects of a tailored 12-week lifestyle intervention including a physical training program. Methods Figure 1 shows our study design and measurements. The tailored 12-week lifestyle intervention consisted of 3 strenuous physical training sessions a week and dietary advice. Effects on exercise capacity, endurance, physical activity levels, disease activity, quality of life, and fatigue were measured in paediatric IBD patients. Mild disease activity was defined as a PCDAI between 10 - 27.5 or PUCAI between 10 - 34. Results Sixteen paediatric IBD patients (median age 15 [9 - 17]) were included, 13 patients successfully completed the training program, 2 patients are still participating. At baseline, most patients had mild disease activity (n=9). Patients had reduced exercise capacity (76.8%±17.7% of predicted PeakVO2 , and reduced physical activity levels as shown by 80.3%±7.4% of measured time being spent in sedentary activity. PCDAI/PUCAI scores decreased significantly over the intervention period (13.8±11.7 vs. 3.65±4.5, P=0.002). Fecal calprotectin also decreased significantly (400 [18–3089] vs. 128 [20–2704], P=0.041). All patients but one had no changes in medical regimens before or during the lifestyle intervention that could have influenced disease activity. After the 12-week lifestyle intervention period, 9 out of 13 patients were in clinical remission. Maximum walked distance increased significantly (503±69 vs. 540±77 meters, P=0.001), although PeakVO2 and percentage of time spent in moderate-to-vigorous activity did not. Patients improved on overall quality of life measured by the Impact III questionnaire (+2.4 points, p=0.017). The Child Health Questionnaire showed a significant improvement on the child-reported physical functioning scale and on 5 parent-reported scales of quality of life. Child-reported fatigue measured by the PedsQol MFS did not improve significantly, parents-reported fatigue did. No changes were found on mentioned outcomes during the control period. After baseline measurements, the COVID-19 lock-down period started, possibly affecting normal daytime activities of the patients during the lifestyle intervention period. Conclusion A 12-week tailored physical training program including dietry advice is safe and beneficial for paediatric IBD patients and may contribute to better control of inflammation.

Background In children and teenagers with Inflammatory Bowel Disease (IBD) and iron deficiency anaemia, administration of iron is recommended to replete empty iron stores, but the most effective route of administration remains unknown. We compared intravenous (IV) and oral iron therapy and evaluated physical fitness and haemoglobin (Hb) improvement over time. Methods We performed an international multicentre randomized controlled trial (NTR: 4487) in patients aged 8-18 years with IBD and anaemia (defined as Hb > 2 standard deviations (SD) below the reference mean according to WHO cut-offs). Children with severely active disease (PUCAI ≥ 65 or PCDAI ≥ 30) at baseline were excluded. Patients were randomly assigned to receive either IV iron via a single infusion of ferric carboxymaltose (15 mg/kg, maximum 750 mg) or oral iron using ferrous fumarate 9 mg/kg/day in 2 doses (maximum 600 mg) for 12 weeks. The primary outcome was improvement of physical fitness, defined as an increase in 6-minute walking distance (6MWD) over time and expressed as z-score to allow correction for age and gender. Secondary outcome was an increase in Hb z-score. Linear mixed models were used to analyse effect of treatment on 6MWD and Hb z-score at each follow-up visit controlling for disease activity, IBD diagnosis, study centre and outcome at baseline. Results We randomised 64 patients (33 IV iron; 31 oral iron). One month after the start of iron therapy, increase of 6MWD z-scores was significantly larger in the IV group compared to the oral group (0.75 SD vs. -0.16 SD, P=0.006, Figure 1). At 3- and 6-months follow-up, no significant differences in 6MWD z-scores were observed between groups. Hb z-scores gradually increased over time in both groups, but there was no significant difference in change from baseline between groups at 1, 3 and 6 months after initiation of iron therapy (overall P=0.97, Figure 2). Figure 1: Mean 6-minute walking distance (6MWD) z-scores in relation to start of iron treatment Figure 2: Mean haemoglobin (Hb) z-scores in relation to start of iron treatment Conclusion In this head-to-head randomized controlled trial involving paediatric patients with IBD and anaemia, IV iron was superior to oral iron with respect to early improvement of physical fitness. However, this effect subsided over time and improvement of Hb was similar for both types of iron therapy.

Background Recently, we established that First-line infliximab (FL-IFX) was superior to conventional treatment (CONV) in achieving and maintaining clinical remission in newly diagnosed paediatric patients with moderate-to-severe Crohn’s disease (CD) (PMID: 33384335). Selection of patients eligible for FL-IFX can be corroborated by combining clinical criteria with immunological biomarkers relating to the patients’ underlying immunopathology. Therefore, we investigated differential effects of FL-IFX and CONV induction treatment on serum inflammatory protein concentrations and assessed whether stratification of CD patients according to baseline serum profiles of IFX-modulated proteins relates to maintaining remission at week 52. Methods In the TISKIDS randomised controlled trial, newly diagnosed therapy-naïve CD patients with a weighted paediatric CD activity index (wPCDAI) >40 were included. FL-IFX consisted of 5 IFX infusions (5 mg/kg) combined with azathioprine (AZA) maintenance treatment. CONV treatment consisted of induction therapy with Exclusive Enteral Nutrition or oral prednisolone combined with AZA maintenance. Serum samples of 48 FL-IFX and 43 CONV patients, collected at time of diagnosis and after 10–14 weeks of induction treatment, were available. Concentrations of 92 inflammatory proteins were determined with Olink Proteomics® proximity extension technology. Hierarchical clustering was performed to stratify patients according to their serum immune profiles. Clinical disease remission was defined as wPCDAI Results At baseline, prior to therapy, clinical disease characteristics and serum inflammatory protein concentrations did not significantly differ between FL-IFX and CONV treated patients. After 10–14 weeks, FL-IFX reduced 28 proteins and enhanced 2 proteins while CONV treatment reduced 13 proteins and enhanced 1 protein. Eighteen proteins were differentially regulated by FL-IFX only. Hierarchical clustering of patients based on their baseline profiles of the 30 IFX-modulated proteins revealed 2 patient clusters. The CD-hi cluster had an increased abundance of 24/30 proteins amongst which Oncostatin-M, TNFSF14, HGF and TGF-alpha and higher clinical inflammatory parameters compared to the CD-lo cluster. Crucially, both baseline inflammatory protein profile and type of induction therapy significantly determined whether patients reached clinical disease remission without treatment escalation at week 52; with CD-hi patients having the lowest change. Conclusion FL-IFX achieves stronger reduction and modulates more proteins than CONV treatment. Stratification of patients according to profiles of IFX-modulated proteins discerns patients with a lower chance of reaching clinical remission without treatment escalation at week 52.

Background. Faecal calprotectin is considered to be a valid test for ruling out inflammatory bowel disease (IBD) in children with chronic gastrointestinal symptoms in specialist care. In contrast, faecal lactoferrin has higher specificity. The recent availability of both as point-of-care tests (POCTs) makes them attractive for use in primary care.Objective. To evaluate the test characteristics of calprotectin and lactoferrin POCTs for diagnosing IBD in symptomatic children.Methods. We defined two prospective cohorts of children with chronic gastrointestinal symptoms: (i) children presenting to primary care (primary care cohort); (ii) children referred for specialist care (referred cohort). Baseline POCT results were compared with the outcome of either endoscopic assessment or 12 months follow-up. Clinicians were blinded to the POCT results.Results. In the primary care cohort, none of the 114 children had IBD, and the calprotectin and lactoferrin POCTs had specificities of 0.95 (0.89-0.98) and 0.98 (0.93-0.99), respectively. In the referred cohort, 17 of the 90 children had IBD: the sensitivity of POCT calprotectin and POCT lactoferrin were both 0.94 (0.72-0.99); and the specificity was 0.93 (0.84-0.97) and 0.99 (0.92-1.00), respectively. The POCT calprotectin could reduce the referral rate by 76% and POCT lactoferrin by 81%, while missing one child with IBD (6%).Conclusion. A diagnostic test strategy in primary care using a simple POCT calprotectin or lactoferrin has the potential to reduce the need for referral for further diagnostic work-up in specialist care, with a low risk of missing a child with IBD.

textabstractOBJECTIVE:: Monogenic defects in the interleukin-10 (IL-10) pathway are extremely rare and cause infantile-onset inflammatory bowel disease (IBD)-like pathology. Understanding how immune responses are dysregulated in monogenic IBD-like diseases can provide valuable insight in “classical” IBD pathogenesis. Here, we studied long-term immune cell development and function in an adolescent IL-10 receptor (IL10RA)-deficient patient who presented in infancy with severe colitis and fistulizing perianal disease and is currently treated with immune suppressants. METHODS:: Biomaterial was collected from the IL10RA-deficient patient, pediatric IBD patients and healthy controls. The frequency and phenotype of immune cells were determined in peripheral blood and intestinal biopsies by flow cytometry and immunohistochemistry. Functional changes in monocyte-derived dendritic cells and T cells were assessed by in vitro activation assays. RESULTS:: The IL10RA-deficient immune system developed normally with respect to numbers and phenotype of circulating immune cells. Despite normal co-stimulatory molecule expression, bacterial lipopolysaccharide-stimulated monocyte-derived dendritic cells from the IL10RA-deficient patient released increased amounts of TNFα compared to healthy controls. Upon T-cell receptor ligation, IL10RA-deficient peripheral blood mononuclear cells released increased amounts of T cell cytokines IFNγ and IL-17 agreeing with high numbers of T-bet and IL-17 cells in intestinal biopsies taken at disease onset. In vitro, the immunosuppressive drug thalidomide used to treat the patient decreased peripheral blood mononuclear cell-derived TNFα production. CONCLUSIONS:: With time and during immunosuppressive treatment the IL10RA- deficient immune system develops relatively normally. Upon activation, IL-10 is crucial for controlling excessive inflammatory cytokine release by dendritic cells and preventing IFNγ and IL-17-mediated T-cell responses.

Background The objective of our study was to assess whether TG2A levels in the healthy childhood population can be predictive of subclinical CD. Methods A total of 4442 children (median age, 6.0 years) participating in a population-based prospective cohort study were screened on serum TG2A. Those with positive TG2A (≥7 U/ml; n = 60, 1.4%) were invited for clinical evaluation (median age, 9.0 years). Medical history, physical examination, serum TG2A, and IgA-endomysium (EMA) were assessed, as well as HLA DQ 2.2/2.5/8 typing. Patients with positive serologies and genetic risk types underwent duodenal biopsies. TG2A levels at the time of biopsy were compared with the degree of enteropathy. Results Fifty-one TG2A-positive children were included in the follow-up: 31 (60.8%) children had CD, ten (19.6%) did not have CD, and ten (19.6%) were considered potential CD cases because of inconclusive serologies. Duodenal biopsies were performed in 26/31 children. CD with Marsh 3a/b enteropathy was observed in 75% (15/20) of children having TG2A levels ≥10ULN at 6 years of age, as well as in 75% (6/8) of children having a positive TG2A

Growth failure is common in children with Crohn's disease. The effect of adalimumab (ADA), a fully human antitumor necrosis factor antagonist, on height velocity in pediatric patients with baseline (BL) linear growth impairment in the IMAgINE 1 trial is presented.This analysis included female and male patients with growth potential (bone age ≤13 and ≤14 yr, respectively), with BL Pediatric Crohn's disease Activity Index30, and who failed or were intolerant to conventional therapy. Patients received open-label induction ADA at weeks 0 and 2 by body weight (≥40 kg, 160 and 80 mg and40 kg, 80 and 40 mg). At week 4, patients were randomized to double-blind high (40 or 20 mg for ≥40 kg or40 kg) or low dose (20 or 10 mg for ≥40 kg or40 kg) every other week ADA to week 52. Height velocity z-score was summarized at BL, week 26, and week 52 by patients with BL growth impairment (z-score ≤-1.0) or normal growth (z-score-1.0).ADA therapy significantly improved and normalized growth rate at weeks 26 and 52 in patients with BL growth impairment (median z-score, BL, -3.25; week 26, -0.34; and week 52, 0.21; P0.001 versus BL for both), but not in patients with normal growth. Growth improvement was significantly greater at week 26 in week 4 responders to induction therapy compared with nonresponders (median z-score 0.09 versus -2.92; P = 0.02).ADA treatment resulted in growth rate normalization as early as week 26 in children with moderately to severely active Crohn's disease and growth impairment.

Article first published online 26 January 2017. Supplemental Digital Content is Available in the Text, Background: IMAgINE 1 assessed 52-week efficacy and safety of adalimumab in children with moderate to severe Crohn's disease. Long-term efficacy and safety of adalimumab for patients who entered the IMAgINE 2 extension are reported. Methods: Patients who completed IMAgINE 1 could enroll in IMAgINE 2. Endpoints assessed from weeks 0 to 240 of IMAgINE 2 were Pediatric Crohn's Disease Activity Index remission (Pediatric Crohn's Disease Activity Index ≤ 10) and response (Pediatric Crohn's Disease Activity Index decrease ≥15 from IMAgINE 1 baseline) using observed analysis and hybrid nonresponder imputation (hNRI). For hNRI, discontinued patients were imputed as failures unless they transitioned to commercial adalimumab (with study site closure) or adult care, where last observation was carried forward. Corticosteroid-free remission in patients receiving corticosteroids at IMAgINE 1 baseline, discontinuation of immunomodulators (IMMs) in patients receiving IMMs at IMAgINE 2 baseline, and linear growth improvement were reported as observed. Adverse events were assessed for patients receiving ≥1 adalimumab dose in IMAgINE 1 and 2 through January 2015. Results: Of 100 patients enrolled in IMAgINE 2, 41% and 48% achieved remission and response (hNRI) at IMAgINE 2 week 240. Remission rates were maintained by 45% (30/67, hNRI) of patients who entered IMAgINE 2 in remission. At IMAgINE 2 week 240, 63% (12/19) of patients receiving corticosteroids at IMAgINE 1 baseline achieved corticosteroid-free remission and 30% (6/20) of patients receiving IMMs at IMAgINE 2 baseline discontinued IMMs. Adalimumab treatment led to growth velocity normalization. No new safety signals were identified. Conclusions: Efficacy and safety profiles of prolonged adalimumab treatment in children with Crohn's disease were consistent with IMAgINE 1 and adult Crohn's disease adalimumab trials.

Background: Vedolizumab, an anti-integrin antibody, has proven to be effective in adults with inflammatory bowel disease [IBD], but the data in paediatrics are limited. We describe the short-term effectiveness and safety of vedolizumab in a European multi-centre paediatric IBD cohort. Method: Retrospective review of children [aged 2–18 years] treated with vedolizumab from 19 centres affiliated with the Paediatric IBD Porto group of ESPGHAN. Primary outcome was Week 14 corticosteroid-free remission [CFR]. Results: In all, 64 children were included (32 [50%] male, mean age 14.5 ± 2.8 years, with a median follow-up 24 weeks [interquartile range 14–38; range 6–116]); 41 [64%] cases of ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U] and 23 [36%] Crohn’s disease [CD]. All were previously treated with anti-tumour necrosis factor [TNF] [28% primary failure, 53% secondary failure]. Week 14 CFR was 37% in UC, and 14% in CD [P = 0.06]. CFR by last follow-up was 39% in UC and 24% in CD [p = 0.24]. Ten [17%] children required surgery, six of whom had colectomy for UC. Concomitant immunomodulatory drugs did not affect remission rate [42% vs 35%; p = 0.35 at Week 22]. There were three minor drug-related adverse events. Only 3 of 16 children who underwent endoscopic evaluation had mucosal healing after treatment (19%). Conclusions: Vedolizumab was safe and effective in this cohort of paediatric refractory IBD. These data support previous findings of slow induction rate of vedolizumab in CD and a trend to be less effective compared with patients with UC.

markdownabstractBackground: This European Crohn's and Colitis Organisation [ECCO] topical review focuses on the transition of adolescents with inflammatory bowel disease [IBD] from child-centred to adult-oriented care. The aim was to provide evidence-supported, expert consensus for health professionals taking part in the transition. Methods: An online survey determined the areas of importance for health professionals involved in the transition of adolescents with IBD. Thereafter an expert panel of nine paediatric and five adult gastroenterologists was formed to identify the critical elements of the transition programme, and to prepare core messages defined as 'current practice points'. There is limited literature about transition, therefore this review is mainly based on expert opinion and consensus, rather than on specific evidence. Results: A total of 21 practice points were generated before the first [online] voting round. Practice points that reached > 80% agreement were accepted, while those that did not reach 80% agreement were refined during a consensus meeting and subjected to voting. Ultimately, 14 practice points were retained by this review. Conclusion: We present a consensus-based framework for transitional care in IBD that provides a guidance for clinical practice.

The present guideline is the first of a new series of “practical guidelines” based on more detailed scientific guidelines produced by ESPEN during the last few years. The guidelines have been shortened and now include flow charts that connect the individual recommendations to logical care pathways and allow rapid navigation through the guideline. The purpose of the present practical guideline is to provide an easy-to-use tool to guide nutritional support and primary nutritional therapy in inflammatory bowel disease (IBD). The guideline is aimed at professionals working in clinical practice, either in hospitals or in outpatient medicine, and treating patients with IBD. In 40 recommendations, general aspects of care in patients with IBD, and specific aspects during active disease and in remission are addressed. All recommendations are equipped with evidence grades, consensus rates, short commentaries and links to cited literature.

BackgroundIn youth with inflammatory bowel disease (IBD), health-related quality of life (HRQOL) has been shown to be affected by individual disease factors and specific psychological factors. The innovative aim of this study is to examine thecombinedimpact of psychological factors (illness perceptions, cognitive coping, anxiety, and depression) on HRQOL, over and above the associations of demographic and disease factors with HRQOL in youth with IBD.MethodData on clinical disease activity, illness perceptions, cognitive coping, anxiety, depression, and HRQOL were prospectively collected in 262 consecutive youth (age 10–20, 46.6% male) with confirmed IBD. Multiple linear regression analyses tested the associations of demographic, disease, and psychological variables with HRQOL in separate groups for Crohn’s disease (CD;N = 147) and ulcerative colitis and IBD unclassified (UC/IBD-U;N = 115), using age-specific validated instruments.ResultsIn both disease groups, more negative illness perceptions (ß = − .412;ß = − .438,p ß = − .454;ß = − .279,p ß = − .201,p = .001). The model with the psychological variables explained a large and significant amount of variance in both groups: 74% and 83%, respectively (p ConclusionIn 10–20-year-old IBD patients, negative illness perceptions and depression were significantly and more strongly associated with lower HRQOL than demographic and disease factors. Thus, it is important to integrate psychological factors in the treatment for IBD patients. To improve HRQOL in young IBD patients, psychological interventions should be targeted at negative illness perceptions and depression.

Background The beneficial effects of antibiotics in Crohn’s disease (CD) depend in part on the gut microbiota but are inadequately understood. We investigated the impact of metronidazole (MET) and metronidazole plus azithromycin (MET+AZ) on the microbiota in pediatric CD and the use of microbiota features as classifiers or predictors of disease remission. Methods 16S rRNA-based microbiota profiling was performed on stool samples from 67 patients in a multinational, randomized, controlled, longitudinal, 12-week trial of MET vs MET+AZ in children with mild to moderate CD. Profiles were analyzed together with disease activity, and then used to construct random forest models to classify remission or predict treatment response. Results Both MET and MET+AZ significantly decreased diversity of the microbiota and caused large treatment-specific shifts in microbiota structure at week 4. Disease remission was associated with a treatment-specific microbiota configuration. Random forest models constructed from microbiota profiles before and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (area under the curve [AUC], 0.879; 95% confidence interval, 0.683–0.9877; sensitivity, 0.7778; specificity, 1.000; P < 0.001). A random forest model trained on pre-antibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC, 0.8; P = 0.24). Conclusions MET and MET+AZ antibiotic regimens in pediatric CD lead to distinct gut microbiota structures at remission. It may be possible to classify and predict remission based in part on microbiota profiles, but larger cohorts will be needed to realize this goal.

Disease heterogeneity hampers achieving long-term disease remission in inflammatory bowel disease (IBD). Monitoring ongoing tissue-localized regulatory and inflammatory T-cell responses in peripheral blood would empower disease classification. We determined whether regulatory and inflammatory phenotypes of circulating CD38+ effector (CD62LnegCD4+) T cells, a population enriched for cells with mucosal antigen specificity, classify disease course in pediatric IBD patients. In healthy individuals, circulating CD38+ effector T cells had a predominant regulatory component with lower frequencies of IFNγ-secreting T cells, higher frequencies of IL-10-secreting T cells and higher frequencies of inhibitory molecule T-cell immunoglobulin and ITIM domain+ (TIGIT) cells than CD38neg effector T cells. TIGIT expression was stable upon stimulation and marked CD38+ T cells with inhibitory properties. In IBD patients with active intestinal inflammation this predominant regulatory component was lost: circulating CD38+ effector T cells had increased activated CD25+CD45RAneg and decreased TIGIT+ cell frequencies. TIGIT percentages below 25% before treatment associated with shorter duration of clinical remission. In conclusion, phenotypic changes in circulating CD38+ effector T cells, in particular the frequency of TIGIT+ cells, classify pediatric IBD patients and predict severity of disease course. These findings have relevance for IBD and can be exploited in graft-versus-host-disease and checkpoint inhibitor-induced inflammation in cancer.

Background Chronicity of inflammatory bowel disease (IBD) is driven by reactivation of inflammatory memory CD4+ T helper (Th) cells which activate an inflammatory cascade involving innate immune cells and structural intestinal tissue cells. Because of disease heterogeneity, novel treatment strategies tailored to more precisely target the patient’s individual immune defect are required to prevent disease reactivation. We hypothesize that analysis of changes in circulating inflammatory protein abundance combined with phenotyping of circulating Th cells allow to dissect underlying immune pathogenesis and we aim to stratify pediatric IBD patients accordingly. Methods We performed plasma analysis of 92 inflammatory proteins in a cohort of pediatric IBD patients (CD: n=62; UC/IBD-U: n=20), patients with suspicion of IBD but negative diagnosis (n=13) and age-matched healthy controls (HC: n=30). Peripheral blood was obtained at diagnosis and after induction treatment (t=10–14 weeks). Plasma protein concentrations were assessed with Olink Proximity Extension Assay technology® and Th cells were analyzed with flow cytometry. Samples were clustered using hierarchical clustering with Ward linkage. Differential protein abundance was assessed with t-tests at t=0 and a mixed effect model after treatment. Results Thirty-six plasma proteins discriminated pediatric IBD patients from HC. CD and UC/IBD-U patients shared increased abundance of 17 proteins amongst which interleukin-6 and oncostatin-M. Increased abundance of the Th1 cytokine interferon-γ was strictly associated with CD while Th17-associated interleukin-17A was significantly more abundant in UC/IBD-U. Hierarchical clustering of plasma protein profiles discriminated 2 clusters of UC patients with different clinical disease activity and disease extent. In CD, three patient clusters were identified. CD#1 patients had lower clinical disease activity, lower C-reactive protein and higher blood albumin concentrations. Clusters CD#2 and CD#3 had comparable clinical parameters. CD#3 patients had higher abundance of 14 proteins associated with neutrophil function and interferon-γ signaling while CD#2 patients had a marked increase in frequencies of activated (HLA-DR+) memory Th cells. The three CD clusters responded differently to therapy with CD#1 patients exhibiting only a few changes, CD#2 patients showing intermediate modulation and CD#3 patients exhibiting more modulated proteins and greater fold changes. Conclusion Combined plasma immune protein and circulating Th cell profiling discriminates subgroups of pediatric IBD patients during active disease which differ in their response to therapy. Abbreviations: CD: Crohn’s disease; UC: ulcerative colitis; IBD-U: IBD-unclassified.

Background Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a T cell driven intestinal inflammation. Current T cell suppressive therapeutic regimens are moderately successful due to a large clinical heterogeneity amongst patients. Detailed understanding of aberrant inflammatory and inhibitory T-cell responses in individual patients is lacking. Previously, we have shown that, in healthy individuals, 40% of peripheral blood CD38+ (CD62LnegCD4+) effector T cells, which are enriched for intestinal antigen specificity, express the inhibitory molecule T cell immunoglobulin and ITIM domain (TIGIT). TIGIT+CD38+ effector T cells have a regulatory function, produce IL-10 and express multiple co-inhibitory receptors. Conversely, TIGITnegCD38+ effector T cells are enriched in inflammatory IFN-γ producing cells. In a small cohort of pediatric-onset IBD patients, low frequencies of TIGIT+CD38+ effector T cells were associated with a reduced duration of clinical remission. We hypothesize that a subgroup of IBD patients has reduced frequencies of circulating inhibitory TIGIT+CD38+ effector T cells, reflecting a distinct pathogenesis associated with a more severe disease course. Methods In the Rotterdam PIBD-SETQuality cohort of newly diagnosed pediatric IBD patients (CD: n=37; UC: n=16), patients with suspicion of IBD but negative diagnosis (n=12) and age-matched healthy controls (n=22), we monitored TIGIT+ and TIGITnegCD38+ effector T cells in peripheral blood and collected plasma at diagnosis and during immunosuppressive therapy. Results At diagnosis, approximately 50% of CD patients had strongly reduced frequencies of inhibitory TIGIT+CD38+ effector T cells compared to UC patients and age-matched controls. CD patients with low frequencies of TIGIT+CD38+ effector T cells at diagnosis needed earlier anti-TNF treatment with 73% of patients receiving anti-TNF treatment within 1 year versus 38% for patients with normal frequencies of TIGIT+CD38+ effector T cells. Inflammatory TIGITnegCD38+ effector T cells were enriched in Ki67, reflecting recent proliferation, and expressed chemokine receptors associated with inflammatory non-classical T-helper-1 IFN-γ hiIL-17lo producing cells. High frequencies of TIGITnegCD38+ effector T cells correlated with high plasma IFN-γ concentrations. Conclusion These results demonstrate that reduced frequencies of circulating inhibitory TIGIT+CD38+ effector T cells discriminate a subgroup of pediatric CD patients with high frequencies of inflammatory IFN-γ hiIL-17lo producing cells, high plasma IFN-γ concentrations, and in need of early anti-TNF treatment, possibly indicative of a distinct pathogenesis with a more severe disease course.

OBJECTIVES Persistent viral infections have been implicated in the etiology of autoimmune diseases in adulthood, but it is not known whether herpesviruses are associated with the development of celiac disease autoimmunity in childhood. We assessed whether herpesvirus infections are associated with transglutaminase type 2 antibody (TG2A) concentrations in children at 6 years of age. METHODS The present study was embedded within a population-based prospective cohort study. Serum immunoglobulin G levels against Epstein-Barr virus, cytomegalovirus (CMV), and herpes simplex virus type 1 were measured by enzyme-linked immunosorbent assay , and TG2A concentrations with fluorescence enzyme immunoassay in 4420 children at 6 years of age. Children were categorized based on TG2A concentrations into negative (