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Current first-line treatments of paediatric ulcerative colitis (UC) maintain a 6-month remission in only half of the patients. Relapse prediction at diagnosis could enable earlier introduction of immunosuppressants. We collected intestinal biopsies from 56 treatment-naïve children, combining mucosal quantitative microbial profiling with host epigenomics, transcriptomics, genotyping, and in vitro and in vivo experiments on selected bacteria. Baseline bacterial diversity is lower in relapsing children, who have fewer butyrate producers but more oral-associated bacteria, whereof Veillonella parvula induces inflammation in epithelial cell lines and IL10 −/− mice. Microbiota has the strongest association with future relapse, followed by host epigenome and transcriptome. Interferon gamma signalling is also linked to relapse-associated bacteria. Relapse-prediction using separate omics data is outperformed by a robust machine learning approach combining microbiomes and epigenomes. In summary, host-microbe data have prognostic potential in paediatric UC. Our translational findings also suggest that pro-inflammatory oral-associated colonizers can exploit the reduced colonic bacterial diversity of relapsing children. Current first-line treatments of pediatric UC maintain a 6-month remission in only half of the patients. Here, applying multi-omics on intestinal biopsies from treatment-naïve children, the authors show that relapse-prediction using separate omics data is outperformed by a robust machine learning approach combining microbiomes and epigenomes.

IntroductionPatients with paediatric-onset inflammatory bowel disease (PIBD) may develop a complicated disease course, including growth failure, bowel resection at young age and treatment-related adverse events, all of which can have significant and lasting effects on the patient’s development and quality of life. Unfortunately, we are still not able to fully explain the heterogeneity between patients and their disease course and predict which patients will respond to certain therapies or are most at risk of developing a more complicated disease course. To investigate this, large prospective studies with long-term follow-up are needed. Currently, no such European or Asian international cohorts exist. In this international cohort, we aim to evaluate disease course and which patients are most at risk of therapy non-response or development of complicated disease based on patient and disease characteristics, immune pathology and environmental and socioeconomic factors.Methods and analysisIn this international prospective observational study, which is part of the PIBD Network for Safety, Efficacy, Treatment and Quality improvement of care (PIBD-SETQuality), children diagnosed with inflammatory bowel disease <18 years are included at diagnosis. The follow-up schedule is in line with standard PIBD care and is intended to continue up to 20 years. Patient and disease characteristics, as well as results of investigations, are collected at baseline and during follow-up. In addition, environmental factors are being assessed (eg, parent’s smoking behaviour, dietary factors and antibiotic use). In specific centres with the ability to perform extensive immunological analyses, blood samples and intestinal biopsies are being collected and analysed (flow cytometry, plasma proteomics, mRNA expression and immunohistochemistry) in therapy-naïve patients and during follow-up.Ethics and disseminationMedical ethical approval has been obtained prior to patient recruitment for all sites. The results will be disseminated through peer-reviewed scientific publications.Trial registration numberNCT03571373.

IntroductionImmunomodulators such as thiopurines (azathioprine (AZA)/6-mercaptopurine (6MP)), methotrexate (MTX) and biologics such as adalimumab (ADA) are well established for maintenance of remission within paediatric Crohn’s disease (CD). It remains unclear, however, which maintenance medication should be used first line in specific patient groups.AimsTo compare the efficacy of maintenance therapies in newly diagnosed CD based on stratification into high and low-risk groups for severe CD evolution; MTX versus AZA/6MP in low-risk and MTX versus ADA in high-risk patients. Primary end point: sustained remission at 12 months (weighted paediatric CD activity index ≤12.5 and C reactive protein ≤1.5 fold upper limit) without relapse or ongoing requirement for exclusive enteral nutrition (EEN)/steroids 12 weeks after treatment initiation.Methods and analysisREDUCE-RISK in CD is an international multicentre open-label prospective randomised controlled trial funded by EU within the Horizon2020 framework (grant number 668023). Eligible patients (aged 6–17 years, new-onset disease receiving steroids or EEN for induction of remission for luminal ± perianal CD are stratified into low and high-risk groups based on phenotype and response to induction therapy. Participants are randomised to one of two treatment arms within their risk group: low-risk patients to weekly subcutaneous MTX or daily oral AZA/6MP, and high-risk patients to weekly subcutaneous MTX or fortnightly ADA. Patients are followed up for 12 months at prespecified intervals. Electronic case report forms are completed prospectively. The study aims to recruit 312 participants (176 low risk; 136 high risk).Ethics and disseminationClinicalTrials.gov Identifier: (NCT02852694), authorisation and approval from local ethics committees have been obtained prior to recruitment. Individual informed consent will be obtained prior to participation in the study. Results will be published in a peer-reviewed journal with open access.Trial registration numberNCT02852694; Pre-results.

Recent studies of children with inflammatory bowel disease (IBD) demonstrate an increased venous thromboembolism (VTE) risk. However, estimates of risk are variable and case numbers are limited. The aim of this study was to provide national estimates of the risk of VTE in children with IBD. Hospital Episode Statistics was used to identify patients diagnosed with either IBD or VTE before reaching 18 years of age between 2001 and 2019. Populations and subgroups are described, and the risks of developing VTE in the general and IBD populations were calculated. Children with VTE following a diagnosis of IBD or in the previous 6 months (n = 85) and with VTE without IBD (n = 4160) were studied. The absolute risk in children with IBD was 9.42 (95% confidence interval [CI], 7.4-11.4) per 10 000 patient-years, compared with 0.18 (95% CI, 18-0.19) in children without IBD. Between 6 months prior to and 1 year following IBD diagnosis was the highest absolute risk period for VTE (18.0; 95% CI, 13.7-22.4). The relative risk of VTE in children with IBD vs children without IBD was greatest in younger patient groups: the relative risk for the age band 0 to 8 years was 96.5 (95% CI, 51.8-179.9) and for 9 to 11 years was 153.1 (95% CI, 81.2-288.8) vs 14.3 (95% CI, 10.3-20.0) for 15 to 17 years. Cerebral venous sinus thrombosis represented 17.6% of pediatric VTE events in IBD patients compared with 4.2% in children without IBD (P = .001). This study confirms the increased risk of VTE in children with IBD compared with children without IBD. The time of greatest VTE risk was around diagnosis. Cerebral venous sinus thrombosis was significantly more common in children with IBD than other children.

Ustekinumab is an effective therapy for adult Crohn’s disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn’s Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7–17.2) with a median follow-up of 7.4 months (IQR 5.6–11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25–57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause.     Conclusion : Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: • Ustekinumab is an effective therapy for adult moderate to severe Crohn’s disease (CD). • Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: • Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. • Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12.

The REDUCE-RISK trial was set up to compare the effectiveness of weekly subcutaneously administered methotrexate with daily oral azathioprine or 6-mercaptopurine in low-risk Crohn disease (CD) or subcutaneously administered adalimumab (ADA) in high-risk CD in a pediatric population (age 6-17 years). The aim of this study is to perform a systematic review to provide input into the research protocol to gather the necessary information to improve the performance of an evidence-based economic evaluation when the trial is finished. The Centre for Reviews and Dissemination (CRD) Health Technology Assessment (HTA) database, websites of HTA institutes, CRD's National Health Service Economic Evaluation Database, MEDLINE (OVID), and Embase databases were consulted to retrieve (reviews of) relevant economic evaluations. Studies were eligible if they included a pediatric or adult population with inflammatory bowel diseases (CD and ulcerative colitis [UC]) treated with ADA (Humira). There were no restrictions on the comparator. Only economic evaluations expressing outcomes in life years gained or quality-adjusted life years gained were selected. A total of 12 primary studies were identified. None of these studies included a pediatric population because of a lack of supporting trials. The economic evaluations identified in our systematic review indicate that ADA is an appropriate intervention for inclusion in such a trial. From a health economic point of view, it is important to make an incremental analysis comparing such an intervention with standard care and not immediately versus another (expensive) biological treatment. Information on the impact of children's school attendance and parents' productivity is currently lacking in economic evaluations, and none of the underlying trials measured quality of life (QoL) using a generic utility instrument. The review of the economic literature on ADA for the treatment of patients with CD supports the performance of a trial with biologicals in pediatric patients, including making a distinction according to disease severity. Conducting an economic literature review enabled us to decide which variables should be added to the research protocol from an economic point of view. Measurements for children's and parents' QoL (EuroQol 5-Dimension questionnaires), children's school attendance, and parents' productivity (WPAI-CD-CG questionnaire) were added to the research protocol. This will provide support for the calculation of the cost-effectiveness of the interventions evaluated in the REDUCE-RISK trial. ClinicalTrials.gov NCT02852694; https://clinicaltrials.gov/ct2/show/NCT02852694.

Enteral nutrition has a positive effect on growth in children with active Crohn's disease. The question arises: is this is due only to improved nutrition? Enteral formulas may also directly reduce inflammation, lowering the expression of cytokines like interleukin (IL)-6 that inhibit growth. Four lines of evidence support the hypothesis that enteral formulas directly lessen inflammation: enteral nutrition directly affects the inflamed intestine; changes in inflammatory markers precede repletion of nutrition status; molecular pathways exist linking changes in luminal contents to the expression of class II MHC genes in intestinal epithelium in animal studies; and enteral formulas have a direct effect on cytokine expression by intestinal epithelial cells.

BACKGROUND There is controversy about whether the inflammatory response observed in the cystic fibrosis (CF) lung occurs secondary to bacterial infection or is caused by a dysregulation of the inflammatory response associated with the basic cellular defect of CF. AIMS To study the inflammatory response in the gastrointestinal tract of children with CF; and to investigate whether there is increased inflammation in the gastrointestinal tract of CF children with fibrosing colonopathy. METHODS Whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF and fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, α1 antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin 1β) were measured. RESULTS Compared to controls, the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1β, and interleukin 8. Similar values were obtained for the CF patients with fibrosing colonopathy. CONCLUSIONS These data suggest that there is immune activation in the gastrointestinal mucosa of children with cystic fibrosis, which may result from the basic cellular defect. Fibrosing colonopathy does not appear to be associated with increased inflammation.

Paediatric endoscopy is an important tool in diagnosing and ruling out gastrointestinal pathology. However, little published data exists to guide selection of patients for endoscopy. Existing guidance contains weak recommendations based on low quality evidence.1 We have previously published data showing the diagnostic yield of macroscopic and histological abnormalities in children undergoing first diagnostic endoscopy2 including 218 procedures in 164 children, of which 49.4% were macroscopically and histologically normal, and only 35% were histologically abnormal.The aim of this project was to assess how the Covid-19 pandemic affected diagnostic yields in paediatric endoscopy. Using the same methodology we analysed first diagnostic endoscopies over two 6-month periods: during the Covid-19 pandemic peak (including lockdowns), and two years later once restrictions were lifted. Clinical factors, endoscopic, and histological findings were assessed. Biopsies were reviewed in weekly histopathology multidisciplinary meetings with final agreed outcomes. Abnormal histology was used as the criterion standard for abnormality.During COVID-19: 69 procedures in 37 children. 65%(n=24) male. 86%(n=32) underwent OGD&Colon/Sigm, small numbers had OGD(n=3) or Colonoscopy(n=2) alone. Mean age 10.9 years. 89%(n=33) had histological abnormality.Macroscopic and histological abnormalities (respectively) were 94%&94% of those undergoing both OGD and colonoscopy (OGD&Col) plus 2 of 2 colonoscopy alone and 1 of 3 OGD alone.Post-Pandemic: 194 procedures in 138 children. 54%(n=75) male. 55%(n=76) underwent OGD; 41%(n=56) underwent OGD&Col/Sigm; 4%(n=6) Colon. Mean age 9.5 years. 66%(n=91) had histological abnormality.Macroscopic and histological abnormalities (respectively): 47%&61% of OGD, 50%&50% of colonoscopy alone, and 76%&78% in OGD&Col.Figure 1 shows the abnormality rates (defined by macroscopic and histologic abnormality), the% column for OGD or colonoscopy alone during Covid was not included due to n<3.Abstract OC70 Figure 1The most common symptoms and laboratory tests prompting endoscopy were chronic diarrhoea (19%, n=26), rectal bleeding (20%, n=27), abdominal pain (33%, n=46), raised calprotectin (18%, n=25), positive TTG/EMA (17%, n=24), anaemia (20% of all negative TTG/EMA, n=23), and raised CRP/ESR (38% of all negative TTG/EMA, n=43). While clinical and laboratory abnormalities mostly correlated with high rates of macroscopic and histological abnormalities, features associated with low rates of macroscopic and histological abnormality were heartburn (38%&46% respectively) and dysphagia (44%&33% respectively). Features most predictive of macroscopic and histological abnormality (respectively) were chronic diarrhoea (88%&86%), rectal bleeding (70%&78%), raised calprotectin (88%&96%), anaemia (87%&91%), raised ESR (90%&100%), and raised CRP (86%&90%).ConclusionsAs expected, the number of first diagnostic endoscopies reduced greatly during the COVID-19 pandemic but post-pandemic returned to similar numbers to the previous study. There was a striking increase in histological abnormalities identified during the pandemic (from 35% of patients in 2014 to 84%). Post-pandemic this has remained high (66%), suggesting a lasting change in practice since the original study. No delayed diagnoses or patient complaints have been noted since this change. Further work will examine reasons for this.ReferencesThomson M, Tringali A, Dumonceau JM, Tavares M, Tabbers MM, Furlano R, et al. Paediatric gastrointestinal endoscopy: european society for paediatric gastroenterology hepatology and nutrition and european society of gastrointestinal endoscopy guidelines. J Pediatr Gastroenterol Nutr. 2017 Jan;64(1):133–53.Wang S, Younus O, Rawat D, Naik S, Giles E, Meadows N, et al. Clinical presentation and outcomes of diagnostic endoscopy in newly presenting children with gastrointestinal symptoms. J Pediatr Gastroenterol Nutr. 2018 Jun;66(6):876–81.