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Background Current data on dual biologic therapy in children are limited. This multicenter study aimed to evaluate the effectiveness and safety of dual therapy in pediatric patients with inflammatory bowel disease (IBD). Methods A retrospective study from 14 centers affiliated with the Pediatric IBD Interest and Porto Groups of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Included were children with IBD who underwent combinations of biologic agents or biologic and small molecule therapy for at least 3 months. Demographic, clinical, laboratory, endoscopic, and imaging data were collected. Adverse events were recorded. Results Sixty-two children (35 Crohn’s disease, 27 ulcerative colitis; median age 15.5 [interquartile range, 13.1-16.8] years) were included. They had all failed previous biologic therapies, and 47 (76%) failed at least 2 biologic agents. The dual therapy included an anti-tumor necrosis factor agent and vedolizumab in 30 children (48%), anti-tumor necrosis factor and ustekinumab in 21 (34%) children, vedolizumab and ustekinumab in 8 (13%) children, and tofacitinib with a biologic in 3 (5%) children. Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively. Normalization of C-reactive protein and decrease in fecal calprotectin to Conclusions Dual biologic therapy may be effective in children with refractory IBD. The potential efficacy should be weighed against the risk of serious adverse events.

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.

Thioguanine (TG) has been shown as a safe alternative in adults with inflammatory bowel disease (IBD) who did not tolerate conventional thiopurines [azathioprine (AZA)/mercaptopurine]. However, data in pediatric IBD are scarce. Therefore, we aimed to assess the safety of TG as maintenance therapy.A retrospective, multicenter cohort study of children with IBD on TG was performed in the Netherlands. TG-related adverse events (AE) were assessed and listed according to the common terminology criteria for AE.Thirty-six children with IBD (median age 14.5 years) on TG (median dose 15 mg/day) were included in 6 centers. Five AE occurred during follow-up [pancreatitis (grade 3), hepatotoxicity (grade 3) (n = 2), Clostridium difficile infection (grade 2), and abdominal pain (grade 2)]. All patients (n = 8) with a previously AZA-induced pancreatitis did not redevelop pancreatitis on TG.In pediatric IBD, TG seems a safe alternative in case of AZA-induced pancreatitis. Further research assessing long-term TG-related safety and efficacy is needed.

In children with gastrointestinal disorders such as inflammatory bowel disease (IBD) and intestinal failure (IF), the risk of venous thromboembolism (VTE) is increased. VTE may lead to pulmonary embolism, sepsis and central line infection, stroke and post-thrombotic syndrome. The purpose of this review is to summarize current knowledge and recent advances around VTE management in pediatric gastroenterology with a focus on IBD and IF. The VTE incidence in children with IBD is reported to be around 4–30 per 10,000 patient-years, with higher incidences for hospitalized children. While in general, IF is less common than IBD, the VTE incidence in children with IF is around 750 per 10,000 patient-years. The most common risk factors for development of VTE involve deviations leading to Virchow's triad (endothelial damage, stasis, and hypercoagulability) and include active inflammation, particularly with colonic involvement, presence of a central venous catheter, underlying thrombophilia, reduced mobility, surgery, and hospitalization. Classes of anticoagulants used for treatment of VTE are low molecular weight heparins and vitamin K antagonists. However, the use of direct oral anticoagulants for treatment or prevention of VTE has not been studied in this pediatric population yet. Pediatric gastroenterologists apply different VTE prevention and treatment strategies due to lack of literature and lack of consensus. We discuss the role of primary and secondary prophylactic use of anticoagulants, and provide tools and recommendations for screening, prevention and management for the specific pediatric populations.

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.

The onset of inflammatory bowel disease (IBD) in children is rising. Current treatment options are based on immunomodulatory therapy. Alternative treatment options are upcoming since they appear to be effective in individual patients. Cannabis might relief IBD symptoms in these cases and improve quality of life. Recent evidence suggests a potential anti-inflammatory effect of cannabis. Areas covered: This review presents an overview of recent literature on the use of cannabis in IBD focussing on pediatric IBD patients. Background information on the role of the endocannabinoid system within the gastrointestinal tract is presented. Other modalities of cannabis and its purified ingredients will be discussed as well, with attention to its applicability in children with IBD. Expert opinion: More research is needed on the efficacy and safety of cannabis in pediatric IBD. Studies are well underway, but until then the use of cannabis in pediatric IBD cannot be recommended.

Biologic therapies have changed the outcome of both adult and pediatric patients with Inflammatory Bowel Disease (IBD). In September 2013, the first biosimilar of infliximab was introduced into the pharmaceutical market. In 2015, a first position paper on the use of biosimilars in pediatric IBD was published by the ESPGHAN IBD Porto group. Since then, more data have accumulated for both adults and children demonstrating biosimilars are an effective and safe alternative to the originator. In this updated position statement, we summarize current evidence and provide joint consensus statements regarding the recommended practice of biosimilar use in children with IBD. ispartof: JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION vol:68 issue:1 pages:144-153 ispartof: location:United States status: published

Objectives: To evaluate the longitudinal evolution of work productivity loss and activity impairment in caregivers of children with inflammatory bowel disease (IBD). We also evaluated the associations between these impairments, IBD-related factors, and caregivers’ health-related quality of life (HRQOL) and estimated the indirect costs related to work absenteeism. Study design: Since January 2017, children with newly diagnosed IBD were enrolled prospectively in the Pediatric Inflammatory Bowel Disease Network for Safety, Efficacy, Treatment and Quality improvement of care study. The impact of pediatric-onset IBD on caregivers' socioeconomic functioning (work and daily activities) and HRQOL was assessed using the Work Productivity and Activity Impairment for caregivers questionnaire and the European Quality of Life Five Dimension Five Level questionnaire, at diagnosis and 3 and 12 months of age. Generalized estimating equation models were applied to evaluate outcomes longitudinally, adjusted for IBD type, disease activity, and child's age at diagnosis. Results: Up to July 2021, 491 children with IBD were eligible for analysis of caregivers' Work Productivity and Activity Impairment questionnaire. At diagnosis, the mean caregivers' employment rate was 78.4%; the adjusted mean work productivity loss was 44.6% (95% CI, 40.2%-49.0%), and the adjusted mean activity impairment was 34.3% (95% CI, 30.8%-37.7%). Work productivity loss and activity impairment significantly decreased over time and were associated with disease activity, but not with IBD type or child's age. Caregivers' HRQOL was associated with both impairments. Costs related to work absenteeism were at least €6272 ($7276) per patient during the first year after diagnosis. Conclusions: Caregivers of children with IBD experience significant impairments in work and daily activities, especially at diagnosis. The impact decreases thereafter and is associated with disease activity and caregivers’ HRQOL. Work absenteeism results in high indirect costs.

Objectives: Blood to measure infliximab (IFX) levels is typically obtained with venipuncture. Dried blood sampling (DBS), using capillary blood obtained from a finger prick, would be an alternative to measure IFX blood levels while being more patient friendly. The aim of this study is to compare IFX blood level measured by venipuncture versus DBS in patients with paediatric inflammatory bowel disease (PIBD) to assure accuracy. Methods: A prospective clinical pilot study was performed in patients with PIBD. Before IFX infusion, blood was collected simultaneously through venipuncture and DBS from a finger prick, using Mitratips (Neoteryx). All IFX concentrations were measured by an enzyme-linked immunosorbent assay. The Bland-Altman analysis was used to measure limits of agreement. The interrater reliability was measured with the interclass correlation coefficient and Cohen kappa. To calculate Cohen kappa, IFX levels were categorized into 3 groups; low 10mg/mL. Results: Twenty patients were included. Median age was 12.1 year (interquartile range 8-16 year). The mean difference between the 2 methods was 0.14 as calculated with Bland-Altman plot. The limits of agreement were between 1.39 and 1.12. The interclass correlation coefficient was with 0.998 excellent. The Cohen kappa between 3 IFX level categories was strong K=0.911 (P=0.0001). There was a strong correlation between venous IFX serum levels and DBS (r=0.991, P=0.0001) in the included patients. Conclusions: This is the first study in patients with PIBD to show that bloodspot technology is a patient friendly alternative method to measure IFX blood levels in PIBD

Introduction: Contemporary pediatric data on pouch outcomes are sparse, especially in the era of laparoscopic surgeries. We aimed to assess outcomes and predictors in children with ulcerative colitis/inflammatory bowel disease (IBD)-unclassified who underwent colectomy and ileal pouch-anal anastomosis. Methods: This was a multicenter retrospective cohort study from 17 IBD centers affiliated with the pediatric IBD Porto group of ESPGHAN. An electronic REDcap system was used to collate baseline characteristics, demographic, clinical, management and surgical data, short- and longterm outcomes, and to identify potential predictors of pouch outcome. Results: Of the 129 patients included, 86 (67%) developed pouchitis during follow-up of median 40 months (interquartile range 26–72), of whom 33 (26%) with chronic pouchitis. Patients operated on by surgeons performing

BACKGROUND & AIMS: A better understanding of prognostic factors in ulcerative colitis (UC) could improve patient management and reduce complications. We aimed to identify evidence-based predictors for outcomes in pediatric UC, which may be used to optimize treatment algorithms. METHODS: Potential outcomes worthy of prediction in UC were determined by surveying 202 experts in pediatric UC. A systematic review of the literature, with selected meta-analysis, was performed to identify studies that investigated predictors for these outcomes. Multiple national and international meetings were held to reach consensus on evidence-based statements. RESULTS: Consensus was reached on 31 statements regarding predictors of colectomy, acute severe colitis (ASC), chronically active pediatric UC, cancer and mortality. At diagnosis, disease extent (6 studies, N = 627; P = .035), Pediatric Ulcerative Colitis Activity Index score (4 studies, n = 318; P < .001), hemoglobin, hematocrit, and albumin may predict colectomy. In addition, family history of UC (2 studies, n = 557; P = .0004), extraintestinal manifestations (4 studies, n = 526; P = .048), and disease extension over time may predict colectomy, whereas primary sclerosing cholangitis (PSC) may be protective. Acute severe colitis may be predicted by disease severity at onset and hypoalbuminemia. Higher Pediatric Ulcerative Colitis Activity Index score and C-reactive protein on days 3 and 5 of hospital admission predict failure of intravenous steroids. Risk factors for malignancy included concomitant diagnosis of primary sclerosing cholangitis, longstanding colitis (>10 years), male sex, and younger age at diagnosis. CONCLUSIONS: These evidence-based consensus statements offer predictions to be considered for a personalized medicine approach in treating pediatric UC.

BACKGROUND & AIMS: A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management. METHODS: A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence. RESULTS: Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density. CONCLUSIONS: These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk.

Background Cancer and death are the most severe outcomes that affect patients with inflammatory bowel disease (IBD). These outcomes are even more severe if they occur at a young age but are rare, even in the general population. We conducted a systematic review to provide an overview of all reported pediatric (PIBD) patients with severe outcome. Methods A literature search identified publications that reported development of cancer or fatal outcome in PIBD patients. Studies were eligible for inclusion when (1) article written in English, (2) original data, (3) individual patient information, (4) full text available, (5) study population consisting of patients diagnosed with IBD under the age of 19 years, and (6) who developed malignancy or fatality at any point later in life. Results A total of 98 included studies comprised data of 271 PIBD patients who developed cancer and/or fatal outcome at any point later in life. Meta-analysis demonstrated an increased risk for cancer in PIBD patients (pooled standardized incidence ratio 2.23, 95% CI: 1.98–2.52). The most frequent type of non-fatal cancer was lymphoma, whereas colorectal carcinomas were the most frequently reported type of fatal cancer in PIBD patients and were particularly associated with primary sclerosing cholangitis. The majority of patients with noncancer-related fatal outcomes were diagnosed with ulcerative colitis and most often died due to infectious complications or severe disease-associated complications. Conclusions The data in this review confirm that PIBD associated malignancy and mortality are rare and detailed clinical characteristics are limited. Prospective and international collaborations are needed to obtain more detailed patient-specific information, which is necessary to investigate the relationship between severe outcomes in PIBD patients and the currently used therapeutic strategies.

Background: The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with similar to 20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of pediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points. Methods: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before 2 face-to-face meetings. All 40 included recommendations and 86 practice points were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate. Results: These guidelines discuss how to optimize the use of mesalamine (including topical), systemic and locally active steroids, thiopurines and, for more severe disease, biologics. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision-making based on clinical assessment and the Paediatric UC Activity Index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology, and transition. A brief section on disease classification using the PIBD-classes criteria and IBD-unclassified is also part of these guidelines. Conclusions: These guidelines provide a guide to clinicians managing children with UC and IBD-unclassified management to provide modem management strategies while maintaining vigilance around appropriate outcomes and safety issues.

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.

Purpose of review After expiry of the patent of originator anti-tumor necrosis factor drug infliximab (Remicade), CT-P13 was in 2013 the first infliximab biosimilar to be approved by the European Medicine Agency (EMA) for the same indications as the reference drug, including paediatric inflammatory bowel disease (IBD). The approval was based on extrapolation, after extensive in-vitro studies and clinical experience in patients with ankylosing spondylitis and rheumatoid arthritis. The extrapolation of CT-P13 to IBD and to paediatric patients raised concerns among paediatric IBD specialists. Recent findings Now, almost 4 years later, we can conclude that those concerns have been resolved. There are a growing number of postmarketing studies and real-life data, so far mostly in adults and some in children with IBD. These studies show reassuring comparable efficacy, safety and immunogenicity between CT-P13 and the reference Infliximab. Conclusion In Europe, biosimilars are increasingly regularly prescribed drugs in paediatric IBD. Due to their lower cost, treatment expenses have gone down considerably (up to 30% or more in some countries) and patient access has improved. However, additional well designed studies to investigate long term follow-up of biosimilars in children are still needed. In addition, clinical studies addressing pharmacokinetics, pharmacodynamics and optimal use of infliximab (originator as well as biosimilar) are still desirable.

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.

BACKGROUND 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). OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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. CLINICALTRIAL ClinicalTrials.gov NCT02852694; https://clinicaltrials.gov/ct2/show/NCT02852694

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 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). Objective 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. Methods 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. Results 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. Conclusions 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. Trial Registration ClinicalTrials.gov NCT02852694; https://clinicaltrials.gov/ct2/show/NCT02852694

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.

Background & Aims Mucosal healing (MH) has become a goal of therapy for Crohn’s disease (CD), but frequent endoscopies are not feasible. We aimed to develop and validate a non-invasive index to assess mucosal inflammation in children with CD. Methods We collected data from the multi-center prospective ImageKids study, in which children with CD underwent ileocolonoscopy with magnetic resonance enterography. We investigated the association of pediatric CD activity index (PCDAI) items and laboratory test results with the simple endoscopic score for CD (SESCD). We used these data in a blended mathematical judgmental clinimetric approach to develop a weighted categorized index to identify children with CD who have MH, which we called the MINI index. We validated the index using data from 3 independent patient cohorts. The derivation and validation cohorts included 154 and 168 children, respectively (age 14.1 ± 2.5 years and 14.2 ± 3.9 years), of whom 16% and 36% had MH (defined as SESCD Results In multivariable models, the stooling item of the PCDAI, erythrocyte sedimentation rate, and level of fecal calprotectin were associated with SESCD (all P Conclusions We developed an index to non-invasively assess mucosal inflammation in children with CD. This index, identifies children with MH with high sensitivity and specificity. The added benefit of MINI over measurement of fecal calprotectin was small but significant, especially for patients with concentrations of fecal calprotectin from 100 to 599 μg/g. ClinicalTrials.gov no: NCT01881490 .

Background In newly diagnosed paediatric Crohn’s disease (CD) patients current guidelines instruct to start exclusive enteral nutrition (EEN) or oral prednisolone in combination with immunomodulators to achieve remission. Infliximab (IFX) is proven to be highly effective in paediatric CD patients, but mostly used once patients are refractory, the so-called step-up (SU) treatment strategy. However, evidence is emerging IFX is more effective if initiated earlier in the disease course. We investigated whether initiation of IFX directly after diagnosis of moderate-to-severe CD, i.e. top-down (TD) treatment, results in a higher long-term remission rate compared with SU treatment. Methods For this international randomised controlled trial (RCT) patients aged 3–17 years, with new-onset, untreated CD with weighted paediatric CD activity index (wPCDAI) >40 were included. TD treatment consisted of 5 IFX (CT-P13) infusions of 5 mg/kg (0, 2, 6, 14, 22 weeks) combined with azathioprine (AZA). After 5 infusions, IFX was stopped while continuing AZA. SU treatment consisted of induction therapy with EEN or oral prednisolone combined with AZA as a maintenance treatment. In both groups, IFX could be (re)started on predefined conditions. The primary endpoint of this study was sustained clinical remission (wPCDAI Results 100 patients were included in 12 centres. Three out of 100 patients did not start with the study after randomisation (n = 97; 49 TD vs. 48 SU). At 52 weeks, 21/48 (44%) of TD patients were in clinical remission without a need for treatment intensification or surgery, while in the SU group this number was significantly lower (8/48, p = 0.004). After induction therapy, IFX was (re)started in 19/49 (39%) TD patients compared with 30/48 (62%) SU patients within 52 weeks (p = 0.019). At week 10, significantly more TD (27/44, 61%) than SU treated patients (17/44, 39%) were in clinical remission (p = 0.033). Fifty-seven of 97 consented to endoscopy at week 10. Endoscopic remission rates were higher in TD (16/27 [59%], median SES-CD 1 [IQR 0–5]) than SU treated patients (5/30 [17%], median SES-CD 6 [IQR 3–16], p = 0.001). Similarly, low faecal calprotectin levels were more frequent in the TD group (n = 75; TD 21/40 [53%] vs. SU 9/35 [26%], p = 0.027). Conclusion We are the first to compare TD IFX to SU treatment in an RCT of paediatric CD patients. TD treatment was superior to SU in achieving sustained clinical remission. Therefore, we advise to start IFX directly after diagnosis in moderate-to-severe paediatric Crohn’s disease patients.

In the original article, author Carsten Posovszky's surname was incorrectly spelt. This has now been corrected.

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

Background and Aims. Use of anti-TNF therapies varies internationally. As an initiative of the international Pediatric IBD Network (PIBDNet), we compared global pediatric IBD anti-TNF practice patterns. Methods. Physicians were surveyed about anti-TNF use in Crohn’s disease (CD) and ulcerative colitis (UC). Chi-squared, independent samples Mann–Whitney U, or related samples Wilcoxon signed rank tests were used to compare groups. Results. 344 physicians treating pediatric IBD responded from 43 countries (54% North America, 29% Europe, 6% Oceania, 6% Asia, 3% Africa, and 2% South America). Respondents treated a median 40 IBD patients. CD was more commonly treated with anti-TNF than UC (40% vs. 10%, p Conclusions. Anti-TNF use in North America varies significantly from elsewhere.

BACKGROUND AND AIMS: A growing body of evidence supports the need for detailed attention to nutrition and diet in children with inflammatory bowel disease (IBD). We aimed to define the steps in instituting dietary or nutritional management in light of the current evidence and to offer a useful and practical guide to physicians and dieticians involved in the care of pediatric IBD patients. METHODS: A group of 20 experts in pediatric IBD participated in an iterative consensus process including 2 face-to-face meetings, following an open call to Nutrition Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition Porto, IBD Interest, and Nutrition Committee. A list of 41 predefined questions was addressed by working subgroups based on a systematic review of the literature. RESULTS: A total of 53 formal recommendations and 47 practice points were endorsed with a consensus rate of at least 80% on the following topics: nutritional assessment; macronutrients needs; trace elements, minerals, and vitamins; nutrition as a primary therapy of pediatric IBD; probiotics and prebiotics; specific dietary restrictions; and dietary compounds and the risk of IBD. CONCLUSIONS: This position paper represents a useful guide to help the clinicians in the management of nutrition issues in children with IBD.

Because the patents for biopharmaceutical monoclonal antibodies have or soon will expire, biosimilars are coming to the market. This will most likely lead to decreased drug costs and so easier access to these expensive agents. Extrapolation, however, of the limited available clinical data from adults with rheumatologic diseases to children with inflammatory bowel disease (IBD) should be done with caution and needs some considerations. Postmarketing surveillance programs for efficacy, safety, and immunogenicity should become mandatory in children with IBD using biosimilars, as for all biological drugs.

Background and aims: Methotrexate [MTX] is an immunomodulating drug that can be used to maintain remission in patients with Crohn's disease [CD], but data on efficacy and tolerability in children and teenagers are scarce. We evaluated the long-term efficacy and tolerability of MTX monotherapy after thiopurine therapy in paediatric CD patients.Methods: A multicenter cohort of paediatric MTX users who stopped thiopurines due to ineffectiveness or intolerance between 2002 and 2012 were included and followed for at least 12 months. Relapse-free use was defined as steroid and biologics-free clinical remission after the introduction of MTX, and included intentional discontinuation of successful therapy before the end of the observation period.Results: A total of 113 patients with CD in remission were followed while on MTX monotherapy, of whom 75 [66%] had failed on thiopurines and 38 [34%] had stopped thiopurines due to side effects. Median age at the introduction of MTX was 14 years [range 7 to 17], and 93% used the subcutaneous route. Kaplan-Meier analysis showed that 52% of the study cohort were still in steroid-and biologics-free remission after 12 months of MTX monotherapy, with a difference that did not reach significance between thiopurine-intolerant and thiopurine-failing patients [p = 0.21, log-rank test].Conclusions: The findings of this cohort study suggest that MTX is an effective immunomodulator to maintain remission after stopping thiopurines. MTX maintenance should be considered before stepping up to anti-tumor necrosis factor alpha therapy. MTX is probably somewhat more effective in patients who stopped thiopurines due to side effects than in those who failed on thiopurines.

Since the introduction of anti-tumor necrosis factor (TNF) therapy as treatment of inflammatory bowel disease (IBD), care of pediatric and adult patients with IBD has significantly improved. To further improve treatment efficacy and durability, multiple trials have compared the efficacy of combination therapy, using anti-TNF therapy combined with an immunomodulator (a thiopurine or methotrexate), with that of anti-TNF monotherapy with contradicting results. The safety of combined therapy has been questioned after several reported cases of hepatosplenic T-cell lymphoma in young patients with IBD so treated. Physicians prescribing anti-TNF therapy to patients with IBD are required to weigh the benefits of combined therapy with its risks. To inform physicians treating children with IBD of these benefits and risks, we reviewed studies in pediatric and adult patients with IBD comparing efficacy, durability, and/or safety of combined therapy with anti-TNF monotherapy.

It has been identified that one of the dosages listed within the above article was incorrectly abbreviated during the production process. This is now presented correctly in this article.

Background & Aims Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 ( PCSK1 ) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. Methods We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1 . We measured enzymatic activity of recombinant PC1/3 proteins. Results We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. Conclusions In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1 , failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

Infliximab, adalimumab, and certolizumab are monoclonal antibodies against tumor necrosis factor-α (TNFα), a proinflammatory cytokine with an increased expression in the inflamed tissues of inflammatory bowel disease (IBD) patients. Currently, infliximab is the only anti-TNF drug that has been approved for use in refractory pediatric Crohn's disease (CD). Nevertheless, adalimumab and certolizumab have been used off-label to treat refractory pediatric IBD. Over the past 10 years, anti-TNF treatment has been of great benefit to many pediatric IBD patients, but their use is not without risks (infections, autoimmune diseases, malignancies). Despite the growing experience with these drugs in children with IBD, optimal treatment strategies still need to be determined. The purpose of this review is to summarize the current knowledge on the use of anti-TNF drugs in pediatric IBD and to discuss the yet-unsolved issues. (Inflamm Bowel Dis 2011;)

Combined immunosuppression by immunomodulators and biological therapy has become standard in the medical management of moderate-to-severe inflammatory bowel disease (IBD) because of clearly demonstrated efficacy. Clinical studies, registries, and case reports warn of the increased risk of infections, particularly opportunistic infections; however, already in the steroid monotherapy era, patients are at risk because it is accepted that a patient should be considered immunosuppressed when receiving a daily dose of 20 mg of prednisone for 2 weeks. Prescriptions increasingly involve azathioprine, methotrexate, and various biological agents. The TREAT registry evaluated safety in >6000 adult patients, half of them treated with infliximab (IFX) for about 1.9 years. IFX-treated patients had an increased risk of infections and this was associated with disease severity and concomitant prednisone use. The REACH study, evaluating the efficacy of IFX in children with moderate-to-severe Crohn disease, refractory to immunomodulatory treatment, reports serious infections as the major adverse events and their frequency is higher with shorter treatment intervals. The combination of immunosuppressive medications is a risk factor for opportunistic infections. Exhaustive guidelines on prophylaxis, diagnosis, and management of opportunistic infections in adult patients with IBD have been published by a European Crohn's and Colitis Organization working group, including clear evidence-based statements. We have reviewed the literature on infections in pediatric IBD as well as the European Crohn's and Colitis Organization guidelines to present a commentary on infection prophylaxis for the pediatric age group.

Background The usefulness of single-balloon enteroscopy (SBE) has not been evaluated in children with known or suspected Crohn's disease (CD). Objective The objectives of this study are to evaluate the diagnostic yield of SBE for pediatric CD by comparing it with US and magnetic resonance enterography (MRE). Design Single-center prospective study. Setting Tertiary-care referral hospital. Patients Between February 2009 and April 2010, 20 pediatric patients (ages 8-18 years) with suspected inflammatory bowel disease (IBD) or with a previous diagnosis of CD with suspected persistent small-bowel disease were enrolled. Interventions All patients underwent proximal and distal SBE, 17 patients also underwent US combined with Doppler flow measurements, and 18 underwent MRE. Main Outcome Measurements The findings of US with Doppler flow measurements and MRE were compared with those with SBE. Results The mean patient age was 15.0 years (range 11.3-18 years, 70% male). Of 14 patients with suspected IBD, 8 had a diagnosis of CD made after SBE. Activity in the small bowel was found in 14 patients (70%) with both suspected and previously diagnosed CD. Twelve patients (60%) had small-bowel disease that was out of reach of conventional endoscopy. Three patients (15%) had small-bowel activity solely in the jejunum, which was not detected by either MRE or US. Limitations Single-center study with small sample size. Conclusions SBE can be used in children to accurately assess small-bowel disease and CD. Small-bowel activity may be identified by SBE in some patients in whom it may not be apparent despite use of conventional upper endoscopy, ileocolonoscopy, US with Doppler flow measurements, or MRE.

Percutaneous endoscopic gastrostomy (PEG) provides for enteral nutrition in children with feeding problems. PEG, however, is not without complications. The present study has a twofold aim: (1) comparing our incidence of major complications after PEG with the incidence in other centers, and (2) identifying risk factors for major complications. All patients receiving a PEG or laparoscopic-assisted PEG (lap PEG) in the period 1992-2008 were reviewed. Primary outcome was the occurrence of major complications, defined as the need for surgery, nonprophylactic antibiotics, or blood transfusion, and procedure-related death. Potential risk factors, eg, age under 1 year, mental retardation, scoliosis, constipation, hepatomegaly, upper abdominal surgery, ventriculoperitoneal shunt, peritoneal dialysis, esophageal stenosis, and coagulopathy, were analyzed. Of the 467 patients (448 PEG, 19 lap PEG), 12.6% developed major complications. The complication rate significantly decreased ( P = 0.003) over the years. A significantly higher complication rate of 32% ( P = 0.02) occurred in children with a ventriculoperitoneal shunt. None of the lap PEG procedures was associated with a major complication, but the difference was not significant, perhaps because of the small numbers in the latter group. The major complication rate after PEG in children is high. Preexisting ventriculoperitoneal shunt is a significant risk factor. Laparoscopically assisted PEG procedures seem to be associated with a lesser major complication rate.