Physical Activity in Pediatric Inflammatory Bowel Disease: A Scoping Review.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic, systemic condition affecting the gastrointestinal tract. IBD can be severe and are associated with impairment in growth, school absences, abdominal pain, and fatigue. Physical activity (PA) could have an anti-inflammatory effect in addition to other benefits. It is important to address the possible risks, physiological effects of PA, and potential barriers, and facilitators for PA participation in pediatric IBD. However, potential barriers and facilitators to PA have yet to be adequately described. METHODS: We conducted a scoping review to map and describe the current literature on PA in pediatric IBD populations between 1980 and April 2022 using Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines for Scoping reviews. RESULTS: Nineteen articles were identified including 10 descriptive, 6 interventional, and 3 physiological responses to PA studies. Patients and healthy controls demonstrated similar responses to exercise. Barriers to participation were low self-esteem, body image, and active IBD symptoms. Facilitators included personal interest, activity with friends, and support from family. CONCLUSION: This review highlighted that PA participation may reduce in children with IBD-related symptoms. Short- and medium-term impacts of PA on immune modulation require further study; it is possible that regular PA does not negatively affect biomarkers of disease activity.

ADALIMUMAB VERSUS INFLIXIMAB IN LUMINAL PEDIATRIC CROHN'S DISEASE: COMPARABLE OUTCOMES IN A PROSPECTIVE MULTICENTER COHORT STUDY.

BACKGROUND: This study compared real-world effectiveness between adalimumab (ADA) and infliximab (IFX) in children with Crohn's disease (CD). METHODS: Children enrolled into the prospective Canadian Children Inflammatory Bowel Disease Network (CIDsCaNN) National Inception Cohort between 2014 and 2020 who commenced ADA or IFX as first anti-tumor necrosis factor (antiTNF) agent for luminal CD were included. Multivariate logistic regression modelled the propensity of commencing ADA; propensity score matching was used to match IFX-treated children to ADA-treated children. The primary outcome at one year was steroid-free clinical remission (SFCR). Secondary outcomes at one year were I) combined SFCR and c-reactive protein (CRP) remission; II) treatment intensification; and III) antiTNF durability. Odds ratios (aOR) and hazard ratio (aHR) adjusted for concomitant immunomodulator use with 95% confidence interval (CI) are reported. RESULTS: In the propensity score matched cohort of 147 ADA-treated and 147 IFX-treated children, 92 (63%) ADA- and 87 (59%) IFX-treated children achieved SFCR at one year (aOR: 1.4, 95% CI 0.9-2.4); 75 of 140 (54%) ADA- and 85 of 144 (59%) IFX-treated children achieved combined SFCR and CRP remission (aOR: 1.0, 95% CI 0.6-1.6). ADA-treated children less frequently underwent treatment intensification (21 [14%]) compared to IFX-treated children (69 [47%]) (P<0.0001). Discontinuation of antiTNF occurred in 18 (12%) ADA-treated and 15 (10%) IFX-treated children (aHR: 1.2, 95% CI 0.6-2.2). CONCLUSION: Children with Crohn's disease achieved favourable outcomes at one year with either ADA or IFX as first antiTNF agents. Those receiving IFX did not have significantly superior outcomes compared to clinically similar children receiving ADA.

Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function.

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/-)Il10rb(-/-) mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

Microbiota signatures and mucosal healing in the use of enteral nutrition therapy v. corticosteroids for the treatment of children with Crohn's disease: a systematic review and meta-analysis.

Corticosteroids (CS) and exclusive and partial enteral nutrition (EEN and PEN) are effective therapies in paediatric Crohn's disease (CD). This systematic review of randomised controlled trials (RCT) and cohort studies analyses the impact of EEN/PEN v. CS on intestinal microbiota, mucosal healing as well as other clinically important outcomes, including clinical remission, relapse, adherence, adverse events and health-related quality of life (HRQL) in paediatric CD. Three RCT (n 76) and sixteen cohort studies (n 1104) compared EEN v. CS. With limited available data (one RCT), the effect on intestinal microbiome indicated a trend towards EEN regarding Shannon diversity. Based on two RCT, EEN achieved higher mucosal healing than CS (risk ratio (RR) 2·36, 95 % CI (1·22, 4·57), low certainty). Compared with CS, patients on EEN were less likely to experience adverse events based on two RCT (RR 0·32, 95 % CI (0·13, 0·80), low certainty). For HRQL, there was a trend in favour of CS based on data from two published abstracts of cohort studies. Based on thirteen cohort studies, EEN achieved higher clinical remission than CS (RR 1·18, 95 % CI (1·02, 1·38), very low certainty). Studies also reported no important differences in relapse and adherence. Compared with CS, EEN may improve mucosal healing with fewer adverse events based on RCT data. While limited data indicate the need for further trials, this is the first systematic review to comprehensively summarise the data on intestinal microbiome, mucosal healing and HRQOL when comparing enteral nutrition and CS in paediatric CD.

Pediatric Patients with a Dual Diagnosis of Inflammatory Bowel Disease and Chronic Recurrent Multifocal Osteomyelitis.

ABSTRACT: There is a paucity of information about the epidemiology, pathophysiology, and treatment of patients with a dual diagnosis of inflammatory bowel disease (IBD) and chronic recurrent multifocal osteomyelitis (CRMO). A retrospective chart review was performed of patients at McMaster Children's Hospital with a diagnosis of either IBD or CRMO, to identify those with the dual diagnosis over a 10-year period. A dual diagnosis was identified in seven patients. Most patients (6/7) had a diagnosis of IBD first and were subsequently diagnosed with CRMO. At the time of CRMO diagnosis, IBD treatment regimens included one or more of, sulfasalazine (1/6), infliximab (3/6), adalimumab (1/6), or no treatment (1/6). Although the etiology of the link remains unknown, there does not seem to be an association to a specific IBD subtype, age, or treatment. Our patient population demonstrated a response to biologic agents, specifically tumor necrosis factor-α inhibitors, as treatment for both conditions.

Canadian Association of Gastroenterology Clinical Practice Guideline for the Medical Management of Pediatric Luminal Crohn's Disease.

BACKGROUND & AIMS: We aim to provide guidance for medical treatment of luminal Crohn's disease in children. METHODS: We performed a systematic search of publication databases to identify studies of medical management of pediatric Crohn's disease. Quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. We developed statements through an iterative online platform and then finalized and voted on them. RESULTS: The consensus includes 25 statements focused on medical treatment options. Consensus was not reached, and no recommendations were made, for 14 additional statements, largely due to lack of evidence. The group suggested corticosteroid therapies (including budesonide for mild to moderate disease). The group suggested exclusive enteral nutrition for induction therapy and biologic tumor necrosis factor antagonists for induction and maintenance therapy at diagnosis or at early stages of severe disease, and for patients failed by steroid and immunosuppressant induction therapies. The group recommended against the use of oral 5-aminosalicylate for induction or maintenance therapy in patients with moderate disease, and recommended against thiopurines for induction therapy, corticosteroids for maintenance therapy, and cannabis in any role. The group was unable to clearly define the role of concomitant immunosuppressants during initiation therapy with a biologic agent, although thiopurine combinations are not recommended for male patients. No consensus was reached on the role of aminosalicylates in treatment of patients with mild disease, antibiotics or vedolizumab for induction or maintenance therapy, or methotrexate for induction therapy. Patients in clinical remission who are receiving immunomodulators should be assessed for mucosal healing within 1 year of treatment initiation. CONCLUSIONS: Evidence-based medical treatment of Crohn's disease in children is recommended, with thorough ongoing assessments to define treatment success.

Clinical disease activity and endoscopic severity correlate poorly in children newly diagnosed with Crohn's disease.

BACKGROUND AND AIMS: Treatment goals in Crohn's disease (CD) have evolved to target mucosal healing. There is now a drive to determine if noninvasive measures can adequately identify the attainment and persistence of this goal. Currently, data describing the relationship between clinical indices and endoscopic appearance in pediatric CD are sparse. Our aim was to compare endoscopic severity with the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) in children with newly diagnosed CD. METHODS: All children aged ≤17 years newly diagnosed with CD enrolled in an inception cohort at sites of the Canadian Children Inflammatory Bowel Disease Network were eligible. Clinical disease activity at presentation was evaluated by the wPCDAI and conventional biochemical parameters. Severity of disease at ileocolonoscopy was assessed by the simple endoscopic score for CD (SES-CD), with segmental subscores noted. We evaluated the association of SES-CD and disease activity markers using the Pearson test of correlation, the Spearman rank coefficient, and linear regression models. RESULTS: Two hundred eighty patients from 11 centers were included in the analysis. The median wPCDAI score was 60 (interquartile range, 40-80; 53% severe). Median SES-CD was 16 (interquartile range 10-22; 51% severe). The wPCDAI correlated weakly with SES-CD (r = .39, P < .001). Examination of the individual components that contribute to the wPCDAI demonstrated weak correlation with the SES-CD for all items apart from stooling (moderate correlation, r = .50, P < .001). Routine blood tests did not correlate well with the SES-CD. In regression models, variation in clinical symptoms accounted for most of the variation in both the wPCDAI and SES-CD, with no additional benefit from routine blood tests. CONCLUSIONS: In children with newly diagnosed CD, wPCDAI correlates poorly with endoscopic disease activity. As treatment paradigms evolve to target mucosal healing, clinical markers should not be used in isolation to determine disease activity.

Enteral nutritional therapy for induction of remission in Crohn's disease.

BACKGROUND: Corticosteroids are often preferred over enteral nutrition (EN) as induction therapy for Crohn's disease (CD). Prior meta-analyses suggest that corticosteroids are superior to EN for induction of remission in CD. Treatment failures in EN trials are often due to poor compliance, with dropouts frequently due to poor acceptance of a nasogastric tube and unpalatable formulations. This systematic review is an update of a previously published Cochrane review. OBJECTIVES: To evaluate the effectiveness and safety of exclusive EN as primary therapy to induce remission in CD and to examine the importance of formula composition on effectiveness. SEARCH METHODS: We searched MEDLINE, Embase and CENTRAL from inception to 5 July 2017. We also searched references of retrieved articles and conference abstracts. SELECTION CRITERIA: Randomized controlled trials involving patients with active CD were considered for inclusion. Studies comparing one type of EN to another type of EN or conventional corticosteroids were selected for review. DATA COLLECTION AND ANALYSIS: Data were extracted independently by at least two authors. The primary outcome was clinical remission. Secondary outcomes included adverse events, serious adverse events and withdrawal due to adverse events. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI). A random-effects model was used to pool data. We performed intention-to-treat and per-protocol analyses for the primary outcome. Heterogeneity was explored using the Chi2 and I2 statistics. The studies were separated into two comparisons: one EN formulation compared to another EN formulation and EN compared to corticosteroids. Subgroup analyses were based on formula composition and age. Sensitivity analyses included abstract publications and poor quality studies. We used the Cochrane risk of bias tool to assess study quality. We used the GRADE criteria to assess the overall quality of the evidence supporting the primary outcome and selected secondary outcomes. MAIN RESULTS: Twenty-seven studies (1,011 participants) were included. Three studies were rated as low risk of bias. Seven studies were rated as high risk of bias and 17 were rated as unclear risk of bias due to insufficient information. Seventeen trials compared different formulations of EN, 13 studies compared one or more elemental formulas to a non-elemental formula, three studies compared EN diets of similar protein composition but different fat composition, and one study compared non-elemental diets differing in glutamine enrichment. Meta-analysis of 11 trials (378 participants) demonstrated no difference in remission rates. Sixty-four per cent (134/210) of patients in the elemental group achieved remission compared to 62% (105/168) of patients in the non-elemental group (RR 1.02, 95% CI 0.88 to 1.18; GRADE very low quality). A per-protocol analysis (346 participants) produced similar results (RR 1.04, 95% CI 0.91 to 1.18). Subgroup analyses performed to evaluate the different types of elemental and non-elemental diets (elemental, semi-elemental and polymeric) showed no differences in remission rates. An analysis of 7 trials including 209 patients treated with EN formulas of differing fat content (low fat: < 20 g/1000 kCal versus high fat: > 20 g/1000 kCal) demonstrated no difference in remission rates (RR 1.03; 95% CI 0.85 to 1.26). Very low fat content (< 3 g/1000 kCal) and very low long chain triglycerides demonstrated higher remission rates than higher content EN formulas. There was no difference between elemental and non-elemental diets in adverse event rates (RR 1.00, 95% CI 0.63 to 1.60; GRADE very low quality), or withdrawals due to adverse events (RR 1.29, 95% CI 0.80 to 2.09; GRADE very low quality). Common adverse events included nausea, vomiting, diarrhea and bloating.Ten trials compared EN to steroid therapy. Meta-analysis of eight trials (223 participants) demonstrated no difference in remission rates between EN and steroids. Fifty per cent (111/223) of patients in the EN group achieved remission compared to 72% (133/186) of patients in the steroid group (RR 0.77, 95% CI 0.58 to 1.03; GRADE very low quality). Subgroup analysis by age showed a difference in remission rates for adults but not for children. In adults 45% (87/194) of EN patients achieved remission compared to 73% (116/158) of steroid patients (RR 0.65, 95% CI 0.52 to 0.82; GRADE very low quality). In children, 83% (24/29) of EN patients achieved remission compared to 61% (17/28) of steroid patients (RR 1.35, 95% CI 0.92 to 1.97; GRADE very low quality). A per-protocol analysis produced similar results (RR 0.93, 95% CI 0.75 to 1.14). The per-protocol subgroup analysis showed a difference in remission rates for both adults (RR 0.82, 95% CI 0.70 to 0.95) and children (RR 1.43, 95% CI 1.03 to 1.97). There was no difference in adverse event rates (RR 1.39, 95% CI 0.62 to 3.11; GRADE very low quality). However, patients on EN were more likely to withdraw due to adverse events than those on steroid therapy (RR 2.95, 95% CI 1.02 to 8.48; GRADE very low quality). Common adverse events reported in the EN group included heartburn, flatulence, diarrhea and vomiting, and for steroid therapy acne, moon facies, hyperglycemia, muscle weakness and hypoglycemia. The most common reason for withdrawal was inability to tolerate the EN diet. AUTHORS' CONCLUSIONS: Very low quality evidence suggests that corticosteroid therapy may be more effective than EN for induction of clinical remission in adults with active CD. Very low quality evidence also suggests that EN may be more effective than steroids for induction of remission in children with active CD. Protein composition does not appear to influence the effectiveness of EN for the treatment of active CD. EN should be considered in pediatric CD patients or in adult patients who can comply with nasogastric tube feeding or perceive the formulations to be palatable, or when steroid side effects are not tolerated or better avoided. Further research is required to confirm the superiority of corticosteroids over EN in adults. Further research is required to confirm the benefit of EN in children. More effort from industry should be taken to develop palatable polymeric formulations that can be delivered without use of a nasogastric tube as this may lead to increased patient adherence with this therapy.

Oral budesonide for induction of remission in ulcerative colitis.

BACKGROUND: Corticosteroids are first-line therapy for induction of remission in ulcerative colitis. Although corticosteroids may improve symptoms, they have significant adverse effects. Steroids which act topically, with less systemic side-effects may be more desirable. Budesonide is a topically acting corticosteroid with extensive first pass hepatic metabolism. There are currently three formulations of budesonide: two standard formulations including a controlled-ileal release capsule and a pH-dependent capsule both designed to release the drug in the distal small intestine and right colon; and the newer Budesonide-MMX® capsule designed to release the drug throughout the entire colon. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in ulcerative colitis. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Group Specialised Register from inception to April 2015. We also searched reference lists of articles, conference proceedings and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials comparing oral budesonide to placebo or another active therapy for induction of remission in ulcerative colitis were considered eligible. There were no exclusions based on patient age or the type, dose, duration or formulation of budesonide therapy. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted data and assessed study quality. Methodological quality was assessed using the Cochrane risk of bias tool. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. The primary outcome was induction of remission (as defined by the primary studies) at week eight. Secondary outcomes included clinical, endoscopic and histologic improvement, adverse events and early withdrawal. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome and the mean difference (MD) and corresponding 95% CI for each continuous outcome. Data were analysed on an intention-to-treat basis. MAIN RESULTS: Six studies (1808 participants) were included. Four studies compared budesonide-MMX® with placebo, one small pilot study looked at clinical remission at week four, and was subsequently followed by three large, studies that assessed combined clinical and endoscopic remission at week eight. Although two placebo-controlled studies had mesalamine and Entocort (standard budesonide) treatment arms, these studies were not sufficiently powered to compare Budesonide-MMX® with these active comparators. One small study compared standard budesonide with prednisolone and one study compared standard budesonide to mesalamine. Four studies were rated as low risk of bias and two studies had an unclear risk of bias. A pooled analysis of three studies (900 participants) showed that budesonide-MMX® 9 mg was significantly superior to placebo for inducing remission (combined clinical and endoscopic remission) at 8 weeks. Fifteen per cent (71/462) of budesonide-MMX® 9 mg patients achieved remission compared to 7% (30/438) of placebo patients (RR 2.25, 95% CI 1.50 to 3.39). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (101 events). A subgroup analysis by concurrent mesalamine use suggests higher efficacy in the 442 patients who were not considered to be mesalamine-refractory (RR 2.89, 95% CI 1.59 to 5.25). A subgroup analysis by disease location suggests budesonide is most effective in patients with left-sided disease (RR 2.98, 95% CI 1.56 to 5.67; 289 patients). A small pilot study reported no statistically significant difference in endoscopic remission between budesonide and prednisolone (RR 0.75, 95% CI 0.23 to 2.42; 72 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to unclear risk of bias and very sparse data (10 events). Standard oral budesonide was significantly less likely to induce clinical remission than oral mesalamine after 8 weeks of therapy (RR 0.72, 95% CI 0.57 to 0.91; 1 study, 343 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (161 events). Another study found no difference in remission rates between budesonide-MMX® 9 mg and mesalamine (RR 1.48, 95% CI 0.81 to 2.71; 247 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (37 events). One study found no difference in remission rates between budesonide-MMX® 9 mg and standard budesonide 9 mg (RR 1.38, 95% CI 0.72 to 2.65; 212 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). Suppression of plasma cortisol was more common in prednisolone-treated patients (RR 0.02, 95% CI 0.0 to 0.33). While budesonide does appear to suppress morning cortisol to some extent, mean morning cortisol values remained within the normal range in 2 large studies (n = 899) and there was no difference in glucocorticoid-related side-effects across different treatment groups. Further, study withdrawal due to adverse events was not more common in budesonide compared with placebo treated patients (RR 0.85, 95% CI 0.53 to 1.38). Common adverse events included worsening ulcerative colitis, headache, pyrexia, insomnia, back pain, nausea, abdominal pain, diarrhoea, flatulence and nasopharyngitis. AUTHORS' CONCLUSIONS: Moderate quality evidence to supports the use of oral budesonide-MMX® at a 9 mg daily dose for induction of remission in active ulcerative colitis, particularly in patients with left-sided colitis. Budesonide-MMX® 9 mg daily is effective for induction of remission in the presence or absence of concurrent 5-ASA therapy. Further, budesonide-MMX® appears to be safe, and does not lead to significant impairment of adrenocorticoid function compared to placebo. Moderate quality evidence from a single study suggests that mesalamine may be superior to standard budesonide for the treatment of active ulcerative colitis. Low quality evidence from one study found no difference in remission rates between budesonide MMX® and mesalamine. Very low quality evidence from one small study showed no difference in endoscopic remission rates between standard budesonide and prednisolone. Low quality evidence from one study showed no difference in remission rates between budesonide-MMX® and standard budesonide. Adequately powered studies are needed to allow conclusions regarding the comparative efficacy and safety of budesonide versus prednisolone, budesonide-MMX® versus standard budesonide and budesonide versus mesalamine.

High Healthcare Costs in Childhood Inflammatory Bowel Disease: Development of a Prediction Model Using Linked Clinical and Health Administrative Data.

BACKGROUND: The incidence of pediatric-onset inflammatory bowel disease (IBD) and the costs of caring for individuals with IBD are both increasing. We calculated the direct healthcare costs of pediatric IBD in the first year after diagnosis and developed a model to predict children who would have high costs (top 25th percentile). METHODS: Using data from the Canadian Children IBD Network inception cohort (≤16 years of age, diagnosed between 2013 and 2019) deterministically linked to health administrative data from Ontario, Canada, we estimated direct healthcare and medication costs accrued between 31 and 365 days after diagnosis. Candidate predictors included age at diagnosis, sex, rural/urban residence location, distance to pediatric center, neighborhood income quintile, IBD type, initial therapy, disease activity, diagnostic delay, health services utilization or surgery around diagnosis, regular primary care provider, and receipt of mental health care. Logistic regression with stepwise elimination was used for model building; 5-fold nested cross-validation optimized and improved model accuracy while limiting overfitting. RESULTS: The mean cost among 487 children with IBD was CA$15 168 ± 15 305. Initial treatment (anti-tumor necrosis factor therapy, aminosalicylates, or systemic steroids), having a mental health care encounter, undergoing surgery, emergency department visit at diagnosis, sex, and age were predictors of increased costs, while having a regular primary care provider was a predictor of decreased costs. The C-statistic for our model was 0.71. CONCLUSIONS: The cost of caring for children with IBD in the first year after diagnosis is immense and can be predicted based on characteristics at diagnosis. Efforts that mitigate rising costs without compromising quality of care are needed.

Cost of caring for children with IBD is high­CA$15 168 between 31 and 365 days from diagnosis in 487 Canadian children. Predictors of high costs included anti-tumor necrosis factor therapy and mental health care, with lower costs in those with a primary-care provider.

Pre-Diagnosis Diet Predicts Response to Exclusive Enteral Nutrition and Correlates with Microbiome in Pediatric Crohn Disease.

Exclusive enteral nutrition (EEN) is effective in inducing remission in pediatric Crohn disease (CD). EEN alters the intestinal microbiome, but precise mechanisms are unknown. We hypothesized that pre-diagnosis diet establishes a baseline gut microbiome, which then mediates response to EEN. We analyzed prospectively recorded food frequency questionnaires (FFQs) for pre-diagnosis dietary patterns. Fecal microbiota were sequenced (16SrRNA) at baseline and through an 18-month follow-up period. Dietary patterns, Mediterranean diet adherence, and stool microbiota were associated with EEN treatment outcomes, disease flare, need for anti-tumor necrosis factor (TNF)-α therapy, and long-term clinical outcomes. Ninety-eight patients were included. Baseline disease severity and microbiota were associated with diet. Four dietary patterns were identified by FFQs; a "mature diet" high in fruits, vegetables, and fish was linked to increased baseline microbial diversity, which was associated with fewer disease flares (p < 0.05) and a trend towards a delayed need for anti-TNF therapy (p = 0.086). Baseline stool microbial taxa were increased (Blautia and Faecalibacterium) or decreased (Ruminococcus gnavus group) with the mature diet compared to other diets. Surprisingly, a "pre-packaged" dietary pattern (rich in processed foods) was associated with delayed flares in males (p < 0.05). Long-term pre-diagnosis diet was associated with outcomes of EEN therapy in pediatric CD; diet-microbiota and microbiota-outcome associations may mediate this relationship.

Infliximab-induced psoriasis and psoriasiform skin lesions in pediatric Crohn disease and a potential association with IL-23 receptor polymorphisms.

BACKGROUND: Infliximab (IFX), an established therapy for pediatric Crohn disease (CD), is also efficacious in treating psoriasis, a skin disorder, in which tumor necrosis factor-α is implicated pathogenically. Paradoxically, there have been numerous reports of new-onset psoriasis following tumor necrosis factor-α antagonist therapy in adult patients with inflammatory bowel disease, but pediatric data are sparse. METHODS: A retrospective review of all IFX-treated patients with CD, who subsequently developed psoriasis, at a single pediatric inflammatory bowel disease center, was performed. A subset of affected patients (10/18) and CD controls (147 of 172) treated with IFX but without the development of psoriasis were genotyped for polymorphisms in the interleukin-23 receptor (IL-23R) gene, which has been identified as conferring susceptibility to both CD and psoriasis. RESULTS: Eighteen (10.5%) of 172 IFX-treated patients with CD developed new-onset psoriasis (n = 17) or worsening of existing psoriasis (n = 1). The duration of IFX exposure was variable, ranging from 1 to 25 infusions. Three patients discontinued IFX because of this complication. Most patients responded well to topical steroid therapy. In comparison to disease-matched controls, patients with CD developing psoriasis following IFX therapy were more likely to be homozygous for specific polymorphisms in the IL-23R gene (rs10489628, rs10789229, and rs1343151). CONCLUSIONS: As in adults, the development of psoriasis or psoriasiform skin lesions occurs in pediatric patients with CD treated with IFX. Adequately powered studies are required to further explore the preliminary findings reported here to determine whether polymorphisms in the IL-23R gene have a role in the pathogenesis of this paradoxical process, which presently remains unexplained.

NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2.

OBJECTIVE: The NOX2 NADPH oxidase complex produces reactive oxygen species and plays a critical role in the killing of microbes by phagocytes. Genetic mutations in genes encoding components of the complex result in both X-linked and autosomal recessive forms of chronic granulomatous disease (CGD). Patients with CGD often develop intestinal inflammation that is histologically similar to Crohn's colitis, suggesting a common aetiology for both diseases. The aim of this study is to determine if polymorphisms in NOX2 NADPH oxidase complex genes that do not cause CGD are associated with the development of inflammatory bowel disease (IBD). METHODS: Direct sequencing and candidate gene approaches were used to identify susceptibility loci in NADPH oxidase complex genes. Functional studies were carried out on identified variants. Novel findings were replicated in independent cohorts. RESULTS: Sequence analysis identified a novel missense variant in the neutrophil cytosolic factor 2 (NCF2) gene that is associated with very early onset IBD (VEO-IBD) and subsequently found in 4% of patients with VEO-IBD compared with 0.2% of controls (p=1.3×10(-5), OR 23.8 (95% CI 3.9 to 142.5); Fisher exact test). This variant reduced binding of the NCF2 gene product p67(phox) to RAC2. This study found a novel genetic association of RAC2 with Crohn's disease (CD) and replicated the previously reported association of NCF4 with ileal CD. CONCLUSION: These studies suggest that the rare novel p67(phox) variant results in partial inhibition of oxidase function and are associated with CD in a subgroup of patients with VEO-IBD; and suggest that components of the NADPH oxidase complex are associated with CD.

Inflammatory Bowel Disease Among Canadian Children: Comparison Between Children of Non-European Descent and Children of European Descent.

BACKGROUND: Inflammatory bowel disease (IBD) phenotypes may differ between countries and ancestral groups. The study aim was to examine ancestry and subtype variations of children newly diagnosed with IBD. METHODS: Children newly diagnosed with IBD enrolled into the Canadian Children Inflammatory Bowel Disease Network inception cohort study were categorized into 8 ancestral groups. Prospectively collected data at diagnosis and follow-up were compared between ancestral groups. RESULTS: Among 1447 children (63.2% Crohn's disease, 30.7% ulcerative colitis), 67.8% were European, 9.4% were South Asian, 3.8% were West Central Asian and Middle Eastern, 2.3% were African, 2.2% were East/South East Asian, 2.0% were Caribbean/Latin/Central/South American, 9.9% were mixed, and 2.6% were other. Children of African descent with ulcerative colitis had an older age of diagnosis compared with children of European descent (median 15.6 years vs 13.3 years; P = .02). Children of European descent had a higher proportion of positive family history with IBD (19.3% vs 12.1%; P = .001) compared with children of non-European descent. Children of European descent also had a lower proportion of immigrants and children of immigrants compared with children of non-European descent (9.8% vs 35.9%; P < .0001; and 3.6% vs 27.2%; P < .0001, respectively) . CONCLUSIONS: Important differences exist between different ancestral groups in pediatric patients with IBD with regard to age of diagnosis, family history, and immigrant status. Our study adds to the knowledge of the impact of ancestry on IBD pathogenesis.

This study explores the ancestral and phenotypic variation of Canadian children newly diagnosed with inflammatory bowel disease. It identifies differences between children of European and non-European descent in phenotypes of inflammatory bowel disease, disease location and behavior, family history, and immigrant status.

Medical therapy for pediatric inflammatory bowel disease.

Pediatric inflammatory bowel disease encompasses a spectrum of disease phenotype, severity, and responsiveness to treatment. Intestinal healing rather than merely symptom control is an especially important therapeutic goal in young patients, given the potential for growth impairment as a direct effect of persistent chronic inflammation and the long life ahead, during which other disease complications may occur. Corticosteroids achieve rapid symptom control, but alternate steroid-sparing strategies with greater potential to heal the intestine must be rapidly adopted. Exclusive enteral nutrition is an alternate short-term treatment in pediatric Crohn's disease. The results of multi-center pediatric clinical trials of both infliximab and adalimumab in Crohn's disease and of infliximab in ulcerative colitis (all in children with unsatisfactory responses to other therapies) have now been reported and guide treatment regimens in clinical practice. Optimal patient selection and timing of anti-TNF therapy requires clinical judgment. Attention must be paid to sustaining responsiveness safely.

Virtual reality simulation training for health professions trainees in gastrointestinal endoscopy.

BACKGROUND: Traditionally, training in gastrointestinal endoscopy has been based upon an apprenticeship model, with novice endoscopists learning basic skills under the supervision of experienced preceptors in the clinical setting. Over the last two decades, however, the growing awareness of the need for patient safety has brought the issue of simulation-based training to the forefront. While the use of simulation-based training may have important educational and societal advantages, the effectiveness of virtual reality gastrointestinal endoscopy simulators has yet to be clearly demonstrated. OBJECTIVES: To determine whether virtual reality simulation training can supplement and/or replace early conventional endoscopy training (apprenticeship model) in diagnostic oesophagogastroduodenoscopy, colonoscopy and/or sigmoidoscopy for health professions trainees with limited or no prior endoscopic experience. SEARCH METHODS: Health professions, educational and computer databases were searched until November 2011 including The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Scopus, Web of Science, Biosis Previews, CINAHL, Allied and Complementary Medicine Database, ERIC, Education Full Text, CBCA Education, Career and Technical Education @ Scholars Portal, Education Abstracts @ Scholars Portal, Expanded Academic ASAP @ Scholars Portal, ACM Digital Library, IEEE Xplore, Abstracts in New Technologies and Engineering and Computer & Information Systems Abstracts. The grey literature until November 2011 was also searched. SELECTION CRITERIA: Randomised and quasi-randomised clinical trials comparing virtual reality endoscopy (oesophagogastroduodenoscopy, colonoscopy and sigmoidoscopy) simulation training versus any other method of endoscopy training including conventional patient-based training, in-job training, training using another form of endoscopy simulation (e.g. low-fidelity simulator), or no training (however defined by authors) were included.  Trials comparing one method of virtual reality training versus another method of virtual reality training (e.g. comparison of two different virtual reality simulators) were also included. Only trials measuring outcomes on humans in the clinical setting (as opposed to animals or simulators) were included. DATA COLLECTION AND ANALYSIS: Two authors (CMS, MES) independently assessed the eligibility and methodological quality of trials, and extracted data on the trial characteristics and outcomes. Due to significant clinical and methodological heterogeneity it was not possible to pool study data in order to perform a meta-analysis. Where data were available for each continuous outcome we calculated standardized mean difference with 95% confidence intervals based on intention-to-treat analysis. Where data were available for dichotomous outcomes we calculated relative risk with 95% confidence intervals based on intention-to-treat-analysis. MAIN RESULTS: Thirteen trials, with 278 participants, met the inclusion criteria. Four trials compared simulation-based training with conventional patient-based endoscopy training (apprenticeship model) whereas nine trials compared simulation-based training with no training. Only three trials were at low risk of bias. Simulation-based training, as compared with no training, generally appears to provide participants with some advantage over their untrained peers as measured by composite score of competency, independent procedure completion, performance time, independent insertion depth, overall rating of performance or competency error rate and mucosal visualization. Alternatively, there was no conclusive evidence that simulation-based training was superior to conventional patient-based training, although data were limited. AUTHORS' CONCLUSIONS: The results of this systematic review indicate that virtual reality endoscopy training can be used to effectively supplement early conventional endoscopy training (apprenticeship model) in diagnostic oesophagogastroduodenoscopy, colonoscopy and/or sigmoidoscopy for health professions trainees with limited or no prior endoscopic experience. However, there remains insufficient evidence to advise for or against the use of virtual reality simulation-based training as a replacement for early conventional endoscopy training (apprenticeship model) for health professions trainees with limited or no prior endoscopic experience. There is a great need for the development of a reliable and valid measure of endoscopic performance prior to the completion of further randomised clinical trials with high methodological quality.

Venous thromboembolism in pediatric inflammatory bowel disease: an 11-year population-based nested case-control study in Canada.

To investigate the occurrence of venous thromboembolism (VTE), clinical characteristics, risk factors, treatment outcomes, and anticoagulation safety in pediatric inflammatory bowel disease (IBD) over an 11-year period. A nested case-control study within an identified cohort was performed amongst children with IBD from 2009 to 2020 in Canada. There were 890 hospitalizations during the study period, and 15 venous thromboembolic events (1.69%) among 12 patients occurred, including 12 with ulcerative colitis and three with Crohn's disease. VTE proportions were significantly different between female (2.7%) and male (0.8%) patients (P = 0.03). VTE in the ulcerative colitis group (4.2%) was significantly higher than in the Crohn's disease group (0.6%) (P = 0.001). Central venous catheter and length of hospital stay were correlated to VTE development. Twelve of 15 (80%) with VTEs presented symptoms related to extremity thrombosis and pulmonary embolism. Nine of the 15 (60%) had a deep vein thrombosis, and 2 (13.3%) developed a severe pulmonary embolism. Seven of 15 (47%) received anticoagulation therapy for 1-6 months. VTE-related symptoms and repeat imaging tests improved with no bleeding complication in those treated with anticoagulation therapy. No patients received long-term thromboprophylaxis after antithrombotic treatment was discontinued. The VTE proportion in pediatric IBD patients was relatively low. Children with VTE were disproportionately females with ulcerative colitis compared with children without VTE. Patients with VTE had a good prognosis after anticoagulation therapy without mortality or increased bleeding events. The role of VTE screening and efficacy of thromboprophylaxis need to be further evaluated.

Clinical and Laboratory Characteristics Are Associated With Biologic Therapy Use in Pediatric Inflammatory Bowel Disease: A Retrospective Cohort Study.

BACKGROUND: Biologic agents are a highly useful class of medications for treating inflammatory bowel disease (IBD). Limited evidence exists to guide initiation of biologic therapy, especially in pediatric patients. It is unclear if disease severity is connected to biologic response. We hypothesized that the clinical, biochemical and radiographic characteristics of pediatric IBD at diagnosis were associated with subsequent initiation of biologic therapy. METHODS: We performed a retrospective analysis of the charts of all pediatric patients diagnosed with IBD at our centre over 14 years. Kaplan-Meier curves evaluated patient characteristics at diagnosis with time to initiation of biologic therapy. A Cox proportional hazards model was used for multivariate characteristic analysis. RESULTS: A total of 198 patients were included, 57.6% had Crohn's disease, 27.8% had ulcerative colitis and 14.6% had IBD type unclassified. Mean follow-up time was 47.8 months. About 55.5% of the patients received a biologic medication, the mean time to biologic initiation was 21.5 months. Earlier initiation of biologic therapy was frequently associated with older age, higher disease activity index and lower serum albumin. CONCLUSIONS: Older pediatric patients with more severely active disease and lower serum albumin levels at the time of IBD diagnosis were more likely to initiate biologic therapy when considering biologic initiation, even many years after diagnosis. Identification of these characteristics may help inform decisions to initiate biologic therapy earlier in the IBD disease course.