The intestinal microbiome of inflammatory bowel disease across the pediatric age range.

Dysbiosis is associated with pediatric and adult-onset inflammatory bowel disease (IBD), but the role of dysbiosis and the microbiome in very early onset IBD (VEO-IBD) has not yet been described. Here, we aimed to demonstrate the impact of age and inflammation on microbial community structure using shotgun metagenomic sequencing in children with VEO-IBD, pediatric-onset IBD, and age-matched pediatric healthy controls (HC) observed longitudinally over the course of 8 weeks. We found disease-related differences in alpha and beta diversity between HC and children with IBD or VEO-IBD. Using a healthy microbial maturity index modeled from HC across the age range to characterize their gut microbiota, we found that children with pediatric-onset IBD and VEO-IBD had lower maturity than their age-matched HC groups, suggesting a disease effect on the microbial community. In addition, patients with pediatric IBD had significantly lower maturity than those with VEO-IBD, who had more heterogeneity at the youngest ages, highlighting differences in these two cohorts that were not captured in standard comparisons of alpha and beta diversity. These results demonstrate that young age and inflammation independently impact microbial community structure. However, the effect is not additive in the youngest patients, likely because of the heterogeneous and dynamic stool microbiome in this population.

Trajectory of body mass index and obesity in children with Crohn's disease compared to healthy children.

BACKGROUND: There is increasing recognition that children with Crohn's Disease (CD) can develop obesity. METHODS: Using the RISK Study, an inception cohort of pediatric CD participants, and Bone Mineral Density in Childhood Study (BMDCS), a longitudinal cohort of healthy children, multivariable linear mixed effects, generalized linear mixed effects, and logistic regression models were used to evaluate factors associated with change in body mass index z-score (BMIZ), obesity, and excessive weight gain, respectively. RESULTS: 1029 CD participants (625 exposed to antitumor necrosis factor (anti-TNF) therapy) and 1880 healthy children were included. Change in BMIZ was higher in CD exposed to anti-TNF as compared to CD unexposed to anti-TNF and the healthy reference group. Sex, age, baseline BMIZ, C-reactive protein, anti-TNF, and steroids were associated with changes in BMIZ in CD. CD exposed (odds ratio [OR] 4.81, confidence interval [CI] 4.00-5.78) and unexposed (OR 3.14, CI 2.62-3.76) had a greater likelihood of becoming obese versus the healthy reference group. While the prevalence of obesity was higher at baseline in the healthy reference group (21.3%) versus CD participants (8.5% exposed vs. 11.1% unexposed), rates of obesity were similar by the end of follow-up (21.4% healthy vs. 20.3% exposed vs. 22.5% unexposed). Anti-TNF therapy was an independent risk factor for the development of obesity and excessive weight gain in CD participants. CONCLUSIONS: Patients with CD have dynamic changes in BMIZ over time, and while for most, this is restorative, for some, this can lead to obesity and excessive weight gain. It is important to understand the factors that may lead to these changes, including anti-TNF therapy. Counseling of patients and early lifestyle intervention may be necessary.

One-shot distributed algorithms for addressing heterogeneity in competing risks data across clinical sites.

OBJECTIVE: To characterize the interplay between multiple medical conditions across sites and account for the heterogeneity in patient population characteristics across sites within a distributed research network, we develop a one-shot algorithm that can efficiently utilize summary-level data from various institutions. By applying our proposed algorithm to a large pediatric cohort across four national Children's hospitals, we replicated a recently published prospective cohort, the RISK study, and quantified the impact of the risk factors associated with the penetrating or stricturing behaviors of pediatric Crohn's disease (PCD). METHODS: In this study, we introduce the ODACoRH algorithm, a one-shot distributed algorithm designed for the competing risks model with heterogeneity. Our approach considers the variability in baseline hazard functions of multiple endpoints of interest across different sites. To accomplish this, we build a surrogate likelihood function by combining patient-level data from the local site with aggregated data from other external sites. We validated our method through extensive simulation studies and replication of the RISK study to investigate the impact of risk factors on the PCD for adolescents and children from four children's hospitals within the PEDSnet, A National Pediatric Learning Health System. To evaluate our ODACoRH algorithm, we compared results from the ODACoRH algorithms with those from meta-analysis as well as those derived from the pooled data. RESULTS: The ODACoRH algorithm had the smallest relative bias to the gold standard method (-0.2%), outperforming the meta-analysis method (-11.4%). In the PCD association study, the estimated subdistribution hazard ratios obtained through the ODACoRH algorithms are identical on par with the results derived from pooled data, which demonstrates the high reliability of our federated learning algorithms. From a clinical standpoint, the identified risk factors for PCD align well with the RISK study published in the Lancet in 2017 and other published studies, supporting the validity of our findings. CONCLUSION: With the ODACoRH algorithm, we demonstrate the capability of effectively integrating data from multiple sites in a decentralized data setting while accounting for between-site heterogeneity. Importantly, our study reveals several crucial clinical risk factors for PCD that merit further investigations.

Enterobacteriaceae Growth Promotion by Intestinal Acylcarnitines, a Biomarker of Dysbiosis in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Altered plasma acylcarnitine levels are well-known biomarkers for a variety of mitochondrial fatty acid oxidation disorders and can be used as an alternative energy source for the intestinal epithelium when short-chain fatty acids are low. These membrane-permeable fatty acid intermediates are excreted into the gut lumen via bile and are increased in the feces of patients with inflammatory bowel disease (IBD). METHODS: Herein, based on studies in human subjects, animal models, and bacterial cultures, we show a strong positive correlation between fecal carnitine and acylcarnitines and the abundance of Enterobacteriaceae in IBD where they can be consumed by bacteria both in vitro and in vivo. RESULTS: Carnitine metabolism promotes the growth of Escherichia coli via anaerobic respiration dependent on the cai operon, and acetylcarnitine dietary supplementation increases fecal carnitine levels with enhanced intestinal colonization of the enteric pathogen Citrobacter rodentium. CONCLUSIONS: In total, these results indicate that the increased luminal concentrations of carnitine and acylcarnitines in patients with IBD may promote the expansion of pathobionts belonging to the Enterobacteriaceae family, thereby contributing to disease pathogenesis.

Progression of Pediatric Crohn's Disease Is Associated With Anti-Tumor Necrosis Factor Timing and Body Mass Index Z-Score Normalization.

BACKGROUND & AIMS: The evolution of complicated pediatric Crohn's disease (CD) in the era of anti-tumor necrosis factor (aTNF) therapy continues to be described. Because CD progresses from inflammatory to stricturing (B2) and penetrating (B3) disease behaviors in a subset of patients, we aimed to understand the risk of developing complicated disease behavior or undergoing surgery in relation to aTNF timing and body mass index z-score (BMIz) normalization. METHODS: Multicenter, 5-year longitudinal data from 1075 newly diagnosed CD patients were analyzed. Descriptive statistics, univariate and stepwise multivariate Cox proportional hazard regression (CPHR), and log-rank analyses were performed for risk of surgery and complicated disease behaviors. Differential gene expression from ileal bulk RNA sequencing was correlated with outcomes. RESULTS: Stricturing complications had the largest increase: from 2.98% to 10.60% over 5 years. Multivariate CPHR showed aTNF exposure within 3 months from diagnosis (hazard ratio [HR], 0.33; 95% CI, 0.15-0.71) and baseline L2 disease (HR, 0.29; 95% CI, 0.09-0.92) to be associated with reduced B1 to B2 progression. For children with a low BMIz at diagnosis (n = 294), multivariate CPHR showed BMIz normalization within 6 months of diagnosis (HR, 0.47; 95% CI, 0.26-0.85) and 5-aminosalicyclic acid exposure (HR, 0.32; 95% CI, 0.13-0.81) were associated with a decreased risk for surgery while B2 (HR, 4.20; 95% CI, 1.66-10.65) and B2+B3 (HR, 8.24; 95% CI, 1.08-62.83) at diagnosis increased surgery risk. Patients without BMIz normalization were enriched for genes in cytokine production and inflammation. CONCLUSIONS: aTNF exposure up to 3 months from diagnosis may reduce B2 progression. In addition, lack of BMIz normalization within 6 months of diagnosis is associated with increased surgery risk and a proinflammatory transcriptomic profile.

Growth hormone use in pediatric inflammatory bowel disease.

OBJECTIVES: Impaired linear growth is a known complication of pediatric inflammatory bowel disease (IBD), but the use of growth hormone (GH) in this population is not well-described. The primary aim of this study is to determine whether growth hormone use in pediatric IBD leads to improved height outcomes. METHODS: This was a retrospective chart review of patients with IBD aged 0-21 years followed at a single center between 2018 and 2021 treated with at least 1 year of GH. Records collected included demographics, IBD phenotype, IBD disease activity scores, medications, weight z-score, height z-score, bone age, and details of GH therapy including testing for GH deficiency. The primary outcome measure was change in height z-score after 1 year of GH treatment. RESULTS: Forty-six patients were identified and 18 were excluded. Of the 28 patients included (7 female; 25.0 %), 26 (92.9 %) had a diagnosis of Crohn's disease (CD) and 2 (7.1 %) had ulcerative colitis (UC). The mean (SD) age at GH initiation was 9.6 (3.4) years. Among all participants, there was a significant mean difference in height z-score from baseline to 1 year on therapy (-2.25 vs. -1.50, respectively; difference, 0.75; 95 % CI, 0.56 to 0.94; p<0.001). Among the 19 subjects that completed GH therapy there was a significant mean difference between baseline and final height z-scores (-2.41 vs. -0.77, respectively; difference, 1.64; 95 % CI, 1.30 to 1.98; p<0.001). CONCLUSIONS: GH use was associated with improved height outcomes. The pediatric IBD patients in this cohort had significant improvements in height z-scores both after one year on therapy and at completion of GH therapy.

Missing data matter: an empirical evaluation of the impacts of missing EHR data in comparative effectiveness research.

OBJECTIVES: The impacts of missing data in comparative effectiveness research (CER) using electronic health records (EHRs) may vary depending on the type and pattern of missing data. In this study, we aimed to quantify these impacts and compare the performance of different imputation methods. MATERIALS AND METHODS: We conducted an empirical (simulation) study to quantify the bias and power loss in estimating treatment effects in CER using EHR data. We considered various missing scenarios and used the propensity scores to control for confounding. We compared the performance of the multiple imputation and spline smoothing methods to handle missing data. RESULTS: When missing data depended on the stochastic progression of disease and medical practice patterns, the spline smoothing method produced results that were close to those obtained when there were no missing data. Compared to multiple imputation, the spline smoothing generally performed similarly or better, with smaller estimation bias and less power loss. The multiple imputation can still reduce study bias and power loss in some restrictive scenarios, eg, when missing data did not depend on the stochastic process of disease progression. DISCUSSION AND CONCLUSION: Missing data in EHRs could lead to biased estimates of treatment effects and false negative findings in CER even after missing data were imputed. It is important to leverage the temporal information of disease trajectory to impute missing values when using EHRs as a data resource for CER and to consider the missing rate and the effect size when choosing an imputation method.

Exome Sequencing Implicates DGKZ , ESRRA , and GXYLT1 for Modulating Granuloma Formation in Crohn Disease.

Non-caseating granulomas may indicate a more aggressive phenotype of Crohn disease (CD). Genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis. Whole-exome sequencing was performed on peripheral blood-derived DNA from 17 pediatric patients with GCD and 19 with non-GCD (NGCD), and from an independent validation cohort of 44 GCD and 19 NGCD cases. PLINK (a tool set for whole-genome association and population-based linkage analyses) analysis was used to identify single nucleotide polymorphisms (SNPs) differentiating between groups, and subgroup allele frequencies were also compared to a public genomic database (gnomAD). The Combined Annotation Dependent Depletion scoring tool was used to predict deleteriousness of SNPs. Human leukocyte antigen (HLA) haplotype findings were compared to a control group (n = 8496). PLINK-based analysis between GCD and NGCD groups did not find consistently significant hits. gnomAD control comparisons, however, showed consistent subgroup associations with DGKZ , ESRRA , and GXYLT1 , genes that have been implicated in mammalian granulomatous inflammation. Our findings may guide future research and precision medicine.

Clinical and lifestyle patterns in Asian children with inflammatory bowel disease in the U.S.

BACKGROUND: While there are many epidemiologic studies of Asian immigrants to the West and risk of inflammatory bowel disease (IBD), the phenotype and lifestyle of Asian patients, particularly children, with IBD are not well described. In this study, we describe lifestyle practices, such as dietary pattern, as well as disease phenotype in Asian American children with IBD. METHODS: We reviewed the records of children with IBD, ages 0 to 21 years old, and race identified as Asian, Indian, or Pacific Islander. Patients who received outpatient IBD care at our center between January 2013 and January 2020 were included. We excluded patients who were international second opinions, who did not have a definitive diagnosis of IBD, and in whom a diagnosis of IBD was made after 18 years of age. A survey, including a food frequency questionnaire adapted from NHANES DSQ with modifications to include culturally appropriate food elements, was designed and conducted within this cohort to assess for dietary patterns. RESULTS: Asian patients in our cohort have similar phenotypes as non-Asians with few distinctive differences. There was a Crohn's disease and male predominance similar with non-Asians. However, there was a high rate of proctitis in ulcerative colitis in Asian patients. Asian patients reported a typical dietary pattern that reflects a Westernized pattern rather than a traditional pattern. Despite a similar dietary pattern, there was a high rate of 25-OH Vitamin D deficiency (44%) and insufficiency (40%). CONCLUSIONS: This single center study showed that the phenotype of Asian children with IBD in the U.S. is similar with that of non-Asian with a few distinct differences. The Asian children in our cohort reported following a Westernized dietary pattern and lifestyle. However, there was a high rate of Vitamin D deficiency surrounding diagnosis, suggesting a need for vigilant monitoring.

Using multiple imputation of real-world data to estimate clinical remission in pediatric inflammatory bowel disease.

Aim: To evaluate the performance of the multiple imputation (MI) method for estimating clinical effectiveness in pediatric Crohn's disease in the ImproveCareNow registry; to address the analytical challenge of missing data. Materials & methods: Simulation studies were performed by creating missing datasets based on fully observed data from patients with moderate-to-severe Crohn's disease treated with non-ustekinumab biologics. MI was used to impute sPCDAI remission statuses in each simulated dataset. Results: The true remission rate (75.1% [95% CI: 72.6%, 77.5%]) was underestimated without imputation (72.6% [71.8%, 73.3%]). With MI, the estimate was 74.8% (74.4%, 75.2%). Conclusion: MI reduced nonresponse bias and improved the validity, reliability, and efficiency of real-world registry data to estimate remission rate in pediatric patients with Crohn's disease.

Prospective Validation of the Lémann Index in Children: A Report From the Multicentre Image Kids Study.

BACKGROUND: The Lémann Index [LI] and the recently updated LI are tools for measuring structural bowel damage in adults with Crohn's disease [CD] but have not been evaluated in children. We aimed to validate the updated LI in the prospective multicentre ImageKids study of paediatric CD. METHODS: We included children with CD undergoing magnetic resonance enterography [MRE], pelvic magnetic resonance imaging [MRI] and ileocolonoscopy. Half were followed for 18 months, when MRE was repeated. Serum was collected for fibrosis-related proteomic markers. The LI was calculated by central readers from the MRE, ileocolonoscopy, physical examination and surgical data. Reliability and construct validity were assessed at baseline, while responsiveness and test-retest reliability were explored longitudinally. RESULTS: In total, 240 children were included (mean age, 14.2 ± 2.5 years; median disease duration, 2.2 years [interquartile range, IQR 0.25-4.42]; median baseline LI, 4.23 [IQR 2.0-8.8]). The updated LI had excellent inter-observer reliability (interclass correlation coefficient [ICC] = 0.94, 95% confidence interval [CI] 0.92-0.95) but poor, although statistically significant, correlation with radiologist and gastroenterologist global assessments of damage and with serum proteomic levels of fibrotic markers [rho = 0.15-0.30, most p < 0.05]. The updated LI had low discriminative validity for detecting damage (area under the receiver operating characteristic curve [AUC-ROC] 0.69, 95% CI 0.62-0.75). In 116 repeated MREs, responsiveness was suboptimal for differentiating improved from unchanged disease [AUC-ROC 0.58, 95% CI 0.45-0.71]. Test-retest reliability was high among stable patients [ICC = 0.84, 95% CI 0.72-0.91]. CONCLUSION: Overall, the updated LI had insufficient psychometric performance for recommending its use in children. An age-specific index may be needed for children with shorter disease duration than typical adult cohorts.

Development and Validation of the TUMMY-UC: A Patient-Reported Outcome for Pediatric Ulcerative Colitis.

BACKGROUND & AIMS: The TUMMY-UC is a patient-reported outcome measure for pediatric ulcerative colitis (UC) with an observer-reported outcome version for children aged <8 years. It includes eight items selected by concept elicitation interviews. We aimed to finalize the TUMMY-UC by cognitive interviews (stage 2) and to evaluate the index for its psychometric properties (stage 3). METHODS: The TUMMY-UC items were first finalized during 129 cognitive debriefing interviews. Then, in a prospective, multicenter validation study, 84 children who underwent colonoscopy or provided stool for calprotectin completed the TUMMY-UC and various measures of disease activity. Assessments were repeated after 7 and 21 days for evaluating reliability and responsiveness. RESULTS: During stage 2, the items were formatted with identical structure to ensure conceptual equivalence and weighted based on ranking of importance. In stage 3, the TUMMY-UC total score had excellent reliability in repeated assessments (intraclass correlation coefficient, 0.90; 95% confidence interval, 0.84-0.94). It also had moderate to strong correlations with all constructs of disease activity: r = 0.70 with UC endoscopic index of severity, r = 0.63 with the IMPACT-III questionnaire, r = 0.43 with calprotectin, r = 0.80 with the Pediatric Ulcerative Colitis Activity Index, r = 0.75 with global assessment of disease activity, and r = 0.46 with C-reactive protein (all P < .015). The index had excellent discrimination of disease activity, with a score of <9 defining remission (area under the receiver operating characteristic curve, 0.95; 95% confidence interval, 0.93-0.99). The ΔTUMMY-UC showed high responsiveness and differentiated well between children who experienced changed from those with no change. CONCLUSIONS: The TUMMY-UC, constructed from patient-reported outcome and observer-reported outcome versions, is a reliable, valid and responsive index that can be now used in practice and clinical trials.

Enterococci enhance Clostridioides difficile pathogenesis.

Enteric pathogens are exposed to a dynamic polymicrobial environment in the gastrointestinal tract1. This microbial community has been shown to be important during infection, but there are few examples illustrating how microbial interactions can influence the virulence of invading pathogens2. Here we show that expansion of a group of antibiotic-resistant, opportunistic pathogens in the gut-the enterococci-enhances the fitness and pathogenesis of Clostridioides difficile. Through a parallel process of nutrient restriction and cross-feeding, enterococci shape the metabolic environment in the gut and reprogramme C. difficile metabolism. Enterococci provide fermentable amino acids, including leucine and ornithine, which increase C. difficile fitness in the antibiotic-perturbed gut. Parallel depletion of arginine by enterococci through arginine catabolism provides a metabolic cue for C. difficile that facilitates increased virulence. We find evidence of microbial interaction between these two pathogenic organisms in multiple mouse models of infection and patients infected with C. difficile. These findings provide mechanistic insights into the role of pathogenic microbiota in the susceptibility to and the severity of C. difficile infection.

Tofacitinib Salvage Therapy for Children Hospitalized for Corticosteroid- and Biologic-Refractory Ulcerative Colitis.

OBJECTIVES: Colectomy rates following acute severe ulcerative colitis have plateaued around 20% despite intravenous corticosteroid and intensified anti-tumor necrosis factor (TNF) biologic dosing. Recent studies have shown tofacitinib to provide additional benefit in further decreasing colectomy rates among hospitalized adult patients with corticosteroid- and anti-TNF-nonresponsive ulcerative colitis. Pediatric data describing the effectiveness of tofacitinib for this indication does not yet exist. We aimed to describe the treatment courses and colectomy-free survival among pediatric patients treated with tofacitinib while hospitalized for refractory ulcerative colitis. METHODS: We performed a retrospective single-center cohort study of consecutive hospitalized pediatric patients initiating tofacitinib for refractory ulcerative colitis from 2018 to 2021. The primary outcome was 90-day colectomy-free survival. Secondary outcomes included colectomy-free clinical remission, corticosteroid independence, colectomy-free tofacitinib drug-persistence, tofacitinib-related adverse events, and postoperative complications. Baseline characteristics and details of the timing and positioning of therapies utilized during hospitalization were described. Outcomes were described using counts, percentages, and Kaplan-Meier curves. RESULTS: Eleven patients met inclusion criteria. All patients demonstrated nonresponse to both intravenous corticosteroids and anti-TNF therapy prior to tofacitinib initiation. Median hospitalization length was 22 days and mean maximum pediatric ulcerative colitis activity index during hospitalization was 68. Eight of 11 patients remained colectomy-free at 90 days following hospital admission and 6 remained colectomy-free over median 182-day follow-up, including 4 of whom remained on tofacitinib. CONCLUSIONS: Tofacitinib may represent a new treatment option for hospitalized pediatric patients with corticosteroid- and anti-TNF-nonresponsive ulcerative colitis. Future research is essential in determining the optimal positioning of these therapies.

Outcomes and Predictors of Sustained Remission After Drug Withdrawal in Pediatric Crohn Disease.

OBJECTIVES: The primary aim of this study was to determine the proportion of pediatric Crohn disease (CD) subjects in sustained drug-free remission 52 weeks after stopping pharmacological therapy. We also aimed to explore the effects of the Crohn Disease Exclusion Diet (CDED) and microbiome composition on remission. METHODS: We performed a prospective study following 18 CD patients ages 13-21 years in deep clinical remission withdrawing from immunomodulator (n = 7) or anti-TNFα (n = 11) monotherapy at two tertiary care centers. Stool for calprotectin and microbiome analyses was collected over 52 weeks. Participants followed either the CDED or free diet after drug withdrawal. The primary endpoint was sustained relapse-free drug-free remission (calprotectin <250 µg/g) at 52 weeks. RESULTS: Seventeen participants were followed through 52 weeks with 11 (64.7%) in sustained remission. There was no improvement in remission among participants following the CDED (5/9; 55.6%), P = 0.63. By 104 weeks, only 8 (47.1 %) participants remained off immunosuppressive therapies. Analysis of shotgun metagenomic sequence data revealed that taxonomic and gene function abundance in the gut microbiome was relatively stable for participants in remission and relapse. However, a predictive model incorporating gut microbial gene pathway abundance for amino sugar/nucleotide sugar metabolism and galactose metabolism from baseline samples predicted relapse at 52 weeks with 80% accuracy. CONCLUSIONS: After withdrawal of immunomodulator or anti-TNFα monotherapy among a small cohort of pediatric CD subjects in deep remission, nearly 65% sustained remission at 52 weeks. Baseline microbiome alterations predicted relapse. Large prospective studies are needed to better understand outcomes after treatment de-escalation.

Targeted Assessment of Mucosal Immune Gene Expression Predicts Clinical Outcomes in Children with Ulcerative Colitis.

BACKGROUND AND AIMS: We aimed to determine whether a targeted gene expression panel could predict clinical outcomes in paediatric ulcerative colitis [UC] and investigated putative pathogenic roles of predictive genes. METHODS: In total, 313 rectal RNA samples from a cohort of newly diagnosed paediatric UC patients (PROTECT) were analysed by a real-time PCR microfluidic array for expression of type 1, 2 and 17 inflammation genes. Associations between expression and clinical outcomes were assessed by logistic regression. Identified prognostic markers were further analysed using existing RNA sequencing (RNA-seq) data sets and tissue immunostaining. RESULTS: IL13RA2 was associated with a lower likelihood of corticosteroid-free remission (CSFR) on mesalamine at week 52 (p = .002). A model including IL13RA2 and only baseline clinical parameters was as accurate as an established clinical model, which requires week 4 remission status. RORC was associated with a lower likelihood of colectomy by week 52. A model including RORC and PUCAI predicted colectomy by 52 weeks (area under the receiver operating characteristic curve 0.71). Bulk RNA-seq identified IL13RA2 and RORC as hub genes within UC outcome-associated expression networks related to extracellular matrix and innate immune response, and lipid metabolism and microvillus assembly, respectively. Adult UC single-cell RNA-seq data revealed IL13RA2 and RORC co-expressed genes were localized to inflammatory fibroblasts and undifferentiated epithelial cells, respectively, which was supported by protein immunostaining. CONCLUSION: Targeted assessment of rectal mucosal immune gene expression predicts 52-week CSFR in treatment-naïve paediatric UC patients. Further exploration of IL-13Rɑ2 as a therapeutic target in UC and future studies of the epithelial-specific role of RORC in UC pathogenesis are warranted.

Increased Lifetime Risk of Intestinal Complications and Extraintestinal Manifestations in Crohn's Disease and Ulcerative Colitis.

Patients with Crohn's disease (CD) or ulcerative colitis (UC) have high morbidity rates owing to debilitating intestinal complications and extraintestinal manifestations (EIMs). We retrospectively identified patients in the Truven MarketScan databases with an incident CD or UC diagnosis from January 2008 to September 2015 to quantify the incremental lifetime risk of experiencing an intestinal complication or EIM after CD or UC diagnosis. Seven intestinal complications and 13 categories of EIMs by site were identified, and lifetime risk of experiencing an intestinal complication or EIM from age at CD or UC diagnosis to end of life was estimated using parametric models. Results were compared with controls' propensity score matched by age, sex, health plan, and pre-index Charlson Comorbidity Index. The CD or UC incremental risk was calculated using the difference in rates between CD or UC patients and matched controls. A total of 34,692 CD patients and 48,196 UC patients with 1:1 matched controls were included. CD and UC patients had an increased lifetime risk of intestinal complications, which varied across ages, inflammatory bowel disease (IBD) types, and categories of intestinal complications and EIMs. CD and UC patients aged 0 to 11 years had the highest incremental lifetime risk for all 7 intestinal complications and the majority of EIMs, with blood EIMs associated with the highest incremental risk (CD: 32%; UC: 21%). CD and UC patients of all ages have a higher lifetime risk of experiencing intestinal complications and EIMs than patients without CD or UC. When evaluating the burden of disease on patients with IBD, it is important to include the burden of these intestinal complications and EIMs in the assessment.

A Microbial Signature for Paediatric Perianal Crohn's Disease.

BACKGROUND AND AIMS: Perianal fistulising disease can affect up to 25% of patients with Crohn's disease [CD] and lead to significant morbidity. Although the role of the gut microbiota in inflammatory bowel disease [IBD] has been increasingly recognised, its role in fistula development has scarcely been studied. Here, we aimed to define the microbial signature associated with perianal fistulising CD in children. METHODS: A prospective observational study including children age 6-18 years with a diagnosis of perianal fistulising CD was conducted. Stool samples and rectal and perianal fistula swabs were collected. Stool samples and rectal swabs from children with CD without perianal disease and healthy children were included as comparison. Whole shotgun metagenomic sequencing was performed. RESULTS: A total of 31 children [mean age 15.5 ± 3.5 years] with perianal CD were prospectively enrolled. The fistula-associated microbiome showed an increase in alpha diversity and alteration in the abundance of several taxa compared with the rectal- and faecal-associated microbiome with key taxa belonging to the Proteobacteria phylum. Genes conferring resistance to the clinically used antibiotic regimen ciprofloxacin and metronidazole were found in the three sample types. In comparison with children without the perianal phenotype [N = 36] and healthy controls [N = 41], the mucosally-associated microbiome of children with perianal CD harboured a reduced butyrogenic potential. Linear discriminant analysis identified key taxa distinguishing the rectal mucosally-associated microbiome of children with perianal CD from children without this phenotype. CONCLUSIONS: The microbial community within CD-related anorectal fistula is compositionally and functionally unique. Taken together, these findings emphasise the need to better understand the ecosystem of the fistula milieu to guide development of novel microbiome-based strategies in this CD phenotype.

Clinical and Host Biological Factors Predict Colectomy Risk in Children Newly Diagnosed With Ulcerative Colitis.

BACKGROUND: Develop a clinical and biological predictive model for colectomy risk in children newly diagnosed with ulcerative colitis (UC). METHODS: This was a multicenter inception cohort study of children (ages 4-17 years) newly diagnosed with UC treated with standardized initial regimens of mesalamine or corticosteroids (CS) depending upon initial disease severity. Therapy escalation to immunomodulators or infliximab was based on predetermined criteria. Patients were phenotyped by clinical activity per the Pediatric Ulcerative Colitis Activity Index (PUCAI), disease extent, endoscopic/histologic severity, and laboratory markers. In addition, RNA sequencing defined pretreatment rectal gene expression and high density DNA genotyping by the Affymetrix UK Biobank Axiom Array. Coprimary outcomes were colectomy over 3 years and time to colectomy. Generalized linear models, Cox proportional hazards multivariate regression modeling, and Kaplan-Meier plots were used. RESULTS: Four hundred twenty-eight patients (mean age 13 years) started initial theapy with mesalamine (n = 136), oral CS (n = 144), or intravenous CS (n = 148). Twenty-five (6%) underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. Further, 32/35 patients who had colectomy failed infliximab. An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001). A logistic regression model predicting colectomy using the PUCAI, hemoglobin, and erythrocyte sedimentation rate had a receiver operating characteristic area under the curve of 0.78 (95% confidence interval [0.73, 0.84]). Addition of a pretreatment rectal gene expression panel reflecting activation of the innate immune system and response to external stimuli and bacteria to the clinical model improved the receiver operating characteristic area under the curve to 0.87 (95% confidence interval [0.82, 0.91]). CONCLUSIONS: A small group of children newly diagnosed with severe UC still require colectomy despite current therapies. Our gene signature observations suggest additional targets for management of those patients not responding to current medical therapies.

Learning Longitudinal Patterns and Subtypes of Pediatric Crohn Disease Treated With Infliximab via Trajectory Cluster Analysis.

BACKGROUND: The objective of this study is to identify subgroups of pediatric Crohn disease (CD) who had differential responses to the infliximab treatment through trajectory cluster analysis of disease activity using data from electronic health records. METHODS: We conducted a retrospective study of 295 pediatric patients with CD who had been treated with infliximab for a minimum of one year at the Center for Inflammatory Bowel Disease at The Children's Hospital of Philadelphia between January 2010 and December 2017. The evolution of disease was described, and subgroups of patients were identified using trajectory analysis of longitudinal data of C-reactive protein (CRP). We compared patient characteristics, biomarker for disease activity, and long-term surgical outcomes across subgroups. Cox regression models were used to evaluate the added value of the subgroup classification to baseline phenotype and location in prediction of long-term surgical outcomes. RESULTS: We identified three subgroups of patients with differential relapse-and-remission profiles (n = 33, 65 and 197 from subgroup 1 to 3), which represented patients with a higher risk of infliximab non-response, with infliximab response but with occasional disease flares, and patients with long-term response. Patients with the best treatment response had a significantly lower frequency of complicated disease phenotypes (P = 0.01), including perianal involvement (P = 0.05), lower baseline CRP (P < 0.01) and calprotectin (P = 0.01), and lowest risk of IBD-related gastrointestinal surgery within 10 years of starting treatment (P < 0.01). CONCLUSIONS: Readily available longitudinal data from electronic health records can be leveraged to provide deeper characterization of treatment response in pediatric CD.