Travel Time to Treating Center is Associated With Diagnostic Delay in Pediatric Inflammatory Bowel Disease.

BACKGROUND & AIMS: Delayed diagnosis of inflammatory bowel disease (IBD) leads to prolonged symptoms and worse long-term outcomes. We sought to evaluate whether race, ethnicity, disease type, and social factors are associated with delayed diagnosis of pediatric IBD. METHODS: We performed a cross-sectional study of newly diagnosed pediatric patients with IBD at 22 United States sites from 2019 to 2022. Parents/guardians reported race, ethnicity, time between symptom onset and diagnosis, and other social determinants of health. Through bivariate and multivariable analyses using generalized estimating equations, we evaluated associations between these factors and diagnosis time defined as ≤60 days, 61 to 180 days, 181 to 365 days, and >365 days. RESULTS: We enrolled 869 participants (mean age at diagnosis, 13.1 years; 52% male; 57% Crohn's disease [CD]; 34% ulcerative colitis [UC]; 8% Hispanic; 30% non-White). Overall, the mean time to diagnosis was 265.9 days. After adjustment, factors associated with longer diagnosis time included CD vs UC (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.9-3.5), 2 or more other health conditions (OR, 1.7; 95% CI, 1.1-2.7), and longer travel time to clinic (>1 hour [OR, 1.7; 95% CI, 1.2-2.4], >2 hours (OR, 1.8; 95% CI, 1.2-2.9] each vs <30 minutes). There was no association with race, ethnicity, birth country, gender, parent education, household income, insurance type, health literacy, and health system distrust. CONCLUSIONS: Consistent with prior literature, diagnostic delay is longer for CD than UC. Reassuringly, time to diagnosis is equitable across racioethnic groups. New models of diagnostic care are needed for communities affected by longer travel times.

HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease: HLA DQA1*05 and Pediatric Crohn's Disease.

OBJECTIVES: HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS: We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs. combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. RESULTS: A trend towards increased treatment failure among HLA DQA1*05 positive participants was not significant (HR 1.58, 95% CI 0.95-2.62; p=0.08). After stratification by HLA DQA1*05 and by methotrexate vs. placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05 positive patients on placebo (HR 0.31, 95% CI 0.13-0.70; p=0.005).A trend toward increased ADA development among HLA DQA1*05 positive participants was not significant (odds ratio [OR] 1.96, 95% CI 0.90-4.31, p=0.09). After further stratification, HLA DQA1*05 negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05 positive patients on placebo (OR 0.12, 95% CI 0.03-0.55; p=0.008). CONCLUSIONS: In a randomized trial of children with CD initiating anti-TNF, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn's Disease.

INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 µg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

Personalized Research on Diet in Ulcerative Colitis and Crohn's Disease: A Series of N-of-1 Diet Trials.

INTRODUCTION: Evidence about specific carbohydrate diet (SCD) for inflammatory bowel disease (IBD) is limited. We conducted 54 single-subject, double-crossover N-of-1 trials comparing SCD with a modified SCD (MSCD) and comparing each with the participant's baseline, usual diet (UD). METHODS: Across 19 sites, we recruited patients aged 7-18 years with IBD and active inflammation. Following a 2-week baseline (UD), patients were randomized to 1 of 2 sequences of 4 alternating 8-week SCD and MSCD periods. Outcomes included fecal calprotectin and patient-reported symptoms. We report posterior probabilities from Bayesian models comparing diets. RESULTS: Twenty-one (39%) participants completed the trial, 9 (17%) completed a single crossover, and 24 (44%) withdrew. Withdrawal or early completion occurred commonly (lack of response [n = 11], adverse events [n = 11], and not desiring to continue [n = 6]). SCD and MSCD performed similarly for most individuals. On average, there was <1% probability of a clinically meaningful difference in IBD symptoms between SCD and MSCD. The average treatment difference was -0.3 (95% credible interval -1.2, 0.75). There was no significant difference in the ratio of fecal calprotectin geometric means comparing SCD and MSCD (0.77, 95% credible interval 0.51, 1.10). Some individuals had improvement in symptoms and fecal calprotectin compared with their UD, whereas others did not. DISCUSSION: SCD and MSCD did not consistently improve symptoms or inflammation, although some individuals may have benefited. However, there are inherent difficulties in examining dietary changes that complicate study design and ultimately conclusions regarding effectiveness.

Inadequate Bowel Preparation in Pediatric Colonoscopy-Prospective Study of Potential Causes.

OBJECTIVES: Inadequate bowel preparation (IBP) for colonoscopy leads to missed diagnosis, longer anesthesia time, higher chance of complications and increased costs. Adult studies have demonstrated that patient characteristics such as male gender and obesity are associated with IBP. Little is known about factors affecting bowel preparation in children. Our aim was to determine factors associated with IBP in children. METHODS: We prospectively enrolled children undergoing outpatient colonoscopy. Quality of bowel preparation was assessed using Boston Bowel Preparation Scale (BBPS) score (range 0-9). Data collected included patient demographics, indication, and type of insurance. Patients were divided into two groups based on BBPS score-adequate (BBPS score > 5) and inadequate (BBPS score < 5) and groups were compared using Student t-test and chi-square test. Possible predictors were analyzed using multivariate logistic regression models. RESULTS: A total of 334 children were prospectively enrolled of whom 321 were studied further (age range 2-18 years; mean age 12.4 years; 60.4% female; 85.9% Caucasian). The mean BBPS score was 6.8 (standard deviation of ±2). IBP was reported in 12.8% (41/321). Multivariable logistic regression analysis did not show statistical differences between the groups in studied patient factors including age, gender, obesity, race, insurance type, and indication for colonoscopy. CONCLUSION: Contrary to several adult studies, the results of our prospective study did not show any relationship between examined patient factors and IBP in children. Interestingly, IBP was less prevalent in our pediatric study compared to published adult data (12.8% vs 20-40%).

Serologic, but Not Genetic, Markers Are Associated With Impaired Anthropometrics at Diagnosis of Pediatric Crohn's Disease.

OBJECTIVES: Children with Crohn's disease may present with malnutrition and linear growth impairment, which can be secondary to insufficient caloric intake, chronic inflammation, malabsorption, and suppression of growth-promoting hormones. We evaluated clinical, serologic, and genetic data to determine risk factors for impaired anthropometrics in Crohn's disease at diagnosis. METHODS: Our study evaluated 772 children newly diagnosed with Crohn's disease, inflammatory phenotype, enrolled in the RISK Stratification Project to determine the factors associated with anthropometric impairment. Data were collected on demographics, growth parameters, disease location, serologic and immunologic markers, and disease severity. We performed a genome-wide association study of genetic polymorphisms associated with inflammatory bowel disease. Regression analysis determined associations between anthropometrics and clinical, serologic, and genetic variables. RESULTS: There were 59 (7%) children with height z score <-2, 126 (14%) with a weight z score <-2, and 156 (17%) with a body mass index z score <-2. Linear growth impairment was associated with hypoalbuminemia (P = 0.0052), elevated granulocyte-macrophage colony stimulating factor autoantibodies (P = 0.0110), and elevated CBir antibodies against flagellin (P = 0.0117). Poor weight gain was associated with female sex (P = 0.0401), hypoalbuminemia (P = 0.0162), and thrombocytosis (P = 0.0081). Malnutrition was associated with hypoalbuminemia (P = 0.0061) and thrombocytosis (P = 0.0011). Children with moderate or severe disease had lower weight (P = 0.02 and P = 1.16×10, respectively) and body mass index z scores (P = 2.7 × 10 and P = 1.01 × 10, respectively) than children with quiescent and mild disease. There was no association between age of diagnosis, Tanner stage, or disease location and having impaired anthropometrics. There was no genome-wide association between the genetic polymorphisms and the serologic variables and anthropometric measurements. CONCLUSIONS: This is the largest study evaluating growth in treatment-naïve children with Crohn's disease, inflammatory phenotype. It is the first study to use genome-wide sequencing to assess for genetic determinants of growth impairment. Granulocyte-macrophage colony stimulating factor autoantibodies and CBir antibodies are more likely to be elevated in children with growth impairment. Future investigations should evaluate the relationship between genetic polymorphisms, pathologic immune responses, and the biological pathways regulating growth.

Incidence of Low Seroimmunity to Hepatitis B Virus in Children With Inflammatory Bowel Disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) often receive immunosuppressive therapy, which may make them vulnerable to infections such as hepatitis B. We hypothesized that hepatitis B virus titers are low in the vaccinated pediatric population with IBD. The aims of our study were to identify the incidence of lower titers of hepatitis B surface antibody (HBsAb) and determine which patient factors may be associated with lower HBsAb titers. METHODS: Patients with diagnosis of IBD, ages 5 to 18 years, were prospectively enrolled. Patients were confirmed to have had a full series of hepatitis B vaccination. Quantitative serum HBsAb titers were measured and logistic regression analysis with independent variables of age, sex, race, disease phenotype, surgery, medications and a dependent variable of adequate HBsAb titers (> 10 mIU/mL) was performed. RESULTS: Of the 116 patients enrolled, 57 were boys and 59 were girls. 75 patients had a diagnosis of Crohn disease; 32 had a diagnosis of ulcerative colitis; and 9 patients had been diagnosed as having indeterminate colitis. At the time of the study, 15 patients were taking corticosteroid, 66 on an immunomodulator, and 53 on a biologic. Sixty percent of patients in the 5- to 10-year age group had protective titers versus 22% to 27% in the older groups, P = 0.04. Only 28% of the 116 patients had HBsAb titers of >10m IU/mL. Twenty percent of the patients taking corticosteroids, 27% taking immunomodulators, and 24% taking biologics were found to be seroimmune. CONCLUSIONS: Nearly two-thirds of pediatric patients with IBD have low titers against hepatitis B virus. Titers were highest in the younger patients. No patient-specific variable, such as the use of immunosuppressants, appeared to influence these low titers.

Can ultrasound be used as the primary imaging in children with suspected Crohn disease?

BACKGROUND: There is growing literature on the use of ultrasound (US) for evaluation of Crohn disease in adults, but few studies have been conducted on children. Several studies demonstrated high accuracy of US in the diagnosis of Crohn disease. Using US as the primary screening imaging modality for Crohn disease can reduce health care costs, the need for sedation and ionizing radiation exposure. OBJECTIVE: The aim of our study is to determine if US can be used for screening evaluation of pediatric Crohn disease. MATERIALS AND METHODS: A prospective cohort study of pediatric patients undergoing MR enterography (MRE) for suspected or known history of Crohn disease was performed, with gray-scale and Doppler US of the terminal ileum done immediately before or after MRE. US images were interpreted by two radiologists (Reader 1 and Reader 2) not involved in image acquisition, in blinded and randomized fashion. US findings of Crohn disease including bowel wall thickening, wall stratification, increased vascularity on Doppler, lymphadenopathy, fat infiltration and extraintestinal complications were evaluated. MRE findings of terminal ileitis were considered the reference standard. Demographic data, body mass index (BMI), symptoms, and laboratory, endoscopic and histopathological data were obtained from electronic medical records. RESULTS: Forty-one patients (mean age: 13.7 years: 4.6-18.9 years) were evaluated. Mean BMI was 21.2 (range: 13-40.2); 10 patients (24.3%) were either overweight or obese. Final diagnoses were Crohn disease (n=24), ulcerative colitis (n=4) and normal/non-inflammatory bowel disease-related diagnoses (n=13). US demonstrated sensitivity of 67% and 78% and specificity of 78% and 83%, by Reader 1 and Reader 2, respectively. MRE sensitivity and specificity were 75% and 100%, respectively, compared to final clinicopathological diagnosis. Interobserver agreement between Reader 1 and Reader 2 was good (0.6< kappa <0.8). CONCLUSION: In screening for Crohn disease in children, US has limited sensitivity for detecting terminal ileitis.

Radiologic Predictors of Surgery in Newly Diagnosed Pediatric Crohn Disease Patients.

OBJECTIVES: The aim of the present study was to assess whether small bowel imaging conducted at the time of diagnosis could be used as a predictor of small bowel surgical intervention in a population of pediatric patients with Crohn disease (CD). METHODS: A retrospective analysis of small bowel imaging within 30 days of diagnosis of pediatric CD was conducted. Patients were divided into 2 groups based on small bowel imaging: those with no or minor abnormalities (71%) and those with more extensive or obstructive abnormalities (29%). Medical records were reviewed for small bowel surgical intervention and clinic follow-up visits. RESULTS: A total of 232 patients were included in the study group (average age at diagnosis 11.7 years). Twenty-seven patients (12%) underwent small bowel surgical intervention. The relative risk for small bowel surgical intervention was 2.91 in the group with more extensive imaging abnormalities. The majority of increased surgical risk occurred in the first year after diagnosis, when the normal-minor group had a 2% surgical risk and the more abnormal group had a 17% surgical risk. Both groups had a 2% to 3% surgical risk per year after the first year. CONCLUSIONS: Small bowel imaging at the time of diagnosis in pediatric CD can help predict the risk of small bowel surgical intervention and should be recommended for all newly diagnosed patients. Nearly one third of our cohort underwent small bowel surgical intervention through 8 years of follow-up. Surgical complications of CD often occur in the small bowel, and counseling families about surgical risk is an integral part of pediatric CD management.

Significant delays exist in industry-sponsored pediatric clinical drug trial start-up and enrollment processes.

BACKGROUND: Significant barriers to advancing pediatric drug development continue despite federal incentives to expedite pediatric drug development. There is an urgent need to improve how clinical trials are designed, implemented, and conducted to increase the number of approved therapeutic interventions for children. METHODS: The Pediatric Improvement Collaborative for Clinical Trials & Research was created to measure timelines and address delays in the pediatric clinical trials process. This multi-site collaborative prospectively monitored sixteen time points in industry-sponsored pediatric clinical drug trials, including times to budget approval, contract execution, ancillary protocol review, Institutional Review Board approval, Site Initiation Visit, and first patient consented. RESULTS: Twenty-four sites contributed data on 330 industry-sponsored pediatric drug studies. The average duration to final study budget approval was 121 (range 3-585) days, to final study Institutional Review Board (IRB) approval was 51 (range 1-205) days, to Site Initiation Visit was 204 (range 23-600) days, and to first patient consented was 239 (range 30-534) days. CONCLUSION: Significant study start-up delays were noted in industry-sponsored clinical drug trials among a large group of pediatric sites. Delays and wide variation in all steps of the study process indicate multiple opportunities for improvement.

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

BACKGROUND: Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). METHODS: We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. RESULTS: Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 µg/mL [P = .49]; adalimumab: 11.1 vs 10.5 µg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 µg/mL [P < .01]; adalimumab: 9.1 vs 12.3 µg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). CONCLUSIONS: LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

For children with Crohn's disease treated with biologic medications, with and without low-dose methotrexate, the role of drug levels on treatment failure in a recent prospective trial is unclear. These data suggest patients on infliximab with therapeutic drug levels are more likely to continue any therapy, and the effect on patients treated with adalimumab requires more investigation.

Treatment and biologic maintenance-dosing patterns among pediatric patients with ulcerative colitis or Crohn's disease.

OBJECTIVES: To assess treatment patterns and initial and maintenance dosing of biologics over 3 years in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD), utilizing data from the ImproveCareNow registry. METHODS: Pediatric patients diagnosed with UC or CD and aged 2-17 years were included in the study. Descriptive statistics were employed to summarize baseline demographics. The proportion of patients on medication for UC or CD were analyzed at the baseline visit, 1-year, and 3-year time points (Cohort 1). Biologic maintenance dosage was calculated only for patients who had data for dose and weight at all-time points (Cohort 2). RESULTS: In Cohort 1 (UC = 1784; CD = 4720), baseline treatment in UC included corticosteroid, 5-ASA, and 6-MP/AZA; at 1-year and 3-year time points, treatment with 5-ASA and corticosteroid decreased, whereas 6-MP/AZA and anti-TNFs increased. In CD, baseline treatment included corticosteroid, anti-TNF, 6-MP/AZA, and methotrexate; use of corticosteroids decreased, whereas the use of methotrexate and anti-TNFs increased over 3 years. In Cohort 2 (UC = 350; CD = 1537), at first maintenance dose, UC patients on infliximab received a mean dose of 10.5 mg/kg/8 wk, adalimumab (weight < 40 kg and ≥40 kg) 1.3 mg/kg/2 wk and 0.8 mg/kg/2 wk, and vedolizumab 6.9 mg/kg/8 wks. At the first maintenance dose, CD patients on infliximab received a mean dose of 8.1 mg/kg/8 wk, adalimumab (weight < 40 kg) 1.1 mg/kg/2 wk, adalimumab (weight ≥ 40 kg) 0.8 mg/kg/2 wk, and vedolizumab 10.5 mg/kg/8 wks. CONCLUSION: The use of corticosteroids was common at the initial visit in patients. Anti-TNFs remain the most used class of biologics, however, reported doses in our study were substantially higher than the standard dosing guidelines.

IBD Camp Oasis: A look at Participants' Social-Emotional Well-Being and Protective Factors During Camp and Beyond.

Background: Camp Oasis is an annual week-long camp serving children with inflammatory bowel disease (IBD) and hosted by the Crohn's and Colitis Foundation. Youth with IBD are at increased risk for mental health challenges, with Camp Oasis potentially mitigating these risks. The aim of this study is to measure change in and predictors of social-emotional well-being and protective factors of self-worth as a result of attending Camp Oasis. Methods: Between 2012 and 2019, a voluntary survey was administered to participants and their caregivers to reflect on their perceptions of social/emotional well-being and protective factors related to chronic disease. T-tests compared change in participants' and caregivers' perceptions before and after camp; path analyses examined the key predictors of social-emotional well-being. Results: A total of 6011 online surveys were analyzed. Participants and caregivers reported consistently positive perceptions of participants' experiences during and after camp. Significant improvements in confidence, independence, activity, comfort around others, being more open about disease, and taking medication as expected were observed. Being new to Camp Oasis was one of the strongest predictors of both disease-related self-efficacy and social connections after camp. Conclusions: The uniformly high rates of participants' perceptions during camp suggest camp is a life-changing experience for youth with IBD, reduces disease-related stigma, and enhances confidence and social skills. Participants' positive experiences appear to foster notable benefits after camp in terms of openness, their sense of belonging, connections, and confidence.

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.

Serum antibodies and anthropometric data at diagnosis in pediatric Crohn's disease.

BACKGROUND: Serum antibodies, including ASCA, anti-OmpC, and ANCA, correlate with disease location and predict disease phenotype in inflammatory bowel disease. AIM: The objective of this study was to determine relationships between serum antibody status and anthropometric data for children with newly diagnosed Crohn's disease. METHODS: A retrospective review was conducted on children diagnosed with Crohn's disease at our institution from 2003 to 2008. Patients who had ASCA IgA, ASCA IgG, anti-OmpC, and pANCA antibodies, and anthropometric data measured before diagnosis and therapy were included. Z-scores for height and weight were compared among groups according to the presence of specific antibodies. Spearman's rank correlation was used to assess association between antibodies and growth data. RESULTS: One hundred and two patients, mean age 11.9 years, met the inclusion criteria. Patients with the presence of any of the four antibodies had lower mean height and weight z-scores than patients without any antibodies present. When individual antibodies were studied, patients with positive ASCA titers had lower mean weight and height z-scores than patients without any antibodies present. Spearman's rank correlation coefficient demonstrated a significant association between increasing ASCA titers and lower weight z-scores, but not lower height z-scores. CONCLUSIONS: Pediatric patients with newly diagnosed Crohn's disease and the presence of ASCA antibodies have lower mean height and weight z-scores. This study provides evidence that specific subsets of children with Crohn's disease may be at greater risk of growth impairment.

Clinical Outcome Assessments in Pediatric Patients With Ulcerative Colitis and Crohn's Disease Receiving Biologics: A Retrospective Cohort Study.

Background: To assess disease activity, steroid-free remission, and other clinical outcome assessments among pediatric patients with ulcerative colitis (UC) and Crohn's disease (CD) in the ImproveCareNow (ICN) registry. Methods: Patients aged 2-17 years diagnosed with UC or CD between June 1, 2013 and December 31, 2019 were enrolled if they initiated a biologic after enrollment in the ICN registry and completed at least 12 months follow-up after first maintenance dose. Baseline (at biologic initiation) demographics were summarized using descriptive statistics. Pediatric UC Activity Index (PUCAI), partial Mayo score, and Physician Global Assessment (PGA) were assessed for UC; and the Short Pediatric Crohn's Disease Activity Index (sPCDAI) and PGA were assessed for CD at first maintenance dose, 1- and 3-year time points. Kappa coefficients were used to assess the level of agreement between the outcome measures. Results: A total of 1887 patients (UC = 350; CD = 1537) were included. Baseline demographics were similar across groups. For UC patients, mean PUCAI scores decreased and the proportion of patients in steroid-free remission, quiescent state based on PGA, and remission based on partial Mayo score increased from first maintenance dose to 1 and 3 years. For CD patients, mean sPCDAI score of CD patients decreased and the proportion of patients in steroid-free remission by sPCDAI and in quiescent state based on PGA increased from first maintenance dose to 1 and 3 years. Kappa coefficients showed only modest correlation between disease activity assessments. Conclusions: Disease activity scores improved over time, with more pediatric patients with UC and CD achieving steroid-free remission at 1 and 3 years after first biologic maintenance dose.

Corticosteroids increase protein breakdown and loss in newly diagnosed pediatric Crohn disease.

Children with Crohn disease have altered growth and body composition. Previous studies have demonstrated decreased protein breakdown after either corticosteroid or anti-TNF-α therapy. The aim of this study was to evaluate whole body protein metabolism during corticosteroid therapy in children with newly diagnosed Crohn disease. Children with suspected Crohn disease and children with abdominal symptoms not consistent with Crohn disease underwent outpatient metabolic assessment. Patients diagnosed with Crohn disease and prescribed corticosteroid therapy returned in 2 wk for repeat metabolic assessment. Using the stable isotopes [d5] phenylalanine, [1-(13)C] leucine, and [(15)N(2)] urea, protein kinetics were determined in the fasting state. Thirty-one children (18 controls and 13 newly diagnosed with Crohn disease) completed the study. There were no significant differences in protein breakdown or loss between patients with Crohn disease at diagnosis and controls. After corticosteroid therapy in patients with Crohn disease, the rates of appearance of phenylalanine (32%) and leucine (26%) increased significantly, reflecting increased protein breakdown, and the rate of appearance of urea also increased significantly (273%), reflecting increased protein loss. Whole body protein breakdown and loss increased significantly after 2 wk of corticosteroid therapy in children with newly diagnosed Crohn disease, which may have profound effects on body composition.

Exploring potential noninvasive biomarkers in eosinophilic esophagitis in children.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EE) continues to present clinical challenges, including a need for noninvasive tools to manage the disease. To identify a marker able to assess disease status in lieu of repeated endoscopies, we examined 3 noninvasive biomarkers, serum interleukin (IL)-5, serum eosinophil-derived neurotoxin (EDN), and stool EDN, and examined possible correlations of these with disease phenotype and activity (symptoms and histology) in a longitudinal study of children with EE. SUBJECTS AND METHODS: Children with EE were studied for up to 24 weeks (12 weeks on 1 of 2 corticosteroid therapies and 12 weeks off therapy). Twenty children with normal esophagogastroduodenoscopies with biopsies were enrolled as controls. Serum IL-5, serum EDN, and stool EDN were measured at weeks 0, 4, 12, 18, and 24 in children with EE, and at baseline alone for controls. Primary and secondary statistical analyses (excluding and including outlier values of the biomarkers, respectively) were performed. RESULTS: Sixty subjects with EE (46 [75%] boys, mean age 7.5 ±â€Š4.4 years) and 20 normal controls (10 [50%] boys, mean age 6.7 ±â€Š4.1 years) were included. Significant changes in serum EDN (significant decrease from baseline to week 4, and then rebound from week 4 to week 12) occurred. Serum EDN levels were stable after week 12. Serum IL-5 and stool EDN levels in subjects with EE were not statistically different from those of the control subjects when each time point for the cases was compared with the controls' 1-time measurement. CONCLUSIONS: Serum EDN levels were significantly higher in subjects with EE than in controls, and the results suggest a possible role, after additional future studies, for serum EDN in establishing EE diagnosis, assessing response to therapy, and/or monitoring for relapse or quiescence.

Mucosal Inflammatory and Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in Pediatric Crohn's Disease.

BACKGROUND AND AIMS: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. METHODS: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. RESULTS: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). CONCLUSION: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.

Ileocecal histoplasmosis simulating Crohn disease in a patient with hyperimmunoglobulin E syndrome.

We describe a 14-year-old girl with hyperimmunoglobulin E (Job) syndrome who presented with fatigue, abdominal pain, fever, and weight loss. Endoscopic examination of the terminal ileum revealed ulceration, edema, and erythema. Histopathologic findings of the terminal ileum demonstrated intracellular yeast forms compatible with Histoplasma capsulatum. The patient was treated with oral itraconazole and had a rapid and complete response.