Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation.

BACKGROUND & AIMS: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. METHODS: We obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. RESULTS: We identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. CONCLUSIONS: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.

Single High-dose Vitamin D3 Supplementation in Pediatric Patients With Inflammatory Bowel Disease and Hypovitaminosis D.

OBJECTIVES: The primary aim was to determine the effectiveness of a single high-dose of oral vitamin D3 (stoss therapy) in children with inflammatory bowel disease (IBD) and hypovitaminosis D. Our secondary aim was to examine the safety of stoss therapy. METHODS: We conducted a randomized, prospective study of 44 patients, ages 6 to 21 years, with IBD and 25-hydroxyvitamin D (25-OHD) concentrations <30 ng/mL. Patients were randomized to receive 50,000 IU of vitamin D3 once weekly for 6 weeks (standard of care, SOC group) or 300,000 IU once (stoss group). Serum 25-OHD levels were obtained at baseline, 4 and 12 weeks. Safety monitoring labs were performed at week 4. RESULTS: Thirty-nine of 44 enrolled patients (19 stoss, 20 SOC) completed the study. Baseline vitamin D levels were not significantly different between the groups. Stoss therapy resulted in a substantial rise in 25-OHD levels at week 4, equivalent to the weekly regimen (53.6 ±â€Š17.3 vs 54.6 ±â€Š17.5 ng/mL). At week 12, serum 25-OHD levels decreased in both groups, significantly lower in the stoss group, but remained close to 30 ng/mL (29.8 ±â€Š7.1 vs 40.4 ±â€Š11.9 ng/mL, P = 0.04). A significant interaction with treatment group over time was observed (P = 0.0003). At the week-4 time point, all patients who received stoss therapy had normal serum calcium and PTH levels. Eighty percentage of patients preferred stoss therapy to the weekly regimen. CONCLUSIONS: Stoss therapy was safe and effective in raising 25-OHD in children with IBD commensurate to that of the weekly regimen.

Prioritizing Crohn's disease genes by integrating association signals with gene expression implicates monocyte subsets.

Genome-wide association studies have identified ~170 loci associated with Crohn's disease (CD) and defining which genes drive these association signals is a major challenge. The primary aim of this study was to define which CD locus genes are most likely to be disease related. We developed a gene prioritization regression model (GPRM) by integrating complementary mRNA expression datasets, including bulk RNA-Seq from the terminal ileum of 302 newly diagnosed, untreated CD patients and controls, and in stimulated monocytes. Transcriptome-wide association and co-expression network analyses were performed on the ileal RNA-Seq datasets, identifying 40 genome-wide significant genes. Co-expression network analysis identified a single gene module, which was substantially enriched for CD locus genes and most highly expressed in monocytes. By including expression-based and epigenetic information, we refined likely CD genes to 2.5 prioritized genes per locus from an average of 7.8 total genes. We validated our model structure using cross-validation and our prioritization results by protein-association network analyses, which demonstrated significantly higher CD gene interactions for prioritized compared with non-prioritized genes. Although individual datasets cannot convey all of the information relevant to a disease, combining data from multiple relevant expression-based datasets improves prediction of disease genes and helps to further understanding of disease pathogenesis.

Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort.

In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC). Using dbGaP data, we performed logistic regression for common variants and optimal unified association tests (SKAT-O) for rare, likely-deleterious variants. We further compared rare variants to ExAC counts with Fisher's exact tests. We did pathway enrichment analysis on the most significant genes from each comparison. Many variants overlapped with known IBD-associated genes (e.g. NOD2). Rare variants were enriched in CD-associated loci (p = 0.009) and showed suggestive enrichment in neutrophil function genes (p = 0.05). Pathway enrichment implicated immune-related pathways, especially cell killing and apoptosis. Variants in extracellular matrix genes also emerged as an important theme in our analysis.

Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients With Crohn's Disease.

BACKGROUND & AIMS: Individuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's disease (CD). We tested for associations between mutations in genes encoding reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, neutrophil function, and phenotypes of CD in pediatric patients. METHODS: We performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases. Blood samples were collected from an additional 129 pediatric patients with CD and 26 children without IBD (controls); we performed assays for neutrophil activation, reactive oxygen species (ROS) production, and bacteria uptake and killing. Whole-exome sequence analysis was performed using DNA from 46 of the children with CD to examine associations with NADPH gene mutations; RNA sequence analyses were performed using blood cells from 46 children with CD to test for variations in neutrophil gene expression associated with ROS production. RESULTS: We identified 26 missense mutations in CYBA, CYBB, NCF1, NCF2, and NCF4. Patients with CD who carried mutations in these genes were 3-fold more likely to have perianal disease (P = .0008) and stricturing complications (P = .002) than children with CD without these mutations. Among patients with CD with none of these mutations, 9% had undergone abdominal surgery; among patients with mutations in these NADPH oxidase genes, 31% had undergone abdominal surgery (P = .0004). A higher proportion of neutrophils from children with CD had low ROS production (47%) than from controls (15%) among the 129 patients tested for ROS (P = .002). Minor alleles of the NADPH genes were detected in 7% of children with CD whose neutrophils produced normal levels of ROS vs 38% of children whose neutrophils produced low levels of ROS (P = .009). Neutrophils that produced low levels of ROS had specific alterations in genes that regulate glucose metabolism and antimicrobial responses. CONCLUSIONS: We identified missense mutations in genes that encode NADPH oxidases in children with CD; these were associated with a more aggressive disease course and reduced ROS production by neutrophils from the patients.

Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn's Disease.

OBJECTIVES: Avoiding fibrostenotic complications is of paramount concern in the management of Crohn's disease (CD). We sought to investigate the association of candidate biomarkers of fibrosis collected at diagnosis with the future development of fibrostenotic CD. METHODS: Using the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort, a multicenter prospective observational pediatric inception cohort, subjects with an inflammatory phenotype (B1) at diagnosis who later converted to a stricturing phenotype (B2) within 3 years were compared with those who remained B1. Serum collected at diagnosis underwent both parallel reaction monitoring-targeted proteomic analysis and conventional enzyme-linked immunosorbent assay for 10 candidate biomarkers of intestinal fibrosis. Cox proportional hazard regression was used for multivariable analysis of time-dependent outcomes. RESULTS: In 116 subjects 58 subjects with verified B1 phenotype at diagnosis who later converted to B2 disease were compared with 58 subjects who remained B1 over 3 years of follow-up. Extracellular matrix protein 1 (ECM1) levels in the upper quartile (hazard ratio [HR] 3.43, 95% confidence limit [CL] 1.33, 8.42) were associated with future fibrostenotic disease. ASCA IgA (HR 4.99, 95% CL 1.50, 16.68) and CBir levels (HR 5.19, 95% CL 1.83, 14.74) were also associated with future intestinal fibrostenosis, although ECM1 continued to demonstrate independent association with conversion to B2 even with adjustment for serologies in multivariable analysis (HR 5.33, 95% CL 1.29, 22.13). CONCLUSIONS: ECM1 and other biomarkers of fibrosis may aid in determining the risk of uncomplicated inflammatory disease converting to B2 stricturing phenotypes in children with CD. Prospective validation studies to verify test performance and optimize clinical utilization are needed before clinical implementation.

A Quality Improvement Approach to External Infliximab Infusions in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: We used a quality improvement (QI) approach to improve access and reduce barriers to care by increasing the number of external infliximab infusions at our pediatric inflammatory bowel disease center. METHODS: Using an iterative QI strategy, pediatric patients ≥12 years of age with inflammatory bowel disease were offered the opportunity to receive infliximab infusions at home/an external infusion center. They were required to first have >5 infusions at the hospital without any significant infusion reactions. Data were collected and tracked monthly using P-charts. Comparisons between control chart centerlines were analyzed using the Fisher exact test. RESULTS: Fifty-four patients received external infusions, 87% had Crohn disease, 63% boys, average age 17.6 ±â€Š2.9 years, and 89% with private insurance. From September 2016 to January 2018, the percentage of eligible patients receiving external infusions was approximately 7%, increasing to approximately 30% by January 2018. A centerline shift, representing a statistically significant change, occurred in October 2016 and June 2017 (P < 0.001). No serious safety concerns have occurred. CONCLUSIONS: Through a multidisciplinary team of stakeholders using QI strategies, we now offer external infusion service options to all appropriate patients as routine practice. Home infusions are a viable option to reduce barriers to care, and our patients did not experience any safety events.

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study.

BACKGROUND: Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. METHODS: We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. FINDINGS: Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%. INTERPRETATION: Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy. FUNDING: Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.

Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn's Disease in Treatment-Naive Pediatric Patients.

BACKGROUND & AIMS: There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)-few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes. METHODS: We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center. RESULTS: We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P = .001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553-26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330-28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132-25.12). CONCLUSIONS: In an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.

Feasibility and validity of the pediatric ulcerative colitis activity index in routine clinical practice.

OBJECTIVES: The Pediatric Ulcerative Colitis Activity Index (PUCAI) is a noninvasive disease activity index developed as a clinical trial endpoint. More recently, practice guidelines have recommended the use of PUCAI in routine clinical care. We therefore sought to evaluate the feasibility, validity, and responsiveness of PUCAI in a large, diverse collection of pediatric gastroenterology practices. METHODS: We extracted data from the 2 most recent encounters for patients with ulcerative colitis in the ImproveCareNow registry. Feasibility was determined by the percentage of patients for whom all PUCAI components were recorded, validity by correlation of PUCAI scores across physician global assessment (PGA) categories, and responsiveness to change by the correlation between the change in PUCAI and PGA scores between visits. RESULTS: A total of 2503 patients were included (49.5% boys, age 15.2 ±â€Š4.1 years, disease duration 3.7 ±â€Š3.2 years). All items in the PUCAI were completed for 96% of visits. PUCAI demonstrated excellent discriminatory ability between remission, mild, and moderate disease; discrimination between moderate and severe disease was less robust. There was good correlation with PGA (r = 0.76 [P < 0.001] and weighted kappa κ = 0.73 [P < 0.001]). The PUCAI change scores correlated well with PGA change scores (P < 0.001). Test-retest reliability of the PUCAI was good (intraclass correlation coefficient 0.72 [95% confidence interval 0.70-0.75], P < 0.001). Guyatt responsiveness statistic was 1.18, and the correlation of ΔPUCAI with ΔPGA was 0.69 (P < 0.001). CONCLUSIONS: The PUCAI is feasible to use in routine clinical settings. Evidence of its validity and responsiveness supports its use as a clinical tool for monitoring disease activity for patients with ulcerative colitis.

Incidence, pattern, and etiology of elevated liver enzymes in pediatric inflammatory bowel disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) often develop elevated liver enzymes (ELE), which are frequently a benign, transient finding, but may be related to treatment or IBD-associated liver diseases. Distinguishing benign from pathologic ELE is crucial for focused diagnostic and therapeutic interventions. We sought to characterize the incidence, character, chronicity, degree, and etiology of ELE in children with IBD. METHODS: Institutional review board-approved retrospective review of all of the patients with IBD (2-21 years) seen between October 2009 and October 2012 with >9 months of follow-up were included in the study. We examined body mass index, disease activity, extent, phenotype, concurrent medications, and character, chronicity, degree of enzyme elevation, and final diagnosis. RESULTS: A total of 219 of 514 patients with IBD had ≥1 episode of ELE. Five patients were excluded for preexisting liver disease, leaving 214 patients (Crohn disease [CD]: 14.8 ±â€Š3.5 years, 46% girls; ulcerative colitis [UC]: 14.4 ±â€Š4.2 years, 37% girls). One hundred forty-eight patients (69%) had a hepatic, 17 (8%) cholestatic, and 49 (23%) mixed character of ELE. There were no significant differences in character, chronicity, or degree of ELE between CD and UC (P = 0.71, P = 0.58, P > 0.33). Of the 128 patients with sufficient data to determine chronicity, 98 (77%) had transient elevations, (CD: n = 66, 75% and UC: n = 32, 80%). Episodes of ELE were idiopathic in 87% of patients with IBD. A final diagnosis of idiopathic ELE was associated with a lower degree of ELE elevation (P < 0.0001). CONCLUSIONS: Pediatric patients with IBD commonly experience transient, idiopathic ELE. Our findings suggest that higher degrees of ELE, specifically alanine aminotransferase, are associated with an etiology that requires more extensive evaluation.

Seasonality and pediatric inflammatory bowel disease.

OBJECTIVES: Seasonal and geographic variations of inflammatory bowel disease (IBD) exacerbations have been described in adults, with inconsistent findings. We sought to determine whether disease activity in pediatric-onset IBD is associated with a seasonal pattern. METHODS: We examined children with Crohn disease (CD) and ulcerative colitis (UC) using data from the ImproveCareNow Collaborative between December 2008 and November 2010. We compared the proportion of patients in continuous remission for all recorded visits in each season. We also compared the distribution of all recorded visits with a physician global assessment (PGA) of remission or active disease across seasons. RESULTS: A total of 1325 patients with CD (6102 visits) and 587 patients with UC (2394 visits) were included. The proportion of patients with UC in continuous remission during each season was highest in the summer (67%) and lowest in the winter (55%) (P=0.01). A similar pattern was found for CD but was not significant. Similarly, the proportion of visits in remission was highest in the summer and lowest in the winter for both UC (29%, 21%; P<0.001) and CD (28%, 23%; P<0.001); however, the distribution of visits with active disease was not significantly different across seasons. CONCLUSIONS: The higher proportion of patients with UC in continuous remission in the summer may be related to the higher proportion of remission visits in the summer, because the proportion of visits with active disease was similar across seasons. These findings do not support any strong associations between season of the year and disease activity in pediatric IBD.

A comprehensive patient safety program can significantly reduce preventable harm, associated costs, and hospital mortality.

OBJECTIVE: To evaluate the effectiveness of a hospital-wide initiative to improve patient safety by implementing high-reliability practices as part of a quality improvement (QI) program aimed at reducing all preventable harm. STUDY DESIGN: A hospital wide quasi-experimental time series QI initiative using high-reliability concepts, microsystem-based multidisciplinary teams, and QI science tools to reduce hospital acquired harm was implemented. Extensive error prevention training was provided for all employees. Change concepts were enacted using the Institute for Healthcare Improvement's Model for Improvement. Compliance with change packages was measured. RESULTS: Between 2010 and 2012, the serious safety event rate decreased from 1.15 events to 0.19 event per 10 000 adjusted hospital-days, an 83.3% reduction (P < .001). Preventable harm events decreased by 53%, from a quarterly peak of 150 in the first quarter of 2010 to 71 in the fourth quarter of 2012 (P < .01). Observed hospital mortality decreased from 1.0% to 0.75% (P < .001), although severity-adjusted expected mortality actually increased slightly, and estimated harm-related hospital costs decreased by 22.0%. Hospital-wide safety climate scores increased significantly. CONCLUSION: Substantial reductions in serious safety event rate, preventable harm, hospital mortality, and cost were seen after implementation of our multifaceted approach. Measurable improvements in the safety culture were noted as well.

Role of sex in the treatment and clinical outcomes of pediatric patients with inflammatory bowel disease.

OBJECTIVE: To examine sex differences in medical therapy and clinical outcomes in pediatric patients with inflammatory bowel disease (IBD). METHODS: We performed a cross-sectional analysis of children with Crohn disease (CD) and ulcerative colitis (UC) using data from the ImproveCareNow Network collected between May 2007 and May 2010. Clinical remission, disease severity, body mass index (BMI) z scores, normal height velocity, and medication use were analyzed by sex and age. RESULTS: One thousand four hundred nine patients were included (993 had CD and 416 had UC). No significant sex differences were found in disease severity, BMI, height velocity, or use of medications. Further analysis of combination therapy with infliximab + 6-mercaptopurine/azathioprine and infliximab + methotrexate also did not reveal any differences. No sex differences were found after mediation use was stratified by age (those younger than 13 years and those 13 years old or older). CONCLUSIONS: In this sample of CD and UC pediatric patients, no significant sex differences were found in disease severity, BMI, height velocity, or medication use. Our data do not support the use of sex as a major factor in patient risk stratification for children with IBD. In addition, despite concerns for sex-specific complications of some medications, our analysis did not suggest any sex differences in medication use.

Gender differences in the social functioning of adolescents with inflammatory bowel disease.

Inflammatory bowel disease (IBD) has been associated with social difficulties. Boys with IBD may have increased risk for social problems due to delayed growth and puberty, but gender differences in social functioning have not been investigated. This study examined gender differences in multiple areas of social functioning for adolescents with IBD compared to healthy adolescents. Participants were 92 adolescents 11-17 years (50 with IBD, 42 healthy) and parents who completed questionnaires assessing social functioning. IBD was associated with poorer social functioning in the areas of social competence and social problems. Boys with IBD had worse social competence, with no gender differences for social problems. Gender predicted the use of social contact as a coping strategy, but no significant group differences were found for other areas of social functioning. Adolescents with IBD experience significant social difficulties in some areas, and boys are at risk for poor social competence. However, previously reported social difficulties may not extend to all areas of social functioning.

The Role of Master Protocols in Pediatric Drug Development.

Master protocols are innovative clinical trial designs that enable new approaches to analytics and operations, creating value for patients and drug developers. To date, the use of master protocols in pediatric drug development has been limited, focused primarily on pediatric oncology with limited experience in rare and ultra-rare pediatric diseases. This article explores the application of master protocols to pediatric programs required by FDA and EMA based on adult developmental programs. These required programs involve multiple assets developed in limited pediatric populations for registrational purposes. However, these required programs include the possibility for extrapolation of efficacy and safety from the adult population. The use of master protocols is a potential solution to the challenge of conducting clinical trials in small pediatric populations provided that such use would improve enrollment or reduce the required sample size. Toward that end, Janssen and Lilly have been working on a collaborative cross-company pediatric platform trial in pediatric Crohn's disease using an innovative Bayesian analysis. We describe how two competing companies can work together to design and execute the proposed platform, focusing on selected aspects-the usefulness of a single infrastructure, the regulatory submission process, the choice of control group, and the use of pediatric extrapolation. Master protocols offer the potential for great benefit in pediatrics by streamlining clinical development, with the goal of reducing the delay in pediatric marketing approvals when compared to adults so that children have timelier access to safe and effective medications.

Variation in care in pediatric Crohn disease.

OBJECTIVES: Variation in medical care can be a barrier to improving clinical outcomes. We aim to describe the variation in care of Crohn disease as provided by a broad sample of pediatric gastroenterologists. METHODS: Two hundred forty-six Crohn disease patients of 93 pediatric gastroenterologists from 48 practice sites starting treatment with either thiopurine or infliximab were studied. We assessed variation in diagnostic testing that had been performed to establish the diagnosis of Crohn disease and to assess the phenotype, extent, and severity of disease. We also assessed variation in initial thiopurine and infliximab dosage and in nutritional therapy. RESULTS: Diagnostic studies in which care was uniform included complete blood count, performed in 100% of patients, erythrocyte sedimentation rate and colonoscopy in 96%, and upper endoscopy in 89%. However, imaging of the small bowel had not been performed in 19%, and a stool test for pathogens had not been performed in 29%. Thiopurine methyltransferase (TPMT) had been measured in 61% of patients before treatment with a thiopurine; in 85%, TPMT was normal. Nonetheless, even when TPMT was normal, 40% of patients received an initial dose of thiopurine that was lower than recommended. Testing for tuberculosis before initiating treatment with infliximab was not performed in 30%. In addition, 36% of severely underweight patients were not receiving a multivitamin supplement, supplemental formula, or tube feeding. CONCLUSIONS: There is variation in diagnostic and therapeutic interventions in the management of pediatric Crohn disease, and gaps exist between recommended and actual care.

Multicenter Evaluation of Emergency Department Treatment for Children and Adolescents With Crohn's Disease According to Race/Ethnicity and Insurance Payor Status.

Background: Racial and socioeconomic disparities exist in the treatment and outcomes of children and adults with Crohn's disease (CD). This study investigated the impact of race and insurance status on emergency department (ED) evaluation and treatment among children with CD in the United States. Methods: Data from the Pediatric Health Information System included ED visits between January 2007 and December 2013 for patients aged ≤21 years with a primary diagnosis of CD, or a secondary diagnosis of CD plus a primary CD-related diagnosis. Analyses were performed using mixed-effects logistic regression. Results: Subjects included 2618 unique patients (black, 612 [23%]; white, 2006 [77%]) with 3779 visits from 38 hospitals, a median age of 14.0 ± 4.0 years, and 50% male. White children had a higher median neighborhood income and were more likely to have private insurance (57% vs 30%; P < 0.001). Emergency department visits for privately insured patients had higher odds of complete blood count (odds ratio [OR], 1.43; 95% CI, 1.08-1.90) and C-reactive protein/erythrocyte sedimentation rate (OR, 1.39; 95% CI, 1.06-1.82) vs Medicaid insured. Visits for white children had higher odds of receiving antiemetics (OR, 1.52; 95% CI, 1.06-2.17) vs black children. The proportion of patients with repeat visits was greater for black children (33%) than white children (22%; P < 0.001) and greater for Medicaid-insured (27%) than privately insured patients (21%; P < 0.01). Conclusions: This cross-sectional database study demonstrated that black children and those with Medicaid insurance made more ED visits and received somewhat fewer treatments, which may be explained by greater use of the ED for routine care. An opportunity exists for better outpatient management of children with IBD so that nonemergent problems are more effectively handled.

Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn's Disease.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS: Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS: We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001). CONCLUSIONS: Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.