Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.

Utilization of Antitumor Necrosis Factor Biologics in Very Early Onset Inflammatory Bowel Disease: A Multicenter Retrospective Cohort Study From North America.

BACKGROUND: Research on the utilization and effectiveness of antitumor necrosis factor (TNF) biologics in children with very early onset inflammatory bowel disease (VEOIBD) is urgently needed. Here we describe anti-TNF use and durability in a multicenter cohort. METHODS: We performed a retrospective cohort study of patients diagnosed with VEOIBD (<6 years) between 2008 and 2013 at 25 North American centers. We performed chart abstraction at diagnosis and 1, 3, and 5 years after diagnosis. We examined the rate of initiation and durability of infliximab and adalimumab and evaluated associations between treatment durability and the following covariates with multivariate Cox proportional hazard regression: age at diagnosis, sex, disease duration, disease classification, and presence of combined immunomodulatory treatment versus monotherapy. RESULTS: Of 294 children with VEOIBD, 120 initiated treatment with anti-TNF therapy and 101 had follow-up data recorded [50% Crohn disease (CD), 31% ulcerative colitis (UC), and 19% IBD unclassified (IBD-U)]. The cumulative probability of anti-TNF treatment was 15% at 1 year, 30% at 3 years, and 45% at 5 years from diagnosis; 56 (55%) were treated between 0 and 6 years old. Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years. The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children. Children with UC/IBD-U had lower durability than those with CD (hazard ratio [HR] 0.17; 95% confidence interval [CI], 0.06-0.51; P = 0.001). CONCLUSIONS: Utilization and durability of anti-TNF in VEOIBD is relatively high and comparable with older children. Having Crohn disease (compared with UC/IBD-U) is associated with greater durability.

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%).

Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study.

BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.

Biologics Delay Progression of Crohn's Disease, but Not Early Surgery, in Children.

BACKGROUND & AIMS: Up to 30% of patients with Crohn's disease (CD) require surgery within the first 5 years from diagnosis. We investigated the recent risk of bowel surgery in an inception cohort of pediatric patients with CD and whether early use of biologics (tumor necrosis factor antagonists) alters later disease course. METHODS: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group registry on 1442 children (age, ≤16 y) diagnosed with CD from January 2002 through December 2014. Data were collected at diagnosis, 30 days following diagnosis, and then quarterly and during hospitalizations for up to 12 years. Our primary aim was to determine the 10-year risk for surgery in children with CD. Our secondary aim was to determine whether early use of biologics (<3 mo of diagnosis) affected risk of disease progression. RESULTS: The 10-year risk of first bowel surgery was 26%. The 5-year risk of bowel surgery did not change from 2002 through 2014, and remained between 13% and 14%. Most surgeries occurred within 3 years from diagnosis. The only predictor of surgery was disease behavior at diagnosis. CD with inflammatory behavior had the lowest risk of surgery compared to stricturing disease, penetrating disease, or both. We associated slowing of disease progression to stricturing or penetrating disease (but not surgery) with early use of biologics, but this effect only became evident after 5 years of disease. Our results indicate that biologics slow disease progression over time (hazard ratio, 0.85; 95% CI, 0.76-0.95). CONCLUSIONS: In an analysis of data from a registry of pediatric patients with CD, we found that among those with significant and progressing disease at or shortly after presentation, early surgery is difficult to prevent, even with early use of biologics. Early use of biologics (<3 mo of diagnosis) can delay later disease progression to stricturing and/or penetrating disease, but this affect could become evident only years after initial management decisions are made.

The Effect of Early-Life Environmental Exposures on Disease Phenotype and Clinical Course of Crohn's Disease in Children.

OBJECTIVES: Environmental factors play an important role in the pathogenesis of Crohn's Disease (CD). In particular, by virtue of the instability of the microbiome and development of immunologic tolerance, early life factors may exert the strongest influence on disease risk and phenotype. METHODS: We used data from 1119 CD subjects recruited from RISK inception cohort to examine the impact of early life environment on disease progression. Our primary exposures of interest were breastfeeding in infancy and exposure to maternal, active, or passive smoke. Our primary outcomes were development of complicated (stricturing or penetrating) disease, and need for CD-related hospitalization, and surgery. Multivariable logistic regression models were used to define independent associations, adjusting for relevant covariates. RESULTS: Our study cohort included 1119 patients with CD among whom 15% had stricturing (B2) or penetrating disease (B3) by 3 years. 331 patients (35%) and 95 patients (10.6%) required CD-related hospitalizations and surgery respectively. 74.5% were breastfed in infancy and 31% were exposed to smoking among whom 7% were exposed to maternal smoke. On multivariable analysis, a history of breastfeeding was inversely associated with complicated (B2/B3 disease) 0.65, CI 95% 0.44-96; P = 0.03) in pediatric CD. Maternal smoking during pregnancy was associated with increased risk of hospitalization during the 3-year follow-up period (OR 1.75, CI 95% 1.05-2.89; P = 0.03). CONCLUSIONS: Early life environmental factors influence the eventual phenotypes and disease course in CD.

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.

Gallbladder Ejection Fraction Is Unrelated to Gallbladder Pathology in Children and Adolescents.

OBJECTIVES: Biliary dyskinesia is a common diagnosis that frequently results in cholecystectomy. In adults, most clinicians use a cut off value for the gallbladder ejection fraction (GBEF) of <35% to define the disease. This disorder is not well characterized in children. Our aim was to determine the relation between GBEF and gallbladder pathology using a large statewide medical record repository. METHODS: We obtained records from all patients of 21 years and younger who underwent hepatic iminodiacetic acid (HIDA) testing within the Indiana Network for Patient Care from 2004 to 2013. GBEF results were obtained from radiology reports using data mining techniques. Age, sex, race, and insurance status were obtained for each patient. Any gallbladder pathology obtained subsequent to an HIDA scan was also obtained and parsed for mention of cholecystitis, cholelithiasis, or cholesterolosis. We performed mixed effects logistic regression analysis to determine the influence of age, sex, race, insurance status, pathologist, and GBEF on the presence of these histologic findings. RESULTS: Two thousand eight hundred forty-one HIDA scans on 2558 patients were found. Of these, 310 patients had a full-text gallbladder pathology report paired with the HIDA scan. GBEF did not correlate with the presence of gallbladder pathology (cholecystitis, cholelithiasis, or cholesterolosis) when controlling for age, sex, race, insurance status, and pathologist using a mixed effects model. CONCLUSIONS: Hypokinetic gallbladders are no more likely to have gallbladder pathology than normal or hyperkinetic gallbladders in the setting of a patient with both a HIDA scan and a cholecystectomy. Care should be used when interpreting the results of HIDA scans in children and adolescents.

Concomitant Use of Immunomodulators Affects the Durability of Infliximab Therapy in Children With Crohn's Disease.

BACKGROUND & AIMS: It is important to determine the effects of immunomodulators on the ability of children to remain on infliximab therapy for Crohn's disease (durability of therapy), given the potential benefits and risks of concomitant therapy-especially with thiopurines in male patients. We investigated how immunomodulatory treatment affects the durability of infliximab therapy. METHODS: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, from January 2002 through August 2014, on 502 children with Crohn's disease who participated in a prospective multicenter study. Data were collected from patients who received at least a 3-dose induction regimen of infliximab, and their concomitant use of immunomodulators: no thiopurine or methotrexate treatment, treatment for 6 months or less during infliximab therapy, or treatment for more than 6 months during infliximab therapy. RESULTS: The probabilities (± standard error) that children remained on infliximab therapy for 1 year, 3 years, and 5 years after the treatment began were 0.84 ± 0.02, 0.69 ± 0.03, and 0.60 ± 0.03, respectively. Age, sex, and disease extent or location did not affect the durability of infliximab therapy. Greater length of concomitant use of immunomodulators was associated with increased time of infliximab therapy. The probability that patients with more than 6 months of immunomodulator use remained on infliximab therapy for 5 years was 0.70 ± 0.04, compared with 0.48 ± 0.08 for patients who did not receive immunomodulators and 0.55 ± 0.06 for patients who received immunomodulators for 6 months or less (P < .001). In boys who received immunomodulators for 6 months or more after starting infliximab, the overall durability of infliximab therapy was greater among patients receiving methotrexate than thiopurine (P < .01); the probabilities that they remained on infliximab therapy for 5 years were 0.97 ± 0.03 vs 0.58 ± 0.08, respectively. CONCLUSIONS: In children with Crohn's disease, concomitant treatment with an immunomodulator for more than 6 months after starting infliximab therapy increases the chances that patients will remain on infliximab. In boys, methotrexate appears to increase the durability of infliximab therapy compared with thiopurine.

Increased effectiveness of early therapy with anti-tumor necrosis factor-α vs an immunomodulator in children with Crohn's disease.

BACKGROUND & AIMS: Standard therapy for children newly diagnosed with Crohn's disease (CD) includes early administration of immunomodulators after initial treatment with corticosteroids. We compared the effectiveness of early (≤3 mo after diagnosis) treatment with an anti-tumor necrosis factor (TNF)α with that of an immunomodulator in attaining clinical remission and facilitating growth of pediatric patients. METHODS: We analyzed data from the RISK study, an observational research program that enrolled patients younger than age 17 diagnosed with inflammatory (nonpenetrating, nonstricturing) CD from 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children (median age, 11.8 y; 61% male; 63% with pediatric CD activity index scores >30; and median C-reactive protein level 5.6-fold the upper limit of normal), we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFα therapy, early immunomodulator, or no early immunotherapy. We evaluated relationships among therapies, corticosteroid and surgery-free remission (pediatric CD activity index scores, ≤10), and growth at 1 year for 204 children. Treatment after 3 months was a covariate. RESULTS: Early treatment with anti-TNFα was superior to early treatment with an immunomodulator (85.3% vs 60.3% in remission; relative risk, 1.41; 95% confidence interval [CI], 1.14-1.75; P = .0017), whereas early immunomodulator therapy was no different than no early immunotherapy (60.3% vs 54.4% in remission; relative risk, 1.11; 95% CI, 0.83-1.48; P = .49) in achieving remission at 1 year. Accounting for therapy after 3 months, early treatment with anti-TNFα remained superior to early treatment with an immunomodulator (relative risk, 1.51; 95% CI, 1.20-1.89; P = .0004), whereas early immunomodulator therapy was no different than no early immunotherapy (relative risk, 1.00; 95% CI, 0.75-1.34; P = .99). The mean height z-score increased compared with baseline only in the early anti-TNFα group. CONCLUSIONS: In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFα produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFα therapy.

Clinical Presentation and Five-Year Therapeutic Management of Very Early-Onset Inflammatory Bowel Disease in a Large North American Cohort.

OBJECTIVE: To evaluate the presentation, therapeutic management, and long-term outcome of children with very early-onset (VEO) (≤ 5 years of age) inflammatory bowel disease (IBD). STUDY DESIGN: Data were obtained from an inception cohort of 1928 children with IBD enrolled in a prospective observational registry at multiple centers in North America. RESULTS: One hundred twelve children were ≤ 5 years of age with no child enrolled at <1 year of age. Of those, 42.9% had Crohn's disease (CD), 46.4% ulcerative colitis (UC), and 10.7% had IBD-unclassified. Among the children with CD, children 1-5 years of age had more isolated colonic disease (39.6%) compared with 6- to 10-year-olds (25.3%, P = .04), and 11- to 16-year-olds (22.3%, P < .01). The change from a presenting colon-only phenotype to ileocolonic began at 6-10 years. Children 1-5 years of age with CD had milder disease activity (45.8%) at diagnosis compared with the oldest group (28%, P = .01). Five years postdiagnosis, there was no difference in disease activity among the 3 groups. However, compared with the oldest group, a greater proportion of 1- to 5-year-olds with CD were receiving corticosteroids (P < .01) and methotrexate (P < .01), and a greater proportion of 1- to 5-year-olds with UC were receiving mesalamine (P < .0001) and thiopurine immunomodulators (P < .0002). CONCLUSIONS: Children with VEO-CD are more likely to have mild disease at diagnosis and present with a colonic phenotype with change to an ileocolonic phenotype noted at 6-10 years of age. Five years after diagnosis, children with VEO-CD and VEO-UC are more likely to have been administered corticosteroids and immunomodulators despite similar disease activity in all age groups. This may suggest development of a more aggressive disease phenotype over time.

Liver enzyme elevations within 3 months of diagnosis of inflammatory bowel disease and likelihood of liver disease.

BACKGROUND: Inflammatory bowel disease-associated liver diseases (IBD-LDs) include autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and an overlap syndrome. Prospective unbiased multicenter data regarding the frequency of IBD-LD in patients with pediatric inflammatory bowel disease (IBD) are lacking. We examined early alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (GGT) elevations in children diagnosed as having IBD and assessed the likelihood of IBD-LD. METHODS: Data collected from the prospective observational Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry enrolling children of age <16 years within 30 days of diagnosis. AIH, PSC, and overlap syndrome were diagnosed using local institutional criteria. RESULTS: A total of 1569 subjects had liver enzymes available. Of the total, 757 had both ALT and GGT, 800 had ALT only (no GGT), and 12 had GGT only (no ALT). Overall, 29 of 1569 patients (1.8%) had IBD-LD. IBD-LD was diagnosed in 1 of 661 (0.15%) of patients with both ALT and GGT ≤ 50 IU/L compared with 21 of 42 (50%) of patients with both ALT and GGT > 50 (odds ratio 660, P < 0.0001). Of the 29 patients with IBD-LD, 21 had PSC, 2 had AIH, and 6 had overlap syndrome. IBD-LD was more common in patients with ulcerative colitis and IBD-unclassified (indeterminate colitis) than in those with Crohn disease (4% vs 0.8%, respectively, P < 0.001). CONCLUSIONS: Elevation of both ALT and GGT within 90 days after the diagnosis of IBD is associated with a markedly increased likelihood of IBD-LD. Both ALT and GGT levels should be measured in all of the pediatric patients newly diagnosed as having IBD.

Outcome following aminosalicylate therapy in children newly diagnosed as having ulcerative colitis.

OBJECTIVES: Despite a paucity of published supporting data, 5-aminosalicylate (5-ASA) use in pediatric ulcerative colitis (UC) is common. The present study describes the use and outcome of a large multicenter inception cohort of children with UC treated with 5-ASA. METHODS: Data were obtained from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, a prospective North American observational study of children newly diagnosed as having inflammatory bowel disease ages 16 years or younger. Patient data are recorded at diagnosis, 30 days, and then quarterly. Patients are managed by physician dictate, not protocol. Disease activity is classified by physician global assessment. The primary outcome examined was corticosteroid (CS) free, inactive UC at 1 year following initiation of 5-ASA within 30 days of diagnosis (with or without concomitant CS use) without the need for rescue therapy (immunomodulators, biologics, or colectomy). RESULTS: Study subjects included 213 patients newly diagnosed as having UC who received oral 5-ASA compounds (115 of whom also received CS) during the first 30 days after diagnosis, and no other oral therapies for the treatment of UC. Of these 213 patients, 86 (40%) were CS free and physician global assessment inactive at 1 year without rescue. Outcome was not associated with disease severity at diagnosis, demographic or laboratory factors examined, or initial dose of 5-ASA used. CONCLUSIONS: Forty percent of children taking 5-ASA as primary maintenance therapy at diagnosis are in CS-free remission after 1 year of treatment. Further pediatric studies will be needed to address whether increased adherence and/or higher dosing schedules will improve outcomes.

Budesonide use in pediatric Crohn disease.

BACKGROUND AND AIM: Budesonide (BUD) is being used in pediatric Crohn disease (CD) because it is believed to have the potential to reduce corticosteroid-related toxicity; however, few data are available describing its use. The aim of the present study was to describe BUD use in an inception cohort of pediatric patients with CD. METHODS: Data were derived from the prospective Pediatric IBD Collaborative Research Group Registry established in 2002 in North America. Use of BUD in children with CD was examined. RESULTS: BUD was used in 119 of 932 (13%) of children with newly diagnosed CD, with 56 of 119 (47%) starting BUD ≤ 30 days of diagnosis (26/56 with ileum and/or ascending colon [IAC] disease). BUD was used as monotherapy (9%), in combination with 5-aminosalicylates (77%), or in combination with immunomodulators (43%). Forty-three percent (24/56) went on to receive conventional corticosteroid at some point following their first BUD course. For the 63 of 119 (53%) who started BUD beyond the diagnosis period, 51 of 63 (81%) also received prednisone, with BUD used as a means of weaning from prednisone in 17 of 63 (27%). Patients with IAC disease who received BUD ≤ 30 days of diagnosis were just as likely to have received conventional corticosteroids by 1 year as were those who did not receive BUD ≤ 30 days of diagnosis. Two-thirds (77/119) of patients received BUD for ≤ 6 months. CONCLUSIONS: BUD is being used among pediatric patients newly diagnosed as having CD, although the majority does not have disease limited to the IAC. BUD monotherapy was rare, and further data are required to better define the role of BUD in the treatment of pediatric CD.

Proactive measurement of infliximab drug levels in children with Crohn's disease.

BACKGROUND: Proactively monitoring infliximab levels is an emerging area of interest in pediatric Crohn's disease. There are only limited data on therapeutic drug monitoring for children with Crohn's disease. The goal of our study was to determine the utility of therapeutic drug monitoring in achieving clinical remission in a cohort of pediatric Crohn's disease patients receiving infliximab. METHODS: This prospective single-center study enrolled 37 patients with Crohn's disease at the start of infliximab infusions and monitored trough levels at 6-month intervals for 18 months. Each participant was matched to a historic control for the modified pediatric Crohn's disease activity index (mPCDAI) at baseline, age and sex. The primary outcome was an mPCDAI score of ≤7.5 at 6, 12 and 18 months. A multivariate logistic regression analysis was performed. RESULTS: Data were available for all 37 cases at 6 and 12 months and for 34 cases at 18 months. Demographics and disease characteristics were similar between groups. All 34 cases demonstrated clinical remission at 18 months (100% vs. 88%, P=0.114). Univariate and multivariate analyses did not show statistical significance. Dose intensification was seen more often in the cases at 18 months. CONCLUSION: All of our moderate-to-severe pediatric Crohn's disease patients who received prospective therapeutic drug monitoring of infliximab were in clinical remission at follow up, but this was not statistically significantly different from the 88% clinical remission rate of the control group.

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.

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.

Outcome following thiopurine use in children with ulcerative colitis: a prospective multicenter registry study.

OBJECTIVES: Despite little supporting data, thiopurine use is common in pediatric ulcerative colitis (UC). Our aim was to determine outcome following thiopurine use in a multicenter inception cohort of children diagnosed with UC. METHODS: Data were obtained from a prospective observational study of newly diagnosed children <16 years of age. Data are recorded at diagnosis, 30 days, and quarterly. Patients are managed by physician dictates not protocol. Disease activity is classified by physician global assessment. The primary outcome was corticosteroid (CS)-free inactive UC at 1 year following thiopurine initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy). RESULTS: Of 1,490 patients in our registry, 394 have UC (mean age at diagnosis 11.3±3.7 years); 197 (50%) received thiopurine (49% ≤3 months from diagnosis). Also, 84% were receiving CSs and 60% 5-aminosalicylates at thiopurine start. Of the 197 patients, there was insufficient follow-up (41), previous or concomitant use of infliximab (16), or calcineurin inhibitor (7), leaving 133 patients evaluable at 1 year. Of these, 65 (49%) had CS-free inactive UC without rescue therapy. CS-free inactive disease at 1 year after initiating thiopurine was not affected by starting thiopurine ≤3 months vs. >3 months from diagnosis, gender, age, or concomitant treatment with 5-aminosalicylates. Kaplan-Meier analysis showed that the likelihood of remaining free of rescue therapy in the thiopurine-treated patients was 73% at 1 year. CONCLUSIONS: Approximately 50% of children with UC starting thiopurine without previous or concomitant biologic or calcineurin inhibitor therapy have CS-free inactive disease 1 year later without the need for rescue therapy.

Significance of esophageal Crohn disease in children.

BACKGROUND AND AIM: Esophageal Crohn disease (ECD) is more common than it was originally thought to be. Only limited information, however, is available regarding its significance and effect on clinical course in the pediatric population. The aim of the study was to determine the prevalence of ECD in our patient population and compare clinical features and severity of disease among patients with ECD and nonesophageal Crohn disease (NECD). PATIENTS AND METHODS: Medical records of all patients with ECD diagnosed during a 12-year period based on specific endoscopic and histological criteria were reviewed and compared with a random group of patients with NECD. RESULTS: During the study period, 81 (20%) patients with ECD were identified. Mean age at diagnosis was 12 (range 4-19 years) with a male predominance of 63%. Only 29 (36%) patients had symptoms suggestive of upper gastrointestinal involvement. Endoscopic ulcers were present in 45 (56%) of patients with ECD, whereas noncaseating granulomas were found in 10 (12%) of those patients. The majority (89%) of these patients had concomitant gastric and/or duodenal involvement. When compared with 160 random patients with NECD, patients with ECD had higher mean Pediatric Crohn Disease Activity Index scores (40.2 vs 23.9; P < 0.001), more penetrating-type disease (12% vs 2%; P = 0.001), and a greater frequency of perianal involvement (51% vs 33%; P = 0.005) at diagnosis. No differences, however, were noted between the 2 groups in terms of need for surgical resection throughout duration of follow-up. CONCLUSIONS: Patients with ECD may represent a phenotype of Crohn disease with a more severe presentation. Patients with perianal disease at the time of initial physical examination should be considered for an upper endoscopy in addition to the colonoscopy to exclude esophageal involvement despite the absence of specific upper gastrointestinal symptoms. These observations should foster additional investigation into ECD phenotype to determine appropriate treatment and prognosis.

Esophageal pH monitoring with the BRAVO capsule: experience in a single tertiary medical center.

AIM: The aim of the present study was to report the global experience with placement, complication rate, and recording of esophageal pH using the BRAVO capsule at our institution. PATIENTS AND METHODS: We recorded the rate of any technical problems and complications during placement in all of the patients (ages 4-22 years) who received this device during a 2-year period. All of the patients undergoing esophagogastroduodenoscopy with the placement of BRAVO pH capsule were included in this analysis. We also examined the pH data recorded on days 1 and 2 for significant day-to-day variability during 2 days of pH monitoring. RESULTS: Two hundred eighty-nine BRAVO pH probes were placed from January 1, 2006 to December 31, 2008. At least 1 day of data was obtained in 278 patients (96.2%). Two days of data were obtained in 274 patients (94.8%). Of all of the reported complications, 1% occurred before deployment of the capsule, 4% occurred during deployment of the capsule, and 9% occurred after successful deployment of the capsule. One patient experienced a superficial esophageal tear that was associated with failure of the capsule to release from the delivery system. No patient requested removal of the capsule and all of the capsules detached within 14 days. In 9.12% of our patients, reflux index was normal on day 1 and abnormal on day 2. There was no statistically significant difference between reflux index recorded on day 1 versus day 2 (P = 0.686). CONCLUSIONS: The BRAVO pH capsule is easy to place, safe, and well tolerated by children. Performing a 48-hour study detected abnormal reflux in an additional 9% of our patients.