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.

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%).

Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response.

Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4ß7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.

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.

Serologic Reactivity Reflects Clinical Expression of Ulcerative Colitis in Children.

Background: In contrast to pediatric Crohn's disease (CD), little is known in pediatric ulcerative colitis (UC) about the relationship between disease phenotype and serologic reactivity to microbial and other antigens. Aim: The aim of this study was to examine disease phenotype and serology in a well-characterized inception cohort of children newly diagnosed with UC during the PROTECT Study (Predicting Response to Standardized Pediatric Colitis Therapy). Methods: Patients were recruited from 29 participating centers. Demographic, clinical, laboratory, and serologic (pANCA, ASCA IgA/IgG, Anti-CBir1, and Anti-OmpC) data were obtained from children 4-17 years old with UC. Results: Sixty-five percent of the patients had positive serology for pANCA, with 62% less than 12 years old and 66% 12 years old or older. Perinuclear anti-neutrophil cytoplasmic antibodies did not correspond to a specific phenotype though pANCA ≥100, found in 19%, was strongly associated with pancolitis (P = 0.003). Anti-CBir1 was positive in 19% and more common in younger children with 32% less than 12 years old as compared with 14% 12 years old or older (P < 0.001). No association was found in any age group between pANCA and Anti-CBir1. Relative rectal sparing was more common in +CBir1, 16% versus 7% (P = 0.02). Calprotectin was lower in Anti-CBir1+ (Median [IQR] 1495 mcg/g [973-3333] vs 2648 mcg/g [1343-4038]; P = 0.04). Vitamin D 25-OH sufficiency was associated with Anti-CBir1+ (P = 0.0009). Conclusions: The frequency of pANCA in children was consistent with adult observations. High titer pANCA was associated with more extensive disease, supporting the idea that the magnitude of immune reactivity may reflect disease severity. Anti-CBir1+ was more common in younger ages, suggesting host-microbial interactions may differ by patient age.

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.

Safety and Pharmacokinetic Study of Fidaxomicin in Children With Clostridium difficile-Associated Diarrhea: A Phase 2a Multicenter Clinical Trial.

BACKGROUND: Fidaxomicin is an approved therapy for Clostridium difficile-associated diarrhea (CDAD) in adults. The safety of fidaxomicin in children has not been reported. METHODS: In this study (ClinicalTrials.gov identifier NCT01591863), pediatric patients with CDAD received twice-daily oral fidaxomicin at a dose of 16 mg/kg per day (up to 200 mg) for 10 days in an open-label study. Plasma and fecal samples were collected for pharmacokinetic assessments. The primary outcome measure was safety, which was assessed by adverse-event (AE), laboratory, and physical examination/vital-sign monitoring. Efficacy was determined through early and sustained clinical response rates (clinical response without recurrence of CDAD). RESULTS: The study enrolled 40 patients (11 months to 17 years of age), many with underlying comorbidity, including neoplasm (23.7%), gastrointestinal disorder (78.9%), and history of CDAD (60.5%). Plasma fidaxomicin and OP-1118 (the major fidaxomicin metabolite) 3- to 5-hour postdose concentrations were 0.6 to 87.4 and 2.4 to 882.0 ng/mL, respectively, and no age-related trends were seen. Fecal fidaxomicin concentrations within 24 hours of the last dose averaged 3228 µg/g, and higher concentrations and greater variability in the youngest age group were found. AEs were reported in 73.7% of the patients; most of them were mild (44.7%) to moderate (21.1%) and were considered treatment-related in 15.8% of the patients. Overall, the early clinical response rate was 92.1%. The rate of sustained clinical response (clinical response without recurrence through 28 days after treatment) was 65.8% overall. CONCLUSIONS: Fidaxomicin was well tolerated in children with CDAD and has a pharmacokinetic profile in children similar to that in adults. The clinical response rate was high.

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.

Retrospective cohort study of methotrexate use in the treatment of pediatric Crohn's disease.

BACKGROUND: Methotrexate (MTX) use as an alternative to thiopurines in the treatment of Crohn's disease (CD) in children is increasing. This study was undertaken to assess safety and efficacy of MTX in children with CD. METHODS: Patients treated with MTX with a minimum of 1-year follow-up were identified in the Pediatric IBD Collaborative Research Group Registry, a prospective inception cohort study started in 2002. The clinical efficacy and safety of MTX were analyzed retrospectively. RESULTS: Two hundred ninety patients treated with MTX were identified. One hundred seventy-two patients received at least 3 months of MTX without thiopurine or biologicals and had ≥1 year of follow-up. Eighty-one of 172 patients (47%) received MTX as first immunomodulator (IMM), of which 22 (27%) achieved ≥12 months of sustained clinical remission without surgery, thiopurine, biologicals, or corticosteroids. Those receiving MTX as second IMM achieved similar remission rate (35%, P = not significant). Fourteen percent received MTX as first IMM in 2002 and 60% in 2010 (P = 0.005). Disease location did not affect outcomes. MTX doses were equivalent in both groups. Fifteen percent of patients developed an alanine aminotransferase >60 international units/liter and 12% developed a white blood cell <4000 cells per microliter while on MTX. Only 4% of these discontinued MTX completely. A small group of 6 centers, which contributed only about one-third of patients with CD in the registry, contributed nearly two-thirds of the patients receiving MTX (P < 0.001). CONCLUSIONS: MTX use as first choice IMM is increasing in pediatric CD. MTX provided sustained clinical remission in nearly one-third of patients with minimal toxicity. There is large center-to-center variability in its use.

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.

Effects of recombinant human growth hormone on protein turnover in the fasting and fed state in adolescents with Crohn disease.

The primary purpose of this study was to test whether recombinant human growth hormone (rhGH) supplementation would enhance protein synthesis and accretion of lean body mass. Eight adolescents (six males and two females; 17.2 +/- 2.6 years; age range, 13.7-21.2 years) participated in a randomized double-blind placebo-controlled cross-over trial of rhGH. We employed stable isotopes to measure proteolysis and protein synthesis during fasting and fed conditions during two 6-month treatment conditions. We also measured bone mineral density (BMD), markers of bone turnover, and body composition. Whole-body proteolysis, phenylalanine catabolism, and protein synthesis did not differ during treatment with rhGH vs. placebo. Enteral nutrition suppressed proteolysis and increased protein synthesis similarly during placebo and rhGH treatments. We conclude that rhGH is unlikely to provide sufficient metabolic benefit to warrant its use as an adjunct treatment in clinically stable adolescents with Crohn disease. A high prevalence of vitamin D deficiency and suboptimal BMD existed, which deserves further investigation and clinical attention.

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.

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.

Factors that determine risk for surgery in pediatric patients with Crohn's disease.

BACKGROUND & AIMS: We examined the incidence of Crohn's disease (CD)-related surgery in a multi-center, inception cohort of pediatric patients with CD. We also examined the effect of starting immunomodulator therapy within 30 days of diagnosis. METHODS: Data from 854 children with CD from the Pediatric Inflammatory Bowel Disease Collaborative Research Group who were diagnosed with CD between 2002 and 2008 were analyzed. RESULTS: Overall, 76 (9%) underwent a first CD-related surgery, 57 (7%) underwent a first bowel surgery (bowel resection, ostomy, strictureplasty, or appendectomy), and 19 (2%) underwent a first non-bowel surgery (abscess drainage or fistulotomy). The cumulative risks for bowel surgery, non-bowel surgery, and all CD-related surgeries were 3.4%, 1.4%, and 4.8%, respectively, at 1 year after diagnosis and 13.8%, 4.5%, and 17.7%, respectively, at 5 years after diagnosis. Older age at diagnosis, greater disease severity, and stricturing or penetrating disease increased the risk of bowel surgery. Disease between the transverse colon and rectum decreased the risk. Initiation of immunomodulator therapy within 30 days of diagnosis, sex, race, and family history of inflammatory bowel disease did not influence the risk of bowel surgery. CONCLUSIONS: In an analysis of pediatric patients with CD, the 5-year cumulative risk of bowel surgery was lower than that reported in recent studies of adult and pediatric patients but similar to that of a recent retrospective pediatric study. Initiation of immunomodulator therapy at diagnosis did not alter the risk of surgery within 5 years of diagnosis.

Utility of fecal lactoferrin in identifying Crohn disease activity in children.

OBJECTIVES: Fecal lactoferrin (FL) is a noninvasive biomarker that is elevated in Crohn disease (CD) compared to irritable bowel syndrome. The purpose of this study was to evaluate FL in identifying children with active versus inactive CD. PATIENTS AND METHODS: Fresh stool samples were collected from children with CD scheduled for endoscopy or a clinic visit, and from new outpatients who were scheduled for colonoscopy. FL was determined using a polyclonal antibody-based enzyme-linked immunosorbent assay. Physical global assessment, endoscopic findings, erythrocyte sedimentation rate (ESR), and the Pediatric CD Activity Index (PCDAI) were recorded for patients with CD. The PCDAI scores symptoms, laboratory parameters, physical examination, and extraintestinal manifestations. A score of ≤10 is inactive disease, 11 to 30 is mild active, and ≤31 is moderate to severe active. RESULTS: Of 101 study patients (4- to 20-year-old, 66 boys), 31 had active CD, 23 had inactive CD, and 37 had noninflammatory bowel disease (non-IBD) conditions. Four patients with ulcerative colitis and 6 patients with polyposis were excluded from analysis. FL was significantly elevated in CD versus non-IBD (P < 0.001) and in active versus inactive CD (P < 0.001). The PCDAI and ESR were higher in active CD than in inactive CD (both P < 0.001). Using an FL cutoff of 7.25 µg/g, FL has 100% sensitivity and 100% negative predictive value in detecting active CD. Using an FL cutoff level of 60 µg/g, FL had 84% sensitivity, 74% specificity, 81% positive predictive value, and 77% negative predictive value for detecting active CD. CONCLUSIONS: FL is a promising biomarker of active CD and may be more practical to use when it is not feasible to obtain all of the necessary clinical information for the PCDAI.

Extraintestinal manifestations of pediatric inflammatory bowel disease and their relation to disease type and severity.

OBJECTIVES: Although it is known that extraintestinal manifestations (EIMs) commonly occur in pediatric inflammatory bowel disease (IBD), little research has examined rates of EIMs and their relation to other disease-related factors in this population. The purpose of this study was to determine the rates of EIMs in pediatric IBD and examine correlations with age, sex, diagnosis, disease severity, and distribution. PATIENTS AND METHODS: Data were prospectively collected as part of the Pediatric IBD Collaborative Research Group Registry, an observational database enrolling newly diagnosed IBD patients <16 years old since 2002. Rates of EIM (occurring anytime during the period of enrollment) and the aforementioned variables (at baseline) were examined. Patients with indeterminate colitis were excluded from the analysis given the relatively small number of patients. RESULTS: One thousand nine patients were enrolled (mean age 11.6 +/- 3.1 years, 57.5% boys, mean follow-up 26.2 +/- 18.2 months). Two hundred eighty-five (28.2%) patients experienced 1 or more EIMs. Eighty-seven percent of EIM occurred within the first year. Increased disease severity at baseline (mild vs moderate/severe) was associated with the occurrence of any EIM (P < 0.001), arthralgia (P = 0.024), aphthous stomatitis (P = 0.001), and erythema nodosum (P = 0.009) for both Crohn disease (CD) and ulcerative colitis (UC) during the period of follow-up. Statistically significant differences in the rates of EIMs between CD and UC were seen for aphthous stomatitis, erythema nodosum, and sclerosing cholangitis. CONCLUSIONS: EIMs as defined in this study occur in approximately one quarter of pediatric patients with IBD. Disease type and disease severity were commonly associated with the occurrence of EIMs.

Retrospective Evaluation of the Safety and Effect of Adalimumab Therapy (RESEAT) in pediatric Crohn's disease.

OBJECTIVES: Adalimumab, an anti-tumor necrosis factor immunoglobulin-1 antibody, is increasingly being reported as a potential treatment option for children with moderate-to-severe Crohn's disease (CD). The aim of this study was to characterize common indications, safety, tolerability, and clinical response to adalimumab in pediatric CD in a large, multicenter, patient cohort. METHODS: Data were obtained using a retrospective, uncontrolled chart review at 12 sites of the Pediatric Inflammatory Bowel Disease Collaborative Research Group. Clinical, laboratory, and demographic data were obtained for CD patients who received at least one dose of adalimumab. Indication for adalimumab, concomitant medications, and clinical outcome at 3, 6, and 12 months for each patient were recorded using physician global assessment (PGA) and Pediatric CD Activity Index scores. Serious adverse events were identified. RESULTS: A total of 115 patients (54% female) received at least one dose of adalimumab. The mean age at the diagnosis of CD was 11.1+/-3.1 years, with the first adalimumab dose administered at 4.7+/-2.8 years after diagnosis. The most common dosing frequency was every other week with induction doses of 160/80 mg in 19%, 80/40 mg in 44%, and 40/40 mg in 15% of patients. Maintenance dosing was 40 mg every other week in 88% of patients. Mean follow-up after initial adalimumab dose was 10+/-8.6 months. Infliximab treatment preceded adalimumab in 95% of patients, with a mean of 12 infliximab infusions (range: 1-44). Infliximab discontinuation was due to loss of response (47%), infusion reaction or infliximab intolerance (45%), or preference for a subcutaneous medication (9%). Concomitant medications at the commencement of adalimumab were corticosteroids (38%), azathioprine/6-mercaptopurine (41%), and methotrexate (23%). Clinical response measured by PGA at 3, 6, and 12 months was 65, 71, and 70%, respectively, with steroid-free remission at 3, 6, and 12 months of 22, 33, and 42%, respectively. There were no malignancies, serious infections, or deaths in the study subjects. CONCLUSIONS: Adalimumab was a well-tolerated and effective rescue therapy for moderate-to-severe pediatric CD patients previously treated with infliximab. Adalimumab demonstrated a steroid-sparing effect, and >70% of patients achieved rapid response that was sustained through 12 months.