Dedrick E. Moulton

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 Crohns 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.

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 Crohns 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 Crohns 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 Crohns 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 models specificity improved to 71%. INTERPRETATION Our findings support the usefulness of risk stratification of paediatric patients with Crohns disease at diagnosis, and selection of anti-TNFα therapy. FUNDING Crohns and Colitis Foundation of America, Cincinnati Childrens Hospital Research Foundation Digestive Health Center.

Dissecting allele architecture of early onset IBD using high-density genotyping

Background The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent. Methods We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn’s disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn’s disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases. Conclusions The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

Endoscopic ultrasound to guide the combined medical and surgical management of pediatric perianal Crohn's disease

Background: Perianal fistulas are a debilitating manifestation of Crohns disease (CD) in the pediatric population and present a management challenge. The aims of this study were to describe our experience using endoscopic ultrasound (EUS) to guide management of perianal CD (PCD) in a pediatric population, and determine whether using EUS to monitor healing after seton placement improves outcomes. Methods: We conducted a retrospective study of 2 cohorts: pediatric subjects with PCD who underwent EUS and pediatric subjects who underwent seton placement between 2002 and 2007. Results: In all, 25 children underwent a total of 42 EUS procedures. Of 28 EUSs performed to evaluate suspected perianal disease, complex fistulizing disease was identified in 15 (54%). Setons were placed after most EUSs demonstrating complex fistulizing disease and after none demonstrating superficial or no fistulizing disease. Of 14 EUSs performed to monitor healing around a seton, 7 (50%) demonstrated persistent peri‐seton inflammation. Setons were more often left in place after an EUS revealing persistent inflammation (86% versus 0%), and the patients were more likely to have a biologic initiated or changed (57% versus 0%). Among all subjects who underwent seton placement, time from seton removal to recurrence was longer for those followed by EUS compared to those followed by physical exam only; however, we were not powered to test for statistical significance. Conclusions: EUS to guide the combined medical and surgical management of PCD is feasible in the pediatric population. Larger prospective studies are needed to determine if EUS‐directed management improves outcomes in pediatric patients with PCD. (Inflamm Bowel Dis 2010)

Outcomes following infliximab therapy for pediatric patients hospitalized with refractory colitis-predominant IBD.

Objectives: Although randomized trials demonstrated the efficacy of infliximab for both pediatric Crohn disease and ulcerative colitis (UC), few patients in these studies exhibited colitis requiring hospitalization. The aims of this study were to determine the rate of subsequent infliximab failure and dose escalation in pediatric patients who started taking infliximab during hospitalization for colitis-predominant IBD, and to identify potential predictors of these endpoints. Methods: This is a single-center retrospective cohort study of patients admitted from 2005 to 2010 with Crohn colitis, UC, or IBD-unspecified (IBD-U) and initiated on infliximab. Results: We identified 29 patients (12 Crohn colitis, 15 UC, and 2 IBD-U; median age 14 years) with a median follow-up of 923 days. Eighteen patients (62%) required infliximab dose escalation (increased dose or decreased infusion interval). Infliximab failure occurred in 18 patients (62%) because of ineffectiveness in 12 (67%) and adverse reactions in 6 (33%). Twelve patients (41%) underwent colectomy. Subsequent need for infliximab dose escalation was associated with lower body mass index z score (P = 0.01), lower serum albumin (P = 0.03), and higher erythrocyte sedimentation rate (ESR) (P = 0.002) at baseline. ESR predicted subsequent infliximab dose escalation with an area under the curve of 0.89 (95% confidence interval [CI] 0.72–1.00) and a sensitivity and specificity at a cutoff of 38 mm/hour of 0.79 (95% CI 0.49–0.95) and 0.88 (95% CI 0.47–0.99), respectively. Conclusions: Most hospitalized pediatric patients with colitis treated with infliximab require early-dose escalation and fail the drug long term. Low body mass index and albumin and high ESR, may identify patients who would benefit from a higher infliximab starting dose.

Expression of a Novel Cadherin in the Mouse and Human Intestine

Members of the cadherin superfamily mediate critical interactions in tissue differentiation and organogenesis, including differentiation and maintenance of the intestine. In this study, we report the identification and expression of a novel cadherin in the intestinal epithelium. We identified this cDNA by subtraction hybridization and obtained subsequent clones by screening a human cDNA library. Tissue distribution of the mRNA encoding the cadherin was assessed by RNA blot, reverse transcriptase PCR, and in situ hybridization. Protein expression was analyzed by protein blot and immunohistochemistry. The cDNA encodes an integral membrane protein with four consecutive cadherin binding domains followed by a series of mucin domains, a unique feature of this cadherin. Differences in the mucin domains account for four splice-forms. Multiple potential SH3-binding domains and a single potential PDZ-binding domain follow the transmembrane domain. Analysis revealed expression in the liver, kidney, and intestine. Three splice variants were found in the embryonic intestine as early as embryonic d 13 and in the adult intestine. The mRNA localizes to the mature enterocytes throughout the mouse small intestine and the protein, including several species from 90 to 100 kD, resides on the enterocyte basolateral membrane. We have identified intestinal expression of a novel cell cadherin with features suggesting the potential to transduce signals from neighboring cells to the cytoplasm.

IBD Serology and Disease Outcomes in African Americans With Crohn’s Disease

Backgrounds Recent studies have identified the role of serologic markers in characterizing disease phenotype, location, complications, and severity among Northern Europeans (NE) with Crohns disease (CD). However, very little is known about the role of serology in CD among African Americans (AA). Our study explored the relationship between serology and disease phenotype in AA with CD, while controlling for genetic ancestry. Methods AAs with CD were enrolled as participants through multicenter collaborative efforts. Serological levels of IgA anti-Saccharomyces cervisiae antibody (ASCA), IgG ASCA, E. coli outermembrane porin C, anti-CBir1, and ANCA were measured using enzyme-linked immunosorbent assays. Genotyping was performed using Illumina immunochip technology; an admixture rate was calculated for each subject. Multiple imputation by chained equations was performed to account for data missing at random. Logistic regression was used to calculate adjusted odds ratio (OR) for associations between serological markers and both complicated disease and disease requiring surgery. Results A total of 358 patients were included in the analysis. The majority of our patients had inflammatory, noncomplicated disease (58.4%), perianal disease (55.7%), and documented colonic inflammation (86.8%). On multivariable analysis, both IgG ASCA and OmpC were associated with complicated disease (OR, 2.67; 95% CI, 1.67-4.28; OR, 2.23; 95% CI, 1.41-3.53, respectively) and disease requiring surgery (OR, 2.51; 95% CI, 1.49-4.22; OR, 3.57; 95% CI, 2.12-6.00). NE admixture to the African genome did not have any associations or interactions in relation to clinical outcome. Conclusions Our study comprises the largest cohort of AAs with CD. The utility of serological markers for the prognosis of CD in NE applies equally to AA populations.

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 Crohns 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 Crohns 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.

Suboptimal Early Outcomes following Standardized Induction Therapy in Children Newly Diagnosed with Ulcerative Colitis: The Protect Study

Jeffrey S. Hyams , Sonia Davis, David R. Mack , Brendan Boyle, Anne M. Griffiths, Neal S. Leleiko, Cary G.Sauer, David J. Keljo, James Markowitz, Susan Baker, Joel Rosh, Robert N. Baldassano, Ashish Patel, Marian Pfefferkorn, Anthony Otley, Melvin Heyman, Joshua Noe, Maria OlivaHemker, Paul Rufo, Jennifer Strople, David Ziring, Stephen Guthery, Boris Sudel, Keith Benkov, Prateek Wali, Dedrick Moulton, Jonathan Evans, Michael Kappelman , Alison Marquis, Francisco A. Sylvester, Margaret H. Collins, Suresh Venkateswaran, Marla Dubinsky, Krista L. Spada, Ashley Britt, Bradley Saul, Nathan Gotman, Jose Serrano, Subra Kugathasan, Thomas Walters, Lee A. Denson