Gitit Tomer

Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohns disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 × 10−8 and 6.95 × 10−8, respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 × 10−8; OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.

Outcome following infliximab therapy in children with ulcerative colitis

OBJECTIVES:Infliximab is effective in treating moderate/severe ulcerative colitis (UC) in adults. The aim of this study was to determine the outcome after treatment with infliximab in pediatric UC.METHODS:We performed a multicenter cohort study of 332 pediatric patients with UC enrolled in the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry. Children ≤16 years of age and newly diagnosed with UC are enrolled in the registry. Disease and medication information are collected prospectively from the treating physician at diagnosis, 30 days, and quarterly thereafter. No interventions were specified, per protocol.RESULTS:Of 332 patients, 52 (16%) received infliximab (23% <3 months from diagnosis, 38% 3–12 months, 38% >12 months). Mean age at infliximab initiation was 13.3±2.6 (range 6–17) years; 87% of patients had pancolitis. Median follow-up was 30 months. Continuous maintenance (CM) therapy was given in 65%, episodic in 21%, episodic converted to CM in 6%, and insufficient data in 8% of patients. Sixty-three percent of patients were corticosteroid refractory, and 35% were corticosteroid dependent. Concomitant medications at first infliximab infusion included corticosteroids (87%), thiopurines (63%), and 5-aminosalicylates (51%). Corticosteroid-free inactive disease by physician global assessment was noted in 12/44 (27%), 15/39 (38%), and 6/28 (21%) patients at 6, 12, and 24 months, respectively. Kaplan–Meier analysis showed that the likelihood of remaining colectomy free after treatment with infliximab was 75% at 6 months, 72% at 12 months, and 61% at 2 years.CONCLUSIONS:In this cohort of children with UC receiving infliximab, corticosteroid-free inactive disease was observed in 38 and 21% of patients at 12 and 24 months, respectively. By 24 months, 61% of patients had avoided colectomy.

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.

NOD2/CARD15 variants are associated with lower weight at diagnosis in children with Crohn's disease

OBJECTIVES:NOD2/CARD15 variants have recently been shown to be associated with Crohns disease (CD). No analysis of NOD2/CARD15 gene variants has so far been reported in pediatric patients. Therefore, our aim was to analyze NOD2/CARD15 gene variants in children with CD and to perform genotype-phenotype analyses.METHODS:We studied 101 children with CD and 136 healthy controls. Detailed phenotypic information was obtained from each patient. Patients were genotyped for the three NOD2/CARD15 variants R702W (single nucleotide polymorphism 8 [SNP8]), G908R (SNP12), and L1007fs (SNP13), and genotype-phenotype correlations were performed.RESULTS:We found 33 NOD2/CARD15 mutations in 29 of 101 patients (29%). The frequency of NOD2 variation was 31% in white (n = 87) compared with 11% in controls (χ2= 14; p = 0.0001; OR = 3.7; 95% CI = 1.7–7.8). Four white patients but not control subjects were compound heterozygotes. NOD2/CARD15 variants were significantly associated with ileal disease (χ2= 4.5; p = 0.03; OR = 5; 95% CI = 0.9–35.9). Of the children with NOD2/CARD15 variants, 44% were ≤5th percentile for weight at diagnosis, whereas only 15% of children without mutations were ≤5th percentile (χ2= 8.7; p = 0.003; OR = 4.5; 95% CI = 1.4–14.4). Similar trends were observed for height but they did not reach statistical significance.CONCLUSIONS:Our results demonstrate that: 1) the three NOD2/CARD15 variants confer risk to CD in children; 2) NOD2/CARD15 variants are associated with ileal disease in children as in adults; and 3) NOD2/CARD15 variants are associated with lower weight percentiles at diagnosis in children and a tendency toward lower height percentile, suggesting an association between growth in children with CD.

Factors That Determine Risk for Surgery in Pediatric Patients With Crohn's Disease

BACKGROUND & AIMS We examined the incidence of Crohns 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.

Differential Developmental Regulation of Rat Liver Canalicular Membrane Transporters Bsep and Mrp2

Bile formation depends on the active secretion of bile salts and other biliary constituents by specific transporters. Recently two major transporters that contribute to bile formation, the bile salt export pump (Bsep) and multidrug resistance protein-2 (Mrp2), have been cloned. The goal of the present study was to define the expression of Bsep and Mrp2 during rat liver development. mRNA expression as assessed by Northern blot and RT-PCR was higher for Mrp2 (40% of adult) at 21 d fetal age relative to Bsep (<20% of adult). The levels of Mrp2 mRNA increased to ˜50% of adult at 1 d of life and then rapidly increased to adult levels by 1-3 wk. Nuclear run-on assays for Bsep and Mrp2 showed minimal transcription during fetal life with an increase in transcription in the postnatal period. A different pattern of expression was observed for both Mrp2 and Bsep proteins. During fetal life, there was low expression of Mrp2 and Bsep proteins (<20% of adult) with a gradual increase neonatally reaching adult levels at 4 wk. Thus, we noted a temporal delay between the maximal expression of the mRNA (1-3 wk) and protein (4 wk) for Bsep and Mrp2. These results show that 1) expression (of mRNA and protein) of canalicular transporters is developmentally regulated by both transcriptional and posttranscriptional mechanisms and 2) Mrp2 and Bsep gene expression (mRNA) are differentially regulated.

Improved outcomes with quality improvement interventions in pediatric inflammatory bowel disease.

Objectives: Variations in chronic illness care are common in our health care system and may lead to suboptimal outcomes. Specifically, inconsistent use and suboptimal medication dosing have been demonstrated in the care of patients with inflammatory bowel disease (IBD). Quality improvement (QI) efforts have improved outcomes in conditions such as asthma and diabetes mellitus, but have not been well studied in IBD. We hypothesized that QI efforts would lead to improved outcomes in our pediatric IBD population. Methods: A QI team was formed within our IBD center in 2005. By 2007, we began prospectively capturing physician global assessment (PGA) and patient-reported global assessment. Significant QI interventions included creating evidence-based medication guidelines, joining a national QI collaborative, initiation of preclinic planning, and monitoring serum 25-hydroxyvitamin D. Results: From 2007 to 2010, 505 patients have been followed at our IBD center. During this time, the frequency of patients in clinical remission increased from 59% to 76% (P < 0.05), the frequency of patients who report that their global assessment is >7 increased from 69% to 80% (P < 0.05), and the frequency of patients with a Short Pediatric Crohns Disease Activity Index (sPCDAI) <15 increased from 60% to 77% (P < 0.05). The frequency of repeat steroid use decreased from 17% to 10% (P < 0.05). We observed an association between the use of a vitamin D supplement (P = 0.02), serum 25-hydroxyvitamin D (P < 0.05), and quiescent disease activity. Conclusions: Our results show that significant improvements in patient outcomes are associated with QI efforts that do not rely on new medication or therapies.

Genetic variants in the autophagy pathway contribute to paediatric Crohn’s disease

Massey and Parkes ( Gut 2007; 56 :1489–92) recently highlighted the impact of genome-wide association (GWA) studies in generating new insights into the aetiology of Crohn’s disease (CD). We share their enthusiasm. However, the mechanisms underlying childhood-onset CD remain unknown. Phenotypic differences among children, the increased risk of CD among family members with early-onset disease and the attractive strategy of stratifying cases by age of onset to understand further the genetic architecture of CD all justify studying children with CD in genetic association studies. To this end, we tested 11 genetic variants in our paediatric CD population who were recently identified in predominantly adult-onset (mean age of onset ranging from 24 to 27 years) CD GWA studies.1–6 We studied 555 CD-affected children with the mean age of onset of 11.7 years, and 486 disease-free controls. Individuals were self-identified as …

Disorders of bile formation and biliary transport

A wide range of cholestatic liver diseases result from various primary defects in bile formation. Clinical features include jaundice, pruritus, failure to thrive, fat malabsorption, cholelithiasis, and variably progressive cirrhosis. Accurate diagnosis of these disorders is essential for determination of prognosis and selection of the most appropriate therapies. Severe genetic defects in canalicular bile acid and phospholipid excretion lead to progressive liver disease that often requires liver transplantation. Defects in bile acid biosynthesis and aminophospholipid transport may be responsive to medical or non-transplant surgical approaches.

Polymorphisms in the IBD5 Locus Are Associated With Crohn Disease in Pediatric Ashkenazi Jewish Patients

Objectives: To analyze the IBD5 locus in a homogenous cohort of Ashkenazi Jewish (AJ) children with Crohn disease (CD). Patients and Methods: A total of 83 AJ children with CD and 73 AJ healthy controls were studied. Genotyping for single nucleotide polymorphisms (SNPs) including OCTN1 (SLC22A4; 1672C→T), OCTN2 (SLC22A5; 207G→C), IGR2096, IGR2198, and IGR2230 genes was performed using the TaqMan system. NOD2/CARD15 variants also were typed using established methods. Results: All IBD5 SNPs tested were in linkage disequilibrium (D′>0.8), and showed significant association with CD in our cohort of AJ children. The IGR2096 SNP, which is not located within the same linkage disequilibrium block as the OCTN1 and 2 SNPs, showed an even stronger association with CD (P = 0.017; odds ratio = 1.7). Patients with CD who had the OCTN1 susceptibility allele were more likely to carry 1 of the 3 NOD2/CARD15 SNPs tested (P = 0.01; odds ratio = 4.8). Conclusions: We have demonstrated a significant association between the IBD5 locus and CD in a homogenous cohort of pediatric AJ patients. Due to the tight linkage disequilibrium in the region, it is not possible to identify the causative IBD5 variant. Future functional studies will ultimately reveal the causative gene variant at this locus.