Eileen Crowley

Long-term outcomes for children with very early-onset colitis: Implications for surgical management

PURPOSE The timing of J-pouch surgery following colectomy for children with very early-onset colitis is controversial, with some advocating early reconstruction and others delaying reconstruction because of fear that the colitis may be owing to Crohns disease (CD). We sought to determine the long-term incidence of CD in this population and whether there may be clinical features that predict the risk of CD. METHODS Children with noninfectious colitis diagnosed prior to age 10, who underwent subtotal colectomy and ileostomy from 2000 to 2015, were reviewed. RESULTS Twenty-five children were identified. Median age at presentation was 5.4years. Four were initially diagnosed with CD (16%), 14 with ulcerative colitis (UC) (56%), and 7 with inflammatory bowel disease unclassified (IBD-U) (28%). Eight eventually had pouch surgery. Five of the children with an initial diagnosis of UC or IBD-U developed findings that changed the diagnosis to CD at a median age of 13.4 (range 10.3 to 16.7) years. None had any indicators of CD at the initial presentation. CONCLUSIONS Approximately one quarter of patients with very early-onset colitis originally diagnosed as UC or IBD-U had a reclassification in diagnosis to CD over time. J-pouch reconstruction should be delayed until adolescence in children with very early-onset colitis. LEVEL OF EVIDENCE 2C.

Symptoms Do not Correlate With Findings From Colonoscopy in Children With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Background & Aims: Approximately 75% of children with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). IBD in patients with PSC (PSC‐IBD) often has a unique phenotype, including a mild clinical course, yet it is associated with an increased risk of colorectal cancer compared with colonic IBD without PSC. We investigated whether subclinical endoscopic and histologic inflammation could account for the increased risk of colorectal cancer in patients with PSC‐IBD, and whether these patients have increased fecal levels of calprotectin, a marker of inflammation. Methods: We performed a prospective study of children (age, <18 y) with colonic IBD with and without PSC who underwent colonoscopy from February 1, 2016, through March 31, 2017, at the Hospital for Sick Children in Toronto, Canada. We collected pediatric ulcerative colitis activity index (PUCAI) scores (to measure symptoms) and fecal levels of calprotectin from 37 children with PSC‐IBD and 50 children with only IBD (controls; UC or IBD‐unclassified). Colonoscopies were scored using the Mayo endoscopic subscore and the UC Endoscopic Index of Severity (UCEIS) scores, and histologic activity was graded. Among patients in clinical remission, endoscopic scores and the odds of active endoscopic disease (based on a UCEIS score ≥1) were compared between patients with and without PSC in univariate and multivariable analyses. Correlations between activity markers were compared between groups. The ability of fecal calprotectin to identify mucosal healing in patients with PSC‐IBD was assessed using receiver operating characteristic curve analyses. Analogous analyses were performed for histologic activity. Results: Patients with PSC‐IBD in clinical remission had higher endoscopic scores and greater odds of active endoscopic disease than controls (odds ratio, 5.9; 95% CI, 1.6–21.5). There was a higher degree of correlation between PUCAI and UCEIS scores in controls (r = 0.82) than in patients with PSC‐IBD (r = 0.51; P = .01). Fecal levels of calprotectin correlated with UCEIS in patients with PSC‐IBD (r = 0.84) and controls (r = 0.82; P = .80). Fecal levels of calprotectin identified mucosal healing in patients with PSC‐IBD with an area under the receiver operating characteristic curve of 0.94 (optimal cut‐point, 93 &mgr;g/g; 100% sensitivity and 92% specificity). Histologic activity scores and the odds of active histologic disease were also greater in patients in clinical remission with PSC‐IBD than controls. Conclusions: Children with PSC‐IBD in clinical remission, based on PUCAI scores, have a significantly higher risk of active endoscopic and histologic disease than children with colitis without PSC. Fecal levels of calprotectin correlate with endoscopic findings in pediatric patients with PSC‐IBD; levels below 93 &mgr;g/g are associated with mucosal healing.

Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn′s Disease

Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. To determine the role of NOD2 and other genes in pediatric IBD, we performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0-18.5 years). We identified 92 probands who were homozygous or compound heterozygous for rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian recessive inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from the Regeneron Genetics Center (RGC)-Geisinger Health System DiscovEHR study, which links whole exome sequences to longitudinal electronic health records (EHRs) from 51,289 participants. We found that ~7% of cases in this adult IBD cohort, including ~10% of CD cases, can be attributed to recessive inheritance of NOD2 variants, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that 14% of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7-10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease. Author Summary Pediatric onset inflammatory bowel disease (IBD) represents ≥25% of IBD diagnoses; yet the genetic architecture of early onset IBD remains largely uncharacterized. To investigate this, we performed whole-exome sequencing and rare variant analysis on a cohort of 1,183 pediatric onset IBD patients. We found that 8% of patients in our cohort were homozygous or compound heterozygous for rare or low frequency deleterious variants in the nucleotide binding and oligomerization domain containing 2 (NOD2) gene. Further investigation of whole-exome sequencing of a large clinical cohort of adult IBD patients uncovered recessive inheritance of rare and low frequency NOD2 variants in 7% of cases and that the relative risk for NOD2 variant homozygosity has likely been underestimated. While it has been reported that having >1 NOD2 risk alleles is associated with increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate what has long been suspected: recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Our data suggest that a subset of IBD-CD patients with early disease onset is characterized by recessive inheritance of NOD2 alleles, which has important implications for the screening, diagnosis, and treatment of IBD.