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Objectives: The incidence of pediatric-onset inflammatory bowel disease (IBD) is increasing worldwide. We used population-based health administrative data to determine national Canadian IBD incidence, prevalence, and trends over time of childhood-onset IBD. Methods: We identified children

Objectives: To determine the association between inflammatory bowel disease (IBD) and rural/urban household at the time of diagnosis, or within the first 5 years (y) of life. Methods: Population-based cohorts of residents of four Canadian provinces were created using health administrative data. Rural/urban status was derived from postal codes based on population density and distance to metropolitan areas. Validated algorithms identified all incident IBD cases from administrative data (Alberta: 1999–2008, Manitoba and Ontario: 1999–2010, and Nova Scotia: 2000–2008). We determined sex-standardized incidence (per 100,000 patient-years) and incident rate ratios (IRR) using Poisson regression. A birth cohort was created of children in whom full administrative data were available from birth (Alberta 1996–2010, Manitoba 1988–2010, and Ontario 1991–2010). IRR was calculated for residents who lived continuously in rural/urban households during each of the first 5 years of life. Results: There were 6,662 rural residents and 38,905 urban residents with IBD. Incidence of IBD per 100,000 was 33.16 (95% CI 27.24–39.08) in urban residents, and 30.72 (95% CI 23.81–37.64) in rural residents (IRR 0.90, 95% CI 0.81–0.99). The protective association was strongest in children

OBJECTIVES We sought to evaluate whether two novel immunoglobulin A (IgA) cell wall polysaccharide antibodies, anti-laminarin (anti-L) and anti-chitin (anti-C), aid in the diagnosis and phenotype differentiation of Crohn's disease (CD) and ulcerative colitis (UC). METHODS A cohort of 818 individuals with inflammatory bowel disease (IBD; 517 CD and 301 UC) from two IBD tertiary referral centers, with median ages of 33 and 39 years, respectively, and disease duration of 8.9 years, were phenotyped using the Montreal classification, and analyzed for seven anti-glycan antibodies (gASCA (anti-Saccharomyces cerevisiae) IgG, gASCA IgA, anti-chitobioside (GlcNAc(beta1,4)GlcNAc(beta)), anti-laminaribioside (Glc(beta1,3)Glb(beta)), anti-mannobioside (Man(alpha1,3)Man(alpha)), anti-L, and anti-C) and perinuclear atypical neutrophil cytoplasmic antibodies (pANCA). RESULTS In the CD patient population, 73% were positive for >/=1 anti-glycan antibody. All glycan markers were specific for CD (85.4-97.7%) and more prevalent in CD vs. UC (P

Toxic megacolon (TMC) denotes a rare clinical syndrome accompanied by colonic dilatation, and is a serious complication of inflammatory bowel disease (IBD). This study assessed the clinical and radiologic characteristics of TMC in children with IBD.A systematic search identified patients with IBD-associated TMC and matched them by age to controls with ulcerative colitis without evidence of TMC. Clinical characteristics and outcomes were compared with conditional logistic regression. Abdominal X-rays were interpreted by two blinded radiologists and findings were compared with controls.Ten children with TMC (median age 12.6 [7.3-15.5] yr) were matched with 20 controls (median age 12.8 [6.8-15.2] yr). Altered level of consciousness and hypotension were rare in children with TMC. Fever (P= 0.005), tachycardia (P= 0.0001), dehydration (P= 0.01), and electrolyte abnormalities (P= 0.0002) were more common in children with TMC than controls. Air-fluid levels (P= 0.005), intestinal thickening (P= 0.006), and abnormal colonic haustra (P= 0.012) were more commonly seen on X-rays of TMC cases. Transverse colon luminal diameteror=56 mm was strongly suggestive of TMC (sensitivity 90%, specificity 90%, area under the ROC curve 0.91). No child with TMC died and 70% required colectomy during admission. Two of the three with intact colons at discharge required second-line therapy during the subsequent year.Colonic dilatationor=56 mm in children with IBD strongly suggests TMC, if clinical signs are present. Mental alteration and hypotension may be less common in children than in adults. TMC in children with IBD is associated with poor outcome, with a high rate of corticosteroid failure.

BACKGROUND: The thiopurines, azathioprine and 6-mercaptopurine, are traditional first-line immunomodulatory agents in adult and pediatric Crohn's disease, but the comparative efficacy and safety of methotrexate have seldom been examined. We report outcomes with methotrexate treatment in pediatric patients previously refractory to or intolerant of thiopurines. METHODS: In a four-center, retrospective cohort study, efficacy of methotrexate in maintaining remission was assessed by PCDAI measurements, steroid use, and height velocity. Patients served as their own historical controls. Multivariable analysis controlled for route of methotrexate administration, reason for thiopurine discontinuation, baseline disease activity, and disease duration. RESULTS: Forty-two percent of 60 children treated with methotrexate were in clinical remission without steroids at both 6 and 12 months. A strong steroid sparing effect was observed compared with the year prior to methotrexate (P < 0.001). Success rates were similar in previously thiopurine-intolerant and refractory patients. Height velocity increased from -1.9 SDS to -0.14 SDS (P = 0.004) in the year following therapy. In a median 3-yr follow-up, a third of the patients did not require escalation of therapy; the others required step-up therapy with infliximab or surgery. Eight children (13%) stopped methotrexate due to adverse events, including, most commonly, elevated liver enzymes, and one serious episode of sepsis. CONCLUSION: Methotrexate appears effective in maintaining remission in pediatric Crohn's disease, when thiopurines have failed. Consideration should be given to its use earlier in pediatric treatment algorithms.

The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci.This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis.We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease.Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.

OBJECTIVES: Acute severe ulcerative colitis (ASC) is a potentially life-threatening disease. We aimed to formulate guidelines for managing ASC in children based on systematic review of the literature and robust consensus process. This manuscript is a product of a joint effort of the ECCO (European Crohn's and Colitis Organization), the Pediatric Porto Inflammatory Bowel Disease (IBD) Working group of ESPGHAN (European Society of Pediatric Gastroenterology, Hepatology, and Nutrition) and ESPGHAN. METHODS: A group of 19 experts in pediatric IBD participated in an iterative consensus process including two face-to-face meetings. A total of 17 predefined questions were addressed by working subgroups based on a systematic review of the literature. RESULTS: The recommendations and practice points were eventually endorsed with a consensus rate of at least 95% regarding: definitions, initial evaluation, standard therapy, timing of second-line therapy, the role of endoscopic evaluation and heparin prophylaxis, how to administer second-line medical therapy, how to assess response, surgical considerations, and discharge recommendations. A management flowchart is presented based on daily scoring of the Pediatric Ulcerative Colitis Activity Index (PUCAI), along with 28 formal recommendations and 34 practice points. CONCLUSIONS: These guidelines provide clinically useful points to guide the management of ASC in children. Taken together, the recommendations offer a standardized protocol that allows effective monitoring of disease progress and timely treatment escalation when needed.

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.We performed a multicenter cohort study of 332 pediatric patients with UC enrolled in the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry. Childrenor=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.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.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.

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.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.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.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, and70% of patients achieved rapid response that was sustained through 12 months.

Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population.Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions.African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4-5.5), colorectal disease (OR = 1.9; 95% CI: 1.1-3.4), perianal disease (OR = 1.7; 95% CI: 1.03-2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32-0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3-13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55-10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8-4.6) and erythema nodosum (3.3; 95% CI: 1.7-6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts.There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.