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Background Develop a clinical and biological predictive model for colectomy risk in children newly diagnosed with ulcerative colitis (UC). Methods This was a multicenter inception cohort study of children (ages 4-17 years) newly diagnosed with UC treated with standardized initial regimens of mesalamine or corticosteroids (CS) depending upon initial disease severity. Therapy escalation to immunomodulators or infliximab was based on predetermined criteria. Patients were phenotyped by clinical activity per the Pediatric Ulcerative Colitis Activity Index (PUCAI), disease extent, endoscopic/histologic severity, and laboratory markers. In addition, RNA sequencing defined pretreatment rectal gene expression and high density DNA genotyping by the Affymetrix UK Biobank Axiom Array. Coprimary outcomes were colectomy over 3 years and time to colectomy. Generalized linear models, Cox proportional hazards multivariate regression modeling, and Kaplan-Meier plots were used. Results Four hundred twenty-eight patients (mean age 13 years) started initial theapy with mesalamine (n = 136), oral CS (n = 144), or intravenous CS (n = 148). Twenty-five (6%) underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. Further, 32/35 patients who had colectomy failed infliximab. An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001). A logistic regression model predicting colectomy using the PUCAI, hemoglobin, and erythrocyte sedimentation rate had a receiver operating characteristic area under the curve of 0.78 (95% confidence interval [0.73, 0.84]). Addition of a pretreatment rectal gene expression panel reflecting activation of the innate immune system and response to external stimuli and bacteria to the clinical model improved the receiver operating characteristic area under the curve to 0.87 (95% confidence interval [0.82, 0.91]). Conclusions A small group of children newly diagnosed with severe UC still require colectomy despite current therapies. Our gene signature observations suggest additional targets for management of those patients not responding to current medical therapies.

Background: We evaluated the psychometric performance of the Pediatric Ulcerative Colitis Activity Index (PUCAI) in a real-life cohort from the Pediatric IBD Collaborative Research Group. Methods: Two consecutive visits of 215 children with ulcerative colitis (UC) were included (mean age 11.2 ± 3.6 years; 112 (52%) males; 63 (29%) newly diagnosed and the others after disease duration of 24 ± 15.6 months). Validity was assessed using several constructs of disease activity. Distributional and anchor-based strategies were used to assess the responsiveness of the PUCAI to change over time following treatment. Results: Reflecting feasibility, 97.6% of 770 eligible registry visits had a completed PUCAI score versus only 47.6% for a contemporaneously collected Pediatric Crohn's Disease Activity Index (odds ratio = 45.8, 95% confidence interval [CI] 28.6–73.5) obtained for children with Crohn's disease accessioned into the same database. The PUCAI score was significantly higher in patients requiring escalation of medical therapy (45 points [interquartile range, IQR, 30–60]) versus those who did not, (0 points [IQR 0–10]; P < 0.001), and was highly correlated with physician's global assessment of disease activity (r = 0.9, P < 0.001). The best cutoff to differentiate remission from active disease was 10 points (area under receiver operating characteristic curve [AUC] 0.94; 95% CI 0.90–0.97). Test–retest reliability was excellent (intraclass correlation coefficient = 0.89; 95% CI 0.84–0.92, P < 0.001) as well as responsiveness to change (AUC 0.96 [0.92–0.99]; standardized response mean 2.66). Conclusion: This study on real-life, prospectively obtained data confirms that the PUCAI is highly feasible by virtue of the noninvasiveness, valid, and responsive index. The PUCAI can be used as a primary outcome measure to reflect disease activity in pediatric UC. (Inflamm Bowel Dis 2009)

Crohn's disease (CD) is often associated with antibodies to microbial antigens. Differences in immune response may offer clues to the pathogenesis of the disease. The aim was to examine the influence of age at diagnosis on the serologic response in children with CD.Data were drawn from 3 North American multicenter pediatric inflammatory bowel disease (IBD) research consortia. At or shortly after diagnosis, pANCA, ASCA IgA, ASCA IgG, anti-ompC, and anti-CBir1 were assayed. The results were compared as a function of age at CD diagnosis (0-7 years versus 8-15 years).In all, 705 children (798 years of age at diagnosis, 626or=8 years) were studied. Small bowel CD was less frequent in the younger group (48.7% versus 72.6%; P0.0001), while colonic involvement was comparable (91.0% versus 86.5%). ASCA IgA and IgG were seen in20% of those 0-7 years old compared to nearly 40% of those 8-15 years old (P0.001), while anti-CBir1 was more frequent in the younger children (66% versus 54%, P0.05). Anti-CBir1 detected a significant number of children in both age groups who otherwise were serologically negative. Both age at diagnosis and site of CD involvement were independently associated with expression of ASCA and anti-CBir1.Compared to children 8-15 years of age at diagnosis, those 0-7 years are more likely to express anti-CBir1 but only half as likely to express ASCA. These age-associated differences in antimicrobial seropositivity suggest that there may be different, and as yet unrecognized, genetic, immunologic, and/or microbial factors leading to CD in the youngest children.

Background: The immunomodulators (IMs) 6-mercaptopurine and azathioprine decrease corticosteroid dependence and maintain remission in Crohn's disease (CD). We describe IM use in newly diagnosed pediatric CD, comparing outcomes of “early” versus “late” initiation of therapy. Methods: Data were obtained from pediatric CD patients enrolled in a prospective, multicenter observational study. Moderate/severe disease patients treated with IM were compared for outcomes of remission, corticosteroid use, infliximab therapy, hospitalizations, and CD-related surgery based on timing of initiation of IM therapy. Results: In all, 247 children met the criteria (60% male, mean age 11.9 years); 199 were treated with IM within 1 year of diagnosis; 150 between 0–3 months (early), 49 between 3–12 months (late). Both groups showed a decrease in corticosteroid use by 12 months, at which time proportionately fewer early group patients had received corticosteroids in the preceding quarter (22%) than late groups patients (41%)(P = 0.013). The number of hospitalizations per patient was also noted to be significantly lower in the early group over the 2-year follow-up (P = 0.03). No difference was noted in the rates of remission, infliximab use over time, or surgery. Conclusions: 80% of children with newly diagnosed moderate to severe CD are treated with IM within 1 year. Early IM use is associated with reduced corticosteroid exposure and possibly fewer hospitalizations per patient. (Inflamm Bowel Dis 2008)

Background: Variation in care is a ubiquitous feature of medical practice and may lead to significant differences in health care costs, quality, and outcomes. We undertook this study to determine the extent of intercenter variation in the initial management of children newly diagnosed with Crohn’s disease. Methods: We analyzed the utilization of 5 classes of medication (immunomodulators, prednisone, antibiotics, 5-aminosalicylates, and infliximab) among 311 children with newly diagnosed Crohn’s disease followed at 10 North American pediatric gastroenterology centers. Multivariate logistic regression was used to compare the utilization rate of each class of medication at each of the 10 centers, adjusting for potential confounders including patient age, sex, race, disease severity, and anatomic location of disease. Results: Median utilization of each class of medication was: immunomodulators, 56% (range 29%–97%); prednisone, 78% (range 32%– 88%); antibiotics, 29% (range 11%– 68%); 5-aminosalicylates, 63.5% (range 18%–92%); and infliximab, 7.5% (range 3%–21%). Each of these treatments showed statistically significant intercenter variation in utilization (P 0.001 for immunomodulators, prednisone, antibiotics, and 5-ASA; P 0.02 for infliximab). After adjusting for the demographic and clinical factors listed above, intercenter variation remained significant; however, the low utilization of infliximab precluded multivariate analysis. Conclusions: Widespread intercenter variation in the medical management of newly diagnosed children with Crohn’s disease was observed, even after adjusting for possible differences in case mix between institutions. This variation may lead to unintended differences in health care costs and outcomes. (Inflamm Bowel Dis 2007;13:890 – 895)