Predicting Response to Mesalamine Induction Therapy in Children Newly Diagnosed with Mild-to-Moderate Ulcerative Colitis: The Protect Study

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AGA Abstracts

C. DIFFICILE INFECTION IN THE FIRST YEAR AFTER DIAGNOSIS IS ASSOCIATED WITH SHORTER TIME TO BOWEL RESECTION SURGERY IN PEDIATRIC CROHN DISEASE Jennifer Hellmann, Aaron Linn, Kathleen Lake, Ramona Bezold, Lin Fei, Lee A. Denson Background and Aims: Individuals with inflammatory bowel disease (IBD) have a higher incidence of C. Difficile infection (CDI) and a greater risk of recurrence. The role of CDI in the progression of pediatric IBD is not well established. We hypothesized that pediatric IBD patients with CDI within the first year after diagnosis would experience a more rapid progression to bowel resection surgery. Methods: We conducted a retrospective single center study of 160 pediatric and young adult IBD patients (age < 22) diagnosed between May 2006 and February 2016. Mean(range) follow-up was 54(1-125) months, with 116 diagnoses of Crohn's Disease (CD) and 44 diagnoses of Ulcerative Colitis (UC). Data regarding antibiotic and anti-TNF exposures, CDI, and surgeries was obtained from the Electronic Medical Record (EMR). Univariate analyses tested for differences in clinical and demographic characteristics and medication exposures between patients stratified by CDI, and Kaplan-Meier survival analysis tested for differences in time to first surgery. Results: Of 160 patients, 112 were tested for CDI within the first year of diagnosis (70%). The majority were tested using PCR. The prevalence of CDI was 13% (21/160). Of the 21 patients with CDI, 14 had CD and 7 had UC (see Table). There was a higher rate of antibiotic use in the 30 days prior to testing in those with CDI (38% v 7.7%, p=.0012). There was no difference in PPI exposure. 28 patients with CDI testing required surgery during follow up, with 2 patients excluded from analysis due to CDI post operatively. Of the remaining 26, 22 had CD and 4 had UC. All patients who had CDI and required surgery had CD; the majority required ileo-colic resection. The rate of surgery increased from 23% in CD patients without CDI to 67% in CD patients with CDI, p=.005. The mean(range) time from diagnosis to surgery was 527(1152254) days for CD patients with CDI compared to 1168(158-2254) days for those without CDI (see Figure). The HR(95%CI) for surgery was equal to 3.949(1.123,13.89), p=0.0007 in CD patients with CDI. All patients with CDI who required surgery were exposed to antibiotics, with a mean(range) number of antibiotic courses of 2.6(1-5) prior to surgery. Those who did not have CDI but required surgery had a rate of antibiotic exposure of 39% (p=.0016 vs CDI group) with a mean(range) number of antibiotic courses of 1.85(0-15). Anti-TNF exposure within the first three months of diagnosis did not differ (25% (2/8) in CDI v. 20% (3/18) in non CDI patients, p=0.53). Conclusions: Antibiotic use is associated with CDI, and CDI within the first 12 months after diagnosis is associated with a shorter time to first bowel resection surgery in pediatric CD. Prospective studies are needed to determine whether CDI specifically, or the associated dysbiosis, drives disease progression. Table 1. Clinical and Demographic Characteristics Associated with CDI

Figure 1. Surgery Free Survival in CD Patients with and without CDI

Tu1751 PROCOLLAGEN III N-TERMINAL PROPEPTIDE (PIIINP) AS A CIRCULATING BIOMARKER FOR ACTIVE STRICTURE DEVELOPMENT IN PEDIATRIC CROHN'S DISEASE Cortney R. Ballengee, Jarod Prince, Robert N. Baldassano, Lee A. Denson, Jeffry Katz, Raymond K. Cross, Ashish S. Patel, Antonio Quiros, Gitit Tomer, Subra Kugathasan Background: Up to 40% of Crohn's disease patients eventually require surgery due to strictures. Extracellular matrix components, including type III collagen, play a vital role in the development of intestinal fibrosis and stricture in Crohn's disease (J Crohns Colitis 2014;8:1147-65). In previous work, we have shown that genes involved in extracellular matrix accumulation are upregulated at diagnosis in pediatric patients with inflammatory (B1) phenotype who later evolve into stricturing (B2) disease as compared to those who do not develop strictures. There are currently no circulating biomarkers being used clinically to predict the risk for development of strictures in patients with inflammatory (B1) Crohn's disease. Aim: To determine if plasma PIIINP concentration is elevated in pediatric patients with inflammatory (B1) Crohn's disease phenotype at diagnosis who subsequently develop strictures (B1 to B2) as compared to patients who never develop strictures (constant B1 phenotype), patients with B2 disease phenotype at diagnosis and patients with no inflammatory bowel disease (controls). Methods: 8 patients with B1 disease phenotype at diagnosis, 8 patients with B2 disease phenotype at diagnosis, and 8 patients with B1 disease phenotype at diagnosis who subsequently developed strictures were matched with 16 patients without inflammatory bowel disease (controls). ELISA for PIIINP was performed on the plasma of each group drawn at diagnosis (Biomatik EKU06786). Mean plasma PIIINP concentration was compared between each group using ANOVA and adjusting for multiple comparisons (Tukey method). Results: Plasma PIIINP concentration was significantly higher in the patients who went on to develop strictures (B1 to B2) when compared with controls (1737 vs 737 pg/mL; P=0.009). Without adjustment for multiple comparisons, serum PIIINP was significantly higher in B1 group as compared with controls (1394 vs 737 pg/mL; P=0.032) and B1-B2 groups as compared with B2 at diagnosis (1737 vs 977 pg/mL; P=0.032). Conclusion: Plasma concentration of PIIINP was significantly elevated in pediatric patients with B1 Crohn's disease phenotype at diagnosis who subsequently developed strictures (B2 phenotype). These results are consistent with previous work and are supported by the known pathogenesis of excess collagen deposition leading to tissue fibrosis. Our ongoing study involves measuring the plasma PIIINP concentration in samples from 2 large cohorts, each with over 1000 pediatric and adult patients with Crohn's disease. We speculate that circulating serum PIIINP may be clinically useful to predict Crohn's disease phenotype in individual patients at the time of diagnosis.

Tu1752 PREDICTING RESPONSE TO MESALAMINE INDUCTION THERAPY IN CHILDREN NEWLY DIAGNOSED WITH MILD-TO-MODERATE ULCERATIVE COLITIS: THE PROTECT STUDY Lee A. Denson, Sonia Davis, David R. Mack, Brendan M. Boyle, Anne M. Griffiths, Neal S. Leleiko, Cary G. Sauer, David J. Keljo, James Markowitz, Susan S. Baker, Joel R. Rosh, Robert N. Baldassano, Ashish S. Patel, Marian D. Pfefferkorn, Anthony Otley, Melvin B. Heyman, Joshua D. Noe, Maria Oliva-Hemker, Paul A. Rufo, Marla Dubinsky, Nathan Gotman, Alison Marquis, Subra Kugathasan, Thomas D. Walters, Jeffrey S. Hyams Background: Pediatric Ulcerative Colitis (UC) patients with mild disease activity are often initially treated with mesalamine (5ASA). Prospective data regarding characteristics associated with success are lacking. Aim: Test for factors associated with corticosteroid (CS)-free remission after 12 weeks of therapy. Methods: The PROTECT Study (U01DK095745) systematically enrolled and initiated standardized 5ASA or CS treatment determined by initial disease activity as measured by the Pediatric UC Activity Index (PUCAI). Mild patients received 5ASA. Standardized guidelines triggered rescue therapy with immunomodulators, biologics, or colectomy. The primary endpoint was week 12 CS-free remission (PUCAI<10 and off CS for at least 14 days) without rescue/colectomy on 5ASA alone. Univariate analyses tested for baseline or week 4 characteristics associated with week 12 response, and stepwise variable selection was used to derive a multivariate logistic regression model for week 12 CS-free remission. Results: 136 children received 5ASA at diagnosis (mean age 12.8±3.3yrs, 51% female, PUCAI 31±13.3, 63% extensive or pancolitis, Mayo endoscopy score 1.8±0.6, 5ASA dose 67±9 mg/kg/day). 135 and 132 were evaluable at weeks 4 and 12. At Week 4

*=p=.0028, **p=.0153, ***p=0.005, ^2 patients CDI positive post operatively were excluded from analysis

AGA Abstracts

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Tu1753 PREDICTING RESPONSE TO ORAL CORTICOSTEROID INDUCTION THERAPY IN CHILDREN NEWLY DIAGNOSED WITH MODERATELY ACTIVE ULCERATIVE COLITIS: THE PROTECT STUDY Lee A. Denson, Sonia Davis, David R. Mack, Brendan M. Boyle, Anne M. Griffiths, Neal S. Leleiko, Cary G. Sauer, David J. Keljo, James Markowitz, Susan S. Baker, Joel R. Rosh, Robert N. Baldassano, Ashish S. Patel, Marian D. Pfefferkorn, Anthony Otley, Melvin B. Heyman, Joshua D. Noe, Maria Oliva-Hemker, Paul A. Rufo, Marla Dubinsky, Nathan Gotman, Alison Marquis, Subra Kugathasan, Thomas D. Walters, Jeffrey S. Hyams Background: Pediatric Ulcerative Colitis (UC) patients with moderate disease activity are often treated with oral corticosteroids (CS) followed by mesalamine (5ASA) for induction of remission. However, prospective data regarding clinical and demographic factors associated with success are lacking. Aim: Test for characteristics associated with remission or need for rescue/colectomy at Week 12 following oral CS and 5ASA therapy. Methods: The PROTECT Study (U01DK095745) systematically enrolled and initiated standardized therapy determined by initial disease activity as measured by the Pediatric UC Activity Index (PUCAI). Moderate patients responding to oral CS began 5ASA at or after week 2. Pre-determined criteria triggered rescue therapy with immunomodulators, biologics, or colectomy. The primary endpoint was week 12 CS-free remission (PUCAI<10) without rescue/colectomy on 5ASA alone and taking no CS for a minimum of 14 days. Univariate analyses tested for baseline or week 4 characteristics associated with week 12 response, and stepwise variable selection was used to derive a multivariate logistic regression model for week 12 CS-free remission. Results: 144 children received oral CS at diagnosis (mean age 12.5±3.3yrs, 42% female, PUCAI 50±14, 80% extensive or pancolitis, Mayo endoscopy score 2.2±0.6, CS dose 0.9±0.3 mg/kg/day). 143 and 141 were evaluable at weeks 4 and 12. At Week 4 remission was 81(57%), rescue/colectomy 6(4%), neither 56(39%). At Week 12 CS-free remission was 47(33%), rescue/colectomy 21(15%), neither 73(52%). Week 12 CS-free remission was not related to age, gender, race, BMI z-score, or initial mucosal severity (see Table 1). Patients who achieved week 12 CS-free remission exhibited a lower baseline clinical severity, but did not differ for hemoglobin (Hgb), albumin, or fecal calprotectin. Patients with high titer ANCA were less likely to achieve week 12 CS-free remission. The oral CS dosage did not vary between groups, and very few utilized topical therapy. At week 4, patients who ultimately achieved week 12 CS-free remission were more likely to be in remission, with lower fecal calprotectin and higher albumin. A multivariate model which included baseline ANCA and PUCAI, and week 4 remission, predicted week 12 CS-free remission (see Table 2). The predicted probability of week 12 CS-free remission increased by 50% with a 10 unit smaller baseline PUCAI score. The test characteristics of the model include sensitivity: 73%, specificity: 72%, PPV:58%, NPV: 84%, AUC(95thCI):0.81 (0.72, 0.89). Conclusions: Only one-third of children with moderately active UC will achieve CS-free remission 12 weeks after diagnosis with oral CS followed by 5ASA therapy. Baseline characteristics including high titer ANCA and PUCAI may be combined with the week 4 response to predict those more likely to do well with this approach. Table 1. Baseline and Week 4 Clinical and Demographic Characteristics of UC Patients Grouped by Week 12 Outcomes

* p<0.05, ** p < 0.001. P-values from a chi-squared or Fisher's exact test (noted by #) for categorical variables, a chi-squared mean-score test for ordinal variables, and ANOVA or Kruskal-Wallis test for continuous variables. Data are shown as mean±SD, median(IQR), or n(%). a n=119; b n=129 at baseline and n=96 at week 4. c Baseline results limited to stool samples collected with up to 3 days of Pentasa treatment, and before or after colonoscopy cleanout. N=74 at baseline and N=90 at week 4. d n=122 Table 2. Baseline and Week 4 Clinical and Demographic Characteristics Associated with Week 12 CS-Free Remission for Pediatric UC Patients Initially Treated with Mesalamine

Logistic regression model based on N=108 participants with complete data Test characteristics of the model include sensitivity: 70%, specificity: 70%, AUC(95thCI): 0.80 (0.71-0.88)

* p<0.05, ** p < 0.001. P-values were computed using a chi-squared or Fisher's exact test (noted by #) for categorical variables, a chi-squared mean-score test for ordinal variables, and ANOVA or Kruskal-Wallis test for continuous variables. a Baseline results limited to stool samples collected with up to 3 days of CS treatment, and before or after colonoscopy cleanout. N=74 at baseline and N=97 at week 4 Data are shown as mean ± SD, median(IQR), or n(%) b sample sizes vary by parameter (Hgb: n=130, ANCA: n=132, week 4 Alb: n=111)

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AGA Abstracts

remission was 73(54%), rescue/colectomy 1(1%), neither 61(45%). At Week 12 CS-free remission was 64(48%), rescue/colectomy 9(7%), neither 59(45%), with 35(27%) also receiving oral CS and 3(2%) IV CS during the 12 week period. Week 12 CS-free remission was not related to age, gender, race, or initial overall clinical or mucosal severity (see Table 1). Patients who achieved week 12 CS-free remission exhibited a higher baseline Hemoglobin (Hgb) and albumin, and were more likely to be ANCA seropositive. Oral 5ASA dosage did not vary between groups, and very few utilized topical therapy. At week 4, patients who ultimately achieved week 12 CS-free remission were more likely to be in remission. A multivariate model which included baseline ANCA seropositivity, PUCAI rectal bleeding sub-score, Hgb, and week 4 remission, predicted week 12 CS-free remission (see Table 2). For a given level of Hgb, the predicted probability of week 12 CS-free remission decreased by approx. two thirds for each 10 unit increase in PUCAI rectal bleeding sub-score . The test characteristics of the model include sensitivity: 70%, specificity: 70%, AUC(95thCI):0.80 (0.71-0.88). Conclusions: Fifty percent of children diagnosed with mild UC will achieve CS-free remission 12 weeks after treatment with 5ASA therapy. Baseline characteristics including Hgb and the PUCAI rectal bleeding sub-score may be combined with the week 4 response to predict success with this approach. Table 1. Baseline and Week 4 Clinical and Demographic Characteristics of Pediatric UC Patients