Abstract Background Long-term data on the use of vedolizumab in children with Crohn’s disease (CD) and ulcerative colitis (UC) are lacking and the drug is not yet approved in pediatrics. The VEDOKIDS prospective multicenter cohort study aimed to assess the effectiveness and safety of vedolizumab as maintenance therapy in children with CD and UC; this study reports the 3-year final visit outcomes (ClinicalTrials.gov, NCT02862132). Methods Children commenced on vedolizumab at any disease duration and with any degree of disease activity were enrolled in 17 pediatric centers in Europe, the USA and the Middle East and followed prospectively through 3 years. The primary outcome was complete remission at 3 years (i.e. steroid-free clinical remission and normal ESR/CRP with sustained vedolizumab treatment and without a surgery). Secondary outcome was loss of response (PUCAI ≥ 10 or wPCDAI ≥ 12.5 for children with UC and CD, respectively) in those achieving clinical remission at week 6. Results Altogether, 137 children were enrolled, of whom 53 (39%) continued vedolizumab treatment through three years. Sustainability rate was higher in UC (35/73 [48%]) than in CD (18/64 [28%]; OR 2.4 [95%CI 1.2-4.8]). Complete remission at three years was achieved in 19/73 (26%) children with UC vs. 9/64 (14%) with CD (OR 2.2 [95%CI 0.9-5.2]) using ITT analysis. The best predictor of complete remission at 3 years was clinical remission at week 6 measured in CD by wPCDAI ≤12.5 (AUROC 0.78 [95%CI 0.64-0.963]), and in UC by PUCAI<10 (AUROC 0.74 [0.63-0.85]). Similarly, in adjusted multivariable logistic regression, complete remission at 3 years was more likely in week-6 remitters or responders compared to non-responders (HR 2.6 [95%CI 1.1-7.2]). Of the 51 (37%) children who achieved clinical remission at week 6 (32 UC and 19 CD), the likelihood of achieving complete remission at 3 years was 41% for UC and 26% for CD (OR 1.9 [95%CI 0.6-6.6]). Of those achieving clinical remission at week 6, 22%, 28%, 31% and 38% lost response by 30, 54, 108 and 162 weeks, respectively, for UC, while for the fewer children with CD who achieved remission at week 6, 5%, 5%, 11% and 16%, respectively, lost response (Figure). Forty adverse events were recorded in 23 children (17%) as possibly related to vedolizumab, none were serious, with the most common being headache, myalgia and fever. Conclusion Vedolizumab was safe and effective for maintaining long-term remission in children with UC and CD. Remission rates were higher in UC compared to CD at the end of induction, but UC patients experienced a higher rate of loss of response over time. Achieving clinical remission by week 6 after initiation of the drug was the best predictor of long-term effectiveness in both UC and CD.

Abstract Background We previously reported the effectiveness of vedolizumab (VDZ) to induce remission in children with CD and UC enrolled in the prospective,multicenter VEDOKIDS study.In this extended analysis,we aimed to explore the effectiveness and safety of VDZ to maintain remission through week 30 Methods Children with CD or UC commenced on VDZ at any stage of the disease were followed at baseline and 2, 6, 14 and 30 weeks thereafter.Explicit demographic,clinical and safety data were prospectively recorded.The primary outcome was steroid-and EEN-free clinical remission (SFR) at 30 weeks,analyzed under the ITT principle with non-response imputation.Response was defined as change of ≥ 20 points in PUCAI or >20 points in wPCDAI and clinical remission as PUCAI<10 or wPCDAI<12.5. Adverse events (AE's) were classified as severe or non-severe and related or unrelated to VDZ Results A total of 142 children were enrolled (65 [46%] CD,77 [54%] UC;Table).At the end of the induction period,the rates of response were 75% in UC vs 64% in CD (p=0.2),of remission 52% vs 38% (p=0.1),and of SFR 47% vs 32% (p=0.08),respectively.At week 30,SFR rates were 47% in UC and 34% in CD (p=0.1);outcomes were also numerically higher in UC,but without statistical significance(Figure) Response to induction therapy predicted week 30 remission.Of the responders,19 (59%) children with CD and 31 (60%) with UC achieved SFR at week 30,while the corresponding figures for those not achieving response were 3 (12%; p=0.004) in CD and 5 (29%; p=0.03) in UC.Similarly,in multivariable model,response to induction treatment was highly associated with SFR at week 30,in both CD (OR 11.2 [95%CI 2.3-73]) and UC (OR 4.8 [95%CI 1.4-19]).Of the 22 patients who were responders but not remitters at week 14,four eventually achieved SFR at week 30 (1/10 [10%] in CD and 3/12 [25%] in UC) By week 30,159 AE's were reported by 72 children including one case of Hodgkin's lymphoma (VDZ was resumed after completing the chemotherapy);the patient was never exposed to thiopurines.No cases of progressive multifocal leukoencephalopathy or deaths were reported.Thirty-six AEs in 23 (16%) children were classified as possibly related to VDZ,11 of which (31%) were moderate and the others mild.Four children (1.4%) discontinued treatment due to AEs (one due to infusion reaction,one leukocytoclastic vasculitis,one azotemia and one due to fever and malaise Conclusion In this prospective multicenter study,VDZ was effective for maintaining remission in children with CD, and more so in UC.Contraty to common notions,children with CD not achieving complete remission by week 14 had a very low likelihood of entering remission thereafter.Safety profile was generally good except for one lymphoma case with questionable relation to VDZ

Abstract Background Limited data are available on the use of Vedolizumab (VDZ) in paediatric Crohn’s Disease (CD) and Ulcerative Colitis (UC). We evaluated the effectiveness and safety of VDZ to induce remission at week 14 in the prospective, multicenter VEDOKIDS study. Methods We enrolled children (age 0–18 years) with CD or UC commenced on VDZ with a standardized dosing of 177mg/BSA up to 300mg at 0, 2, 6 and q8 weeks thereafter. Non-responders had their dose escalated to q4wks at the discretion of the local physician. Explicit demographic, clinical and safety data were prospectively recorded via REDcap. Clinical remission was defined as steroid- and EEN-free remission (i.e. wPCDAI<12.5 or PUCAI<10) without the need for new medications. Complete remission was defined as clinical remission with normal CRP and ESR. Predictors of response were explored by Logistic regression. Results 128 children were enrolled, 60 (47%) with CD, and 68 (53%) with UC (58 (45%) males, mean age 13.8±3.6, 93 (73%) failed previous anti-TNF, median disease duration 2.3 years (IQR 0.9–4.7)). Using the ITT principle, clinical and complete remission rates for CD at week 14 were 30% and 20%, respectively, and for UC 50% and 38%, respectively (Fig 1). Clinical remission rates of those receiving VDZ as first line biologics versus second line were 57% and 34%, respectively (p=0.019; Fig 2); the corresponding complete remission rates were 49% and 23% (p=0.004). In the UC group, disease activity at baseline measured by the PUCAI predicted clinical remission at week 14 (OR=0.95, 95%CI 0.93–0.98; median baseline PUCAI 15 (IQR 0–30) in those achieving remission and 45 (20–55) in those who did not; p=0.002). ESR (OR=0.94, 95%CI 0.89–0.98; p=0.009) and a trend towards extensive disease (L3 vs. L1 and L2; OR 0.14, 95%CI 0.18–1.036, p=0.054) predicted clinical remission in CD. During the 14 weeks, 113 adverse events (AE) were recorded in 58 children: 28 AEs were possibly related to VDZ, all of which were mild-moderate and only 3 (11%) led to discontinuation of VDZ (leukocytoclastic vasculitis, myalgia and dyspnea). There were 18 serious AEs, only one was graded as possibly related to VDZ (headache). There were 18 non-serious cases (19%) of upper respiratory infections (pharyngitis, tonsilitis, parotitis, and otitis media) and one Campylobacter jejuni which was graded as serious. Conclusion In this prospective multicenter study, VDZ was safe and effective for inducing remission in a refractory cohort of paediatric IBD, more so in UC. Disease severity and extent at baseline may predict clinical response.

O-11 Real world outcomes of contemporary treatments in children with Crohn’s disease: observations from the pediatric IBD collaborative research group registry J. Markowitz1 *, T. Lerer2, J. Morganstern2, C. Deslandres2, G. Tomer2, M. Schaefer3, S. Kugathasan2, W. Faubion2, M. Kappelman2, B. Sudel2, M. Hitch2, D. Keljo2, A. Grossman2, R. Carvalho2, N. Leleiko2, S. Saeed2, M. Oliva-Hemker2, M. Kay2, J. Rosh2, M. Pfefferkorn2, A. Otley2, J. Rick2, D. Mack2, J. Cabrera2, A. Griffiths2, J. Hyams2. 1Cohen Children’s Medical Center of NY, Lake success, United States of America, 2The Pediatric IBD Collaborative Research Group, Hartford, United States of America, 3The Pediatric IBD Collaborative Group, Hartford, United States of America

Objective To compare four faecal markers for their ability to predict steroid refractoriness in severe paediatric ulcerative colitis (UC). Construct validity and responsiveness to change were also assessed. Methods This was a prospective multicentre cohort study. Stool samples from 101 children (13.3±3.6 years; Pediatric UC Activity Index (PUCAI) at admission 72±12 points) were obtained at the third day of intravenous steroid therapy. Repeated samples at discharge were obtained from 24 children. Predictive validity was assessed using diagnostic utility statistics to predict steroid failure (ie, the need for salvage treatment). Concurrent validity was assessed using correlational analysis with the following constructs: PUCAI, Lindgren and Seo scores, physician's global assessment, albumin, erythrocyte sedimentation rate and C-reactive protein (CRP). Responsiveness was assessed using test utility and correlational strategies. Results Median values (IQR) were very high at baseline for all four markers (calprotectin 4215 μg/g (2297–8808); lactoferrin 212 μg/g (114–328); M2-pyruvate kinase (M2-PK) 363 U/g (119–3104); and S100A12 469 μg/g (193–1112)). M2-PK was numerically superior to the other three markers and CRP in predicting response to corticosteroid treatment (area under the receiver operating characteristic (ROC) curve 0.75 (95% CI 0.64 to 0.85; p<0.001) vs <0.65 for the others). However, it did not add to the predictive ability of the PUCAI (area under the ROC 0.81 (95% CI 0.73 to 0.89)). M2-PK also had the highest construct validity but with a modest mean correlation with all constructs (r=0.3; p<0.05). None of the markers was responsive to change (Spearman's rho correlation with change in the PUCAI <0.1; p>0.05, area under the ROC curve <0.65; p>0.05). Conclusions The four markers were greatly elevated in severe paediatric UC. Only M2-PK had good construct and predictive validity, and none was responsive to change. The PUCAI, a simple clinical index, performed better than the faecal markers in predicting outcome following a course of intravenous corticosteroids in severe UC.

One third of children admitted for acute severe ulcerative colitis (UC), are refractory to intravenous corticosteroids and require second line therapy or colectomy. Potential factors determining response vs. refractoriness have seldom been explored. In an attempt to elucidate the basis for corticosteroid-resistance in UC, we evaluated whether corticosteroid-bioactivity and/or specific inflammatory cytokines influence response to corticosteroids in severe pediatric UC, independent of disease severity. In a prospective multi-center study, serum samples were obtained on the third day of steroid treatment from 79 children hospitalized with severe UC. Twenty three (29%) required second line therapy (mean age 13.9±3; 56% males; median disease duration 8.2 months (IQR 3-29)). Clinical, demographic and outcome data were prospectively recorded at several times during the admission on standardized case report forms. A cytokine antibody array panel (version 3.0; TransSignal, Panomics, Fremont, CA) was constructed to include 12 cytokines, se-lected based on a systematic literature search: TNF-α INF-γ IL-1β IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, and IL-17. Factor analysis and logistic regression models were used to explore the relationship between the various cytokines and corticosteroid response. Biologic activity of corticosteroids was assessed using a previously established transactivation glucocorticoid bioassay (GBA) on COS-1 tranfected cells. GBA can measure the biological activity of corticosteroids by quantifying glucocorticoid response elements, reflecting the down-stream effect of the steroids. This approach eliminates differences between the various steroids regarding their ability to activate the glucocorticoid receptor. In univariate analyses, only IL-6 differed between responders and nonresponders (P= 0.003; Bonferroni corrected). The risk for steroid-refractoriness increased by 40% per each incremental unit of IL-6. In factor analysis, IL-6 loaded with IL-17 on the same component, reflecting the association of IL-6 with the Th17 pathway. However, in a multiple regression analysis IL-6 was no longer significant when adjusting for disease severity, measured by the PUCAI index (P= 0.32, PUCAI score P<0.001). In accordance, IL-6 was highly correlated with C-reactive protein (r= 0.41, P<0.001) and albumin (r= -0.64, P<0.001). Reflecting internal validity of the assay, GBA was highly correlated with the last corticosteroid dose and the time interval to bloodletting (r= -0.41 and r= -0.54, respectively; both P<0.001). There was no statistically significant difference in the GBA levels between responders and non-responders (249nM · versus 200nM · cortisol equivalent, P= 0.18). In a multivariate regression model adjusted for time elapsed from corticosteroids and the administered dose, GBA did not predict response or refractoriness to corticosteroids (P= 0.34). Disease severity is associated with response to steroid therapy, while steroid bioavailability, steroid dosing, and the type of inflammation are not. IL-6 is a strong predicting variable for refractoriness, but it merely reflects disease severity. Nonetheless, IL-6 levels may have a role in predicting response to steroids in pediatric UC, thereby influencing treatment decision making.

An inception cohort of pediatric Crohn's disease (CD) patients is being prospectively followed to determine the contemporary natural history of CD within members of the Pediatric IBD Collaborative Research Group (PIBDCRG). There has been an increase in the use of immunomodulators and biologics in pediatric CD over the last decade1,2 that may decrease a pediatric CD patient's risk for bowel surgery. Previous studies reflect the incidence of bowel surgery in pediatric CD patients diagnosed prior to 20033,4,5 and may not reflect these changes in medical management. The PIBDCRG Registry database was examined to determine the contemporary incidence of bowel surgery, as well as all CD-related surgery (including abscess drainages), in a multi-center prospectively followed cohort of pediatric CD patients diagnosed between 2002 and 2008. In addition, disease characteristics were analyzed to evaluate for the risk of bowel surgery. Of 854 patients with CD (mean 12 years old, 42% female, mean follow-up of 2.3 years), 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). Overall, 76 (9%) underwent a first CD-related surgery. The cumulative risk of bowel surgery, non-bowel surgery, and all CD-related surgery was 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, stricturing or penetrating disease increased the risk of bowel surgery. Disease between the transverse colon and rectum decreased the risk of bowel surgery. Gender, race, family history of IBD, and large bowel disease did not influence the risk of bowel surgery. In our prospective CD cohort the five-year cumulative risk of bowel surgery was markedly lower than recent studies of adult and pediatric patients,3,4,6,7 but similar to one recent retrospective pediatric study.5 Strategies to identify phenotypes associated with stricturing and penetrating disease and preventing these complications are needed.

Children with inflammatory bowel disease present formidable therapeutic challenges. As both Crohn's disease and ulcerative colitis remain medically incurable conditions associated with potentially significant morbidity, the focus of treatment must be to reduce or eliminate symptoms, optimize nutritional status, promote normal growth and development, prevent complications and minimize the potential psychological effects of these chronic illnesses. This review focuses on the evidence supporting the treatments currently used in children with inflammatory bowel disease, and suggests potential treatment algorithms for particular clinical circumstances.

Eosinophilic esophagitis (EE) in children is often food induced via IgE and/or cell mediated hypersensitivity. We report on the role and sensitization patterns of food testing in 26 consecutive children with EE. 26 children (male:female, 2:1), 7.8±4.9 yrs, with EE (>24 eos/hpf) underwent food allergy testing. Prick skin tests (PST) were performed using the Multitest II device or bifurcated needle. Wheals 3 mm > negative control were considered positive. Atopy patch tests (APT) were performed using 6-12 mm Finn chambers. Erythema + induration, papules, vesicles at 72 hrs were considered positive. Prick tests were positive in 19 (73.1%) patients, reacting to 4.54 ± 4.75 foods. Most common sensitivities were to grains, soy, legumes, rice, and nuts. Patch tests were positive in 16 (61.5%) patients, reacting to 2.54 ± 4.16 foods. Most common sensitivities were grains, legumes, milk, and fowl. 12/26 pts were PST +/APT + ; 7/26 pts were PST+/APT - ; 4/26 pts were PST-/APT+ ; 3/26 pts were PST-/APT-. Most patients had at least one food APT reaction undetected by PST. There was no discordance between the 6 and 12 mm chambers. 88% of children with EE had evidence of food sensitization. APT is a necessary component of the evaluation of children with EE for food allergy.

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.

EFFREY HYAMS,* WALLACE CRANDALL, SUBRA KUGATHASAN, ANNE GRIFFITHS, ALLAN OLSON, EWEL JOHANNS, GRACE LIU, SUZANNE TRAVERS, ROBERT HEUSCHKEL, JAMES MARKOWITZ,** TANLEY COHEN, HARLAND WINTER, GIGI VEEREMAN–WAUTERS, GEORGE FERRY, ROBERT BALDASSANO, nd The REACH Study Group*** Connecticut Children’s Medical Center, Hartford, Conneticut; Columbus Children’s Hospital, Columbus, Ohio; Medical College of Wisconsin, Milwaukee, isconsin; The Hospital for Sick Children, Toronto, Canada; Centocor Inc., Malvern, Pennsylvania; Royal Free Hospital, London, England; **North hore–LIJ Health System, New Hyde Park, New York; Children’s Center for Digestive Health Care, Atlanta, Georgia; Massachusetts General Hospital for Children, oston, Massachusets; Queen Paola Children’s Hospital, Antwerp, Belgium; Texas Children’s Hospital, Houston, Texas; and Children’s Hospital of Philadelphia, hiladelphia, Pennsylvania

Purpose: To describe resource utilization in the first year after diagnosis for children with IBD in the US and Canada. Methods: Data originated from the Pediatric IBD Collaborative Research Group Registry, a prospective, observational study of children <16 yrs with newly diagnosed IBD. Patient evaluation/treatment are dictated by each physician and not by protocol. Resources studied included: office visits, endoscopy beyond diagnostic procedures, hospitalizations and inpatient therapies. ANOVA and Fisher's exact test (FET) compared data between US and Canada. Results: 385 patients (264 Crohn's disease (CD), 95 ulcerative colitis (UC) and 26 indeterminate colitis (IC)) completed one year of follow-up. Data are shown for CD and UC. 71 patients were hospitalized at least once. Most patients were hospitalized 1-5 days total (mean 11.6, median 5.5, range 1-83). Conclusions: In the first year after IBD diagnosis, 68% of children had ≤5 office visits. Only 10% underwent endoscopy beyond primary diagnostic procedures, <20% were hospitalized and only 4% of CD and 3% of UC patients had a surgical procedure. The resource utilization for these patients was no different in the US compared to Canada, except for greater IV steroid use for hospitalized CD patients in the US.Table: Outpatient visits and endoscopic proceduresTable: Inpatient therapies