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Background and Aims: Data on upadacitinib therapy in children with ulcerative colitis (UC) or unclassified inflammatory bowel disease (IBD-U) are scarce. We aimed to evaluate the effectiveness and safety of upadacitinib as an induction therapy in pediatric UC or IBD-U., Methods: In this multicenter retrospective study, children treated with upadacitinib for induction of remission of active UC or IBD-U from 30 centers worldwide were enrolled. Demographic, clinical and laboratory data as well as adverse events (AEs) were recorded at week 8 post induction., Results: One hundred children were included (90 UC and 10 IBD-U, median age 15.6 [interquartile range 13.3-17.1] years). Ninety-eight were previously treated with biologic therapies, and 76 were treated with ≥2 biologics. At the end of the 8-week induction period, clinical response, clinical remission, and corticosteroid-free clinical remission (CFR) were observed in 84%, 62%, and 56% of the children, respectively. Normal C-reactive protein and fecal calprotectin (FC) <150 mcg/g were achieved in 75% and 50%, respectively. Combined CFR and FC remission was observed in 18/46 (39%) children with available data at 8 weeks. AEs were recorded in 37 children, including one serious AE of an appendiceal neuroendocrine tumor. The most frequent AEs were hyperlipidemia (n=13), acne (n=12), and infections (n=10, five of whom with herpes viruses)., Conclusion: Upadacitinib is an effective induction therapy for refractory pediatric UC and IBD-U. Efficacy should be weighed against the potential risks of AEs., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objectives: Current data on ustekinumab therapy in children with ulcerative colitis (UC) or unclassified inflammatory bowel disease (IBDU) are limited. We aimed to evaluate the effectiveness and safety of ustekinumab in pediatric UC and IBDU., Methods: This multicenter retrospective study included 16 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. Children with UC or IBDU treated with ustekinumab were enrolled. Demographic, clinical, laboratory, endoscopic, and imaging data as well as adverse events were recorded. Analyses were all based on the intention-to-treat principle., Results: Fifty-eight children (39 UC and 19 IBDU, median age 14.5 [IQR 11.5-16.5] years) were included. All had failed biologic therapies, and 38 (66%) had failed two or more biologics. Corticosteroid-free clinical remission (CFR) was observed in 27 (47%), 33 (57%), and 37 (64%) children at 16, 26, and 52 weeks, respectively. Normalization of C-reactive protein and calprotectin < 150 μg/g were achieved in 60% and 52%, respectively, by 52 weeks. Endoscopic and radiologic remissions were reached in 8% and 23%, respectively. The main predictors of CFR were diagnosis of UC compared with IBDU (hazard ratio [HR] 2.2, 95% CI 1.03-4.85; p = 0.041) and no prior vedolizumab therapy (HR 2.1, 95% CI 1.11-4.27; p = 0.023). Ustekinumab serum levels were not associated with disease activity. Adverse events were recorded in six (10%) children, leading to discontinuation of the drug in three., Conclusion: Based on these findings, ustekinumab appears as an effective therapy for pediatric refractory UC and IBDU. The potential efficacy should be weighed against the risks of serious adverse events., (© 2024. The Author(s).)

Background and Aims: Ulcerative proctitis [UP] is an uncommon presentation in paediatric patients with ulcerative colitis. We aimed to characterize the clinical features and natural history of UP in children, and to identify predictors of poor outcomes., Methods: This was a retrospective study involving 37 sites affiliated with the IBD Porto Group of ESPGHAN. Data were collected from patients aged <18 years diagnosed with UP between January 1, 2016 and December 31, 2020., Results: We identified 196 patients with UP (median age at diagnosis 14.6 years [interquartile range, IQR 12.5-16.0]), with a median follow-up of 2.7 years [IQR 1.7-3.8]. The most common presenting symptoms were bloody stools [95%], abdominal pain [61%] and diarrhoea [47%]. At diagnosis, the median paediatric ulcerative colitis activity index [PUCAI] score was 25 [IQR 20-35], but most patients exhibited moderate-severe endoscopic inflammation. By the end of induction, 5-aminosalicylic acid administration orally, topically or both resulted in clinical remission rates of 48%, 48%, and 73%, respectively. The rates of treatment escalation to biologics at 1, 3, and 5 years were 10%, 22%, and 43%, respectively. In multivariate analysis, the PUCAI score at diagnosis was significantly associated with initiation of systemic steroids, or biologics, and subsequent acute severe colitis events and inflammatory bowel disease-associated admission, with a score ≥35 providing an increased risk for poor outcomes. By the end of follow-up, 3.1% of patients underwent colectomy. Patients with UP that experienced proximal disease progression during follow-up [48%] had significantly higher rates of a caecal patch at diagnosis and higher PUCAI score by the end of induction, compared to those without progression., Conclusion: Paediatric patients with UP exhibit high rates of treatment escalation and proximal disease extension., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The consensus guidelines of the European Crohn's and Colitis Organization (ECCO) for the diagnosis and treatment of iron deficiency anemia (IDA) were published in 2015. We examined the management practices of both adult gastroenterologists (AGs) and pediatric gastroenterologists (PGs) in Israel in treating ID among patients with inflammatory bowel disease (IBD)., Methods: An 18-question multiple-choice anonymous questionnaire was electronically delivered to AGs and PGs. Questions explored 3 areas of interest: physician demographics, adherence to ECCO guidelines, and management practices of IDA in patients with IBD., Results: Completed questionnaires were returned by 72 AGs and 89 PGs. Practice setting and years of practice were similar. A large majority of AGs and PGs (89% and 92%, respectively) measure complete blood count (CBC) and serum ferritin (S-Fr) at least every 3 months in outpatients with active IBD, as recommended by the ECCO guidelines. In contrast, in IBD patients in remission, only 53% and 26% of AGs and PGs, respectively ( P < 0.001), reported adherence to ECCO guidelines, measuring CBC and S-Fr every 6 months. The ECCO treatment guidelines recommend that intravenous (IV) iron should be considered the first-line treatment in patients with clinically active IBD, with previous oral iron intolerance and those with a hemoglobin level <10 g/dL. Study results indicate that only 43% of AGs recommend IV iron for these indications, compared to 54% of PGs ( P > 0.1)., Conclusions: In this study we have demonstrated a relatively low level of adherence to ECCO guideline recommendations among both AGs and PGs, regarding the management of IDA in patients with IBD., Competing Interests: Dr Zittan has received research support and consulting fees from Janssen, AbbVie, Takeda, Neopharm, Celgene, and Pfizer. The remaining authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background and Aims: Thiopurines are an established treatment for pediatric ulcerative colitis (UC). However, data regarding safety and efficacy are lacking. We aimed to determine short and long-term outcome following thiopurines use in children with UC., Methods: We conducted a retrospective review of children (2-18 years) with UC treated with thiopurines between January 2008 and January 2019 at 7 medical centers in Israel. The primary outcome was corticosteroid (CS)-free clinical remission at week 52 following thiopurines initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy)., Results: A total of 133 children were included [median age at diagnosis of 12.4 (interquartile range 11.0-15.8) years, 30 (23%) left-sided colitis, 113 (85%) with moderate or severe disease at diagnosis]. At diagnosis 58 patients (44%) were treated with 5-aminosalicylates and 72 (54%) with CS. Sixty patients (45%) received thiopurines as 1st line maintenance therapy. Seventy-four patients (56%) had CS-free clinical remission at week 52 without rescue therapy. Predictors of clinical remission were not identified. In a sub-analysis among patients with steroid-responsive moderate to severe UC, 59 (55%) patients achieved this outcome. The likelihood of remaining free of rescue therapy among thiopurines-treated patients was 83%, 62%, 45%, and 37% at 1, 2, 3, and 4 years, respectively., Conclusion: More than half of children with UC starting thiopurines without previous or concomitant biologic therapy have CS-free clinical remission at 52 weeks later without the need for rescue therapy. Thiopurines are effective in pediatric UC and could be considered prior to biologics., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background and Objectives : Potential Celiac Disease (PCD) is defined by positive celiac serology without villous atrophy. We aimed to describe the short-term outcome of pediatric PCD while consuming a gluten-containing diet (GCD). Materials and Methods : Retrospective analysis of pediatric PCD patients continuing GCD, between December 2018-January 2022. Baseline demographics, celiac serology and duodenal biopsy results were reviewed. Follow-up data included repeated serology and biopsy results when performed. Minimum follow-up was 12 months unless celiac disease (CeD) was diagnosed earlier. Results : PCD was diagnosed in 90 children (71% females) with a mean age of 7.2 (range 1.8-16.5) years. Baseline anti-tissue transglutaminase (TTG) levels were above 10 times the upper limit of normal (ULN) in 17/90 (18.9%), 3-10 × ULN in 56/90 (62.2%) and 1-3 × ULN in 17/90 (18.9%). During follow-up, the mean time was 17.6 (range 5-35) months, TTG normalized in 34/90 (37.8%), was stable in 48/90 (53.3%), and increased or remained >10 × ULN in 8/90 (8.9%). In 20/90 (22.2%) patients, a repeat endoscopy was performed, leading to CeD diagnosis in 12/20 (60%). Thus, at the end of follow-up, CeD was diagnosed in 12/90 (13.3%). In patients with TTG >10 × ULN at diagnosis, TTG normalized in 5/17, decreased to 3-10 × ULN in 8/17, and remained above 10 × ULN in 4/17. Conclusions : During the short-term follow-up of pediatric PCD patients, less than 15% progressed to CeD. A third had normalized TTG levels, including children with TTG >10 × ULN, indicating the need for periodic serological and histological follow-up among PCD patients.

Objectives: Escalation of the ustekinumab (UST) maintenance dosage was effective in adults with Crohn disease (CD), but no data are available for children. We evaluated the effectiveness and safety of dose escalation of UST in pediatric CD., Methods: This was a retrospective multicenter study from 25 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. We included children with CD who initiated UST at a standard dosing and underwent either dose escalation to intervals shorter than 8 weeks or re-induction of UST due to active disease. Demographic, clinical, laboratory, endoscopic, imaging, and safety data were collected up to 12 months of follow-up., Results: Sixty-nine children were included (median age 15.8 years, interquartile range 13.8-16.9) with median disease duration of 4.3 years (2.9-6.3). Most children were biologic (98.6%)- and immunomodulator (86.8%)- experienced. Clinical response and remission were observed at 3 months after UST escalation in 46 (67%) and 29 (42%) children, respectively. The strongest predictor for clinical remission was lower weighted Pediatric Crohn Disease Activity Index (wPCDAI) at escalation ( P = 0.001). The median C-reactive protein level decreased from 14 (3-28.03) to 5 (1.1-20.5) mg/L ( P = 0.012), and the fecal calprotectin level from 1100 (500-2300) to 515 (250-1469) µg/g ( P = 0.012) 3 months post-escalation. Endoscopic and transmural healing were achieved in 3 of 19 (16%) and 2 of 15 (13%) patients, respectively. Thirteen patients (18.8%) discontinued therapy due to active disease. No serious adverse events were reported., Conclusions: Two-thirds of children with active CD responded to dose escalation of UST. Milder disease activity may predict a favorable outcome following UST dose escalation., Competing Interests: GPM has received speakers fees and congress support from Abbvie, Nestlé Health Science, Janssen and Nutricia. KLK has received consultancy fees from Abbvie, Biocodex, Ferring and Tillotts Pharma and funding for research from Pediatric Research Foundation and Helsinki University Hospital Research Fund. OH reports lectures/congress fees/consultancy (outside the submitted work): MSD, AbbVie, Takeda, Nutricia, Nestlé and Ferring. OH reports lectures/congress fees/consultancy (outside the submitted work): MSD, AbbVie, Takeda, Nutricia, Nestlé and Ferring. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Complex perianal fistulas (CPFs) in children even in the absence of luminal symptoms prompt evaluation for Crohn's disease (CD). Reports of isolated CPF in children, however, are sparse. In perianal CD, antitumor necrosis factor α (anti TNF) therapy is recommended. We aimed to describe our experience with anti TNF therapy in children with isolated CPF without evidence of luminal CD., Methods: We retrospectively reviewed charts of patients with isolated CPF who were treated with anti TNF agents between 2011 and 2019 in a tertiary center. MRI pelvis findings at baseline versus end of follow up were scored using MAGNIFI-CD. Outcomes included clinical remission, radiological response and radiological remission based on MAGNIFI-CD score at end of follow up., Results: Overall, 17 patients were identified, [10 males (59%), mean age at anti TNF initiation 13.4 ± 2.9 years]. Median time from perianal disease onset to anti TNF was 16.5 months (IQR 9.4-36.4). None of the patients had luminal inflammation. Prior to anti TNF, all patients had been treated with antibiotics without sufficient improvement, and 9/17 with abscess drainage and or Seton insertion. Nine patients (53%) were treated with infliximab while 8 (47%) received adalimumab. Median duration of follow up was 30.7 months (IQR = 12.7-44.8). At the end of follow up 9 patients (53%) achieved clinical remission. When comparing MRI prior to and after anti TNF, 36% (5/14) had radiologic response, of whom 2 (14%) achieved radiologic resolution., Conclusion: Anti TNF agents may be an effective treatment option for children with isolated CPF. Whether these patients should be considered part of the CD phenotypic spectrum or a distinct entity is unclear., Levels of Evidence: Therapeutic., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aim: To assess correlation between successful Helicobacter pylori (HP) eradication and resolution of iron deficiency in children, without iron supplementation., Methods: Medical records of children diagnosed with HP infection based on endoscopy were retrospectively reviewed. Among those with non-anaemic iron deficiency (NAID) or iron deficiency anaemia (IDA), haemoglobin, ferritin and CRP levels were compared prior and 6-9 months' post-successful HP eradication. Predictors of resolution of iron deficiency following HP eradication were assessed., Results: Among 60 included children (median age 14.8, IQR12.3-16 years; 62% males), 35% had IDA while the remaining 65% had NAID. Following successful HP eradication, iron normalised in 60% of patients with iron deficiency (ID), without iron supplementation. There were significant improvements in haemoglobin and ferritin concentrations following HP eradication with haemoglobin increasing from 12.3 g/dL to 13.0 g/dL and ferritin increasing from 6.3 μg/L to 15.1 μg/L (p < 0.001). In multiple logistic regression, older age was the only factor associated with resolution of anaemia following HP eradication (OR 1.65, 95% CI 1.16-2.35, p = 0.005)., Conclusion: Successful HP eradication could be helpful in improving iron status among children with refractory NAID or IDA. Older age may predict this outcome. Screening for HP might be considered in the workup of refractory IDA or ID., (© 2022 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background/aims: Pediatric Crohn disease (CD) treatment goals have evolved. Among children receiving adalimumab (ADA) we examined long-term durability of clinical remission, linear growth, and associations of trough concentration (TC) with biomarker, endoscopic and imaging outcomes., Methods: Single-center retrospective study. Pediatric CD activity index, C-reactive protein, fecal calprotectin, and height measured longitudinally. Discontinuation due to secondary loss of response (LOR) was assessed using Cox proportional hazards model. Associations between TC and clinical and biomarker remission, endoscopic and magnetic resonance imaging (MRI) improvements were assessed using Cox regression with time-dependent covariates., Results: Between January 2007 and June 2018, 213 children (median age 14.1 years (interquartile range [IQR] 12.5-15.7) 65% males) initiated ADA. One hundred and seventy-four (82%) achieved clinical remission (PCDAI < 10). During 24.8 (IQR 15.6-38.4) months follow-up, 26 (15%) discontinued ADA due to LOR, and 10 (6%) due to adverse events. Being anti-tumor necrosis factor (TNF) naïve and inflammatory behavior associated with increased likelihood of clinical remission (odds ratio [OR] 2.39, P = 0.033, and 3.13, P = 0.013, respectively) and with decreased LOR (hazard ratio [HR] 0.3, P = 0.002, and HR 0.35, P = 0.01, respectively). Cumulative LOR among 135 anti-TNF naïve patients: 0%, 8%, 15% within 1, 2, 3 years, similarly durable with mono- and immunomodulator combination therapy. Among pre-/early pubertal children mean height (-0.82) normalized to -0.07. TC consistently >7.5 ug/mL was associated with durable clinical remission (HR = 17.24, P < 0.001); TC >10 ug/mL with durable biomarker remission (HR = 6.56, P < 0.001) and endoscopic (OR 10.4, P = 0.002) and MRI (OR 7.6, P = 0.001) improvements., Conclusion: ADA monotherapy maintains durable clinical remission. Biomarker remission, mucosal and transmural improvements were associated with greater ADA exposure., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Data on the association between early postinduction serum adalimumab (ADA) trough levels (TLs) and objective outcomes are scarce. The aim of this study was to investigate whether early ADA TLs at weeks 4 and 8 are associated with clinical and biomarker remission at week 24 in pediatric Crohn's disease (CD)., Methods: Adalimumab TLs at weeks 4 and 8 were prospectively measured in anti-TNF-naïve children initiating treatment with ADA monotherapy for luminal inflammatory CD. The primary outcome was combined clinical and biomarker remission at week 24, defined as achieving steroid-free clinical remission (Pediatric CD activity index <10) and biomarker remission (fecal calprotectin <250 µg/g and CRP <5 µg/mL)., Results: Among 65 patients, 39 (60%) achieved combined clinical/biomarker remission at week 24 without dose escalation. Adalimumab TLs at both weeks 4 and 8 were significantly higher in remitters vs nonremitters at week 24 (P < 0.001 and P = 0.002, respectively). Adalimumab levels at weeks 4 and 8 were good predictors of combined clinical/biomarker remission at week 24 (area under the curve, 0.887, 95% CI, 0.798-0.942; and area under the curve, 0.761, 95% CI, 0.632-0.899, respectively). The best ADA TL cutoffs at weeks 4 and 8 for predicting clinical/biomarker remission at week 24 were 22.5 µg/mL (80% sensitivity, 90% specificity, positive likelihood ratio [LR+] 8.0, negative LR [LR-] 0.2) and 12.5 µg/mL (94% sensitivity, 60% specificity, LR+ 2.4, LR- 0.1), respectively. Higher induction doses per m2 correlated positively with TLs at weeks 4 and 8., Conclusion: Greater early ADA exposure is associated with superior clinical/biomarker outcomes at week 24., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The pediatric inflammatory bowel disease (PIBD) classes algorithm was developed to bring consistency to labelling of colonic IBD, but labels are exclusively based on features atypical for ulcerative colitis (UC)., Aim: The aim of the study was to develop an algorithm and identify features that discriminate between pediatric UC and colonic Crohn disease (CD)., Methods: Baseline clinical, endoscopic, radiologic, and histologic data, including the PIBD class features in 74 colonic IBD (56: UC, 18: colonic CD) patients were collected. The PIBD class features and additional features common to UC were used to perform initial clustering, using similarity network fusion (SNF). We trained a Random Forest (RF) classifier on the full dataset and used a leave-one-out approach to evaluate model accuracy. The top-features were used to build a new classifier, which we tested on 15 previously unused patients. We then performed clustering with SNF on the top RF features and assessed ability to discriminate between UC and colonic-CD independent of a supervised model., Results: The initial SNF clustering with 58 patients demonstrated 2 groups: group 1 (n = 39, 90% UC) and group 2 (n = 19, 68% colonic-CD). Our RF classifier correctly labelled 97% of the 58 patients based on leave-one-out cross validation and identified the 7 most important features (3 histological and 4 endoscopic) to clinically distinguish these groups. We trained a new RF classifier with the top 7 features and found 100% accuracy in a set of 15 held-out patients. Finally, post hoc clustering with these 7 features revealed 2 groups of patients: group 1 (n = 55, 98% UC) and group 2 (n = 18, 94% colonic-CD)., Conclusions: A combination of supervised and unsupervised analyses identified a short list of features, which consistently distinguish UC from colonic CD. Future directions include validation in other populations., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: As inflammatory bowel disease (IBD) might be associated with environmental factors such as seasonal patterns and low vitamin D levels we aimed to assess their association with IBD onset and flares in a large cohort of children., Methods: The records of 623 pediatric onset IBD patients were reviewed retrospectively including age at onset, gender, severity indices, month of first symptom, and vitamin D levels at diagnosis. For a subgroup of patients, data included date of first flare and vitamin D levels during flare and remission., Results: Median age at diagnosis was 14 years (IQR 11.66-15.58). Disease onset did not vary significantly between either month (P=0.367) or seasons (P=0.460). Vitamin D deficiency at the time of diagnosis was prevalent in 21% of patients with no significant association with month, season or disease's type. Vitamin D deficiency was significantly more prevalent in patients with malnutrition (P<0.001) and was associated with hypoalbuminemia (P=0.02) but did not correlate with low bone mineral density. Analysis of 169 first flares showed that flares were more common in June and less common in April (P=0.016). Mean vitamin D level was significantly lower during flares compared with remission (55.25±19.28 vs. 64.16±26.6, respectively, P=0.012)., Conclusions: IBD onset in school aged children is not associated with seasonal patterns whereas flares may follow a specific monthly pattern. Disease flares are associated with low vitamin D blood levels. Vitamin D deficiency is associated with malnutrition and hypoalbuminemia.

Background: The PAILOT trial was a randomized controlled trial aimed to evaluate proactive vs reactive therapeutic drug monitoring in children with Crohn's disease (CD) treated with adalimumab. Our aim in this post hoc analysis of the PAILOT trial was to assess the efficacy and safety of adalimumab combination treatment in comparison with monotherapy at week 72 after adalimumab induction., Methods: Participants were children 6-17 years old, biologic naïve, with moderate to severe CD, who responded to adalimumab induction at week 4. Patients receiving immunomodulators at baseline maintained a stable dose until week 24; patients could then discontinue immunomodulators. At each visit, patients were assessed for disease index, serum biomarkers, fecal calprotectin, adalimumab trough concentration, and anti-adalimumab antibodies., Results: Out of the 78 patients (29% female; mean age, 14.3 ± 2.6 years), 34 patients (44%) received combination therapy. During the study period, there was no significant difference in the rates of sustained corticosteroid-free clinical remission (25/34, 73%, vs 28/44, 63%; P = 0.35) or sustained composite outcome of clinical remission, C-reactive protein ≤0.5 mg/dL, and calprotectin ≤150 µg/g (10/34, 29%, vs 14/44, 32%; P = 0.77) between the combination group and the monotherapy group, respectively. Clinical and biological outcomes did not differ between the proactive and reactive subgroups within the combination and monotherapy groups. Adalimumab trough concentrations and immunogenicity were not significantly different between groups. The rate of serious adverse events was not significantly different between groups but was numerically higher in the monotherapy group., Conclusions: Combination therapy of adalimumab and an immunomodulator was not more effective than adalimumab monotherapy in children with CD (ClinicalTrials.gov No. NCT02256462)., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Growth impairment is common in children with Crohn disease (CD). We aimed to assess the effect of adalimumab (ADL) treatment on linear growth in children with CD in a post-hoc analysis of the Pediatric Crohn's Disease AdalImumab Level-based Optimization Treatment randomized controlled trial., Methods: Children 6 to 17 years who responded to ADL induction were assessed consecutively for anthropometric parameters. Associations of these parameters with disease characteristics and disease activity were analyzed., Results: Overall, 66 patients completed 72 weeks of follow-up (25% girls, mean age of 15.6 ± 2.5 years). Median (interquartile range [IQR]) height z score improved from -0.6 (-1.6-0.15) at baseline to -0.33 (-1.3-0.5) at week 72 (P = 0.005) with lesser improvement in patients with perianal disease. Similar effect was noted in children with growth potential (boys younger than 16 years, girls younger than 14 years). Median (IQR) height velocity standard deviation was -0.32 (-1.5-0.8) at week 26, and +0.11 (-1.1-1.3) at week 72. Median weight z score increased from -0.54 (-1.2-0.15) to -0.1 (-0.9-0.6), P < 0.001 and body mass index from -0.4 (-1.0-0.5) to 0.0 (-0.8-0.9), P = 0.005. Pediatric CD activity index and erythrocyte sedimentation rate at week 4 correlated negatively with height z score changes (P = 0.043 and P = 0.048, respectively), whereas sustained clinical and biologic remission (week 4-72) were positively associated with changes in height z scores. Significant improvement in linear growth was predicted by lower pediatric CD activity index and erythrocyte sedimentation rate at the end of induction and sustained clinical remission (P = 0.05) and sustained normal C-reactive protein (P = 0.001) at all visits., Conclusion: In children with moderate-to-severe CD, ADL treatment had a significant effect on linear growth, with normalization of weight and body mass index (clinicaltrials.gov no: NCT02256462).

Objectives: The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2012 guidelines, enabled for the first time, a nonbiopsy approach in the diagnosis of celiac disease (CD). We aimed to prospectively assess 4 tissue-transglutaminase (tTg) IgA assays of 4 random-access analyzers and examine their accuracy in diagnosing CD without a biopsy., Methods: We enrolled 186 consecutive children referred to upper endoscopy and intestinal biopsy. One group included 109 patients with positive tTg that was referred for suspected CD. Another group included 77 patients with negative tTg referred because of other indications. All participants had a blood sample taken at the time of endoscopy. Samples were tested with 4 tTg IgA assays on automated analyzers and 1 Elisa kit. All intestinal biopsies were evaluated by a local pathologist, a central pathologist, and a CD expert blinded to each other. CD was diagnosed when full agreement was reached. Analytical performance of the assays included precision with controls and samples, lot to lot variation, and carryover., Results: In our cohort, all tested tTg IgA-automated assays showed sensitivities above 98% and specificities above 99%. ROC analysis demonstrated AUC (area under the curve) >0.99 for all 4 analyzers. The positive-predictive values (PPV) were all >0.99 and negative-predictive values (NPV) were >0.97. The Elisa kit had sensitivity of 95%, specificity of 96%, AUC of 0.96, PPV of 0.98 and NPV of 0.93., Conclusion: CD can be accurately diagnosed without biopsy based on tTg IgA levels at least 10 times the ULN using the 4 high-volume random-access analyzers used in our study.

Background: Children with inflammatory bowel diseases (IBDs) are at risk of developing nutrition deficiencies, particularly because of reduced intake, restrictive diets, malabsorption, and excessive nutrient loss. In this study, we aimed to assess the status of trace elements, minerals, and vitamins in a large cohort of children with IBDs., Methods: Medical records of children diagnosed with IBDs during 2000-2016 were reviewed retrospectively. Retrieved data included demographics, disease characteristics, disease activity indices, anthropometric measures, and specific trace elements, minerals, and vitamins at diagnosis and during follow-up., Results: Out of 359 children with IBD (158 [44%] females, median age at diagnosis 14.1 years, interquartile range [IQR] 12.0-16.0), 240 (67%) were diagnosed with Crohn's disease (CD) and 119 (33%) with ulcerative colitis (UC). Median follow-up time was 7 years (IQR 5-10). The prevalence of deficiencies in patients with CD at diagnosis and last follow-up, respectively, were iron (88% and 39.5%), zinc (53% and 11.5%), vitamin D (39% and 36%), and folic acid (10% and 13%). In patients with UC, frequencies were: iron (77% and 40%), vitamin D (49% and 33%), zinc (31% and 10%), and folic acid (3.8% and 9.7%). Magnesium and vitamin B12 deficiencies were rare. For both diseases, iron deficiency was associated with hypoalbuminemia. Deficiencies in iron and zinc were more common in patients with CD than those with UC., Conclusions: Deficiencies in iron, zinc, and vitamin D are common at pediatric IBD diagnosis with limited improvement during follow-up, whereas deficiencies in magnesium and vitamin B12 are rare., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Objectives: Differentiation of Crohn disease (CD) from ulcerative colitis (UC) is challenging when inflammation is predominantly colonic. The paediatric inflammatory bowel disease (PIBD) classes algorithm was developed to bring consistency to labelling, but used physician-assigned diagnosis as the criterion standard. We aimed to reassess the PIBD classes using pathology of subsequently resected colon as the criterion standard., Method: Single-centre study of patients diagnosed with colonic IBD between 2002 and 2017 and subsequently treated with colectomy. Baseline pretreatment data were reviewed and the PIBD classes algorithm was independently applied by 2 reviewers to assign a label of UC/IBD-unclassified (IBD-U)/colonic-CD. Concordance between the algorithm-based, precolectomy clinical, and pathologic examination of resected colon diagnosis were assessed. Changes in diagnosis during postcolectomy follow-up were recorded., Results: Sixty-two children underwent colectomy for medically refractory colonic IBD. Diagnosis based on pathologic review of resected colon CD:4;UC:56;IBDU:2. The clinical, PIBD classes algorithm, and colectomy diagnoses were concordant in 51 of 62 patients (81%, Fleiss kappa 0.48). Precolectomy clinical diagnosis was concordant with colectomy diagnosis in 58 of 62 patients (94%, weighted-kappa 0.65). The PIBD classes label was concordant with colectomy diagnosis in 51 of 62 patients (82%, weighted-kappa 0.38); resected colon pathology was typical of UC in 6 patients with PIBD classes label of IBD-U based on single class 2 feature and in 3 with PIBD classes label of CD based on single class 1 feature., Conclusions: Concordance of PIBD classes algorithm diagnosis applied before colectomy with a diagnostic label based on pathologic examination of a subsequently resected colon is only fair. Caution is needed in stringent application of colonic CD and IBD-U labels based on presence of single feature.

Background and Aims: Growth impairment is common in children with inflammatory bowel diseases (IBD). However, the magnitude of short stature at adulthood is not well characterized. We aimed to determine the prevalence and predictors of growth impairment at diagnosis and adulthood in children with IBD., Methods: Height z-scores at diagnosis of IBD and at adulthood among 291 children with Crohn's disease (CD) and 125 with ulcerative colitis (UC) were retrieved retrospectively and compared to matched controls. Growth impairment at diagnosis was defined as height z-score for age less than or equal to -1 and short stature at adulthood as less than or equal to -2., Results: Mean height z-score at adulthood in subjects with CD or UC was significantly different from controls although mean height did differ in males only (CD 172.3 cm ± 6.7, UC 172.7 cm ± 5.3, controls: 174.2 cm ± 7.3, p = 0.003 and p = 0.047, respectively). Diagnosis prior to final stage of puberty and male gender were risk factors for being short statured at adulthood in CD (mean difference [MD] 2.5, p = 0.013 and MD 6.25, p = 0.001, respectively) and UC (MD 4.9, p = 0.011 and MD 3.3, p = 0.034, respectively)., Conclusion: Increased proportion of pediatric-onset IBD patients has growth impairment at adulthood. Male gender and diagnosis prior to puberty were found to impose risk for reduced adult height in both diseases., (© 2019 S. Karger AG, Basel.)

Background & Aims: Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD)., Methods: We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 μg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72)., Results: The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 μg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001)., Conclusions: In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

A comparison of 23 children with inflammatory bowel disease presenting with musculoskeletal symptoms and 46 children with arthritis of other causes yielded significantly higher rates in the inflammatory bowel disease group of sacroiliitis, arthralgia, additive and recurrent arthritis, microcytic anemia, elevated inflammatory markers, and hypoalbuminemia. Clinical awareness of these findings could expedite diagnosis and treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: Elevated levels of anti-tissue transglutaminase (anti-tTG) antibody may spontaneously normalise in children with newly diagnosed type 1 diabetes, even if they eat gluten. The prevalence of this phenomenon and predictors of a subsequent coeliac disease (CD) diagnosis were determined., Methods: The medical records of children diagnosed with type 1 diabetes at Ha'Emek Medical Centre, Israel, from 2007 to 2015, were retrospectively reviewed for elevated anti-tTG antibody levels. Demographic, clinical, laboratory and histological findings were compared between CD patients and those with transient coeliac serology., Results: Of 425 patients with new onset type 1 diabetes, 34 (8%) had elevated anti-tTG antibodies: CD was diagnosed in 14, anti-tTG normalisation occurred in 13 and duodenal biopsies did not suggest CD in seven without anti-tTG antibody normalisation. Protective factors for a subsequent CD diagnosis were older age (p = 0.009) and mildly elevated anti-tTG antibody levels at the time of the type 1 diabetes diagnosis (p = 0.007), and decreased anti-tTG levels within six months of diagnosis (p = 0.03)., Conclusion: Serological follow-up of a diet containing gluten is recommended for children who have newly diagnosed type 1 diabetes and slightly elevated anti-tTG antibodies with no symptoms that suggest CD., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Data describing extent change (progression or regression) in pediatric-onset ulcerative colitis (UC) are scarce., Goal: We aimed to describe extent change in pediatric-onset UC during long-term follow-up and to assess predictors of extent change., Study: Medical charts of pediatric-onset UC patients with at least 5-year follow-up were analyzed retrospectively. Disease extent was determined using the Paris classification. It was examined at diagnosis and during follow-up at different time points. The impact of possible predictors on extent change including age at diagnosis, gender, clinical manifestations, disease, severity indices, and different therapeutic regimens during disease course was assessed., Results: Patients (n=134, 55% males) were followed for a median duration of 13.1 (range, 5 to 28) years. Median age at diagnosis was 13.1 (range, 2 to 17.8) years. Of 134 patients, 40.5% had extensive or pancolitis, 33.5% left-sided colitis, and 26% had proctitis at diagnosis. On follow-up (n=117), 45% had unchanged disease extent, 35% experienced extent progression, whereas 20% experienced regression of disease extent. The multivariate Cox models demonstrated that among children with left-sided disease at diagnosis, presence of extraintestinal manifestations (hazard ratio, 5.19; P=0.022), and higher pediatric UC activity index (hazard ratio, 8.77; P=0.008) were associated with extent progression to extensive disease. Predictors of extent regression have not been identified., Conclusions: Disease extent changes significantly over time in pediatric-onset UC. In our cohort, presence of extraintestinal manifestation and higher pediatric UC activity index score at diagnosis were associated with progression from limited to extensive disease during follow-up.

Introduction: The Paris modification of the Montreal classification for children with inflammatory bowel disease was accepted in 2011. We aimed to investigate the long-term clinical outcomes of patients diagnosed with IBD during childhood in a population-based cohort according to the Paris classification at diagnosis., Methods: The medical records of paediatric inflammatory bowel disease patients, diagnosed from 2000 to 2016, were reviewed retrospectively. Main outcome measures included time to first flare, hospitalisation, surgery, and biologic therapy., Results: In Crohn's disease patients [n = 301, median age 14.2 years], colonic location was associated with higher prevalence of extraintestinal manifestations, whereas ileal location and complicated behaviour were associated with anti-Saccharomyces cerevisiae antibody positivity. During a median follow-up of 9.1 years (interquartile range [IQR]of 4.7-12.3), complicated behaviour at diagnosis was associated with increased risk for surgery (hazard ratio[ HR] = 2.7, p < 0.001] and hospitalisation [HR = 1.5, p = 0.01] but not with the risk for flare or stepping-up to biologic therapy. Isolated colonic disease was associated with a decreased risk of surgery [HR = 0.25, p = 0.02]. During a median follow-up of 8.5 years [interquartile range of 5.1-12], in patients with ulcerative colitis [n = 126, median age 13.7 years], severe disease at diagnosis but not disease extent was associated with the risk for colectomy [HR = 3.5, p = 0.002], hospitalisation [HR = 3.3, p < 0.001], flare [HR = 2.4, p < 0.001] and biologic therapy [HR = 2.6, p = 0.001]., Conclusions: The Paris classification for paediatric inflammatory bowel disease has clear predictive properties. Complicated disease and ileal location at diagnosis in Crohn's disease, and severity of disease but not its extension in ulcerative colitis, predict long-term worse outcomes., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background: There is limited evidence on the long-term outcome of intestinal resection in pediatric-onset Crohn's disease (POCD) with no established predictors of adverse outcomes. We aimed to investigate clinical outcomes and predictors for adverse outcome following intestinal resection in POCD., Methods: The medical records of patients with POCD who underwent at least 1 intestinal resection between 1990 and 2014 were reviewed retrospectively. Main outcome measures included time to first flare, hospitalization, second intestinal resection, and response to nonprophylactic biologic therapy., Results: Overall, 121 patients were included. Median follow-up was 6 years (range 1-23.6). One hundred and seven (88%) patients experienced at least 1 postsurgical exacerbation, 52 (43%) were hospitalized, and 17 (14%) underwent second intestinal resection. Of 91 patients who underwent surgery after the year 2000, 37 (41%) were treated with antitumor necrosis factor ɑ (anti-TNFɑ) (nonprophylactic) following intestinal resection. Time to hospitalization and to second intestinal resection were shorter among patients with extraintestinal manifestations (EIMs) (HR 2.7, P = 0.006 and HR = 3.1, P = 0.03, respectively). Time to initiation of biologic treatment was shorter in patients with granulomas (HR 2.1, P = 0.038), whereas being naïve to anti-TNFɑ treatment before surgery was a protective factor for biologic treatment following surgery (HR 0.3, P = 0.005). Undergoing intestinal resection beyond the year 2000 was associated with shorter time to first flare (HR 1.9, P = 0.019) and hospitalization (HR 2.6, P = 0.028)., Conclusion: Long-term risk for flares, hospitalization, or biologic treatment is significant in POCD following bowel resection. EIMs increase the risk for hospitalization and second intestinal resection., (© 2017 Crohn’s & Colitis Foundation of America. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objective: The natural history of pediatric inflammatory bowel disease (IBD) patients with joint involvement has not been clearly described. Thus, we aimed to investigate phenotypic features and clinical outcomes of this distinct association., Methods: The medical records of patients with pediatric IBD diagnosed from 2000 to 2016 were reviewed retrospectively. Main outcome measures included time to first flare, hospitalization, surgery, and biologic therapy., Results: Of 301 patients with Crohn disease (median age 14.2 yrs), 37 (12.3%) had arthritis while 44 (14.6%) had arthralgia at diagnosis. Arthritis and arthralgia were more common in women (p = 0.028). Patients with arthritis and arthralgia demonstrated lower rates of perianal disease (2.7% and 4.5% vs 16.9%, p = 0.013), whereas patients with arthritis were more likely to be treated with biologic therapy (HR 2.05, 95% CI 1.27-3.33, p = 0.009). Of 129 patients with ulcerative colitis (UC; median age 13.7 yrs), 3 (2.3%) had arthritis and 16 (12.4%) had arthralgia at diagnosis. Patients with arthralgia were treated more often with corticosteroids (p = 0.03) or immunomodulator therapies (p = 0.003) compared with those without joint involvement. The likelihood to undergo colectomy was significantly higher in patients with arthralgia (HR 2.9, 95% CI 1.1-7.4, p = 0.04). During followup (median 9.0 yrs), 13 patients developed arthritis (3.3%). Arthralgia at diagnosis was a significant predictor for the development of arthritis during followup (HR 9.0, 95% CI 2.86-28.5, p < 0.001)., Conclusion: Pediatric IBD patients with arthritis have distinct phenotypic features. Arthralgia at diagnosis is a predictor for colectomy in UC and a risk factor for the development of arthritis during followup.

Objectives: Data describing the incidence and risk factors for colectomy in pediatric ulcerative colitis (UC) is inconsistent. Our aim was to describe the colectomy rate and to identify risk factors associated with colectomy in a large cohort of children with UC with long-term follow-up., Materials and Methods: We performed a retrospective chart review of pediatric UC cases that were diagnosed at Schneider Children's Medical Center of Israel between 1981 and 2013. Potential predictors for colectomy including age at diagnosis, sex, disease extent, severity indices, and different therapeutic regimens during disease course were assessed., Results: Of 188 patients with pediatric onset UC, 34 (18%) underwent colectomy. Median follow-up was 6.9 years (range, 1-30). Kaplan-Meier survival estimates of the cumulative probability for colectomy were 4% at 1 year and 17% at 10 years from diagnosis. Multivariate Cox models showed that male sex (hazard ratio 4.2, P = 0.001) and severe disease at diagnosis reflected by Pediatric Ulcerative Colitis Activity Index score ≥65 (hazard ratio 8.9, P < 0.001) were associated with increased risk for colectomy. Age, disease extent, ethnicity, family history of inflammatory bowel disease, early introduction of immunomodulators, or treatment with antitumor necrosis factor α agent did not affect the risk of colectomy., Conclusions: Male sex and higher Pediatric Ulcerative Colitis Activity Index score at diagnosis are independent risk factors for colectomy.

Background: Data on the outcomes of children with perianal Crohn's disease are limited. We aimed to assess phenotypic features at diagnosis and long-term disease-specific outcomes of this phenotype., Methods: The medical records of 296 pediatric onset patients with Crohn's disease, diagnosed from 2001 to 2015, were reviewed retrospectively. Baseline characteristics included age, sex, severity indices, laboratory data, endoscopic findings, and anthropometric measurements. Main outcome measures included time to first flare, hospitalization, surgery, and biological therapy., Results: Of the 296 included patients (median age 14.2 years), 70 (24%) had nonfistulizing perianal findings, whereas only 40 (13%) had fistulizing perianal disease at diagnosis. Perianal involvement was associated with female sex (P = 0.01), whereas fistulizing perianal disease resulted in a greater use of immunomodulators (P = 0.01). Time to hospitalization was shorter for both nonfistulizing and fistulizing perianal disease (hazard ratio [HR] 1.66 and 1.34, respectively, P = 0.027) and time to biological therapy (HR 2.1 and 1.7, respectively, P = 0.002). There were no differences in time to first flare or surgery. During a median follow-up of 8.5 years, additional 26 patients (10%) developed fistulizing perianal disease after a median time of 3.5 years. The presence of nonfistulizing disease at diagnosis was a significant risk factor for the development of fistulizing perianal disease (HR 3.4, P = 0.002). At the end of follow-up, complicated disease was more common in patients with any perianal involvement (P = 0.01)., Conclusions: Pediatric patients with Crohn's disease with both nonfistulizing and fistulizing disease have worse clinical outcomes. Nonfistulizing disease is a risk factor for the development of fistulizing disease over time.

Objectives: Few studies have reported on the incidence and risk factors for pouchitis following colectomy and ileal pouch-anal anastomosis (IPAA) in patients with pediatric-onset ulcerative colitis (UC). We aimed to determine clinical predictors for the development of pouchitis following IPAA in this population., Patients and Methods: We performed a retrospective chart review of all pediatric UC cases that were diagnosed at the Schneider Children's Medical Center of Israel between 1981 and 2013 and who underwent colectomy during disease course. Potential predictors for pouchitis and chronic pouchitis including various demographic, clinical, endoscopic, and histological variables at diagnosis and at the time of surgery were assessed., Results: Of 188 patients with pediatric-onset UC, 33 (18%) underwent colectomy and IPAA surgery. During a median postsurgical follow-up of 7.6 (range: 1-21.5) years following IPAA, 20/33 (60%) patients developed pouchitis including 11/33 (33%) patients who developed chronic pouchitis. Kaplan-Meier survival estimates of the cumulative probability for pouchitis were 9% at 1 year and 36 and 55% at 5 and 10 years, respectively. Multivariate Cox models showed that older age at colectomy (hazard ratio: 0.86, P=0.024) was a protective factor, whereas preoperative vitamin-D deficiency (≤20 ng/ml) (hazard ratio: 4.4, P=0.021) increased the risk for pouchitis. Age at diagnosis, sex, disease extent, and preoperative therapeutic regimens did not affect the risk of pouchitis., Conclusion: Long-term risk for pouchitis is significantly high in pediatric-onset UC after IPAA. Vitamin-D deficiency and younger age at colectomy may increase the risk for pouchitis.

Objectives: An association between coeliac disease (CD) and eosinophilic oesophagitis (EoE)/oesophageal eosinophilia (EE) has been suggested. We sought to characterise children with CD+EE in-depth and assess the contribution of each condition to the clinical presentation and treatment response., Study Design: Medical records of children with both CD+EE, or isolated EoE diagnosed between 2000 and 2014, were retrospectively reviewed and compared with patients with isolated CD or epigastric pain. Frequency of EE was calculated from endoscopy results of patients with suspected CD or epigastric pain between 2011 and 2014. Missing data were obtained via a telephone questionnaire., Setting: Single large, tertiary paediatric centre., Patients: 17 CD+EE, 46 EoE, 302 isolated CD and 247 epigastric pain., Results: The patients with CD+EE shared characteristics of both individual conditions. While age at diagnosis, family history of autoimmunity/CD and anaemia were similar to patients with CD, other characteristics such as male gender, personal/family history of atopy, peripheral eosinophilia and oesophageal white papules were more similar to patients with EoE. Combined patients (CD+EE) tended to present with CD-associated symptoms; the majority (63%) later developed typical EoE symptoms. Only a minority (21%) of combined patients had EE that resolved after a gluten-free diet; another 21% had normalisation of EE upon proton pump inhibitor treatment. The remainder required EoE-specific treatment., Conclusion: Patients with CD found to have EE share characteristics with both isolated CD and EoE. It appears that these are two coexisting entities presenting in the same patient rather than eosinophilia associated with CD, and therefore, interventions separately addressing each condition may be considered., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Data on inflammatory bowel disease (IBD) phenotypes among the Arab population in Israel or in the neighboring Arab countries is scarce., Aim: We aimed to assess differences in disease phenotype among Arab and Jewish children living in Israel., Methods: We performed a retrospective chart review of pediatric IBD cases, which were diagnosed at the Schneider Children's Medical Center and Ha'Emek Medical Center in Israel between 2000 and 2014. Demographic, clinical, and phenotypic variables were compared between Arabs and Jews from Eastern (Sephardic) and Western (Ashkenazi) origin., Results: Seventy-one Arab children with IBD were compared with 165 Ashkenazi and 158 Sephardic Jewish children. Age and gender did not differ between groups. Sephardic and Ashkenazi Jewish Crohn's disease (CD) patients had significantly more stenotic behavior (24 and 26 vs. 5%, p = 0.03) and less fistulzing perianal disease (15 and 11 vs. 31%, p = 0.014) compared with Arab patients. Arab children with ulcerative colitis (UC) had more severe disease at diagnosis compared to Sephardic and Ashkenazi Jews reflected by higher Pediatric UC Activity Index (45 vs. 35 and 35, respectively, p = 0.03). Arab patients had significantly lower proportion of anti-Saccharomyces cerevisiae antibodies positivity (in CD) and perinuclear anti-neutrophil cytoplasmic antibodies positivity (in UC) than both Sephardic and Ashkenazi Jewish children (23 vs. 53 and 65%, p = 0.002 and 35 vs. 60 and 75%, respectively, p = 0.002)., Conclusion: Arab and Jewish children with IBD differ in disease characteristics and severity. Whether genetic or environmental factors are the cause for these differences is yet to be determined.

Objectives: Granulomas have long been considered the histological hallmark of Crohn's disease (CD). Currently, there is considerable dispute with regards to their prognostic implications. We aimed to determine the effect of granulomas on phenotypic features and disease's long-term outcomes in a large cohort of pediatric CD patients., Materials and Methods: Medical records of pediatric CD patients diagnosed at the Schneider Children's Medical Center were reviewed retrospectively. Patients were categorized into two groups based on the presence or absence of granulomas at diagnosis. Baseline characteristics included anthropometric, clinical, laboratory, radiological and endoscopic data. Outcome measures included flares, hospitalizations, biological therapy and surgery., Results: Of 289 CD patients diagnosed between 2001 and 2015, 99 patients (34%) had granulomas. Median age of the entire cohort at diagnosis was 14.2 years (females, 42.6%), with a median follow-up of 8.5 years. Patients with granulomas had a significantly higher percentage (47.5% vs. 23.7%, p = .001) of upper gastrointestinal involvement and ileo-colonic disease (64.9% vs. 49.5%, p = .01). Extraintestinal manifestations were twice as common in patients without granulomas (16.3% vs. 8.1%, p = .05). Patients with granulomas were more likely to be hospitalized (HR =1.43, 95% CI: 1.0-2.0) and to receive biologic therapy (HR = 1.52, 95% CI: 1.1-2.11). Additionally, both of these disease outcomes occurred significantly earlier (p = .013 and p = .027, respectively). In contrast, patients with granulomas did not exhibit increased risk of flares or bowel resection., Conclusion: Patients with granulomas exhibited a distinct phenotype at diagnosis and demonstrated a more severe disease course.

Background: Inflammatory bowel disease (IBD) is known to pose a risk for low bone mineral density (BMD) in children and adults. We aimed to evaluate the impact of pediatric-onset IBD on BMD in adulthood., Methods: Records of pediatric-IBD patients were retrospectively reviewed for documentation of dual-energy X-ray absorptiometry (DXA) scans in adulthood. BMD was expressed as z-score., Results: Sixty one patients were included. Mean (±SD) age at diagnosis was 14.7 (±2.4) years. Mean age at first DXA scan in adulthood was 23.9 years (±4.8). Median BMD z-score was -1.2 SD (IQR, -1.8 to -0.4), significantly lower than expected in normal population (p<0.001). Osteopenia (BMD z-score ≤-1 SD) was noted in 44.3% (n=27), and osteoporosis (BMD z-score ≤-2.5 SD) in 8.2% (n=5). Bone-status showed no correlation with age, disease severity, vitamin D status at diagnosis, IBD subtype or duration of disease. Positive correlation (r=0.306) was identified between low weight z-score at diagnosis and abnormal bone-status in adulthood. Among 36 patients with multiple DXA scans, there was no significant change in BMD during follow-up of 2.4 years., Conclusions: Osteopenia and osteoporosis are frequent in adult IBD patients with pediatric-onset disease and correlates with low weight z-score at diagnosis., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) in patients who were initially diagnosed as inflammatory bowel disease-unclassified (IBDU) remains challenging. Our aims were to describe the natural history of pediatric-onset IBDU patients during prolonged period of follow up and to identify associated predictors for CD reclassification among them., Materials and Methods: In this retrospective single center study, out of 723 patients with pediatric onset IBD, we identified 53 patients (7.3%) diagnosed with IBDU at the Schneider Children's Medical Center of Israel between 1986 and 2013. Potential predictors for CD reclassification including age at diagnosis, gender, clinical manifestations, disease extent and laboratory findings were assessed., Results: The median follow-up was 6.8 (± 6.7) years. Reclassification to CD was observed in 24/53 (45%) of patients. The median interval from diagnosis to CD reclassification was 9.4 years. In 58% of these patients, CD reclassification occurred within 5 years from diagnosis. Multivariate Cox models showed that familial history of CD and hypoalbuminemia at diagnosis were significantly associated with CD reclassification (HR 11.3, p = .02 and HR 5.3, p = .03, respectively). All other assessed clinical, laboratory and endoscopic parameters did not serve as predictors for CD reclassification later on., Conclusions: In our cohort, a substantial high proportion of pediatric onset IBDU patients were later re-diagnosed as CD. Only a family history of CD and hypoalbuminemia could predict reclassification among IBDU patients.

Aims: The aim of these guidelines is to update and extend evidence-based recommendations for the diagnosis and management of children with acute gastroenteritis (AGE) in Israel, based on new data and the recently published European update., Methods: The recommendations, which are based on a systematic review of the literature, were graded by the level of evidence. The guidelines were endorsed by the Israeli societies for Pediatric Gastroenterology, Pediatric Infectious Diseases and the Israeli Association of Pediatrics., Results: Gastroenteritis severity is mainly linked to etiology, and rotavirus is most frequently associated with dehydration. Dehydration reflects severity and should be monitored by established score systems. Laboratory tests are generally not needed. Oral rehydration with hypo-osmolar solution is the major treatment and should start as soon as possible. Breast-feeding should not be interrupted; regular feeding should usually be continued with no dietary changes including milk. Data suggest that in the hospital setting, in non-breast-fed infants and young children, lactose-free feeds can be considered in the management of gastroenteritis. Antimicrobial therapy should be given in exceptional cases. Hospitalization should generally be reserved for children requiring enteral/parenteral rehydration, and most cases may be managed in an outpatients setting. Enteral rehydration is superior to intravenous rehydration., Conclusions: Implementation of the scientifically-based guidelines in clinical practice may improve the standard of care of pediatric AGE in Israel.

Background/aims: The significance of hypergammaglobulinemia as a phenotypic feature of inflammatory bowel disease is unknown. Thus, we aimed to analyze the magnitude and significance of hypergammaglobulinemia in newly diagnosed pediatric inflammatory bowel disease patients., Materials and Methods: The medical records of 296 pediatric onset inflammatory bowel disease patients who were evaluated from 2002 to 2015 were retrospectively reviewed. Patients with recorded immunoglobulin G (IgG) levels were categorized as either normal or high IgG levels at diagnosis. Baseline characteristics included age at onset, sex, severity indices, laboratory data, extraintestinal manifestations, endoscopic findings, and anthropometric measurements., Results: Of 184 subjects [mean age, 13.2±2.8 years; 105 (60%) males] with recorded IgG levels, 129 (70%) had Crohn disease, 46 (25%) had ulcerative colitis, and 9 (5%) had unclassified inflammatory bowel disease. Overall, 46 patients (25%) had hypergammaglobulinemia, including 30 (23%) with Crohn disease, 14 (30%) with ulcerative colitis, and 2 (22%) with unclassified disease. Hypergammaglobulinemia was associated with the female sex (55% vs. 35%; p=0.03) and extraintestinal manifestations (70% vs. 10%; p<0.0001), including arthritis, skin disorders, and primary sclerosing cholangitis but not with arthralgia. It was also associated with corticosteroid induction (68% vs. 45%; p=0.02) and maintenance with an immunomodulator (61% vs. 21%; p=0.0001) after diagnosis. In ulcerative colitis patients, hypergammaglobulinemia was associated with a high pancolitis prevalence (p=0.002)., Conclusion: Hypergammaglobulinemia is a marker of extraintestinal manifestations in pediatric inflammatory bowel disease and may assist in distinguishing arthritis from arthralgia.

Background: Eosinophils are implicated in the pathogenesis of ulcerative colitis., Aims: To evaluate the magnitude of mucosal and blood eosinophils in newly diagnosed pediatric ulcerative colitis patients and its significance in predicting disease outcomes., Methods: We retrospectively evaluated colorectal biopsies of 96 pediatric patients with ulcerative colitis and 50 age- and sex-matched controls. Samples were taken from diseased areas of the colon and examined by a gastrointestinal pathologist. The most inflamed site was used for assessment of mucosal eosinophils., Results: Samples from 96 diagnostic and 70 follow-up colonoscopies were evaluated. Median age was 13.3 years (IQR 10.1-15.3). Median duration of follow-up was 12.8 years (IQR 7.2-17.1). Median number of tissue eosinophils at diagnosis was 45 (IQR 22-73) compared to 10 eosinophils (IQR 8-25) during histologic remission (p<0.0001). Peripheral absolute eosinophil counts correlated with tissue inflammation and eosinophilia (p=0.001). Mucosal eosinophilic infiltration (p=0.02) and peripheral eosinophilia (p=0.04) was associated with clinical severity at diagnosis. Multivariate analysis showed that severe eosinophilic infiltration is associated with corticosteroid therapy following diagnosis (p=0.04) but not with long-term risk for step-up therapy or colectomy., Conclusion: Tissue and peripheral eosinophilia correlate with ulcerative colitis severity at diagnosis and with short-term corticosteroid requirement but not with long-term outcomes., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Acute bronchiolitis in infancy is considered a risk factor for recurrent wheezing episodes in childhood. The present study assessed prevalence, clinical manifestations and risk factors for recurrent wheezing events during the first 3 years of life and persistent wheezing events beyond this age in children hospitalized as young infants with acute bronchiolitis., Methods: Two groups of children aged 6 years were included. The study group comprised 150 children with a history of hospitalization for bronchiolitis, with the first event at <6 months of age. The control group comprised 66 age- and sex-matched children with no history of bronchiolitis before 6 months of age. Children in both groups had been followed until 6 years of age by their pediatricians; data were obtained retrospectively by reviewing ambulatory records during children's visits in pediatricians' clinics. The data included epidemiological parameters, prevalence, age at onset, number of and treatments given for episodes of wheezing events prior to 6 years of age, pathogens detected, and severity of acute bronchiolitis in the study group., Results: Overall, 58% and 27% of children in the study and control groups, respectively (P=0.001) had recurrent wheezing episodes prior to the age of 3 years. Children in the study group had earlier onset of recurrent wheezing, had more episodes of wheezing, and required more bronchodilator and systemic steroids treatments compared to the control group., Conclusion: Hospitalization within the first six months of life for acute bronchiolitis is an independent risk factor for recurrent wheezing episodes during the first 3 years of life.