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Adir Gamliel,1,2 Lael Werner,1,2 Marina Pinsker,1,3 Naomi Salamon,1 Batia Weiss,1,2 Dror S Shouval1,2 1Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Institute of Nanotechnology and Advanced Materials, Bar Ilan University, Ramat Gan, IsraelCorrespondence: Dror S ShouvalPediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, IsraelTel +972-3-5305006Email dror.shouval@gmail.comBackground: The integrin α 4β 7 is highly expressed on activated T cells and is thought to direct homing of lymphocytes to the intestine. Since ulcerative colitis (UC) and Crohn’s disease (CD) are characterized by mucosal oligoclonal T cells’ expansion, we aimed to assess whether similar repertoire features are identified in circulating gut-specific memory T cells.Methods: Memory CD3+ T cells were isolated from blood samples of control subjects and patients with active UC or CD and then FACS-sorted into α 4β 7+ and α 4β 7− populations. DNA was extracted from each subset and subjected to next-generation sequencing of the TCRβ. Different repertoire characteristics were compared between α 4β 7+ and α 4β 7− subsets for each subject, and between groups.Results: The percentages of memory T cells and α 4β 7+ cells were comparable between groups. α 4β 7+ memory T cells displayed a polyclonal distribution, in control subjects and in UC or CD patients, with similar indices of diversity. Strikingly, the clonal overlap between α 4β 7+ and α 4β 7− T cells for each subject in all three groups was high, ranging between 20%– 50%. We were unable to identify shared T cell clones that were specific to one of the groups.Conclusion: α 4β 7+ memory T cells exhibited a polyclonal repertoire in both control subjects and patients with active inflammatory bowel disease, with high rates of overlap with α 4β 7− memory T cells. Our study, along with additional recent reports, may suggest that the suppression of intestinal inflammation by vedolizumab is independent of the drug’s effect on T cell migration to the gut.Keywords: IBD, TCR, integrin, α 4β 7, T cells, immune repertoire

Background: Tumour necrosis factor α (TNF-α) inhibitor (TNFi)-induced psoriasiform eruptions are a well-known phenomenon among adults. However, data are limited regarding this reaction in children., Objectives: To describe in paediatric patients with inflammatory bowel disease (IBD) the clinical characteristics of TNFi-induced psoriasiform eruptions and the outcomes of various therapeutic options., Methods: We reviewed the medical charts of paediatric patients (aged < 18 years) with IBD who developed TNFi-induced psoriasiform eruptions during 2006-2022., Results: Among 454 patients with IBD treated with TNFis, 58 (12.8%) were diagnosed with TNFi-induced psoriasiform eruptions, of whom 51 were included in the study. The female to male ratio was 1 : 1.3. The median age at skin eruption was 14.11 [interquartile range (IQR) 12.11-16.05] years. The median elapsed time to eruption appearance was 15.00 months (IQR 7.00-24.00) after initiation of the treatment. All 51 patients were treated with topical steroids and 17 (33%) needed systemic treatment (phototherapy, methotrexate or acitretin). Sixteen of 51 patients (31%) needed to stop TNFi treatment because of an intractable eruption. Female patients, patients with inflammatory alopecia and patients who were treated with methotrexate or phototherapy were more prone to stop TNFis., Conclusions: TNFi-induced psoriasiform eruptions are common in paediatric patients with IBD. The eruption may appear months or even years after treatment initiation. Almost one-third of the described patients had to replace their treatment because of a recalcitrant cutaneous eruption. This indicates that a multidisciplinary approach is required., Competing Interests: Conflicts of interest: The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. 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.)

Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a "compositional dysbiosis" and a concomitant species-specific "functional dysbiosis" driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease., Competing Interests: Declaration of interests A patent application has been submitted by the Weizmann Institute of Science., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There are scarce data available on upadacitinib in children with Crohn's disease (CD)., Aim: To evaluate the effectiveness and safety of upadacitinib as an induction therapy in paediatric CD., Methods: This was a multicentre retrospective study between 2022 and 2024 of children treated with upadacitinib for induction of remission of active CD conducted in 30 centres worldwide affiliated with the IBD Interest and Porto group of the ESPGHAN. We recorded demographic, clinical and laboratory data and adverse events (AEs) at week 8 post-induction. The analysis of the primary outcome was based upon the intention-to-treat (ITT) principle., Results: We included 100 children (median age 15.8 [interquartile range 14.3-17.2]). All were previously treated with biologic therapies including 89 with ≥ 2 biologics. At the end of the 8-week induction period, we observed clinical response, clinical remission and corticosteroid- and exclusive enteral nutrition-free clinical remission (CFR) in 75%, 56% and 52%, respectively. By the end of induction, 68% had achieved normalisation of C-reactive protein, and 58% had faecal calprotectin (FC) < 150 mcg/g. There was combined CFR and FC remission in 13/31 children with available data at 8 weeks (13% of the ITT population). AEs were recorded in 24 children; the most frequent was acne in 12. Two AEs (severe acne and hypertriglyceridemia) led to discontinuation of therapy., Conclusion: Upadacitinib is an effective induction therapy for refractory paediatric CD. Efficacy should be weighed against the potential risks of AEs., (© 2025 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Tofacitinib has recently been approved for treatment of moderate-to-severe ulcerative colitis (UC) in adults, yet pediatric data are limited. This international multicenter study describes the effectiveness and safety of tofacitinib in pediatric UC., Methods: This is a retrospective review of children diagnosed with UC treated with tofacitinib from 16 pediatric centers internationally. The primary outcome was week 8 corticosteroid-free clinical remission (Pediatric Ulcerative Colitis Activity Index <10). Secondary outcomes were clinical response (≥20-point decrease in Pediatric Ulcerative Colitis Activity Index) at week 8, corticosteroid-free clinical remission at week 24, and colectomy rate and adverse safety events through to last follow-up. The primary outcome was calculated by the intention-to-treat principle., Results: We included 101 children with a mean age at diagnosis of 12.8 ± 2.8 years and a median disease duration of 20 months (interquartile range [IQR], 10-39 months). All had treatment failure with at least 1 biologic agent, and 36 (36%) had treatment failure with 3 agents. Median follow-up was 24 weeks (IQR, 16-54 weeks). Sixteen (16%) children achieved corticosteroid-free clinical remission at week 8, and an additional 30 (30%) demonstrated clinical response. Twenty (23%) of 88 children achieved corticosteroid-free clinical remission at week 24. A total of 25 (25%) children underwent colectomy by median 86 days (IQR, 36-130 days). No serious drug-related adverse events were reported; there was 1 case of herpes zoster and 2 cases of minor blood test perturbations., Conclusions: In this largest real-life pediatric cohort to date, tofacitinib was effective in at least 16% of patients with highly refractory UC by week 8. Adverse events were minor and largely consistent with adult data., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. 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.)

Objectives: Mucosal healing (MH) is a key therapeutic target in Crohn's disease (CD) and is associated with improved outcomes. While adult studies indicate a positive correlation between serum anti-tumor necrosis factor (TNF) levels and MH, data in pediatric patients is limited. We aimed to define the association of serum anti-TNF levels with MH in pediatric patients with CD during maintenance therapy., Methods: Retrospective data (2014-2023) was collected from pediatric CD patients treated with infliximab or adalimumab who performed an ileocolonoscopy at least 26 weeks after initiating therapy. Serum anti-TNF levels around endoscopic time were compared with endoscopic findings. MH was defined as complete absence of inflammatory or ulcerative lesions across all segments of the gastrointestinal tract. Univariable and multivariable logistic regression analysis was conducted to identify factors associated with MH., Results: Data were obtained from 107 patients (41 infliximab and 66 adalimumab), with a median age at diagnosis of 12.6 (9.9-14.0) years. Median time until ileocolonoscopy following anti-TNF initiation was 89.0 (56.3-152.3) weeks. MH was identified in 31 (29.0%) patients. Anti-TNF serum levels were comparable in the MH and non-MH groups (9.5 [4.9-13.9] vs. 9.3 [6.4-15.7] µg/mL; p = 0.73), without differences in patients treated with infliximab or adalimumab. In multivariable analysis, diagnosis weight Z-score (odds ratio [OR] = 2.860, 95% confidence interval [CI] = 1.005-8.138; p = 0.049), along with C-reactive protein (OR = 0.037, 95% CI = 0.002-0.687; p = 0.027) and fecal calprotectin (OR = 0.995, 95% CI = 0.990-1.000; p = 0.037) at time of ileocolonoscopy were significantly associated with MH., Conclusions: In our cohort, anti-TNF levels during maintenance were not associated with MH in pediatric CD., (© 2025 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background and Aims: Patients with very early-onset inflammatory bowel disease (VEO-IBD), with an age of onset < 6 years, can present with severe manifestations and may require biologic therapy. Infliximab and adalimumab are approved for induction and maintenance in pediatric IBD patients but are licensed only above the age of 6 years. Effectiveness and safety data on adalimumab in this patient population are lacking. We assessed the therapeutic response to help close this gap., Methods: This retrospective study involved 30 sites worldwide. Demographic, clinical, and laboratory data were collected from patients with VEO-IBD who commenced adalimumab therapy before the age of 6 years., Results: Seventy-eight patients (37 Crohn's disease, 26 ulcerative colitis, and 15 with IBD-unclassified) were included. Median age of IBD onset was 2.6 (1.3-4.1) years, with 30 (38.5%) patients diagnosed at age <2 years. Median age at adalimumab initiation was 4.2 (2.8-5.1) years. Adalimumab was used as second-line biologic therapy in 45 (57.7%) patients after infliximab. The median time to last follow-up was 63 (22-124) weeks. Significant improvement in clinical scores, CRP, fecal calprotectin, and weight Z-score were observed by Week 52. Adalimumab durability rates were 61.9%, 48.1%, and 35.6% after 1, 2, and 3 years, respectively. Drug discontinuation rates were not dependent on IBD type, age, prior anti-TNF exposure, or concomitant immunomodulatory treatment. Four (5.1%) patients developed serious infections, including 1 patient with TTC7A deficiency who died following adenovirus sepsis., Conclusion: Adalimumab therapy is a viable therapeutic option in patients with VEO-IBD with an acceptable safety profile., (© The Author(s) 2025. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. 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.)

Objectives: The PRASCO trial reported the short-term superiority of an antibiotic cocktail plus intravenous corticosteroids (IVCS) over IVCS alone in children with acute severe colitis (ASC). Here, we report the extension of the PRASCO trial and the long-term outcomes of the antibiotic cocktail in ASC., Methods: This prospective follow-up of the PRASCO trial documented disease outcomes and treatments annually through 5 years. The primary outcome was colectomy, and the secondary outcome was escalation to biologics, analyzed descriptively., Results: A total of 26 children were included (12 receiving IVCS and 14 receiving IVCS + antibiotics), 19% of whom underwent colectomy during the follow-up period. The estimated probability of colectomy at 3, 6, and 12 months from admission were 7.1%, 7.1%, and 21% with IVCS + antibiotics and 0%, 8.3%, and 17% with IVCS. No children required colectomy after the first year of follow-up. The estimated probability of escalating to biologics were 66%, 77%, and 77% after 1, 2, and 3 years with IVCS + antibiotics and 42%, 51%, and 76% with IVCS. Clinical remission was higher in the IVCS + antibiotics group at each timepoint (e.g., 30% vs. 11% at 5-years). Delta of Pediatric Ulcerative Colitis Activity Index (PUCAI) score from baseline to day three of admission predicted future escalation to biologics (area under curves (AUC) 0.84 [95%CI 0.59-1.0])., Conclusion: While adding antibiotics to IVCS may provide better short-term outcomes, the long-term benefits were comparable to IVCS alone. At 5 years, about one-fifth of children had undergone colectomy, and almost four-fifths had escalated to biologics, particularly during the first year after admission., (© 2024 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

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: To advance personalized medicine in pediatric Crohn's disease (CD), we aimed to explore the utility of serological biomarkers in predicting response to anti-tumor necrosis factor (TNF)., Methods: Children with CD were enrolled at initiation of anti-TNF and followed prospectively at 4 and 12 months thereafter, as well as at last follow-up. At baseline, 10 serological markers of the "PROMETHEUS® IBD sgi Diagnostic test" were measured, including pANCA, ASCA IgG and IgA, anti-CBir1, anti-OmpC, anti-A4-Fla2, anti-Fla-X, SAA, ICAM-1 and VCAM-1. The primary outcome was sustained steroid-free remission (SSFR, i.e. clinical remission without steroids at both 4 and 12 months) and the secondary outcome was primary non-response (PNR)., Results: Of the 72 included children (mean age, 12.8 ± 3.1 years; median disease duration, 6.4 months [IQR 2.5-17.3]), 42 (58%) were treated with adalimumab and 30 (42%) with infliximab. PNR was noted in 20 (28%) children and failure to achieve SSFR in 36 (50%). The most common positive serological markers were SAA (86%) and ICAM-1 (82%). In univariate analyses, none of the serological markers achieved statistical significance in association with SSFR or with PNR. In multivariable analysis, positivity of ASCA IgG (OR 3.3 [95%CI 0.8-14.4]) and pANCA (OR 5.3 [95%CI 0.9-48]) were the closest to achieving significance in predicting SSFR, with fair predictive performance for the model (AUC 0.67 [95%CI 0.55-0.80])., Conclusion: The serological markers tested here have limited utility in predicting response to anti-TNF treatment. Further studies with larger sample sizes are needed to confirm the utility of ASCA IgG and pANCA., Competing Interests: Declarations. Competing interests: Competing interest declaration: YLG – None GF – None EOM – None DY – None RLT – None OL – None AA – None VMNL – None RNB – None AO – None DS – None AMG – None DT – For the past three years, has received consultation fees, research grants, royalties, or honorariaum from Janssen, Pfizer, Hospital for Sick Children (Canada), Ferring, AbbVie, Takeda, Atlantic Health System, Shire, Celgene, Lilly, Roche, ThermoFisher, BMS OA – none. Ethical approval: This study was approved by the local ethics committee of the participating medical centers and all participants signed informed consent., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The Nancy Histological Index (NHI) is used to score histologic disease activity in patients with ulcerative colitis (UC). Our goal was to assess the utility of NHI at diagnosis in predicting clinical outcomes in pediatric patients with UC, in comparison to clinical and endoscopic scores. We retrospectively reviewed data at diagnosis of 106 children with UC (59 [55.7%] females; median age 14.4 [11.2-15.9] years, median Pediatric Ulcerative Colitis Activity Index [PUCAI] 35 [25-55]). During a follow-up of 116 (55-171) weeks, 33 patients (31.1%) required azathioprine therapy, and 32 (30.2%) were escalated to anti-tumor necrosis factor alpha (anti-TNFa). The PUCAI and Mayo endoscopic scores at diagnosis were significantly associated with escalation to anti-TNFa (p = 0.036 and p = 0.02, respectively), but not with initiation of azathioprine or subsequent acute severe colitis (ASC) events. However, the NHI was not associated with subsequent immunomodulators or anti-TNFa therapy (p = 0.42 and p = 0.78, respectively), nor with future ASC events (p = 0.70). In conclusion, the NHI failed to predict clinical outcomes in newly diagnosed pediatric patients with UC., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Multiple studies in patients with Crohn's disease (CD) treated with anti-tumor necrosis factor alpha agents have shown that proactive therapeutic drug monitoring (TDM) during the maintenance phase leads to improved outcomes. We aimed to assess whether accelerated (IFX) administration during induction resulted in improved outcomes., Methods: This retrospective study included CD patients aged 5-17.9 years that were treated with IFX. We compared outcomes of patients treated during induction with 5-8 mg/kg dosing at Weeks 0, 2, 6, and 14 (Group 1), versus accelerated dosing (≥8 mg/kg and/or >4 infusions until Week 14, Group 2) of IFX. Primary outcome was steroid-free clinical remission by Week 52., Results: Sixty-eight patients were included, of whom seven discontinued IFX before Week 14, due to infusion reactions, immunogenic failure, or primary nonresponse. Comparison of Group 1 (n = 25) and Group 2 (n = 36) showed similar clinical characteristics, as well as inflammatory markers, at IFX initiation. Despite receiving significantly more IFX, and reaching a higher trough level by Week 14 (10.3 ± 1.2 vs. 3.3 ± 0.7, p < 0.001), the median Pediatric Crohn's disease Activity Index (PCDAI) was slightly higher in Group 2 versus Group 1 (14 [5-20] vs. 5 [0-15], p = 0.02). However, at Weeks 26 and 52 the PCDAI and inflammatory markers were comparable between the groups. Moreover, about 70% in both groups achieved the desirable trough IFX levels by Week 52., Conclusion: Accelerated IFX dosing during induction did not result in improved outcomes up to 12 months follow-up. Prospective studies are required to determine the exact timing in which proactive TDM should be applied., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Autoimmune gastritis (AIG) is a rare chronic inflammatory disorder with potential long-term sequelae including gastric neoplasia. There is limited data on the natural history of pediatric AIG. We aimed to characterize the clinical course and outcomes of children with AIG., Methods: This was a multicenter retrospective study that included pediatric patients diagnosed with AIG between January 1, 2000 and December 31, 2021. Diagnosis of AIG was based on the demonstration of histological corpus-predominant atrophic gastritis, with or without positive antiparietal cell (APCA) or anti-intrinsic factor (IF) antibodies. Demographic, clinical, laboratory, endoscopic, and histologic data were retrieved, along with follow-up data., Results: Thirty-three patients, (23 females [69.7%], median age 12.0 [interquartile range 7.0-15.0] years at diagnosis) were identified. Twenty-two patients (66.7%) had positive APCA and/or anti-IF serology. The most common presenting manifestation was iron deficiency anemia (75%), and accompanying autoimmune disorders were significantly more common in patients with positive serology (62% vs. 18%, p < 0.05). Pseudo-pyloric or intestinal-type metaplasia was present at diagnosis in eight patients (24%), and 11 additional patients (33%) developed metaplasia during a median follow-up time of 27 (17.5-48.3) months. One patient developed a type 1 gastric neuroendocrine tumor. Helicobacter pylori was identified in only one patient, while two patients had prior eradication. Endoscopic and histologic improvements weren't identified in any patients., Conclusions: AIG should be considered in patients with autoimmunity and resistant iron-deficiency anemia. H. pylori infection may not be associated with pediatric AIG. The development of neuroendocrine tumor in one patient, and the high rates of metaplasia, highlight the importance of surveillance., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Ustekinumab is an effective therapy for adult Crohn's disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn's Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7-17.2) with a median follow-up of 7.4 months (IQR 5.6-11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25-57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause.    Conclusion: Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: • Ustekinumab is an effective therapy for adult moderate to severe Crohn's disease (CD). • Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: • Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. • Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: This study described disease characteristics and long-term outcomes in patients diagnosed with very early onset inflammatory bowel disease (VEOIBD) (diagnosed before 6 years of age) and infantile-IBD (before 2 years)., Methods: Cases from 21 centers worldwide diagnosed with VEOIBD (2008-2018), with minimum 2 years of follow-up, were retrospectively reviewed., Results: The cohort included 243 patients (52% males, median follow-up of 5.8 [range 2-18] years, including 69 [28%]) with infantile-IBD. IBD subtypes included Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU) in 30%, 59%, and 11%, respectively. Among patients with CD, 94% had colonic involvement, and among patients with UC/IBDU, 75% had pancolitis. Patients with infantile-IBD presented with higher rates of IBDU, lower hemoglobin and albumin levels, and higher C-reactive protein, and had lower response rates to first-induction therapy and corticosteroids therapy (P < .05 for all). Colectomy and diversion surgeries were performed in 11% and 4%, respectively, with no significant differences between age groups. Corticosteroid-free remission rates were 74% and 78% after 3 and 5 years, respectively, and 86% at end of follow-up. Genetic testing was performed in 96 (40%) patients. Among tested population, 15 (16%) were identified with monogenic disease. This group demonstrated lower response rates to induction therapies, higher rates of surgical intervention, and higher rates of major infections (P < .05 for all)., Conclusions: Patients with VEOIBD, including infantile-IBD, exhibit low rate of complications and surgical interventions at the long term. Patients with monogenic IBD are at risk for more severe disease course., (Copyright © 2024 by the American Academy of Pediatrics.)

The mouse small intestine shows profound variability in gene expression along the crypt-villus axis 1,2 . Whether similar spatial heterogeneity exists in the adult human gut remains unclear. Here we use spatial transcriptomics, spatial proteomics and single-molecule fluorescence in situ hybridization to reconstruct a comprehensive spatial expression atlas of the adult human proximal small intestine. We describe zonated expression and cell type representation for epithelial, mesenchymal and immune cell types. We find that migrating enterocytes switch from lipid droplet assembly and iron uptake at the villus bottom to chylomicron biosynthesis and iron release at the tip. Villus tip cells are pro-immunogenic, recruiting γδ T cells and macrophages to the tip, in contrast to their immunosuppressive roles in mouse. We also show that the human small intestine contains abundant serrated and branched villi that are enriched at the tops of circular folds. Our study presents a detailed resource for understanding the biology of the adult human small intestine., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Aim: Although sexual health (SH) impairment and sexually transmitted infections (STI) are occasionally encountered in patients with inflammatory bowel disease (IBD), paediatric gastroenterologists (PedGI) do not often discuss these issues. Literature about SH in the paediatric IBD population is limited. We aimed to assess PedGI knowledge and common practice related to sexual advice and STI workups in patients with IBD., Methods: A questionnaire comprising 25 questions addressing sexual activity in youth, SH, recommendations, and workup for STI in adolescents with IBD was sent to all registered PedGI in Israel., Results: Fifty-two physicians completed the questionnaire (27 males,52%). Only 50% correctly predicted the mean age that Israeli youth start practicing sex. Seventy-five per cent responded that providers should discuss sexual activity with their patients, but only 19% do so, most often in response to a patient's query. Ninety six percent answered that they do not have enough knowledge about SH in IBD. Finally, only 2% obtain rectal swabs for STI in patients with refractory proctitis., Conclusion: Sexual issues and recommendations are not routinely discussed by the majority of PedGI in paediatric IBD clinics. Providers should obtain more knowledge in the field and initiate discussion of these issues with adolescent patients with IBD., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background and Aims: Inflammatory Bowel Diseases (IBD) and Familial Mediterranean Fever (FMF) are auto-inflammatory diseases with common clinical and biological features. We aimed to determine their association and characterize the natural history in patients with both diagnoses., Methods: Utilizing data from the epi-IIRN cohort, which includes 98% of Israel's population, we calculated the adjusted prevalence of FMF among IBD patients vs non-IBD controls. Case ascertainment of IBD was determined according to validated algorithms and for FMF by ICD-9 codes and colchicine purchase., Results: In total, 34 375 IBD patients (56% Crohn's disease [CD] and 44% ulcerative colitis [UC]) were compared with 93 602 matched controls. Among IBD patients, 157 (0.5%) had FMF compared with 160 (0.2%) of non-IBD controls (OR = 2.68 [95%CI 2.2-3.3]; p< 0.001). Pediatric-onset IBD had a higher prevalence of FMF compared with adult-onset IBD (30/5,243 [0.6%] vs 127/29 132 [0.4%]), without statistical significanse (OR = 1.31 [0.88-1.96]; p= 0.2). FMF was more prevalent in CD (114/19 264 [0.6%]) than UC (43/15 111 [0.3%]; OR = 2.1 [1.5-3.0]), p< 0.001). FMF diagnosis preceded that of IBD in 130/157 cases (83%). FMF was associated with a more severe disease activity in UC patients at diagnosis, but not in CD patients. Outcomes were comparable between patients with CD+FMF vs CD alone; however in patients with UC+FMF, time to biologic treatment was shorter., Conclusion: FMF is more prevalent in IBD patients than in the general population, particularly in CD. The diagnosis of FMF precedes the diagnosis of IBD in most cases, and may be associated with a more severe course in UC., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Patients with active ulcerative colitis (UC) display a misalignment of the circadian clock, which plays a vital role in various immune functions. Our aim was to characterize the expression of clock and inflammation genes, and their mutual regulatory genes in treatment-naïve pediatric patients with UC. Using the Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) platform and R algorithms, we analyzed rectal biopsy transcriptomic data from two cohorts (206 patients with UC vs. 20 healthy controls from the GSE-109142 study, and 43 patients with UC vs. 55 healthy controls from the GSE-117993 study). We compared gene expression levels and correlation of clock genes ( BMAL1 , CLOCK , PER1 , PER2 , CRY1 , CRY2 ), inflammatory genes ( IκB , IL10 , NFκB1 , NFκB2 , IL6 , TNFα ) and their mutual regulatory genes ( RORα , RORγ , REV-ERBα , PGC1α , PPARα , PPARγ , AMPK , SIRT1 ) in patients with active UC and healthy controls. The clock genes BMAL1 , CLOCK , PER1 and CRY1 and the inflammatory genes IκB , IL10 , NFκB1 , NFκB2 , IL6 and TNFα were significantly upregulated in patients with active UC. The genes encoding the mutual regulators RORα , RORγ , PGC1α , PPARα and PPARγ were significantly downregulated in patients with UC. A uniform pattern of gene expression was found in healthy controls compared to the highly variable expression pattern in patients with UC. Among the healthy controls, inflammatory genes were positively correlated with clock genes and they all showed reduced expression. The difference in gene expression levels was associated with disease severity and endoscopic score but not with histological score. In patients with active UC, clock gene disruption is associated with abnormal mucosal immune response. Disrupted expression of genes encoding clock, inflammation and their mutual regulators together may play a role in active UC.

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.)

Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis 1 . Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta 2 . Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency 3,4 , and in patients diagnosed with coeliac disease 5-7 . However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Owing to advances in genomics that enable differentiation of molecular aetiologies, patients with monogenic inflammatory bowel disease (mIBD) potentially have access to genotype-guided precision medicine. In this Expert Recommendation, we review the therapeutic research landscape of mIBD, the reported response to therapies, the medication-related risks and systematic bias in reporting. The mIBD field is characterized by the absence of randomized controlled trials and is dominated by retrospective observational data based on case series and case reports. More than 25 off-label therapeutics (including small-molecule inhibitors and biologics) as well as cellular therapies (including haematopoietic stem cell transplantation and gene therapy) have been reported. Heterogeneous reporting of outcomes impedes the generation of robust therapeutic evidence as the basis for clinical decision making in mIBD. We discuss therapeutic goals in mIBD and recommend standardized reporting (mIBD REPORT (monogenic Inflammatory Bowel Disease Report Extended Phenotype and Outcome of Treatments) standards) to stratify patients according to a genetic diagnosis and phenotype, to assess treatment effects and to record safety signals. Implementation of these pragmatic standards should help clinicians to assess the therapy responses of individual patients in clinical practice and improve comparability between observational retrospective studies and controlled prospective trials, supporting future meta-analysis., (© 2023. Springer Nature Limited.)

Objectives: Infliximab is considered superior to adalimumab in patients with ulcerative colitis, especially in severe cases. Whether this is true for Crohn disease (CD) patients with colonic involvement is unclear. Our aim was to compare the clinical effectiveness of infliximab versus adalimumab in pediatric ileocolonic (L3) CD., Methods: This retrospective study included patients <18 years with ileocolonic CD treated with infliximab or adalimumab between 2014 and 2021. Primary outcome was steroid-free clinical remission by week 52. Secondary outcomes were treatment modifications, drug discontinuation, inflammatory bowel disease (IBD)-associated hospitalizations, and surgery during the first year of treatment., Results: We identified 74 patients treated with adalimumab and 41 with infliximab, with comparable demographic features. Concomitant immunomodulator therapy at biologic initiation was significantly lower in the adalimumab group (28% vs 85%, P < 0.001). Rates of drug intensification were higher in the infliximab group at end of induction (EOI) and at 52 weeks (55% vs 32% and 88% vs 46%, P < 0.001). Given significant differences between initial median Pediatric Crohn Disease Activity Index scores (20.0 [interquartile range, IQR 15.0-27.5] vs 11.0 [IQR 7.5-20.0] for infliximab and adalimumab groups, respectively, P < 0.001), propensity score matching was performed. Following matching, the rate of patients in steroid-free clinical remission by EOI was significantly higher in the adalimumab group (93.8% vs 46.9%, P < 0.001), but comparable by 1 year. Moreover, inflammatory markers and fecal calprotectin values were also similar at these time points. Rates of drug discontinuation, IBD-associated admissions, and surgery were similar between groups., Conclusions: In a retrospective study of patients with ileocolonic CD, adalimumab and infliximab had comparable outcomes by 52 weeks., 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 & Aims: In this nationwide study from the Israeli Inflammatory Bowel Disease Research Nucleus, we aimed to describe the incidence of very early onset inflammatory bowel diseases (VEOIBDs) with a focus on infantile-onset disease and to compare management and disease course with older children., Methods: Data were retrieved from the 4 Israeli Health Maintenance Organizations covering 98% of the population. Pediatric-onset IBD was categorized as follows: adolescent onset (10 to <18 y), early onset (6 to <10 y), VEOIBD (0 to <6 y), toddler onset (2 to <6 y), and infantile onset (<2 y)., Results: A total of 5243 children with 35,469 person-years of follow-up evaluation, were diagnosed with IBD during 2005 to 2020: 4444 (85%) with adolescent onset, 548 (10%) with early onset, and 251 (4.8%) with VEOIBD, of whom 81 (1.5%) had infantile onset. The incidence of pediatric-onset IBD increased from 10.8 per 100,000 in 2005 to 15.3 per 100,000 in 2019 (average annual percentage change, 2.8%; 95% CI, 2.2%-3.4%), but that of VEOIBD remained stable (average annual percentage change, 0%; 95% CI, -2.5% to 2.6%). The infantile-onset and toddler-onset groups were treated less often with biologics (36% and 35%, respectively) vs the early onset (57%) and adolescent-onset groups (53%; P < .001). The time to steroid dependency was shorter in infantile-onset (hazard ratio [HR], 2.1; 95% CI, 1.5-2.9) and toddler-onset disease (HR, 1.6; 95% CI, 1.2-2.0) vs early onset and adolescent-onset disease, but time to hospitalizations, time to surgery, and growth delay were worse only in infantile-onset disease. In a multivariable model, infantile-onset patients had a higher risk for surgery (HR, 1.4; 95% CI, 1.1-1.9) and hospitalization (HR, 1.7; 95% CI, 1.2-2.4) than the toddler-onset group., Conclusions: The incidence of VEOIBD remained stable. Infantile-onset IBD had worse outcomes than older children, while toddler onset had mostly similar outcomes, despite less frequent use of biologics., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Several studies have proposed models to predict disease outcomes in paediatric ulcerative colitis (UC), notably PROTECT, Schechter and PIBD-ahead, but none has been validated by external cohorts AIM: To explore these models in a prospective multicentre inception cohort METHODS: Children newly diagnosed with UC in 17 centres were followed at disease onset and 3 and 12 months thereafter, as well as at last visit. Outcomes included steroid-free remission (SFR) and acute severe colitis (ASC)., Results: Of the 223 included children, 74 (34%), 97 (43%) and 52 (23%) presented with mild, moderate and severe disease, respectively. SFR rate was 35% at 3 months and 47% at 12 months (62% of those with mild disease at diagnosis vs. 41% in moderate-severe disease; p = 0.01). Thirty-six (16%) children developed ASC during the first month after diagnosis, and 53 (24%) during the first year. The AUC of the PROTECT model for predicting SFR at 3 and 12 months was 0.78 [95% CI 0.65-0.92] and 0.57 [95% CI 0.47-0.66], respectively. The sensitivity/specificity/PPV/NPV of Schechter's criteria to predict sustained SFR at 12 months was 50%/60%/35%/74%. ASC was predicted only by the PUCAI score at diagnosis and at 3 months., Conclusions: The PROTECT model had a good predictive utility for SFR at 3 months, but not at 12 months. The other predictive models did not achieve sufficient accuracy, which was far from that reported in the original studies. This highlights the necessity for external validation of any prediction model prior to its implementation into clinical practice., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

The notion that psychological stress can deteriorate our health is widely accepted. However, the mechanisms at play are poorly understood. In this issue of Cell, Schneider et al. identify the impact of glucocorticoids on enteric glia and neurons and elucidate the underlying mechanisms that link psychological stress to the exacerbation of gut inflammation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The Nancy Histological Index (NHI) was developed to assess histological disease activity in adult ulcerative colitis (UC) patients. However, data in pediatrics is limited. Our aim was to determine whether the NHI correlates with different indices of disease activity in pediatric UC patients. We retrospectively reviewed the NHI in rectal biopsies from 61 pediatric UC patients (median age 14.3 years), of whom 34 (55.7%) were newly diagnosed. The median Pediatric Ulcerative Colitis Activity Index (PUCAI) score among participants was 30 (interquartile range 5-55). Most patients exhibited an NHI of 3 (41/61, 67.2%) or 4 (8/61, 13.1%), reflecting moderate-severe histologic inflammation. A moderate positive correlation was identified between the NHI and PUCAI, fecal calprotectin, and Mayo endoscopic scores ( r = 0.60, 0.54, and 0.56 respectively, P ≤ 0.001), but not with CRP or albumin. These results indicate that the NHI has a modest correlation with clinical, laboratory and endoscopic indices of disease activity in pediatric UC patients., 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.)

Objective and Aim: Infantile-onset inflammatory bowel disease (IO-IBD), defined as IBD diagnosed at age 2 years or younger, tends to be more severe and refractory to conventional treatment than IBD diagnosed at a later age. However, data about IO-IBD and its long-term follow up are limited. We thus aimed to evaluate the presentation and long-term outcomes of patients with IO-IBD in a retrospective multicenter study., Methods: Medical records of patients diagnosed with IO-IBD in eight medical centers during 2000-2017 with at least 1-year follow up were reviewed. Demographics and disease characteristics at diagnosis including age of onset, disease phenotype and location, surgeries, medical therapy, and comorbid conditions were recorded., Results: Twenty-three patients with IO-IBD (16 males, 70%) were identified and followed for a median (range) of 51.2 (26.0-110.3) months. The mean ages at presentation and at the last follow up were 14 ± 9.8 and 101 ± 77 months, respectively. Six (26%) patients needed ileostomy already at the time of diagnosis and 20 (87%) were treated with corticosteroids. During long-term follow up, remission was achieved in 16 (73%) patients; of whom, 3 (14%) were without medications and 7 (32%) were in remission with the use of 5-aminosalicylic acid only. One patient needed hemicolectomy and one developed a severe EBV related infection., Conclusion: The majority of patients with IO-IBD achieved long-term remission, despite a severe disease presentation at diagnosis. Surgery rate however is high, mainly during the first months from diagnosis., Competing Interests: The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JO declared a shared consortium [Very Early Onset Inflammatory Bowel Disease Consortium] with the author DS to the handling editor., (© 2023 Krauthammer, Weintraub, Shaoul, Lev-Tzion, Broide, Wilschanski, Lerner, Yerushalmi, Shouval, Shamaly, Haberman-Ziv and Weiss.)

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28., (© 2022 Lévy et al.)

Background: Ileo-colic resection (ICR) is an important therapeutic option for Crohn's disease (CD) patients. There are limited updated data of clinical and endoscopic post-operative recurrence (POR) in pediatric patients with CD for the long run. We aimed to determine recurrence rates following ICR over an extended period of time and asses its risk factors., Methods: This is a single-center retrospective review of 35 patients with CD between the ages of 6 and 17.9 years who required ICR between 2003 and 2021 at Schneider Children Medical Center of Israel. Medical charts were reviewed at different time-points post-ICR., Results: Clinical recurrence following ICR was demonstrated in only 11.4% and 28.6% (n = 4, n = 10) in the first two and five years-much lower rates than what was reported so far. We found no specific risk factor that correlated with clinical recurrence, although patients that were treated with early prophylaxis of anti-TNF medications following ICR tend to have less recurrence., Conclusions: We found lower POR following ICR, especially in the first years after surgery-which can be attributed to close surveillance and early medical treatment. Such surveillance seems to improve recurrence rates in the first years following ICR., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Crohn's disease (CD) is a chronic relapsing-remitting inflammatory disorder of the gastrointestinal tract that is characterized by altered innate and adaptive immune function. Although massively parallel sequencing studies of the T cell receptor repertoire identified oligoclonal expansion of unique clones, much less is known about the B cell receptor (BCR) repertoire in CD. Here, we present a novel BCR repertoire sequencing data set from ileal biopsies from pediatric patients with CD and controls, and identify CD-specific somatic hypermutation (SHM) patterns, revealed by a machine learning (ML) algorithm trained on BCR repertoire sequences. Moreover, ML classification of a different data set from blood samples of adults with CD versus controls identified that V gene usage, clusters, or mutation frequencies yielded excellent results in classifying the disease (F1 > 90%). In summary, we show that an ML algorithm enables the classification of CD based on unique BCR repertoire features with high accuracy., (© 2023 Safra et al.; Published by Cold Spring Harbor Laboratory Press.)

Purpose: Receptor-interacting serine/threonine-protein kinase 1 ( RIPK1) is an important regulator of necroptosis and inflammatory responses. We present the clinical features, genetic analysis and immune work-up of two patients with infantile-onset inflammatory bowel disease (IBD) resulting from RIPK1  mutations., Methods: Whole exome and Sanger sequencing was performed in two IBD patients. Mass cytometry time of flight (CyTOF) was conducted for in-depth immunophenotyping on one of the patient's peripheral blood mononuclear cells, and compared to control subjects and patients with Crohn's disease., Results: The patients presented with severe colitis and perianal fistulas in the first months of life, without severe/atypical infections. Genetic studies identified pathogenic genetic variants in RIPK1 (Patient 1, A c.1934C>T missense mutation in Exon 11; Patient 2, c.580G>A missense mutation residing in Exon 4). Protein modeling demonstrated that the mutation in Patient 1 displaces a water molecule, potentially disrupting the local environment, and the mutation in Patient 2 may lead to disruption of the packing and conformation of the kinase domain. Immunofluorescence RIPK1 staining in rectal biopsies demonstrated no expression for Patient 1 and minimal expression for Patient 2, compared to controls and patients with active Crohn's disease. Using CyTOF unbiased clustering analysis, we identified peripheral immune dysregulation in one of these patients, characterized by an increase in IFNγ CD8 +  T cells along with a decrease in monocytes, dendritic cells and B cells. Moreover, RIPK1-deficient patient's immune cells exhibited decreased IL-6 production in response to lipopolysaccharide (LPS) across multiple cell types including T cells, B cells and innate immune cells., Conclusions: Mutations in  RIPK1  should be considered in very young patients presenting with colitis and perianal fistulas. Given RIPK1's role in inflammasome activation, but also in epithelial cells, it is unclear whether IL1 blockade or allogeneic hematopoietic stem cell transplantation can suppress or cure the hyper-inflammatory response in these patients. Additional studies in humans are required to better define the role of RIPK1 in regulating intestinal immune responses, and how treatment can be optimized for patients with RIPK1 deficiency., Competing Interests: DS declares speaker’s fees from Abbvie and research grant from Takeda. SS declares the following interests: Scientific advisory board participation for Pfizer, Pandion, Celgene, Lilly, Takeda, Cosmo Pharmaceuticals, Merck, Sonoma Biotherapeutics, and EcoR1. Grant support Pfizer, Amgen Takeda, and Novartis. Consulting for Amgen, Kyverna, Bristol Myers Squibb, Third Rock, 89bio, GentiBio and Apple Tree Life Sciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sultan, Adawi, Kol, McCourt, Adawi, Baram, Tal, Werner, Lev, Snapper, Barel, Konnikova, Somech and Shouval.)

Objectives: Infants with non-IgE-mediated food allergies are often referred to gastroenterologists or immunologists. We hypothesized that there are practice variations between these disciplines in the diagnosis and management of such infants., Methods: A computerized questionnaire was distributed between pediatric gastroenterologists and immunologists. The questions addressed diagnosis, management, and follow-up in 3 scenarios of infants with concern for food protein-induced allergic proctocolitis (FPIAP) due to non-IgE-mediated responses to cow's milk., Results: Three cases of infants with suspected FPIAP were presented: milk-based formula-fed (case 1) or breast-fed (case 2) infants that are well appearing and thriving, and a breast-fed infant who is not growing appropriately along with a personal and family history of atopy (case 3). Fifty-eight pediatric gastroenterologists and 32 immunologists completed the questionnaire. Significant differences between gastroenterologists and immunologists were noted regarding the recommended dietary changes in these scenarios. Moreover, despite available guidelines generated by both societies, most physicians confirm the diagnosis based on resolution of symptoms after the dietary change, without re-exposure to the the suspected trigger. In addition, time for recommended re-exposure in infants with FPIAP was also different; most gastroenterologists recommended waiting until 12 months of age, while immunologists suggested reintroduction earlier, up to 6 months of age., Conclusions: We identified significant practice variations in diagnosis and management of FPIAP between pediatric gastroenterologists and immunologists, with lack of adherence to society guidelines. Joint task forces of primary care pediatricians, gastroenterologists, and immunologists should provide uniform guidelines to standardize care., Competing Interests: The 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.)

ADAM17, encoding ADAM metallopeptidase domain 17, is a membrane-bound shedding protease, which plays an essential role during normal development and in the regulation of inflammation. Biallelic variants in ADAM17, resulting in complete loss of ADAM17 expression, have been reported in individuals affected by rare neonatal inflammatory skin and bowel disease 1 (NISBD1). Here, we report on a young female individual with NISBD1 featuring erythroderma, atrichia, nail dystrophy, oesophageal strictures, intractable diarrhoea, profound failure to thrive and recurrent cutaneous and systemic infections. In this case, NISBD1 was found to result from a complex compound heterozygous defect consisting of a large genomic deletion spanning exons 6 and 7 in addition to a splice site variant causing exon 17 skipping. Skin manifestations dramatically improved in response to combined anti-tumour necrosis factor-α and interleukin-12/23 blockade, while gastrointestinal symptoms were controlled with budesonide. Our study further expands the phenotypic and genetic spectrum of NISBD1 and suggests that combined immunosuppressive treatments may be indicated in this complex condition. What is already known about this topic? Biallelic loss-of-function variants in ADAM17, encoding ADAM metallopeptidase domain 17, have to date been reported in only four families with neonatal inflammatory skin and bowel disease 1 (NISBD1). NISBD1 features variable disease phenotypes associated with different degrees of severity. What does this study add? We report a case of a patient with NISBD1 caused by a unique genetic defect consisting of a combination of a splice site variant leading to exon 17 skipping and a large deletion spanning exons 6-7 of the ADAM17 gene. The severe cutaneous phenotype in our patient responded to a combination of ustekinumab and certolizumab., (© 2022 British Association of Dermatologists.)

Avoidance of fasting and regular ingestion of uncooked-cornstarch have long been the mainstay dietary treatment of Glycogen Storage Disease type Ia (GSD-Ia). However, GSD-Ia patients who despite optimal dietary treatment show poor glycemic control and are intolerant to cornstarch, present a complex clinical challenge. We pursued Whole Exome Sequencing (WES) in three such unrelated patients, to both confirm a molecular diagnosis of GSD-Ia, and seek additional variants in other genes (e.g. genes associated with amylase production) which may explain their persistent symptoms. WES confirmed the GSD-Ia diagnosis, with all three probands harboring the homozygous p.R83C variant in G6PC. While no other significant variants were identified for patients A and B, a homozygous p.G276V variant in the SI gene was detected in patient C, establishing the dual-diagnosis of GSD-Ia and Sucrase-Isomaltase Deficiency. To conclude, we suggest that WES should be considered in GSD-Ia patients who show persistent symptoms despite optimal dietary management., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background/objectives: The current treatment goal for inflammatory bowel disease (IBD) is achievement of mucosal healing (MH). While established with biologic or azathioprine (AZA) therapies, the data on MH with methotrexate (MTX( treatment is scarce. We aimed to compare MH rate as reflected by FC in children with Crohn's disease (CD) treated with either MTX or thiopurines monotherapy., Methods: A cross-sectional multicenter study including children with CD (<18 years), with documented mucosal ulcerations/erosions on their first endoscopy, who were in clinical and biochemical remission for at least 6 months on MTX or AZA/6-MP monotherapy and had fecal calprotectin (FC) measurements during remission. Clinical remission was defined as PCDAI<10 and normal C-reactive-protein (CRP) level. FC < 100 μg/gr was used as a marker of MH. Demographic, clinical and laboratory data were retrieved from the medical charts., Results: 64 patients (41 males, age 16.6±4.2 years) were included; 36 with MTX, 26 with AZA and 2 with 6-MP treatment. The mean treatment dose was 14.0±1.8 mg/m2 for MTX, and 1.8±0.66 mg/kg for AZA, and mean therapy duration was 22 ±17.1 months. MH (FC < 100 μg/gr) was demonstrated in 14/36 (39%) and 18/28 (64%) of patients on MTX and AZA/6-MP therapy, respectively (p=0.04). Rates of FC < 300 μg/gr were comparable [27/36 (75%) MTX, 24/28 (86%) AZA/6-MP, p=0.29]. MH was associated with longer treatment duration (p=0.03)., Conclusions: MH as reflected by FC < 100 μg/gr, was higher with AZA/6-MP compared to MTX treatment in pediatric CD.

Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Background & Aims: Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut homeostasis., Methods: To build a taxonomy model, we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by (1) overlapping syndromic features, (2) response to hematopoietic stem cell transplantation, (3) bulk RNA-sequencing of 32 tissues, (4) single-cell RNA-sequencing of >50 cell subsets from the intestine of healthy individuals and patients with IBD (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4)., Results: Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8 + T cells, neutrophils, epithelial subsets, and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mammalian target of rapamycin activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD., Conclusion: Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses., (Copyright © 2022 AGA Institute. All rights reserved.)

Objectives: Adult studies suggest that patients with isolated colonic Crohn disease (L2 CD) exhibit unique characteristics differentiating them from patients with ileo-caecal (L1) CD and ulcerative colitis (UC). We aimed to characterize clinical features and outcomes of paediatric patients with L2., Methods: Retrospective data was collected through the Porto Inflammatory Bowel Disease group of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) on Paediatric patients with L2, L1 or UC at different time-points. Outcome measures included time to first flare, hospital admissions, initiation of anti-tumor necrosis factor-alpha (TNFα) drug, stricture and surgery., Results: Three hundred patients were included: 102 L1, 94 L2 and 104 UC. Rates of hematochezia at presentation were 14.7%, 44.7% and 95.2%, while rates of fever were 12.7%, 26.6% and 2.9%, for patients with L1, L2 and UC, respectively (P < 0.001 for all comparisons). Skip lesions were identified in 65% of patients with L2, and granulomas in 36%, similar to L1 patients. Rates of anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic (pANCA) positivity significantly differed between the three groups: 25.4% and 16.7% for patients with L2, compared with 55.2% and 2.3%, and 1.8% and 52.9% for patients with L1 and UC, respectively. Response rates to exclusive enteral nutrition were comparable between L1 and L2 (78.3-82.4%), as was the response to oral steroids (70.4-76.5%) in the three groups. While times to first flare and admission were similar between groups, patients with L1 were commenced on anti-TNFα earlier. Moreover, stricturing phenotype and need for colectomy were very rare in patients with L2., Conclusions: Significant differences are observed in the clinical presentation and outcomes of Paediatric patients with L2, compared to patients with L1 and UC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Messenger RNA-based vaccines against COVID-19 induce a robust anti-SARS-CoV-2 antibody response with potent viral neutralization activity. Antibody effector functions are determined by their constant region subclasses and by their glycosylation patterns, but their role in vaccine efficacy is unclear. Moreover, whether vaccination induces antibodies similar to those in patients with COVID-19 remains unknown. We analyze BNT162b2 vaccine-induced IgG subclass distribution and Fc glycosylation patterns and their potential to drive effector function via Fcγ receptors and complement pathways. We identify unique and dynamic pro-inflammatory Fc compositions that are distinct from those in patients with COVID-19 and convalescents. Vaccine-induced anti-Spike IgG is characterized by distinct Fab- and Fc-mediated functions between different age groups and in comparison to antibodies generated during natural viral infection. These data highlight the heterogeneity of Fc responses to SARS-CoV-2 infection and vaccination and suggest that they support long-lasting protection differently., Competing Interests: Declaration of interests R.D. serves as a consultant for Teva Pharmaceutical Industries and NucleAi and receives research grant support from Teva Pharmaceutical Industries. The other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Anti-tumor necrosis factor alpha (anti-TNFα) therapy is commonly used to treat refractory pediatric inflammatory bowel disease (IBD) and carry risks for adverse events. We aimed to assess the relationship between anti-TNFα trough concentrations and adverse events rate among pediatric patients with IBD. The medical records of pediatric patients with IBD who were treated with anti-TNFα agents from 2015 to 2020 and had sequential monitoring of trough concentration (TC) were reviewed retrospectively for the presence of adverse events. The study cohort included 135 eligible patients (59 [43.7%] girls, mean age at diagnosis 12.9 [±3] years, 111 [82.2%] Crohn disease) who had 1589 measurements of TCs (1037 [63%] infliximab). During a median follow-up period of 1.7 years (IQR 1.1-2.7), we recorded 156 adverse events in 50 patients (37%). Higher TCs were not associated with higher rate of anti-TNFα-related adverse events whereas these events (excluding increase in liver transaminases) were associated with younger age., Competing Interests: D.S.S. received for last 3 years consultation and lecturing fees from AbbVie and research support from Takeda. A.A. received for last 3 years consultation and lecturing fees from Abbvie and Takeda and research grants from Abbvie and Janssen. The remaining authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: In this quality improvement program, named quality in pediatric inflammatory bowel disease, we constructed a nation-wide platform that prospectively recorded clinically important quality indicators in pediatric inflammatory bowel diseases (PIBD), aiming at improving clinical management across the country., Methods: Representatives of all 21 PIBD facilities in Israel formed a Delphi group to select quality indicators (process and outcomes), recorded prospectively over 2 years in children with Crohn's disease 2-18 years of age seen in the outpatient clinics. Monthly anonymized reports were distributed to all centers, allowing comparison and improvement. Trends were analyzed using the Mann-Kendall test, reporting τ (tau) values., Results: The indicators of 3254 visits from 1709 patients were recorded from September 2017 to September 2019 (mean age 14.7 ± 3.1 years, median disease duration 1.8 years (interquartile range 0.69-4.02)). An increase in three of five process indicators was demonstrated: obtaining drug levels of anti-tumor necrosis factor (TNF) (τ = 0.4; P = 0.005), utilization of fecal calprotectin (τ = 0.38; P = 0.008) and bone density testing (τ = 0.45; P = 0.002). Among outcome indicators, three of nine improved as measured during the preceding year: calprotectin <300 μg/mg (τ = 0.35; P = 0.015), and "resolution of inflammation" defined as a composite of endoscopy, imaging and fecal calprotectin (τ = 0.39; P = 0.007). Endoscopic healing reached borderline significance (τ = 0.28; P = 0.055). An increase in the use of biologics throughout the study was observed (τ = 0.47; P = 0.001) with a concurrent decrease in the use of immunomodulators (τ = -0.47; P = 0.001)., Conclusions: Quality improvement nationwide programs can be implemented with limited resources while facilitating standardization of care, and may be associated with improvements in measured indicators., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Serological markers can assist in accurate differentiation between Crohn's disease (CD) and ulcerative colitis (UC). One such marker is anti-glycoprotein 2 (anti-GP2) which was shown to be a specific marker for CD in adult patients. The aim of our study was to assess the utility of anti-GP2 and GP2 as biomarkers for pediatric CD, and determine whether they correlate with disease activity., Methods: Serum samples were tested by ELISA for anti-GP2 isoform 4 IgG and IgA, and also for GP2. Results were correlated with demographic and clinical data., Results: The cohort consisted of 53 pediatric patients with CD, 42 with UC, and 53 controls. Levels of anti-GP2 were significantly increased in pediatric patients with CD in comparison with patients with UC, and control subjects, with high positive predictive value for both IgG and IgA (97.9% and 82.6%, respectively). While specificity of anti-GP2 IgG and IgA was very high (98.7% and 90.0%, respectively), sensitivity was low (42.0% and 35.5% for IgG and IgA, respectively). In CD, anti-GP2 correlated with disease activity, and decreased in treatment-naïve patients following successful induction therapy. A higher IgA anti-GP2 was also demonstrated in patients with ileo-colonic involvement, and was associated with a younger age. Finally, positive GP2 level was identified in only 1/211 serum samples., Conclusions: A positive anti-GP2 level is highly associated with CD, while a negative result does not exclude CD. Additional studies are required to determine whether these markers can be used in pediatric patients with CD for risk stratification., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Trabecular bone score (TBS) is a textural index that evaluates bone microarchitecture of the lumbar spine. Our aim was to assess TBS in children with inflammatory bowel diseases and to evaluate correlations with clinical, laboratory and densitometric variables., Methods: A retrospective study of TBS and areal bone mineral density measurements by dual-energy X-ray absorptiometry (DXA) of children with either Crohn's disease (CD) or ulcerative colitis (UC). Bone mineral apparent density was calculated for size adjustment. TBS Z-score for each child were calculated based on data from a healthy population of similar age and gender distribution. Variables significantly associated with TBS were included in stepwise linear regression models to examine independent predictors of TBS., Results: Fifty patients (age at DXA scan 13.8 ± 3.0 years, 29 males) were included. No significant differences were observed between the patients with CD and UC, in age at diagnosis, age at DXA scan and disease duration. The mean TBS of patients with CD (n = 35) was lower than of patients with UC (n = 15): 1.340 ± 0.080 vs 1.395 ± 0.092, p = 0.040. The mean TBS Z-score of patients with CD, -0.443 ± 0.788, was significantly lower than expected in healthy children (p = 0.002), while the mean TBS Z-score of patients with UC, 0.231 ± 0.685, was similar to that of healthy children (p = 0.212). In the stepwise linear regression analysis, BMI Z-score at diagnosis, phosphorus level at diagnosis and age at the time of the DXA scan were significant independent predictors of TBS (r² = 0.604; β = 0.037, 95% confidence interval (CI) for β 0.022-0.051, p < 0.001; β = 0.045, 95% CI: 0.017-0.073, p = 0.002; and β = 0.031, 95% CI: 0.005-0.021, p < 0.002, respectively)., Conclusions: TBS is significantly reduced in pediatric patients with CD but not in patients with UC. This finding likely reflects the effect of CD on bone microarchitecture., (Copyright © 2020 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)