Shlomi Cohen

Background: We aimed to assess the rates of physician-documented fatigue according to diagnostic codes among patients with inflammatory bowel diseases (IBDs) in a nationwide cohort and to identify clinical factors associated with its documentation. Methods: We used the nationwide epi- Israeli IBD Research Nucleus cohort derived from 4 HMOs covering approximately 98% of the Israeli population, matched to non-IBD controls. Physician-documented fatigue was defined using routinely collected ICD9 and textual codes and explored in association with demographic, laboratory-derived disease severity clusters, comorbidities, medications, healthcare utilization, and sickness absence. Predictors for fatigue documentation were explored using multivariable Cox models incorporating time-varying covariates. Results: Fatigue was documented in 16.4% of the 31 945 patients with IBD and 11.0% of the 73 106 matched controls (odds ratio [OR] = 1.60, 95% confidence interval [CI] 1.54-1.66). Fatigue was more prevalent in IBD than matched controls across age groups and comorbidity strata. Among patients with IBD, there was no difference in fatigue rate between those with Crohn’s disease and ulcerative colitis. Time-to-fatigue was shorter among females (P < .001). Across adult males and females and pediatric boys and girls, anemia, anxiety, and ≥3 healthcare contacts were independently associated with higher rates of fatigue documentation, with the strongest associations observed for frequent healthcare contact (HRs ranging from 4.21 [95% CI 1.49-11.70] to 10.22 [95% CI 7.47-13.90]). Longer disease duration was consistently associated with a lower hazard, while additional subgroup-specific associations were observed for sleep disorders, steroid dependency, and IBD-related medications. Conclusions: Fatigue is more frequently documented among patients with IBD than matched non-IBD controls, especially in females. Several risk factors were associated with fatigue which should be considered in clinical practice. The lower frequency of documented fatigue compared with patient-reported estimates suggests that routine clinical coding captures only part of the overall fatigue burden.

Background and aims: Data on upadacitinib maintenance therapy in pediatric Crohn’s disease (CD) are scarce. We aimed to evaluate the effectiveness, safety, and dosing of upadacitinib as maintenance therapy in pediatric CD. Methods: Children treated with upadacitinib for maintenance of remission of active CD from 35 centers affiliated with the Porto Group of ESPGHAN were included in this retrospective cohort study. Data on demographic, clinical, laboratory, endoscopic, and imaging findings and on adverse events (AEs) were recorded over 52 weeks of follow-up. Results: A total of 120 children were included (91 receiving upadacitinib as monotherapy and 29 as combination advanced therapy, mean age 15.4 ± 2.5 years). Prior to upadacitinib induction, 119/120 (99%) children had been treated with biologic therapies, 104 (87%) with two or more biologics and 98 (82%) had failed both vedolizumab and ustekinumab. Clinical remission and corticosteroid-free clinical remission (CFR) were observed after upadacitinib induction in 77 (64%) and 72 (60%) children, respectively. By week 52, 74 (62%) children achieved both clinical remission and CFR, and CFR was sustained in 66 (55%) children. CFR with normal C-reactive protein levels was achieved in 50% of children and CFR with fecal calprotectin levels <150 µg/g was achieved in 33% of children by week 52. Fifty-three (44%) children sustained AEs, two of which were serious (severe acne and intestinal perforation). The most frequent AEs were acne (n = 23), hyperlipidemia (n = 18), and infections (n = 14). Conclusion: Upadacitinib is an effective maintenance therapy for refractory pediatric CD. Effectiveness should be weighed against the potential risks of AEs.

Objective: Nutritional therapy is a cornerstone for the induction of remission in pediatric Crohn's disease (CD); however, the optimal dietary strategy remains uncertain. This study aimed to compare the short‐ and long‐term therapeutic outcomes of exclusive enteral nutrition (EEN) and the Crohn's disease exclusion diet (CDED) in a large cohort of children with CD. Methods: This historical cohort study included children diagnosed with CD between 2014 and 2023 who were treated exclusively with either EEN or the CDED for the induction of disease remission. Demographic, clinical, and laboratory data were collected over a 52‐week follow‐up period. Results: A total of 159 patients were included: 75 treated with EEN and 84 with the CDED. Baseline demographic and disease characteristics were comparable between groups. At 6 weeks, clinical remission was achieved in 58 (77%) children in the EEN group and 63 (75%) children in the CDED group ( p = 0.730). Treatment adherence rates were similarly high (EEN 89% vs. CDED 88%, p = 0.810). Week 6 normalization of C‐reactive protein (EEN 43% vs. CDED 46%, p = 0.709) and fecal calprotectin p = 0.982) were also comparable between the groups. A Mucosal Inflammation Noninvasive index score p = 0.219). There were no group differences in rates of disease exacerbation, corticosteroid or biologic therapy use, hospitalizations, or need for surgery during 52 weeks of follow‐up. Conclusions: EEN and the CDED demonstrated no significant differences in efficacy across all assessed clinical and biochemical outcomes throughout the 52‐week follow‐up period.

Summary: Routine esophageal biopsies during pediatric esophagogastroduodenoscopy (EGD) are recommended by current guidelines, even in the absence of macroscopic abnormalities; however, their clinical value remains uncertain. We conducted a retrospective review of all diagnostic EGDs performed at our institute between January 2019 and December 2021, a period during which esophageal biopsies were routinely obtained. Endoscopic findings and histologic results were analyzed to determine the diagnostic yield and clinical impact of biopsies in patients with a normal-appearing esophagus. A total of 1400 procedures were included, of which 1279 (91.3%) demonstrated a normal macroscopic esophagus. Among these, histological inflammation was identified in 73 cases (5.7%). However, only 27 cases (2.1%) were considered clinically significant. These included eosinophilic esophagitis in 7 patients (0.5%) and nonspecific esophagitis in 20 patients (1.6%), all of whom were treated with proton pump inhibitors. The remaining cases represented histological findings without clinical consequences during follow-up. To conclude, routine esophageal biopsies in children and adolescents with a normal-appearing esophagus during EGD appear to have a low diagnostic yield and limited impact on clinical management.

Aim: The aim of this study was to assess the clinical implications of upper gastrointestinal (UGI) involvement in paediatric inflammatory bowel disease (IBD). Methods: This retrospective cohort study included children diagnosed with IBD between 2010 and 2023, who underwent a UGI endoscopic evaluation at diagnosis and were followed for at least 12 months. Demographic, clinical, laboratory, endoscopic and histologic data were collected. Outcomes included clinical remission, biomarker remission, need for biologic therapy, IBD‐related hospitalizations and IBD‐related surgeries. Results: UGI involvement was observed in 210 of 310 (68%) children, with a higher prevalence in CD compared to UC (73% vs. 57%, p = 0.004). Children with UGI involvement had a significantly lower probability to achieve clinical remission (Hazard ratio [HR] = 0.76, 95% confidence interval [CI] 0.59–0.98, p = 0.035) and biomarker remission (HR = 0.60, 95% CI 0.45–0.78, p < 0.001) and were more likely to initiate biologic therapy (HR = 1.77, 95% CI 1.24–2.52, p = 0.001). Conclusion: UGI involvement is associated with a more severe course of IBD in children and characterized by lower rates of clinical and biomarker remission and a higher likelihood of initiating biologic therapy. These findings highlight the importance of early endoscopic evaluation of the UGI tract in paediatric IBD to guide monitoring and treatment strategies.

Background: Data on upadacitinib therapy for pediatric acute severe ulcerative colitis (ASC) are scarce. We aimed to evaluate the effectiveness and safety of upadacitinib as a salvage therapy in pediatric ASC. Methods: Children and adolescents with ASC who were treated with upadacitinib for the induction of remission were enrolled in this retrospective multicenter study. Demographic, clinical, and laboratory data as well as adverse events (AEs) were recorded after the 8-week induction period and throughout 26 weeks of therapy. Analyses were based on the intention-to-treat principal. Results: Twenty-two patients were included (median age 15.7 [interquartile range 13.5-16.6] years, 12 hospitalized), all with anti-tumor necrosis factor (TNF) therapy refractory disease. Ten patients were treated with corticosteroids at baseline, and upadacitinib was added to an ongoing biologic therapy in five patients. At week 8 of therapy, 11 (50%) patients of the cohort remained colectomy-free and in corticosteroid-free clinical remission (CFR), and 17 (77%) patients remained colectomy-free. Normal C-reactive protein (CRP) was achieved in 9 of 11 (82%) patients who were in CFR, and fecal calprotectin <150 mcg/g in 4 of 6 (67%) patients with available data. By week 26, 14 (64%) were in CFR and 16 (73%) patients remained colectomy-free. All these patients had normal CRP levels, and 4 of 7 patients with available data had fecal calprotectin <150 mcg/g. Twelve patients reported AEs, including two serious AEs of an appendiceal neuroendocrine tumor and cytomegalovirus colitis. Conclusion: Upadacitinib is an effective induction therapy for children and adolescents with ASC after failing anti-TNF.

Aim: The adherence to a gluten‐free diet ( GFD ) in celiac disease ( CD ) is influenced by socioeconomic factors and language barriers, which are especially relevant to minority populations. The study aimed to compare CD outcomes in children of Eritrean asylum seekers living in Israel to those of native Israeli children. Methods: This retrospective case–control study included demographic, clinical, laboratory, endoscopic, and histologic data of all Eritrean children diagnosed with CD during 2015–2023. For each Eritrean child, 5 consecutive Israeli children served as controls. Results: The study included 22 Eritrean children and 110 controls. Over a 12‐month follow‐up under a GFD , more Eritrean children maintained anti‐tissue transglutaminase ( TTG ) antibodies > 10 times above the ULN compared to controls (43% vs. 1.4%, p < 0.001). A multivariate analysis indicated a greater likelihood of achieving normalisation of anti‐ TTG antibodies in the controls (hazard ratio = 4.97, 95% confidence interval 1.17–21.13, p = 0.030). Complete compliance to a GFD was reported by 7 (50%) Eritrean children versus 69 (99%) controls ( p < 0.001). Conclusion: Eritrean asylum seekers' children with CD have a significantly slower decline in anti‐ TTG antibody levels compared to native Israeli children. Intervention to improve adherence to a GFD may positively impact CD outcomes in this population.

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.

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.