A real-life pediatric experience of Crohn's disease exclusion diet at disease onset and in refractory patients.

OBJECTIVES: We aimed to appraise the real-life efficacy of Crohn's disease exclusion diet (CDED) coupled with partial enteral nutrition (PEN) in inducing clinical and biochemical remission at disease onset and in patients with loss of response to biologics and immunomodulators. METHODS: We retrospectively gathered data of patients aged less than 18 years of age with a diagnosis of Crohn's disease (CD), who received CDED coupled with PEN at a tertiary level pediatric inflammatory bowel disease center. RESULTS: Sixty-six patients were identified. Forty (60.6%) started CDED plus PEN at disease onset and 26 (39.4%) received CDED with PEN as add-on therapy. Forty-six (69.7%) patients achieved clinical remission (weighted Pediatric Crohn's Disease Activity Index < 12.5) at the end of Phase 1, 44 (66.7%) normalized c-reactive protein levels (<0.5 mg/dL) and 18 (27.2%) patients normalized calprotectin levels (<150 microg/g). Nine of 19 (47.3%) of patients with clinically severe disease (defined by Physician Global Assessment) achieved clinical remission at the end of Phase I. Patients with extraintestinal manifestations had statistically lower clinical response rates to the dietary regimen (p = 0.018). Among patients who received CDED + PEN as add-on treatment, a previous successful course of Exclusive Enteral Nutrition was associated with statistically higher clinical remission rates at Week 8 (p = 0.026). Clinical response at Week 4 was an independent predictor of clinical remission and fecal calprotectin normalization at Week 8 (p = 0.002). CONCLUSION: CDED with PEN confirmed its efficacy in a real-life setting, proving to be effective also in refractory patients and those with severe disease. Early clinical response predicts clinical remission at the end of Phase 1.

Histological healing as a predictor of sustained clinical remission in paediatric ulcerative colitis.

BACKGROUND: The study aimed to assess the longitudinal impact of endoscopic healing (EH) and histological healing (HH) in a cohort of paediatric patients affected by ulcerative colitis (UC). METHODS: This was a retrospective single-centre longitudinal study. 86 children with UC who underwent endoscopic re-assessment while in clinical and biochemical remission were included. Partial EH was defined as a Mayo Endoscopic Subscore (MES) of 1 and complete EH was defined as a MES of 0. HH was defined as the absence of active inflammation in all biopsies. The cumulative incidence of clinical relapse was evaluated during follow-up. RESULTS: At the second endoscopic re-evaluation, 59 (68.6%) patients achieved EH (MES ≤1). Of these patients, 39 (66%) achieved complete EH. 20 of the 39 patients who achieved complete EH attained complete HH. Patients who achieved partial and complete EH showed higher recurrence-free survival rates compared to those who did not (p < 0.01 and p < 0.01, respectively). Amongst patients with complete EH, those who achieved complete HH had lower recurrence rates when compared to patients who still showed microscopic inflammation (p = 0.049). CONCLUSION: Achievement of EH and HH is associated with fewer disease relapses, with patients achieving HH showing longer relapse-free survival rates.

Gene expression profiling in white blood cells reveals new insights into the molecular mechanisms of thalidomide in children with inflammatory bowel disease.

Thalidomide has emerged as an effective immunomodulator in the treatment of pediatric patients with inflammatory bowel disease (IBD) refractory to standard therapies. Cereblon (CRBN), a component of E3 protein ligase complex that mediates ubiquitination and proteasomal degradation of target proteins, has been identified as the primary target of thalidomide. CRBN plays a crucial role in thalidomide teratogenicity, however it is unclear whether it is also involved in the therapeutic effects in IBD patients. This study aimed at identifying the molecular mechanisms underpinning thalidomide action in pediatric IBD. In this study, ten IBD pediatric patients responsive to thalidomide were prospectively enrolled. RNA-sequencing (RNA-seq) analysis and functional enrichment analysis were carried out on peripheral blood mononuclear cells (PBMC) obtained before and after twelve weeks of treatment with thalidomide. RNA-seq analysis revealed 378 differentially expressed genes before and after treatment with thalidomide. The most deregulated pathways were cytosolic calcium ion concentration, cAMP-mediated signaling, eicosanoid signaling and inhibition of matrix metalloproteinases. Neuronal signaling mechanisms such as CREB signaling in neurons and axonal guidance signaling also emerged. Connectivity Map analysis revealed that thalidomide gene expression changes were similar to those exposed to MLN4924, an inhibitor of NEDD8 activating enzyme, suggesting that thalidomide exerts its immunomodulatory effects by acting on the ubiquitin-proteasome pathway. In vitro experiments on cell lines confirmed the effect of thalidomide on candidate altered pathways observed in patients. These results represent a unique resource for enhanced understanding of thalidomide mechanism in pediatric patients with IBD, providing novel potential targets associated with drug response.

Changing Dietary Habits: The Impact of Urbanization and Rising Socio-Economic Status in Families from Burkina Faso in Sub-Saharan Africa.

(1) Background: Sub-Saharan Africa is experiencing the fastest urbanization worldwide. People in rural areas still have a traditional and rural lifestyle, whereas the Westernization of diet and lifestyle is already evident in urban areas. This study describes dietary habits of families in Burkina Faso living at different levels of urbanization. (2) Methods: Data on lifestyle, socio-economic conditions, health status and anthropometry were collected from 30 families living in rural villages, a small town and the capital city. A food frequency questionnaire and a 24 h recall diary were used to estimate dietary habits and macronutrients intake. (3) Results: The urban cohort showed a more diversified diet, with a higher intake of animal protein and, especially in children, a higher consumption of simple sugars. Fiber intake was significantly higher in the rural and semi-urbanized cohorts. As expected, overweight and obesity gradually increased with the level of urbanization. In semi-urbanized and urban families, we observed coexistence of under- and over-nutrition, whereas in rural families, a portion of children were wasted and stunted, and adults were underweight. (4) Conclusions: These three cohorts represent a model of the effect on diet of rural-to-urban migration. Rural diet and traditional habits are replaced by a Western-oriented diet when families move to urbanized areas. This dietary transition and increased socio-economic status in newly developing urban areas have a major impact on disease epidemiology, resembling the past evolution in Western countries.

Anti-Tumor Necrosis Factor-Alpha Withdrawal in Children With Inflammatory Bowel Disease in Endoscopic and Histologic Remission.

BACKGROUND: The aim of the present study was to investigate outcomes of anti-TNF-alpha (ATA) withdrawal in selected pediatric patients with inflammatory bowel disease who achieved clinical remission and mucosal and histological healing (MH and HH). METHODS: A retrospective analysis was performed on children and adolescents affected by Crohn disease (CD) and ulcerative colitis (UC) who were followed up at 2 tertiary referral centers from 2008 through 2018. The main outcome measure was clinical relapse rates after ATA withdrawal. RESULTS: One hundred seventy patients received scheduled ATA treatment; 78 patients with CD and 56 patients with UC underwent endoscopic reassessment. We found that MH was achieved by 32 patients with CD (41%) and 30 patients with UC (53.6%); 26 patients with CD (33.3%) and 22 patients with UC (39.3%) achieved HH. The ATA treatment was suspended in 45 patients, 24 affected by CD and 21 by UC, who all achieved concurrently complete MH (Simplified Endoscopic Score for CD, 0; Mayo score, 0, respectively) and HH. All the patients who suspended ATA shifted to an immunomodulatory agent or mesalazine. In contrast, 17 patients, 8 with CD and 9 with UC, continued ATA because of growth needs, the persistence of slight endoscopic lesions, and/or microscopic inflammation. Thirteen out of 24 patients with CD who suspended ATA experienced disease relapse after a median follow-up time of 29 months, whereas no recurrence was observed among the 9 patients with CD who continued treatment (P = 0.05). Among the patients with UC, there were no significant differences in relapse-free survival among those who discontinued ATA and those who did not suspend treatment (P = 0.718). CONCLUSIONS: Despite the application of rigid selection criteria, ATA cessation remains inadvisable in CD. In contrast, in UC, the concurrent achievement of MH and HH may represent promising selection criteria to identify patients in whom treatment withdrawal is feasible.

Gastrointestinal involvement in IgA vasculitis: a single-center 11-year study on a cohort of 118 children.

INTRODUCTION AND OBJECTIVES: Immunoglobulin A vasculitis (IgAV), the most common childhood vasculitis, is associated with gastrointestinal (GI) involvement in 50-75% of cases. The aim of this study was to describe the characteristics of GI involvement in a cohort of hospitalized children with IgAV. METHODS: We retrospectively evaluated patients hospitalized for IgAV at Meyer Children's University Hospital, from January 2010 to December 2020. The children's families were interviewed by phone and asked about disease relapses. RESULTS: In the study period, 118 children had GI involvement, corresponding to 75% of children hospitalized for IgAV. Their median age was 7 years (interquartile range 6-9). The most frequent GI manifestations were abdominal pain (96%), bleeding (71%, mostly occult), vomiting (58%), and diarrhea (17%). GI complications, observed in 18%, were intussusception (14%), appendicitis (3%), gallbladder hydrops (2%), and ileal perforation (1%). Abdomen ultrasound, performed in all cases, was abnormal in 68%. Abdomen X-ray, performed in 19 patients, showed pathologic findings in 84% of them. Selected children with severe manifestations also underwent abdomen computed tomography (2/118; 2%) and GI endoscopy (5/118; 4%). Steroids were used in 80 (67.8%) cases. The use of second- and third-line therapies was necessary in three cases. Relapses, investigated in 80 cases (68%), occurred in 21% of them. Key Points • The present retrospective study describes a cohort of 118 patients hospitalized for gastrointestinal (GI) involvement in immunoglobulin A vasculitis (IgAV) at a tertiary care children's hospital from January 2010 to December 2020. • The most frequent GI manifestations were abdominal pain (96%), vomiting (58%), and diarrhea (17%). GI bleeding was reported in 71% of children, and it was occult in most cases. • GI complications, occurring in 18% of cases, were intussusception (14%), appendicitis (3%), gallbladder hydrops (2%), and ileal perforation (1%). • Steroid treatment has been successfully used in severe GI manifestations; however, our data do not support its association with low relapse risk. CONCLUSIONS: The present study describes a large pediatric cohort of GI involvement in IgAV. Steroid treatment should be used when GI manifestations are severe. The association of steroid use with relapse risk is not currently established.

Scoring Endoscopy in Pediatric Inflammatory Bowel Disease: A Way to Improve Quality.

OBJECTIVES AND STUDY: There is a large interobserver variability in evaluating mucosal lesions of inflammatory bowel disease (IBD), especially in pediatric patients. This multicenter prospective observational study aims to evaluate interobserver agreement (IOA) among pediatric endoscopists in assigning validated IBD endoscopic scores in children. METHODS: Fifteen videos of follow-up ileocolonoscopies in children with IBD were recorded and selected as cases. Eleven pediatric endoscopists from different centers blindly evaluated all videos and calculated scores: either Ulcerative Colitis Endoscopic Index of Severity (UCEIS) or Simple Endoscopic Score for Crohn Disease (SES-CD). Scores from all reviewers were compared in order to calculate IOA for general videos and specific sections. Scores from an expert adult reader were used to calculate possible reviewer's characteristics affecting scores' reliability. RESULTS: Intraclass correlation was 0.298 (95% confidence interval [CI]: 0.13-0.55) for ulcerative colitis (UC) and 0.266 (0.11-0.52) for Crohn disease (CD). When a disease activity categorization was adopted (remission, mild, moderate, severe activity) Fleiss kappa coefficient was 0.408 (0.29-0.53) for UC and 0.552 (0.43-0.73) for CD. When stratified by item, vascular pattern of UC was the most reliable item IC: 0.624 (0.321-0.854). In multivariable analysis, none of the reviewer's characteristics affected the readers' errors. CONCLUSIONS: This multicenter study shows low agreement among pediatric endoscopists in evaluating endoscopic scores in children with IBD. By using disease activity categorization, agreement slightly increased, mostly for CD. All readers showed a low-grade concordance with the expert adult gastroenterologist's evaluations. Future-specific training programs should be considered to increase IOA in using IBD endoscopic activity scores.

Mucosal and Histologic Healing in Children With Inflammatory Bowel Disease Treated With Antitumor Necrosis Factor-Alpha.

OBJECTIVES: Mucosal healing (MH) and histological healing (HH) have been recently proposed as a novel treatment target for inflammatory bowel disease (IBD). The aim of the present study was to evaluate real-life achievement of such outcomes in a cohort of pediatric patients with IBD treated with anti-TNF-alpha (ATA) agents. METHODS: A retrospective analysis was performed on patients affected by IBD who received ATA and were followed up at two referral centers. Incidence and cumulative rates for MH and HH for each group were calculated. RESULTS: Of 170 (105 Crohn's disease [CD] and 65 ulcerative colitis [UC]) patients, 78 with CD and 56 with UC underwent endoscopic re-assessment during the study period. MH was achieved by 32 CD (41%) and 30 UC (53.6%) patients; 26 CD (33.3%) and 22 UC (39.3%) patients achieved HH. MH incidence rate was 19.1/1000 and 47/1000 person-months, whereas HH incidence rate was 15.5/1000 and 34.7/1000 person-months for CD and UC, respectively. Remission at the end of induction was associated with higher MH and HH rates (HR: 2.43, P = 0.049 and HR: 2.94, P = 0.046, respectively) in CD. In UC, adalimumab was associated with lower MH and HH rates (HR: 0.16, P = 0.004 and HR: 0.07, P = 0.003). CONCLUSIONS: We reported a real-life experience arising from a large cohort of pediatric IBD who received ATA scheduled treatment. Less than half of patients with CD and only a little >50% of UC patients achieved MH. Microscopical inflammation was observed in 18.8% CD and 26.7% UC patients who achieved MH. Overall, MH and HH rates appear lower compared to previously published data.

Bowel Ultrasound Scan Predicts Corticosteroid Failure in Children With Acute Severe Colitis.

BACKGROUND AND OBJECTIVE: Acute severe colitis (ASC) is a potentially life-threatening event. Optimal timing for second-line treatment in children is mainly based on the clinical score Pediatric Ulcerative Colitis Activity Index. The aim of our study was to evaluate the potential role of bowel ultrasound scan (BUS) in predicting the need of second-line therapy in ASC. METHODS: Patients younger than 18 years admitted to a single tertiary referral center with ASC were included. We retrospectively reviewed medical records collecting clinical and BUS data. Colonic wall thickness (CWT), loss of colonic wall stratification (CWS), presence of hyperechoic lymph nodes, and colonic wall flow evaluated at power Doppler were assessed at BUS performed within the third day of hospitalization. RESULTS: Sixty-nine ASC episodes from 52 different patients were identified. CWT showed significantly higher values in patients who required second-line therapy (5.14 vs 3.69 mm; P < 0.001). Loss of CWS was present in 17 of 36 (47.2%) of steroid-resistant ASC versus only 1 of 33 of those responding to intravenous corticosteroids (P < 0.001, sensitivity = 47%, specificity = 97%). Using a receiver operating characteristic curve, a cut-off of 3.4 mm was individuated for CWT to predict steroid treatment failure, showing a sensitivity of 92% and a specificity of 52%. The multivariable binary logistic regression analysis identified thickened colonic wall (CWT >3.4 mm) and loss of CWS as independent predictors of steroid resistance. CONCLUSIONS: BUS is a noninvasive, easily accessible, and cost-effective resource that may identify at an early stage first-line therapy failure in pediatric ASC.

Efficacy and safety of infliximab in very early onset inflammatory bowel disease: a national comparative retrospective study.

Background: Very few data regarding the use of infliximab in children with very early-onset inflammatory bowel disease (VEO-IBD) have been reported. Objective: We aimed to assess the efficacy and the safety of infliximab in children with VEO-IBD compared with older children. Methods: Children treated with infliximab were identified within the Italian IBD registry. The primary outcome was the rate of clinical remission at weeks 14 and 54. Secondary outcomes included the proportion of partial clinical response, treatment duration, and incidence of adverse events. Results: Forty-two children with VEO-IBD were compared with 130 children with IBD. Despite significantly higher infliximab withdrawals in VEO-IBD patients during induction (42.9% vs 7.7% p < 0.01), remission rates at week 14 were similar (28.6% vs 43.8%, p = 0.10). At week 54 fewer VEO-IBD children were in remission (15.8% vs 54.3%, p < 0.01). The treatment duration was shorter in VEO-IBD (median 12.0 vs 18.4 months, p < 0.01). During the induction phase, adverse events were more common in the VEO-IBD group (p < 0.01). Conclusion: Compared with older children, VEO-IBD patients have higher rates of infliximab failures, lower remission rates at one year, and more often experience adverse events during induction.

Late Relapse of Henoch-Schönlein Purpura in an Adolescent Presenting as Severe Gastroduodenitis.

Henoch-Schönlein purpura is a systemic vasculitis, commonly affecting children. Gastrointestinal manifestations are observed in 50-75% of patients; it is well known they may occur before skin lesions in about 20% of cases during the first vasculitic episode. Relapses occur in about one third of patients, typically within 4 months from the initial presentation and with milder symptoms. We report the case of a 17-year old girl with an atypical relapse of Henoch-Schönlein purpura, presenting with acute abdominal symptoms 5 years after the first episode. Esophagogastroduodenoscopy showed duodenal multiple hyperemic and hemorrhagic lesions. To our knowledge this is the first case of hemorrhagic-erosive duodenitis representing a relapse of Henoch-Schönlein purpura occurring several years after the initial episode. Duodenojejunal inflammation should be considered as primary manifestation of Henoch-Schönlein purpura, not only during the first episode, but also in relapses. Endoscopy can be helpful for differential diagnosis, especially in patients with atypical manifestations. Further studies are needed to evaluate risk factors for Henoch-Schönlein purpura recurrence and the possible role of fecal calprotectin as an early marker for gastrointestinal involvement.