The aim was to explore factors associated with intestinal tissue levels of anti-TNF alpha (anti-TNF), anti-TNF antibodies, and cytokines in pediatric patients with Crohn Disease (CD). In a prospective exploratory study of CD patients undergoing ileocecal resection or colonoscopy between 6/2020 and 1/2023, we analysed tissue levels of anti-TNF, anti-TNF antibodies, and cytokines (TNF-α, IL-17, IL-1β, IFN-γ) from intestinal biopsies. Mixed-effects regression models, adjusted for potential confounders, were used. Data from 27 CD patients (18 females, 66.7%) were analysed. Fourteen (52%) received adalimumab (ADA) and thirteen received infliximab (IFX), with a median therapy duration of 17 (IQR 4.5-41.5) months. Higher levels of free anti-TNF were found in macroscopically inflamed tissue compared to non-inflamed tissue (β = 3.42, 95% CI 1.05-6.10). No significant association was found between serum and tissue anti-TNF levels (β= -0.06, 95% CI - 0.70-0.58). Patients treated longer with anti-TNF had increased IL-17 levels (β = 0.19, 95% CI 0.05-0.33), independent of disease duration and age. IFN-γ levels were linked with both follow-up duration and anti-TNF length. Our study shows significantly higher free drug levels in inflamed tissue. Long-term anti-TNF treatment has been linked to increased IL-17 levels, suggesting a possible impact on the cytokine response pathway. We did not observe a relationship between serum and tissue anti-TNF levels.

• Keywords
• Biologics, Crohn disease, Inflammatory bowel disease, Paediatrics,
• MeSH
• Adalimumab * therapeutic use   MeSH
• Crohn Disease * drug therapy   metabolism   blood   pathology   MeSH
• Cytokines * metabolism   blood   MeSH
• Child MeSH
• Infliximab * therapeutic use   MeSH
• Humans MeSH
• Adolescent MeSH
• Prospective Studies MeSH
• Intestines pathology   drug effects   MeSH
• Intestinal Mucosa metabolism   pathology   MeSH
• Tumor Necrosis Factor-alpha * antagonists & inhibitors   metabolism   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adalimumab * MeSH
• Cytokines * MeSH
• Infliximab * MeSH
• Tumor Necrosis Factor-alpha * MeSH

PURPOSE: Children diagnosed with Crohn's disease (CD) often undergo ileocecal resection (ICR) during childhood. Anastomotic recurrence is a frequent finding following this procedure. Data addressing the effect of the anastomosis type on disease recurrence are scarce in the pediatric population. The Kono-S anastomosis has shown promise in reducing endoscopic, clinical, and surgical recurrence rates in adults. We aimed to report our experience with Kono-S anastomosis in children, focusing on its feasibility and postoperative complications. METHODS: We retrospectively analyzed pediatric CD patients who underwent ICR with Kono-S anastomosis between August 2022 and May 2023. Data on demographics, clinical characteristics, surgery, hospitalization, and follow-up including colonoscopy were collected. Complications were classified using the Clavien-Dindo classification. RESULTS: Twelve patients (7 females, 58.3%) were included. Six (50%) of the patients had the B3 luminal form of the disease (according to Paris classification). Median surgery duration was 174 (interquartile range [IQR] 161-216) minutes. Anastomosis creation took a median of 62 (IQR, 54.5-71) minutes. Median hospitalization length was 6 (IQR 4-7) days. No short- or mid-term complications were observed. Median follow-up duration was 9.5 (IQR 6.8-12) months. CONCLUSION: According to our results, Kono-S anastomosis is safe and feasible in pediatric CD patients, with no observed postoperative complications. These findings support the potential benefit of using Kono-S anastomosis as a treatment approach in children with CD.

• Keywords
• Crohn’s disease, Endoscopy, Kono-S, Pediatric surgery, Postoperative complication,
• MeSH
• Anastomosis, Surgical MeSH
• Crohn Disease * surgery   MeSH
• Child MeSH
• Adult MeSH
• Humans MeSH
• Postoperative Complications epidemiology   MeSH
• Retrospective Studies MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND AND AIMS: Treatment with anti-tumour necrosis factor α antibodies [anti-TNF] changes the dysbiotic faecal bacteriome in Crohn's disease [CD]. However, it is not known whether these changes are due to decreasing mucosal inflammatory activity or whether similar bacteriome reactions might be observed in gut-healthy subjects. Therefore, we explored changes in the faecal bacteriome and metabolome upon anti-TNF administration [and therapeutic response] in children with CD and contrasted those to anti-TNF-treated children with juvenile idiopathic arthritis [JIA]. METHODS: Faecal samples collected longitudinally before and during anti-TNF therapy were analysed with regard to the bacteriome by massively parallel sequencing of the 16S rDNA [V4 region] and the faecal metabolome by 1H nuclear magnetic resonance imaging. The response to treatment by mucosal healing was assessed by the MINI index at 3 months after the treatment started. We also tested several representative gut bacterial strains for in vitro growth inhibition by infliximab. RESULTS: We analysed 530 stool samples from 121 children [CD 54, JIA 18, healthy 49]. Bacterial community composition changed on anti-TNF in CD: three members of the class Clostridia increased on anti-TNF, whereas the class Bacteroidia decreased. Among faecal metabolites, glucose and glycerol increased, whereas isoleucine and uracil decreased. Some of these changes differed by treatment response [mucosal healing] after anti-TNF. No significant changes in the bacteriome or metabolome were noted upon anti-TNF in JIA. Bacterial growth was not affected by infliximab in a disc diffusion test. CONCLUSIONS: Our findings suggest that gut mucosal healing is responsible for the bacteriome and metabolome changes observed in CD, rather than any general effect of anti-TNF.

• Keywords
• Crohn’s disease, IBD, anti-TNF, children, metabolomics, microbiome,
• MeSH
• Bacteria MeSH
• Crohn Disease * pathology   MeSH
• Child MeSH
• Infliximab pharmacology   therapeutic use   MeSH
• Tumor Necrosis Factor Inhibitors pharmacology   therapeutic use   MeSH
• Humans MeSH
• Metabolome MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Infliximab MeSH
• Tumor Necrosis Factor Inhibitors MeSH

Inflammatory bowel diseases (IBD) are systemic immune-mediated conditions with predilection for the gastrointestinal tract and include Crohn's disease and ulcerative colitis. Despite the advances in the fields of basic and applied research, the etiopathogenesis remains largely unknown. As a result, only one third of the patients achieve endoscopic remission. A substantial portion of the patients also develop severe clinical complications or neoplasia. The need for novel biomarkers that can enhance diagnostic accuracy, more precisely reflect disease activity, and predict a complicated disease course, thus, remains high. Genomic and transcriptomic studies contributed substantially to our understanding of the immunopathological pathways involved in disease initiation and progression. However, eventual genomic alterations do not necessarily translate into the final clinical picture. Proteomics may represent a missing link between the genome, transcriptome, and phenotypical presentation of the disease. Based on the analysis of a large spectrum of proteins in tissues, it seems to be a promising method for the identification of new biomarkers. This systematic search and review summarize the current state of proteomics in human IBD. It comments on the utility of proteomics in research, describes the basic proteomic techniques, and provides an up-to-date overview of available studies in both adult and pediatric IBD.

• Keywords
• Crohn’s disease, inflammatory bowel disease, pediatric, proteome, proteomics, ulcerative colitis,
• MeSH
• Biomarkers metabolism   MeSH
• Crohn Disease * metabolism   MeSH
• Child MeSH
• Adult MeSH
• Inflammatory Bowel Diseases * metabolism   MeSH
• Humans MeSH
• Proteomics methods   MeSH
• Colitis, Ulcerative * metabolism   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Biomarkers MeSH

BACKGROUND: Maintaining of remission early in the disease course of Crohn's disease (CD) is essential and has major impact on the future prognosis. This study aimed to identify baseline predictors to develop model allowing stratification of patients who will not benefit from long-term azathioprine (AZA) treatment and will require more intensive therapy. METHODS: This study was designed to develop clinical prediction rule using retrospective data analysis of pediatric CD patients included in prospective inception cohort. Clinical relapse was defined as necessity of re-induction of remission. Sequence of Cox models was fitted to predict risk of relapse. RESULTS: Out of 1190 CD patients from 13 European centers, 441 were included, 50.3% patients did not experience clinical relapse within 2 years of AZA treatment initiation. Median time to relapse was 2.11 (CI 1.59-2.46) years. Of all the tested parameters available at diagnosis, six were significant in multivariate analyses: C-reactive protein (p = 0.038), body mass index Z-score >0.8 SD (p = 0.002), abnormal sigmoid imaging (p = 0.039), abnormal esophageal endoscopy (p = 0.005), ileocolonic localization (p = 0.023), AZA dose in specific age category (p = 0.031). CONCLUSIONS: Although the possibility of predicting relapse on AZA treatment appears limited, we developed predictive model based on six baseline parameters potentially helpful in clinical decision. IMPACT: The possibility of predicting relapse on AZA treatment appears to be possible but limited. We identified six independent predictors available at diagnosis of early AZA/6-MP treatment failure in pediatric CD patients. Using combination of these factors, a model applicable to clinical practice was created. A web-based tool, allowing estimation of individual relapse risk in pediatric CD patients on a particular therapeutic regimen, has been developed.

• MeSH
• Azathioprine therapeutic use   adverse effects   MeSH
• Crohn Disease * complications   diagnosis   drug therapy   MeSH
• Child MeSH
• Immunosuppressive Agents therapeutic use   adverse effects   MeSH
• Remission Induction MeSH
• Humans MeSH
• Prospective Studies MeSH
• Recurrence MeSH
• Retrospective Studies MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Azathioprine MeSH
• Immunosuppressive Agents MeSH

PURPOSE: Ileocecal resection (ICR) is the most frequently performed surgery in paediatric Crohn's disease (CD) patients. The aim of the study was to compare laparoscopic-assisted and open ICR. METHODS: Retrospective review of consecutive CD patients undergoing ICR between March 2014 and December 2021 was performed. The patients were divided into open (OG) and laparoscopic (LG) groups. Compared parameters included patients' demographics, clinical characteristics, surgery, duration of hospitalisation and follow-up. Complications were classified according to the Clavien-Dindo classification (CDc). Risk factors were identified using multivariable analysis. RESULTS: Sixty-two patients (29 females, 46.7%) were included in the analysis, forty-two patients in OG. The median duration of surgery was 130 in OG versus 148 in LG (p = 0.065) minutes. Postoperative complications were reported in 4 patients (12.1%). There was no significant difference in postoperative complications according to CDc (OG 7.14 vs LG 5%, p = 1). The median length of hospitalisation was 8 in OG and 7 days in LG (p = 0.0005). The median length of follow-up was 21.5 months. CONCLUSION: The laparoscopic-assisted approach had shorter hospital stay and was not associated with increased risk of 30-day postoperative complications. Laparoscopic surgery should be considered the preferred surgical approach for primary ICR.

• Keywords
• Crohn’s disease, Ileocecal resection, Laparoscopy, Paediatric surgery, Single-incision laparoscopic surgery,
• MeSH
• Crohn Disease * surgery   MeSH
• Child MeSH
• Hospitalization MeSH
• Laparoscopy * MeSH
• Humans MeSH
• Hospitals MeSH
• Postoperative Complications epidemiology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: Two antitumor necrosis factor therapies (infliximab [IFX] and adalimumab [ADA]) have been approved for the treatment of pediatric Crohn's disease (CD) but have not been compared in head-to-head trials. The aim of this study was to compare the efficacy and safety of ADA and IFX by propensity score matching in a prospective cohort of pediatric patients with luminal CD and at least a 24-month follow-up. METHODS: Among 100 patients, 75 met the inclusion criteria, and 62 were matched by propensity score. We evaluated time to treatment escalation as the primary outcome and primary nonresponse, predictors of treatment escalation and relapse, serious adverse events, pharmacokinetics, and effect of concomitant immunomodulators as secondary outcomes. RESULTS: There was no difference between ADA and IFX in time to treatment escalation (HR = 0.63 [95% CI 0.31-1.28] P = 0.20), primary nonresponse (P = 0.95), or serious adverse events. The median (interquartile range) trough levels at the primary outcome were 14.05 (10.88-15.40) and 6.15 (2.08-6.58) µg/mL in the ADA and IFX groups, respectively. On a multivariate analysis, the combination of anti-Saccharomyces cerevisiae antibody negativity and antineutrophil cytoplasmic antibody positivity was a strong independent predictor of treatment escalation (HR 5.19, [95% CI 2.41-11.18], P < 0.0001). The simple endoscopic score for CD, L3 disease phenotype, and use of concomitant immunomodulators for at least the first 6 months revealed a trend toward significance on a univariate analysis. DISCUSSION: Propensity score matching did not reveal substantial differences in efficacy or safety between ADA and IFX. The anti-S. cerevisiae antibody negativity and antineutrophil cytoplasmic antibody positivity combination is a strong predictor of treatment escalation.

• MeSH
• Adalimumab adverse effects   MeSH
• Crohn Disease * diagnosis   drug therapy   MeSH
• Child MeSH
• Immunologic Factors MeSH
• Infliximab therapeutic use   MeSH
• Humans MeSH
• Prospective Studies MeSH
• Antibodies, Antineutrophil Cytoplasmic MeSH
• Propensity Score MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adalimumab MeSH
• Immunologic Factors MeSH
• Infliximab MeSH
• Antibodies, Antineutrophil Cytoplasmic MeSH

Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients < 10 years. TDM data were collected retrospectively in 14 centres. Children treated with IFX were included if IFX was started as IBD treatment at age < 10 years (young patients, YP) and PK data were available. Older IBD patients aged 10-18 years were used as controls (older patients, OP). Two hundred and fifteen paediatric inflammatory bowel disease (PIBD) patients were eligible for the study (110 < 10 year; 105 ≥ 10 years). Median age was 8.3 years (IQR 6.9-8.9) in YP compared with 14.3 years (IQR 12.8-15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 μg/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0-12.9) vs. OP; 5.5 mg/kg (IQR 5.0-9.3); p < 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI - 1.2 to - 1.01); p < 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP; p = 0.56).Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years. What is Known? •Infliximab trough levels of paediatric IBD patients are influenced by several factors as dosing scheme, antibodies and inflammatory markers. •In 4.5-30% of the paediatric IBD patients, infliximab treatment was stopped within the first year. What is New? •The majority of young PIBD (< 10 years) have inadequate IFX trough levels at the start of maintenance treatment. •Young PIBD patients (< 10 years) were in need of a more intensive treatment regimen compared with older paediatric patients during 1 year of IFX treatment. •The chance to develop antibodies to infliximab was relatively higher in young PIBD patients (< 10 years).

• Keywords
• Anti-TNF, Biologics, Clinical pharmacology, Crohn’s disease, Gastroenterology, Paediatric, Ulcerative colitis,
• MeSH
• Child MeSH
• Gastrointestinal Agents * therapeutic use   MeSH
• Inflammatory Bowel Diseases * drug therapy   MeSH
• Infliximab * therapeutic use   MeSH
• Humans MeSH
• Child, Preschool MeSH
• Retrospective Studies MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Gastrointestinal Agents * MeSH
• Infliximab * MeSH

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long-term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event-free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver-related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P= not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P= 0.002), but 5-year event-free survival was similar (74% versus 77%, P= NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5-year event-free survival was better (91% versus 67%, P< 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5-year event-free survival 88% versus 61%, P= 0.005). Conclusion:A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5-year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.

• Publication type
• Journal Article MeSH

Exclusive enteral nutrition (EEN) has been recommended as the first-line therapy in children with active Crohn disease (CD). The primary aim of our study was to determine whether it is possible to use the difference between basal fecal calprotectin (F-CPT) and the value at week 2 of EEN to predict clinical response at week 6. We prospectively collected stool samples for F-CPT analysis and clinical and laboratory parameters during EEN from 38 pediatric patients (28 boys, median age 12.8 years) with newly diagnosed active luminal CD. The difference between F-CPT concentrations before EEN and at week 2 did not predict clinical non-response at week 6 (OR 0.9996 95% CI 0.9989-1.0002, p = 0.18); however, it predicted patients who did not achieve clinical remission at week 6 (OR 0.9993, 95% CI 00.9985-0.9998, p = 0.006) with sensitivity of 58%, and specificity of 92% for cut-off of F-CPT increase by 486 μg/g.Conclusions: An early decrease in F-CPT levels in children with newly diagnosed active luminal CD did not predict clinical response at week 6 of EEN induction therapy, and clinical remission was predicted with low accuracy. Therefore, F-CPT cannot be used as a predictor to select the patients in whom EEN should be terminated. What is Known: • The fecal calprotectin (F-CPT) is an important marker of intestinal inflammation. • Approximately 25% of pediatric patients with Crohn disease (CD) do not achieve clinical remission, and there is still no sufficient predictor of response to exclusive enteral nutrition (EEN) treatment. What is New: • The difference between the F-CPT concentrations before EEN treatment and at week 2 did not predict clinical response to treatment at week 6, even if it predicted clinical remission, however, with low accuracy. F-CPT is not a suitable predictor to select the patients for discontinuing of EEN induction therapy.

• Keywords
• Calprotectin, Inflammatory bowel disease, Prediction, Remission, Response,
• MeSH
• Biomarkers analysis   MeSH
• Crohn Disease metabolism   therapy   MeSH
• Child MeSH
• Enteral Nutrition adverse effects   MeSH
• Feces chemistry   MeSH
• Leukocyte L1 Antigen Complex analysis   MeSH
• Humans MeSH
• Adolescent MeSH
• Prospective Studies MeSH
• Sensitivity and Specificity MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Names of Substances
• Biomarkers MeSH
• Leukocyte L1 Antigen Complex MeSH