This study aimed to characterize pain intensity (average, worst) and disease severity in youth with inflammatory bowel disease in the 12-month postdiagnosis, and to examine the relation between pain and risk (disease severity) and resilience (optimism, pain self-efficacy) factors over time.

Data collection ran from February 2019 to March 2022. Newly diagnosed youth aged 8 to 17 with IBD completed numerical rating scales for average and worst pain intensity, Youth Life Orientation Test for optimism, and Pain Self-Efficacy Scale for pain self-efficacy through REDCap; weighted Pediatric Crohn's Disease Activity Index and the Pediatric Ulcerative Colitis Activity Index were used as indicators of disease severity. Descriptive statistics characterized pain and disease severity. Multilevel modeling explored relations between variables over time, including moderation effects of optimism and pain self-efficacy.

At baseline, 83 youth ( Mage =13.9, SD=2.6; 60.2% Crohn's disease; 39.8% female) were included. Attrition rates at 4 and 12 months were 6.0% and 9.6%, respectively. Across time, at least 52% of participants reported pain. Participants in disease remission increased from 4% to 70% over 12 months. Higher disease severity predicted higher worst pain, regardless of the time since diagnosis. Higher pain self-efficacy (1) predicted lower average and worst pain, especially at later time points and (2) attenuated the association between disease severity and worst pain when included as a moderator. Higher optimism predicted lower worst pain.

Pain is prevalent in pediatric inflammatory bowel disease and impacted by disease severity, pain self-efficacy, and optimism. Findings highlight modifiable intervention targets.

The incidence of pediatric-onset inflammatory bowel disease (IBD) and the costs of caring for individuals with IBD are both increasing. We calculated the direct healthcare costs of pediatric IBD in the first year after diagnosis and developed a model to predict children who would have high costs (top 25th percentile).

Using data from the Canadian Children IBD Network inception cohort (≤16 years of age, diagnosed between 2013 and 2019) deterministically linked to health administrative data from Ontario, Canada, we estimated direct healthcare and medication costs accrued between 31 and 365 days after diagnosis. Candidate predictors included age at diagnosis, sex, rural/urban residence location, distance to pediatric center, neighborhood income quintile, IBD type, initial therapy, disease activity, diagnostic delay, health services utilization or surgery around diagnosis, regular primary care provider, and receipt of mental health care. Logistic regression with stepwise elimination was used for model building; 5-fold nested cross-validation optimized and improved model accuracy while limiting overfitting.

The mean cost among 487 children with IBD was CA$15 168 ± 15 305. Initial treatment (anti-tumor necrosis factor therapy, aminosalicylates, or systemic steroids), having a mental health care encounter, undergoing surgery, emergency department visit at diagnosis, sex, and age were predictors of increased costs, while having a regular primary care provider was a predictor of decreased costs. The C-statistic for our model was 0.71.

The cost of caring for children with IBD in the first year after diagnosis is immense and can be predicted based on characteristics at diagnosis. Efforts that mitigate rising costs without compromising quality of care are needed.

Exclusive enteral nutrition (EEN) is highly effective in achieving remission and improving nutritional status in pediatric Crohn's disease (CD), commonly associated with altered body mass composition (BC). Bioimpedance analysis (BIA) with phase angle (PA) assessment is a noninvasive, reliable tool in screening for BC alterations. In the present study we aimed to assess the PA's usefulness in the detection of malnutrition in newly diagnosed pediatric CD, ongoing EEN treatment, and during 1-year follow-up. Patients and study design: Fourty-three patients with CD, qualified for EEN, were enrolled in the study. Additionally, 22 healthy children, being in the same age category, served as controls. Fat-free mass (FFM), fat-free mass index (FFMI), and BIA-derived PA were assessed at diagnosis, after EEN completion, and at week 52. The same parameters were obtained in the control group once. The majority of patients presented with normal body mass index at diagnosis. PA values were lower than 5 degrees in 65% of the study group. FFMI deficiencies were observed in 74% of patients. After EEN completion, an increase in FFM (P < .001) was observed. The highest mean of FFM (P < .001) and PA (P < .001) were observed at week 52. A strong correlation between PA and FFM at CD diagnosis (Spearman's rho = 0.671, r = 0.702, P < .001), after EEN completion (Spearman's rho = 0.781, P < .00) and at week 52 (Spearman's rho = 0.657, P < .001) was present. PA has been observed as positively associated with albumin concentrations both at diagnosis and after EEN. Our study provides some support that PA may be a reliable tool for screening alteration in BC, especially FFM and lean tissue mass (LTM). Moreover, PA has been observed as positively associated with albumin levels at CD diagnosis, which provides some evidence that it may be considered as a risk indicator of malnutrition and protein deficiency in newly diagnosed CD pediatric patients.

There are scarce data available on upadacitinib in children with Crohn's disease (CD).

To evaluate the effectiveness and safety of upadacitinib as an induction therapy in paediatric CD.

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.

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.

Upadacitinib is an effective induction therapy for refractory paediatric CD. Efficacy should be weighed against the potential risks of AEs.

CD4+ memory T cell (TM) reactivation drives chronicity in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis. Defects driving loss of TM regulation likely differ between patients but remain undefined. In health, approximately 40 % of circulating gut-homing CD38+TM express co-inhibitory receptor T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). TIGIT+CD38+TM have regulatory function while TIGITnegCD38+TM are enriched in IFN-γ-producing cells. We hypothesized TIGITnegCD38+TM are inflammatory and drive disease in a subgroup of IBD patients. We characterized TIGIT+CD38+TM in a uniquely large cohort of pediatric IBD patients from time of diagnosis into adulthood. Circulating TIGITnegCD38+TM frequencies were higher in a subgroup of therapy-naïve CD patients with high plasma IFN-γ and a more severe disease course. TIGITnegCD38+TM were highly enriched in HLA-DR+ and ex-Th17/Th1-like cells, high producers of IFN-γ. Cultures of healthy-adult-stimulated TM identified IL-12 as the only IBD-related inflammatory cytokine to drive the pathogenic ex-Th17-TIGITnegCD38+ phenotype. Moreover, IL12RB2 mRNA expression was higher in TIGITnegCD38+TM than TIGIT+CD38+TM, elevated in CD biopsies compared to controls, and correlated with severity of intestinal inflammation. Overall, we argue that in a subgroup of pediatric CD, increased IL-12 signaling drives reprogramming of Th17 to inflammatory Th1-like TIGITnegCD38+TM and causes more severe disease.

We determined the prevalence of anemia and its characteristics in children with newly diagnosed inflammatory bowel disease (IBD) and investigated its trend during follow-up.

An observational, multicenter cohort study of IBD children with anemia at the diagnosis enrolled in the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition IBD registry. Data were collected at the diagnosis and at 1 year.

Five hundred eighty-nine (295 Crohn's disease [CD] [50%] and 294 ulcerative colitis [UC]/IBD unclassified [IBDU] [50%]) of 1634 patients with IBD presented with anemia (36%). Anemia rate was higher in CD than in UC (39% vs. 33%, p = 0.009), and most patients had moderate anemia (55%). Children with CD had higher rates of mild anemia than UC (38% vs. 33%, p < 0.0001), while severe anemia was more common in UC (13% vs. 6%, p = 0.001). In CD, lower age at the diagnosis and lower albumin level correlated with anemia severity (p = 0.0007 and <0.0001, respectively). In UC, severe disease was more common in patients with severe anemia compared to those with mild and moderate anemia (20.6% vs. 43.6%, p = 0.01; 17% vs. 43.6%, p = 0.001). At 1 year, 99 children (22.9%) were persistently anemic and were characterized by a more severe disease compared to those who had resolved their anemia.

More than one third of IBD children present with anemia, most commonly moderate. Severe anemia is more common in UC compared to CD. One in four patients is still anemic after 1 year from the diagnosis, suggesting inadequate attention to the issue and the need for dedicated therapeutic management and careful monitoring.

Exclusive enteral nutrition (EEN) is recommended as first-line therapy for children with mild to moderate Crohn's disease (CD), given its effectiveness in inducing clinical remission (CR) and promoting mucosal healing (MH). However, the identification of reliable early predictors of EEN response remains an area requiring further investigation.

Patients with CD diagnosed between 2015 and 2024 were divided into training and validation cohorts. Baseline clinical and laboratory covariates were analyzed separately to evaluate their associations with CR and MH after 8 weeks of EEN therapy. Significant covariates were identified through univariate analysis and correlation tests, followed by their inclusion in stepwise logistic regression to develop separate predictive models for CR and MH. Model performance was evaluated using receiver operating characteristic (ROC) curves.

A total of 56 patients were included in the derivation cohort, and 28 were included in the validation cohort. The CR diagnostic model achieved an Area Under Curve (AUC) of 0.93 in the derivation cohort (95% confidence interval (CI) 0.87-1.00; p < 0.05) and 0.82 in the validation cohort (95% CI 0.62-1.02; p < 0.05). Higher baseline levels of IBIL (> 4.95 µmol/L), T-cell cluster of differentiation 3 (CD3) (> 76.78%), and iron (> 9.025 mmol/L) were associated with reduced CR rates. The MH diagnostic model yielded an AUC of 0.87 in the derivation cohort (95% CI 0.73-1.00; p < 0.05) and 0.66 in the validation cohort (95% CI 0.43-0.89; p = 0.231). Factors associated with lower MH rates included an Interleukin 10 (IL-10) level > 4.35 µmol/L and a red cell distribution width (RDW) > 14.55%.

IBIL, CD3 and iron levels are reliable predictors of the induction of CR with EEN, whereas the IL-10 level and RDW serve as early predictors of MH.

One in three children with Crohn's disease develop perianal fistula complications (PFCs), among the most disturbing and difficult-to-treat disease-related complications. Retrospective evidence suggests PFCs may be preventable.

We aimed to determine if early antitumour necrosis factor-alpha (anti-TNF⍺) therapy prevents PFC development in a well-characterised prospective cohort of paediatric patients with Crohn's disease who were free from PFC at enrolment.

RISK was a multicentre inception cohort of children newly diagnosed with Crohn's disease. We included all patients who had never experienced PFCs 30 days after study enrolment. We conducted nearest-neighbour propensity score-matched triad analyses. Matching was performed to balance patient characteristics across three mutually exclusive treatment groups based on therapy prior to either PFC development or the end of the observation period.

Among 873 patients without perianal fistula, 447 matched patients were included (149 per treatment group). The presence of non-penetrating perianal lesions (large skin tags, ulcers and/or fissures) was significantly associated with PFC development, with 4-fold greater odds of PFC (OR 4.08, 95% CI (95% CI) 1.70 to 9.78; p=0.0016). Early anti-TNF⍺ therapy was associated with an 82% decrease in the odds of PFC (OR 0.18, 95% CI 0.05 to 0.66; p=0.01). Among those with perianal lesions, anti-TNF⍺ therapy was associated with 94% reduced odds of PFC development (OR 0.055, 95% CI 0.006 to 0.50; p=0.010). No other treatment group was associated with reduced risk of PFC.

Early anti-TNF therapy prevents perianal fistula development, especially among patients at increased risk.

The immunological effects of treatment with exclusive enteral nutrition (EEN) in Crohn's disease (CD) remain unknown. We characterized the plasma levels of inflammation-related proteins (IRPs) in children with CD and ulcerative colitis (UC) compared with noninflammatory controls (non-IBD) and explored the effect of EEN in CD.

Ninety-two IRPs were quantified using Olink proteomics in children with CD (n = 53), UC (n = 11), and non-IBD (n = 19). For 18 children with active CD, IRPs were measured before and after 8 weeks of EEN. Relationships with disease phenotype and response to EEN were studied.

Compared with non-IBD, patients with active UC and CD had different levels of 27 (24 raised, 3 decreased) and 29 (26 raised, 3 decreased) IRPs, respectively. Exclusive enteral nutrition modified the levels of 19 IRPs (13 increased, 6 decreased including CCL23, interleukin-24, interleukin-6, and MMP-1). More pronounced changes in IRP profile were observed in patients with ileal involvement and a ≥50% decrease in fecal calprotectin during EEN compared with those with colonic involvement and a <50% decrease in fecal calprotectin, respectively. A machine-learning model utilizing baseline IRP profile predicted response to EEN with a sensitivity of 89%, specificity of 57%, and accuracy of 73%. Thymic stromal lymphopoietin was the most important IRP in the model, this being higher in responders.

Inflammation-related proteins may be useful in the differential diagnosis of IBD. Exclusive enteral nutrition extensively modulated IRPs levels in children with active CD with more pronounced effects observed in patients who showed a reduction in FC and had ileal disease involvement.

Infliximab and adalimumab are the only biologics thus far approved for paediatric patients with inflammatory bowel disease (IBD), so other biologics, such as vedolizumab, are prescribed off-label. Despite its frequent use, prospective data for vedolizumab treatment in children are available only for short-term induction outcomes. We aimed to evaluate the long-term efficacy and safety of maintenance therapy with vedolizumab in paediatric patients with IBD.

In this multicentre, prospective, cohort study (VEDOKIDS), children younger than 18 years with Crohn's disease, ulcerative colitis, or IBD unclassified (analysed with the ulcerative colitis group) who had initiated intravenous vedolizumab were enrolled from 17 centres in six countries (Israel, the USA, Italy, Ireland, Denmark, and Slovenia). Patients initiating vedolizumab to prevent postoperative recurrence were excluded. Vedolizumab dose or schedule were not standardised, and concomitant treatment with any other medication was permitted. Patients were prospectively followed up for 54 weeks, with repeated biosampling. The primary outcome was complete remission at week 54, defined as clinical remission (weighted Paediatric Crohn's Disease Activity Index [wPCDAI] of <12·5 points in Crohn's disease and Paediatric Ulcerative Colitis Activity Index [PUCAI] of <10 in ulcerative colitis) without the need for surgery, exclusive enteral nutrition for children with Crohn's disease, or steroids (steroid-free and exclusive enteral nutrition-free clinical remission) plus CRP concentration lower than 1·5 times the upper limit of normal (ULN) of 0·5 mg/dL. In cases of missing data on CRP, ESR was used instead (concentrations <1·5 times the ULN, which was 25 mm/h). Data were analysed by intention to treat. This study is registered with ClinicalTrials.gov, NCT02862132.

Between May 19, 2016, and April 1, 2022, we enrolled 142 patients. Five children who had received only one or two infusions of their three-infusion induction before switching drugs due to COVID-19 pandemic-related reasons were excluded, leaving 137 children (64 [47%] with Crohn's disease, 64 [47%] with ulcerative colitis, and nine [7%] with IBD unclassified; 63 [46%] male and 74 [54%] female; age range of 0·7-17·6 years) in the intention-to-treat population. The median wPCDAI score in children with Crohn's disease decreased from 35 (IQR 18 to 49) at baseline to 13 (0 to 25; median of differences -14 [95% CI -33 to 0]) at week 54, and the median PUCAI score in children with ulcerative colitis decreased from 25 (IQR 15 to 50) at baseline to 5 (0 to 25) at week 54 (median of difference -10 [-30 to 0]). Improvements in disease activity were significant by week 6, with no further significant changes between visits. At week 54, 16 (25%) of 64 children with Crohn's disease and 34 (47%) of 73 with ulcerative colitis or IBD unclassified were in complete remission. 38 vedolizumab-related adverse events were recorded in 29 (21%) of 137 children, the most common being headache (n=7), myalgia (n=4), and fever (n=4), and none were serious.

Vedolizumab maintenance seems safe and efficacious in children, with a higher efficacy in those with ulcerative colitis than in those with Crohn's disease.

The European Crohn's and Colitis Organisation, the European Society for Paediatric Gastroenterology Hepatology and Nutrition, and Takeda.

The pharmacokinetics of biologic agents can differ between children and adults with inflammatory bowel disease (IBD), often necessitating modified paediatric dosing strategies.

To define the exposure-response relationship of vedolizumab in the paediatric IBD VedoKids cohort including the effect of baseline clearance on deep biochemical remission (normal C-reactive protein [CRP]/erythrocyte sedimentation rate [ESR] and steroid-free remission) at 30 weeks, and to use population pharmacokinetic models to find the best matches between adult and paediatric pharmacokinetic profiles.

We sought a pharmacokinetic model on 312 serum vedolizumab concentrations from 129 children, assisted by a published adult model as a Bayesian prior. We employed the model for exposure-response evaluation and for investigating doses in paediatric patients to match the adult exposure at the labelled dose.

At Week 30, 104/129 (81%) children (53% female and 47% Crohn disease) remained on vedolizumab, of whom 39 (31%) in the exposure-response evaluation were in deep biochemical remission. Increased baseline drug clearance was associated with lower deep biochemical remission rates at Week 30 based on ESR/CRP (OR 0.47 [95% CI 0.2-1.05, p = 0.08]) and calprotectin < 100 μg/g (OR 0.13 [95% CI 0.1-0.79, p < 0.05]). Higher weight and lower serum albumin were associated with increased clearance (p < 0.001). Simulation models found that, for children ≤ 30 kg, tiered fixed dosing regimens best matched adult drug concentrations.

Drug clearance was strongly influenced by serum albumin. Baseline clearance predicted deep biochemical remission at Week 30. Further investigation is needed to better understand optimal dosing strategies-especially for lower-weight children receiving vedolizumab.

Epidemiological studies have suggested an association between the inflammatory potential of dietary patterns and Crohn's disease (CD). However, the relationships of these inflammatory dietary determinants with the microbiome remain largely unknown. In this cross-sectional study, we evaluate the association between the inflammatory potential of habitual diet, as assessed by the modified Children-Dietary Inflammatory Index (mC-DII), and the fecal microbiome and metabolome of children with CD in comparison to healthy children.

A cross-sectional study including 51 children with CD between 6 and 18 years of age and 50 healthy controls was conducted. Dietary inflammatory potential was measured using the mC-DII, and diet quality was assessed by the Healthy Eating Index (HEI)-2015 and alternate Mediterranean Eating Index (aMed). The microbiome was analyzed using shotgun metagenomic sequencing and untargeted metabolomic analysis.

A poor-quality, pro-inflammatory diet, with similar mC-DII, HEI-2015, and aMed scores, was found across healthy children and children with CD. In children with active disease, a pro-inflammatory diet was associated with decreased diversity, increased virulence potential, and expansion of the Proteobacteria phylum dominated by Escherichia coli (E. coli) spp. A positive correlation between E. coli relative abundance and mC-DII was associated with a low intake of a cluster composed of fibers, vitamins, and minerals with anti-inflammatory potential. A negative association between metabolites of fatty acid metabolism and HEI was found.

In total, our results suggest that a pro-inflammatory diet may potentiate hallmarks of the inflammation-associated dysbiosis in CD and highlight the need for microbiome-targeted dietary interventions optimizing the anti-inflammatory potential of habitual diet in the management of pediatric CD.

Enterostomy is utilized to mitigate severe clinical symptoms in children with very early-onset inflammatory bowel disease (VEO-IBD) and to provide a window for stem cell transplantation. Nevertheless, the incidence of postoperative complications is significant, and there is currently a lack of research exploring the risk factors associated with complications related to the stoma and incision following the procedure. The objective of this study is to investigate the risk factors for stoma and incision complications after enterostomy in patients with VEO-IBD. From January 2015 to December 2023, 49 children with VEO-IBD who underwent enterostomy were enrolled in the study. Demographic characteristics, blood biochemical indices, weighted Pediatric Crohn's Disease Activity Index (wPCDAI), and enterostomy-related information were prospectively collected. Multivariate logistic regression was employed to identify the risk factors for ostomy and incision-related complications. All 49 included VEO-IBD children had interleukin-10 (IL-10) signaling defects, with 27 (55.1%) having stomal-related complications and 10 (20.4%) had incision complications after enterostomy. Univariate analysis revealed that wPCDAI (OR, 1.03; 95% CI, 1.00-1.07; P = 0.05) showed a tendency towards statistical significance in the occurrence of ostomy complications. Weight-for-age Z-score (WAZ) (OR, 0.57; 95% CI, 0.39-0.84; P = 0.004), height-for-age Z-score (HAZ) (OR, 0.57; 95% CI, 0.37-0.88; P = 0.01), type of surgery (OR, 0.12; 95% CI, 0.03-0.56, P = 0.007), C-reactive protein (CRP) (OR, 1.02; 95% CI, 1.01-1.04; P = 0.007), and wPCDAI (OR, 1.08; 95% CI, 1.01-1.14; P = 0.009) demonstrated statistical significance in the occurrence of incision complications. However, multivariate binary logistic regression did not reveal any statistically significant factors.

Although emergency surgery is unavoidable, our study suggests that improving nutritional status, reducing CRP levels, and increasing preoperative wPCDAI scores may help reduce post-enterostomy stoma and incision complications in VEO-IBD children with interleukin-10 (IL-10) signaling defects. Further large-scale studies are needed to confirm these findings.

• Enterostomy is commonly used to manage severe symptoms in children with VEO-IBD and to provide a window for stem cell transplantation. • The incidence of postoperative complications, including stoma and incision-related issues, is significant in these patients.

• This study identifies potential risk factors for stoma and incision complications following enterostomy in children with VEO-IBD, particularly those with IL-10 signaling defects. • Factors such as nutritional status (WAZ and HAZ), CRP levels, type of surgery, and the wPCDAI were found to be associated with stoma and incision complications in univariate analysis, although multivariate analysis did not show statistical significance for these factors.

Accurate, reliable, and responsive disease activity indices are important to streamline drug approval and treatment modalities for pediatric inflammatory bowel disease (pIBD). We aimed to identify all scoring indices used in pIBD randomized controlled trials (RCTs) and to evaluate their operating properties.

MEDLINE, EMBASE, and CENTRAL were searched on December 6, 2022, to identify studies evaluating clinical, endoscopic, imaging, or patient-reported outcome measures (PROMs) in pIBD including Crohn's disease (CD) and ulcerative colitis (UC). Validity, reliability, responsiveness, and feasibility were summarized.

Seventy RCTs evaluating pIBD indices were identified. Forty-one studies reported on the operating properties of 14 eligible indices (n = 9 CD, n = 5 UC). The Pediatric Crohn's Disease Activity Index (PCDAI) varied widely in terms of validity and reliability and was less feasible overall. In contrast, the Mucosal Inflammation Noninvasive Index, which includes fecal calprotectin, had better operating properties than the PCDAI. The Simplified Endoscopic Mucosal Assessment of Crohn's Disease appears more feasible and had similar operating properties than the longer Simple Endoscopic Score for Crohn's Disease. The Pediatric Ulcerative Colitis Activity Index was feasible, valid, and reliable, but responsiveness needs to be evaluated further. The Endoscopic Mayo score and the Ulcerative Colitis Endoscopic Index of Severity were reliable, but validity and responsiveness need to be evaluated further. Imaging and PROMs/quality of life indices need further evaluation.

The operating properties of pIBD clinical trial end points varied widely. These results highlight the need for further validation and development of novel indices.

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).

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).

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]).

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.

Only a few studies have reported the long-term effects of ustekinumab on pediatric Crohn's disease. Therefore, this study aimed to describe the long-term clinical and endoscopic outcomes of ustekinumab and its safety profile in pediatric-onset Crohn's disease with anti-tumor necrosis factor failure.

Medical records of patients with pediatric-onset Crohn's disease in whom anti-tumor necrosis factor therapy failed and ustekinumab treatment was initiated from 2017 to 2022 at a Japanese tertiary children's hospital were retrospectively reviewed. The primary outcome was the continuation rates at weeks 8, 52, and 106. The secondary outcomes were the steroid-free remission rates at weeks 8, 52, and 106, changes in the Simple Endoscopic Score for Crohn's Disease, and adverse events during follow-up.

Forty-three patients were enrolled. The median ages at diagnosis and ustekinumab introduction were 9.7 (interquartile range: 6.7-13.0) years and 13.6 (interquartile range: 8.0-16.0) years. The median follow-up period was 136 (interquartile range: 102-172) weeks. The continuation rates were 100%, 91%, and 80% at weeks 8, 52, and 106, respectively. The incidence of discontinuation was 6.2% per patient-year of follow-up. The steroid-free remission rates were 44%, 71%, and 80% at weeks 8, 52, and 106, respectively. The Simple Endoscopic Score for Crohn's Disease of patients in clinical remission at the last follow-up significantly decreased (P < 0.01), and the safety profile was acceptable.

Ustekinumab appeared effective in maintaining long-term clinical remission with endoscopic improvement in pediatric-onset Crohn's disease with anti-tumor necrosis factor failure.

Background/Objectives: Chronic gastrointestinal disorders often involve nutritional management strategies. On the one hand, inflammatory bowel disease (IBD) is a condition in which most of the patients experience frequent diet manipulation in order to obtain long term remission. On the other hand, for celiac disease (CelD), diet is the only known treatment strategy so far, requiring a life-long gluten-free diet. We aimed to evaluate the comparative food-related quality-of-life (FR-QoL) in light of these dietary interventions between these two conditions. Methods: This is a cross-sectional study, involving children aged 7-18 years diagnosed with IBD and CelD. Assessment of this aspect was performed using the self-reported FR-QoL 29 questionnaire. For CelD, the questionnaires were modified with "CelD" instead of "IBD". Results: Fifty-one patients were included, 17 in each subgroup (Crohn's disease (CD), ulcerative colitis (UC), and Celd). FR-QoL scores were negatively correlated with age at inclusion (Spearman's ρ = -0.284, p = 0.04) and also with age at diagnosis (Spearman's ρ = -0.291, p = 0.038). The scores were significantly lower in the CD group (64.1 ± 13.4) compared with CelD patients (78.6 ± 20.3), p = 0.036 and UC, p = 0.294. For the IBD group, the scores were not influenced by disease activity. Furthermore, we identified a negative significant correlation between anthropometric indices and FR-QoL scores. Conclusions: The burden of dietary intervention is highest for the CD patients, regardless of their disease activity when compared with UC and CelD patients, most probably because of the unpredictable course and fast response to dietary changes. Although it requires incessantly vigilant eating behavior, CelD has apparently become more "manageable" in recent years.

The gut microbiome plays a crucial role in the pathogenesis and progression of inflammatory bowel disease (IBD). Understanding the dynamics of the gut microbiome in relation to treatment can provide valuable insights into disease management and therapy strategies. The aim of this study is to investigate if diversity and composition of the gut microbiome correlate with time since treatment and disease activity during maintenance infliximab (IFX) therapy among children with IBD.

Data was collected from IBD patients aged 10-17 participating in an IFX-eHealth study. IFX infusions were administered in 4-12-week intervals based on weekly faecal calprotectin (FC) combined with symptom scores. Excess stool samples underwent microbiome profiling using 16S rRNA gene sequencing. Microbiome features, including alpha diversity and single taxa, were analysed for three key variables: 1) weeks-since-treatment, 2) FC, and 3) symptom score.

From 25 patients (median age 14.4 years) diagnosed with Crohn´s Disease (n = 16) or ulcerative colitis (n = 9), microbiota were analysed in 671 faecal samples collected across 15 treatment intervals. A significant decrease over time in Shannon diversity, following the initial increase within four weeks of treatment, was found across patients. FC levels showed no association with alpha diversity (p>0.1), while symptom scores showed a negative association with Shannon and observed diversity in patients with UC. At the genus level, a lower abundance of the genera Anaerostipes and Fusicatenibacter (Firmicutes), and a greater abundance of the genus Parasutterella (Proteobacteria), were associated (p.adj<0.05) with the time elapsed since last infusion in UC specifically, while only Parasutterella was associated across the full cohort (p.adj = 1e-10).

We found a recurring reduction over time in alpha diversity following the initial increase in diversity after an IFX infusion. Changes in an individual's microbiome may be an early sign of increasing disease activity that precedes clinical symptoms and increased FC.

This study aimed to define clusters of disease activity and prognostic factors of disease course in a well-characterized cohort of children with Crohn's disease (CD).

All patients from the SIGENP IBD (Italian Society of Pediatric Gastroenterology Hepatology and Nutrition Inflammatory Bowel Disease) registry with a 5-year follow-up and 6-monthly evaluation were included. Active disease was defined for each semester as follows: clinical activity (weighted Pediatric Crohn's Disease Activity Index ≥12.5 or Mucosal Inflammation Noninvasive Index ≥8) and active disease on endoscopy (Simple Endoscopic Score for Crohn's Disease >3 or fecal calprotectin >250 µg/g) or imaging. Formula-based clusters were generated based on previously published patterns in adults.

Data from 332 patients were analyzed. A total of 105 (32%) experienced a quiescent disease course; 49 (15%) and 31 (9%) a moderate-to-severe chronically active and chronic intermittent disease, respectively; 104 (31%) and 43 (13%) had active disease in the first 2 years after diagnosis and remission thereafter and vice versa, respectively. Surgery at diagnosis was significantly associated with a quiescent course (odds ratio [OR], 10.05; 95% confidence interval [CI], 3.05-25.22; P=.0005), while growth impairment at the diagnosis and active disease requiring corticosteroids at 6 months were inversely related to the quiescent group (OR, 0.48; 95% CI, 0.27-0.81; P= .007; and OR, 0.35; 95% CI, 0.16-0.71; P= .005, respectively). Perianal involvement at diagnosis and moderate-severe activity at 6 months correlated with disease progression (OR, 3.85; 95% CI, 1.20-12.85; P=.02).

During the first 5 years of follow-up, one-third of children with CD experience a quiescent course. However, another one-third have a moderate-to-severe disease course. Surgery at the diagnosis is related to a quiescent course, while growth impairment and lack of response to induction therapy correlate with more severe disease activity during follow-up.

Limited approval of second-line treatments in pediatric inflammatory bowel disease (pIBD) necessitates optimized use of infliximab (IFX) with proactive therapeutic drug monitoring (TDM). We investigated whether early combo-therapy with an immunomodulator (IMM) provides additional benefit.

In the retrospectively reviewed medical records of all children treated with IFX and proactive TDM between 2013 and 2022, IMMearly (IMM ≤3 months since IFX start) was evaluated against IMMother/no (late/short or no IMM) over follow-up of 3 to 60 months. Kaplan-Meier analysis was used to analyze time to loss of response (LOR) with IFX discontinuation or time to antibodies-to-IFX (ATI) development.

Three hundred fifteen patients with pIBD were reviewed; of those, 127 with 2855 visits were included (77 CD, 50 UC/IBD-unclassified). Sixty patients received IMMearly, 20 patients IMMother, and 47 had IFX monotherapy. Median follow-up time was 30 and 26 months for IMMearly and IMMother/no, respectively, with comparable proactive TDM. Infliximab treatment persistence was 68% after 60 months. Loss of response was observed in 7 IMMearly and 15 IMMother/no patients (P = .16). Early combo-therapy significantly delayed LOR with IFX discontinuation (median LOR free interval IMMearly 30 months vs IMMother/no 9 months, P = .01). Patients with IMMother/no were 10-, 3- and 2-times more likely to experience LOR with IFX discontinuation after 1, 3, and 5 years, respectively. There were no significant group differences regarding the presence of any positive (>10 arbitrary units per milliliter [AU/mL]) or high (>100 AU/mL) ATI, median ATI concentrations, and ATI-free interval.

Early IMM combo-therapy in proactively monitored patients with pIBD significantly prolonged the median LOR free interval compared with late/short or no IMM treatment.

We investigated relationships between disease activity measures and the gut microbiome in children with Crohn's disease (CD) and how these were confounded by gastrointestinal transit time.

Microbiome was profiled (16S rRNA sequencing) in feces from 196 children with CD. Sixty participants also provided samples after 18 months. Mural inflammation (Pediatric Inflammatory Crohn's Magnetic Resonance Enterography Index, PICMI), the simple endoscopic score for CD, and the weighted pediatric Crohn's disease activity index (wPCDAI) were assessed. Fecal calprotectin, plasma C-reactive protein (CRP), and fecal water content (FWC), a proxy of gastrointestinal transit time, were measured too.

Microbiome α diversity, clustering, and differential taxa were related to disease status, but varied remarkably by disease activity measure used. The strongest relationships between microbiome and disease activity status were observed using wPCDAI; fewer or no relationships were seen using more objective measures like PICMI. Taxa predictive of disease activity status were dependent on the disease activity measure used with negligible overlap. Active disease was associated with more pathobionts (eg, Viellonella, Enterobacterales) and fewer fiber-fermenting organisms. The effect FWC had on microbiome superseded the effect of active disease for all disease activity measures, particularly with wPCDAI. Accounting for FWC, the differences in microbial signatures explained by disease activity status were attenuated or lost.

In CD, microbiome signatures fluctuate depending on the measure used to assess disease severity; several of these signals might be secondary disease effects linked with changes in gut motility in active disease. PICMI appears to be less influenced when studying relationships between microbiome and mural inflammation in CD.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gut affecting both adults and children. Neutrophil extracellular traps (NETs) are structures released by activated neutrophils, potentially contributing to tissue damage in various diseases. This study aimed to explore the presence and role of NETs in pediatric IBD. We compared intestinal biopsies and peripheral blood from 20 pediatric IBD patients (UC and CD) to controls. Biopsy staining and techniques for neutrophil activation were used to assess neutrophil infiltration and NET formation. We also measured the enzymatic activity of key NET proteins and evaluated NET formation in UC patients in remission. Both UC and CD biopsies showed significantly higher levels of neutrophils and NETs compared to controls (p < 0.01), with UC exhibiting the strongest association. Peripheral blood neutrophils from UC patients at diagnosis displayed increased NET formation compared to controls and CD patients. Interestingly, NET formation normalized in UC patients following remission-inducing treatment. This pilot study suggests a potential role for NETs in pediatric IBD, particularly UC. These findings warrant further investigation into the mechanisms of NET involvement and the potential for targeting NET formation as a therapeutic strategy.

Combination therapy consists of both anti-tumor necrosis factor (anti-TNF) and an immunomodulator (IMM) and has been shown to improve outcomes in patients with inflammatory bowel disease (IBD). This study assesses the impacts of IMM withdrawal from combination therapy to anti-TNF monotherapy in children with IBD.

This single-center retrospective cohort study included children with IBD initiated on combination therapy between 2014 and 2019 who discontinued the IMM. We evaluated whether IMM withdrawal impacts laboratory values and disease activity. Linear mixed effects models with random intercepts were used to compare differences between groups. Chi-square and Kruskal-Wallis tests were used for comparisons between patients who did and did not require subsequent escalation of therapy.

One hundred and fifty-two patients discontinued the IMM which did not significantly affect disease activity. However, 18% of patients escalated therapy after IMM withdrawal, primarily due to low anti-TNF levels. Lower anti-TNF and higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels before IMM withdrawal were associated with subsequent escalation of therapy. Overall, there was no statistically significant effect on anti-TNF drug levels. Patients with Crohn's disease (CD) on infliximab (IFX) and methotrexate (MTX) who discontinued the IMM had an increase in mean ESR and CRP (p < 0.05).

IMM withdrawal from anti-TNF combination therapy may be considered safe in the setting of higher anti-TNF levels and normal serum inflammatory markers. Clinicians should consider assessing anti-TNF levels and inflammatory markers after IMM withdrawal, especially in patients with CD receiving IFX who discontinued MTX.

Patients with inflammatory bowel disease (IBD) tend to self-modify their dietary habits according to disease activity and symptoms. This study aimed to assess the adequacy of the usual diet in Italian children with IBD in comparison to a control group and to the recommended dietary allowances (RDA).

Dietary habits of IBD children and age- and gender-matched healthy controls were investigated using a validated Food Frequency Questionnaire in five Italian pediatric IBD centers. Adherence to the Mediterranean diet (MD) was assessed using the KID-MED test. Energy (EI), macro, and micronutrients intakes were compared between the two groups, to the RDA and the predicted total energy expenditure (EI/total energy expenditure [TEE]%).

IBD subjects (n = 110) reported a lower EI, EI/RDA%, and EI/TEE% compared to controls (n = 110) (p = 0.012, p < 0.0002, and p = 0.014), lower total protein and fat intakes (p = 0.017, p < 0.0001) and lower minerals/RDA, vitamins/RDA and micronutrients/RDA ratio (%). Poor adherence to the MD was more frequent in IBD children compared to controls (p = 0.013). The total EI and carbohydrate intake were inversely correlated with higher disease activity.

Italian children with IBD report an inadequate diet in terms of energy, macro, and micronutrients and have a low adherence to a high-quality MD pattern.

The management of inflammatory bowel disease (IBD) in children and adolescents is challenging. Clear evidence-based guidelines are required for this population. This article provides recommendations for managing IBD in Saudi children and adolescents aged 6-19 years, developed by the Saudi Ministry of Health in collaboration with the Saudi Society of Clinical Pharmacy and the Saudi Gastroenterology Association. All 57 guideline statements are based on the most up-to-date information for the diagnosis and management of pediatric IBD.

The immunological effects of exclusive enteral nutrition (EEN) in the treatment of active Crohn's disease (CD) are yet to be unveiled. The present study investigated changes in peripheral blood mononuclear cell profiles in children with active CD following 8-week treatment with EEN. In nine children, EEN significantly decreased the number and frequency of circulating effector memory CD8+ T cells re-expressing CD45RA, with corresponding increases observed in the frequency of circulating central and effector memory CD8+ T cells. These signals were conserved when looking at a subgroup of patients who achieved remission, and another who demonstrated the highest level of compliance to EEN. We speculate that the increases in circulating central and effector memory CD8+ T cells may be related to the extensive microbiome-modifying effects of EEN dampening immune response within the gastrointestinal tract.

The incidence and prevalence of inflammatory bowel disease (IBD) is on the rise in North America and worldwide, with young children being the fastest growing patient population. It is therefore essential for pediatricians and pediatric sub-specialists to be able to recognize signs and symptoms suspicious for a new diagnosis of IBD, as well as potential complications associated with IBD or its treatment. This article reviews the most recent literature regarding clinical presentation, helpful diagnostic clues, newer monitoring tools being used by pediatric gastroenterologists, and emerging new biologic and small molecule treatments.

Previous studies have shown rates of surgical resection of up to 41% in stricturing pediatric Crohn's disease (CD). In this retrospective multicenter study, our aims were to identify clinical risk factors and magnetic resonance enterography (MRE) features of small bowel strictures associated with surgery.

Pediatric patients with symptomatic stricturing small bowel CD (defined as obstructive symptoms or proximal dilatation on MRE) confirmed by MRE between 2010 and 2020 were recruited from 12 French tertiary hospitals. Patient characteristics were compared by surgical outcome multivariable Cox regression.

Fifty-six patients (61% boys) aged 12.2 ± 2.7 years at diagnosis of CD were included. Median duration of CD before diagnosis of stricture was 11.7 months (interquartile range [IQR]: 25-75: 1.2-29.9). Nineteen (34%) patients had stricturing phenotype (B2) at baseline. Treatments received  before stricture diagnosis included MODULEN-IBD (n = 31), corticosteroids (n = 35), antibiotics (n = 10), anti-TNF (n = 27), immunosuppressants (n = 28). Thirty-six patients (64%) required surgery, within 4.8 months (IQR: 25-75: 1.8-17.3) after stricture diagnosis. Parameters associated with surgical resection were antibiotic exposure before stricture diagnosis (adjusted odds ratio [aOR]: 15.62 [3.35-72.73], p = 0.0005), Crohn's disease obstructive symptoms score (CDOS) > 4 (aOR: 3.04 [1.15-8.03], p = 0.02) and dilation proximal to stricture >28 mm (aOR: 3.62 [1.17-11.20], p = 0.03).

In this study, antibiotic treatment before stricture diagnosis, intensity of obstructive symptoms, and diameter of dilation proximal to small bowel stricture on MRE were associated with risk for surgical resection.

In an era of increasing paediatric obesity and inflammatory bowel disease (IBD), this study evaluates the disease phenotype and clinical course of Crohn's disease (CD) in paediatric patients who are obese or overweight.

This is a retrospective, single-center, descriptive observational study from January 2010 to May 2020. Participants were included if they were: aged 2 to 18 years at the time of diagnosis, had a confirmed diagnosis of CD, and met WHO criteria for overweight or obesity at the time of diagnosis or within one year before diagnosis.

A total of 345 patient charts with CD were screened during the study period, with 16 patients meeting inclusion criteria. Median age of patients was 15.5 years (IQR = 13.6, 16.1). Of the 15 patients over 10 years of age, median anthropometrics at diagnosis included body mass index (BMI) of 27.2 (IQR = 24.9, 29.4) and BMI for age z-score of 1.82 (IQR = 1.58, 2.19). Presenting symptoms included abdominal pain (80.0%), diarrhea (66.7%), hematochezia (66.7%), and weight loss (26.7%). Five patients (33.3%) had obesity-related complications. Median time from symptom onset to diagnosis was 146 days (IQR = 31, 367), and median time from diagnosis to remission was 229 days (IQR = 101.8, 496.3).

Patients with elevated BMI and CD present with typical symptoms of IBD, although weight loss was a less common presenting symptom. Time to disease remission is delayed, and obesity-related complications are common. Primary care providers must have a high degree of clinical suspicion in patients to prevent delays to gastroenterology referral and to improve time to disease remission.

Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed.

To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease.

We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks.

We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first-line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03-2.35, p = 0.036).

First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease.

NCT02517684.