BACKGROUND:Interleukin-10 (IL-10) is an essential regulator of intestinal immune homeostasis. Neutralising autoantibodies against IL-10 (anti-IL-10) have been identified in children and also adult patients with IBD. Positivity for anti-IL-10 autoantibodies was associated with carriage of HLA-DRB1*01:03 allele. OBJECTIVE:To determine the prevalence of anti-IL-10 in paediatric IBD and assess the associated clinical phenotype. DESIGN:We conducted a cross-sectional multicentre study across paediatric IBD cohorts from four countries. Anti-IL-10 antibodies were investigated in serum and plasma from paediatric patients with IBD (mean age of IBD onset 11.2±3.8 years). IL-10-neutralisation capacity was confirmed by functional IL-10 reporter assay, competitive ELISA and cytokine release assay. Clinical data were analysed to evaluate disease phenotype and treatment outcomes, with comparison with matched controls. HLA-DRB1*01:03 analysis was performed. RESULTS:Anti-IL-10 positivity was identified in 26/1045 paediatric patients with IBD (2.5%) (Crohn's disease n=6, UC n=19, IBD unclassified n=1; IBD diagnosis age of 13±3 years). Anti-IL-10 autoantibodies were of the IgG class and amplified pro-inflammatory cytokine responses in vitro. Anti-IL-10-positive patients exhibited more severe disease compared with matched controls, including an increased prevalence of difficult-to-treat disease (23% vs 6%, p=0.03), higher rate of acute severe UC (26% vs 6%; p=0.038) and higher rates of colectomy (27% vs 6%, p=0.01). Eighty percent (16/20) of anti-IL-10-positive patients with available HLA data carried the HLA-DRB1*01:03 allele, compared with 1.5% in the anti-IL-10-negative group. CONCLUSION:Anti-IL-10 autoantibodies are present in a subgroup of paediatric patients with IBD and are associated with difficult-to-treat disease.

Background:Infliximab and adalimumab are effective anti-tumor necrosis factor (anti-TNF) therapies for the treatment of pediatric Crohn's disease (CD). The aim of this study was to compare the effectiveness of infliximab and adalimumab in a real-world cohort of children with CD. Methods:Data from biological-naïve children with luminal CD (age 3-18 years) who commenced anti-TNF and completed at least 1 year of follow-up were collected from the prospective multicenter observational PIBD-SETQuality study. The primary outcome was steroid-free clinical remission (SFCR), defined as clinical remission (weighted pediatric Crohn's disease activity index [wPCDAI] <12.5) without systemic steroids or luminal surgery at 1 year. The relative risk (RR) of SFCR was calculated using standardization, correcting for the following baseline covariates: age, upfront anti-TNF, C-reactive protein, erythrocyte sedimentation rate, albumin, leukocytes, disease behavior, wPCDAI, perianal disease, and concomitant immunomodulator use. Secondary outcomes included the durability of anti-TNF treatment without luminal surgery. Results:Between January 1, 2017, and June 14, 2024, 178 patients with anti-TNF were included (infliximab: n = 121 [68%], adalimumab: n = 57 [32%]). At 12 months, 34/56 (61%) patients treated with adalimumab and 66/120 (55%) patients treated with infliximab had reached SFCR. The RR of SFCR at 1 year with adalimumab compared to infliximab was 1.25 (95% confidence interval [CI] 0.94-1.66], P = .13. Adalimumab was associated with a significant lower adjusted hazard ratio (aHR) of treatment discontinuation than infliximab in patients with a concomitant immunomodulator (aHR 0.17 [95% CI 0.04-0.75], P = .020), adjusted for upfront anti-TNF. Conclusions:In this prospective cohort of children with CD, adalimumab and infliximab showed comparable clinical effectiveness 1 year after the start of anti-TNF treatment. Clinical trial registration:The ClincalTrials.gov ID of this study is NCT03571373.

OBJECTIVES:Children with inflammatory bowel disease (IBD) have an increased risk of developing kidney disorders, which may cause significant kidney function impairment (SKI) or lead to chronic kidney disease (CKD). In this study we aimed to provide insights in causes and diagnoses of SKI cases and to provide recommendations for pediatric gastroenterologists for children with IBD and SKI. METHODS:Cases of SKI in children with IBD (<19 years) were collected from the international, prospective PIBD-SETQuality Safety Registry. A monthly survey was sent to participating pediatric gastroenterologists to report cases of SKI (defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2). Additionally, a panel consisting of 16 members (including experts in pediatric IBD and nephrology) rated the most likely cause of the cases and formulated recommendations for screening, follow-up and referral for children with IBD and SKI. RESULTS:Between November 1, 2016 and December 31, 2023, 42 cases of SKI were eligible for analysis. Tubulo-interstitial nephritis (TIN) was the most common diagnosis (n = 15). Sixteen (38%) cases were confirmed with renal biopsy (10 cases of TIN). Twelve patients developed CKD. IBD medication was the most frequently reported cause (n = 15), however, there was low concordance between panelists about the most likely etiology (Fleiss' kappa 0.143 and 0.102). CONCLUSIONS:This is the first prospective study to report cases of SKI in children with IBD. SKI may lead to CKD. Confirming the etiology of the SKI proved to be very challenging. The study provides recommendations for screening and follow-up of SKI in children with IBD. TRIAL REGISTRATION:NCT03571373, date of registration: June 27, 2018, URL: https://clinicaltrials.gov/study/NCT03571373.

Corticosteroids (CS) and exclusive enteral nutrition (EEN) are effective induction therapies for pediatric Crohn’s disease (CD), but comparative studies evaluating long-term outcomes in small bowel CD are lacking. Children (2–18 years) with newly diagnosed small bowel CD involving the ileum prospectively enrolled in the multicenter Canadian CIDsCaNN or European PIBD-SETQuality inception cohorts receiving CS or EEN induction treatment were evaluated longitudinally. The primary outcome was sustained steroid-free remission (SSFR) at 1 year. Secondary outcomes included changes in height z-scores, time-to-first-biologic and time-to-luminal-resection. Results were confirmed after propensity score matching (PSM). In total, 208 children (61

BACKGROUND:Environmental enteropathy (EE) is an asymptomatic lesion of the small intestine, likely an adaptive response to environmental noxa, including enteropathogens, leading to recurrent intestinal injury, mucosal inflammation, and microbial translocation. Inflammatory bowel disease (IBD) is increasing in incidence in newly industrialised countries. Given that EE is seen in individuals living in insanitary environments in low-income countries (LICs) and IBD has traditionally been viewed as a disease of developed countries, we hypothesised that these two conditions would not co-exist. AIMS:To investigate whether EE is seen in individuals with IBD living in a low-income country in sub-Saharan Africa. METHODS:Enteropathy was assessed in adult Zambians with IBD and controls from high and low socio-economic status (SES) groups with duodenal biopsies and biomarkers of intestinal and systemic inflammation. Enteropathogen carriage rates between the groups were compared. RESULTS:28 cases and 59 controls (38 high SES and 21 low SES) were included. Histological features of EE were present in all cases and controls, with median villus height to crypt depth ratio <2 in all groups. Enteropathogen carriage was lower in cases (median of 1 pathogen per case to 2 per control). CONCLUSION:The co-existence of IBD and EE within the same individuals may prove to be a confounding factor when assessing patients presenting with symptoms suggestive of IBD in this setting and could be interpreted as evidence that improved environmental hygiene does not play a significant role in the emergence of IBD.

Background The genetic contribution to inflammatory bowel disease (IBD), encompassing both Crohn's disease (CD) and ulcerative colitis (UC), accounts for around 20% of disease variance, highlighting the need to characterize environmental and epigenetic influences. Recently, considerable progress has been made in characterizing the adult methylome in epigenome-wide association studies. Methods We report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD and UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform. Results We derived and validated a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI, and ARHGEF3), with specificity and high diagnostic accuracy for pediatric IBD in UK and North American cohorts (area under the curve: 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-methylation quantitative trait loci (meQTL) analysis identifies genetic determinants underlying epigenetic alterations notably within the HLA 6p22.1-p21.33 region. Passive smoking exposure is associated with the development of UC rather than CD, contrary to previous findings. Conclusions These data provide new insights into epigenetic alterations in IBD and illustrate the reproducibility and translational potential of epigenome-wide association studies in complex diseases.

Abstract Background The heterogeneity of paediatric ulcerative colitis (P-UC) can complicate diagnosis and prompt start of optimal induction treatment, which is crucial for adequate disease control. Recognizing and understanding atypical disease patterns in P-UC will decrease misclassification and contribute to the development of standardized classification tools. This study aims to provide insight in the real world prevalence of atypical phenotypes in newly diagnosed P-UC patients. Methods Data were collected from the Paediatric Inflammatory Bowel Diseases Network for Safety, Efficacy, Treatment and Quality improvement of care (PIBD-SETQuality) cohort, a multicenter, international, prospective, observational study including therapy naive children <19 years old with IBD. Patients diagnosed with UC between January 1st 2017 and June 14th 2024 were enrolled. Diagnostic criteria and macroscopical atypical disease were based on the validated PIBD-classes algorithm by revised Porto Criteria1. The Mann-Whitney U test and Chi-square tests were used to compare, respectively, numerical and categorical data between patient groups. Results Baseline data of 197 P-UC patients were included. At diagnosis, 68% of the patients presented with pancolitis. Atypical disease occurred in 35.0% (69/197) of the patients of which relative rectal sparing was most common (Table 1). Aspecific upper gastrointestinal inflammation occurred in 10.6% (17/161) of the patients, of whom 6 also exhibited atypical disease phenotypes. Approximately 1 out of 10 patients with atypical disease presented with multiple atypical phenotypes. Patients with atypical disease did not show significant differences compared to patients without atypical disease in time to diagnosis (107 days vs. 104 days, P=0.19), absolute PUCAI score (40 [IQR 30-55] vs. 35 [IQR 25-58.75], p=0.10), initial induction therapy and need for treatment intensification during induction therapy (8 vs. 4 patients, p=0.22). Conclusion Atypical disease presentations are common in P-UC in this real world cohort, as is the presence of combined atypical disease features. Recognition of atypical disease features in P-UC, and understanding their impact on disease course, are crucial for prompt start of optimal tailored therapy. In this cohort, the presence of atypical disease did not result in a diagnostic delay or treatment intensification during induction period. References 1.Birimberg-Schwartz L, Zucker DM, Akriv A, et al. Pediatric IBD Porto Group of ESPGHAN. Development and validation of diagnostic criteria for IBD subtypes including IBD-unclassified in children: a multicentre study from the Pediatric IBD Porto Group of ESPGHAN. J Crohns Colitis. 2017;11(9):1078-1084. doi:10.1093/ecco-jcc/jjx053.

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 Tcell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). TIGIT+CD38+TM have regulatory function while TIGITnegCD38+TM are enriched in IFN-gamma-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-na & iuml;ve CD patients with high plasma IFN-gamma and a more severe disease course. TIGITnegCD38+TM were highly enriched in HLA-DR+ and ex-Th17/Th1-like cells, high producers of IFN-gamma. 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.

Current first-line treatments of paediatric ulcerative colitis (UC) maintain a 6-month remission in only half of the patients. Relapse prediction at diagnosis could enable earlier introduction of immunosuppressants. We collected intestinal biopsies from 56 treatment-naïve children, combining mucosal quantitative microbial profiling with host epigenomics, transcriptomics, genotyping, and in vitro and in vivo experiments on selected bacteria. Baseline bacterial diversity is lower in relapsing children, who have fewer butyrate producers but more oral-associated bacteria, whereof Veillonella parvula induces inflammation in epithelial cell lines and IL10-/- mice. Microbiota has the strongest association with future relapse, followed by host epigenome and transcriptome. Interferon gamma signalling is also linked to relapse-associated bacteria. Relapse-prediction using separate omics data is outperformed by a robust machine learning approach combining microbiomes and epigenomes. In summary, host-microbe data have prognostic potential in paediatric UC. Our translational findings also suggest that pro-inflammatory oral-associated colonizers can exploit the reduced colonic bacterial diversity of relapsing children.

Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-na & iuml;ve pediatric IBD (Crohn's disease, CD: n = 62; ulcerative colitis, UC: n = 20; age-matched controls n = 43), and after 10-12 weeks' induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-gamma production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-gamma pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.

Background and Aims: Treatment guidelines for paediatric Crohn's disease [CD] suggest early use of anti-tumour necrosis factor alpha [anti-TNF alpha] in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort.Methods: Children with newly diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF [<90 days after diagnosis] and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission [SSFR] without treatment intensification [specified as SSFR*] and sustained steroid-free mild/inactive disease without treatment intensification [specified as SSFMI*]. Penalised logistic regression model-based standardisation was applied to estimate the relative risks [RR] of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients, based on presence of predictors of poor outcome [POPOs] and disease activity at diagnosis.Results: In total, 331 children (median age 13.9 years [IQR 12.2-15.3]) were enrolled, with 135 [41%] receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* [30% vs 14%, p <0.001] and SSFMI* [69% vs 33%, p <0.001], with RRs of 2.95 [95% CI 1.63-5.36] and 4.67 [95% CI 2.46-8.87], respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared with mild/inactive disease at diagnosis (5.50 [95% CI 2.51-12.05] vs 2.91 [95% CI 0.92-9.11]), and those with any POPO compared with no POPO (5.05 [95% CI 2.45-10.43] vs 3.41 [95% CI 0.54-21.7]).Conclusion: In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients.

Objectives:The objective of this study was to explore the correlation between paediatric Crohn's disease (CD) characteristics, bone health and growth parameters at diagnosis and follow-up. Methods:Retrospective data was collected for 47 children aged 4-16 who were newly diagnosed with CD between January 2018 and December 2019. Mean follow-up time was 2.5 years. Results:Eleven (24%) children had growth delay at diagnosis, which persisted in 4 (44%) of 9 recorded children at follow-up. Of the 35 children tested, 20 (57%) had inadequate Vitamin D levels (<50 mmol/L) at diagnosis. Thirty-seven (79%) children had a dual-energy X-ray absorptiometry scan at diagnosis, with 20 of them having at least 1 low Z-score. Children with poorer bone mineral density and bone mineral concentration Z-scores for age had a younger age at diagnosis (p = .042 and p = .021), more severe disease (p = .04 and p = .029) and a lower BMI (p < .001) at diagnosis. Children diagnosed with CD ≥11 years had a lower-than-expected height velocity (p < .0001 and p < .001). Multivariate regression analysis demonstrated an older age of diagnosis was a significant predictor of a lower height velocity at follow-up. Conclusion:Disease severity and age of diagnosis are important CD-related factors that influence bone health and growth. Vitamin D is an accessible component that if optimised can improve all three factors. Monitoring and optimising each aspect systematically has the potential to enable children to achieve their bone health and growth potentials.

Abstract Background Patients with very early onset inflammatory bowel disease (VEOIBD) often present with severe disease course and require escalation to biologics. Exclusion of pediatric patients from clinical trials lead to scarcity of efficacy and safety data on TNFa antagonists therapy in VEOIBD. We aimed to assess safety and efficacy of adalimumab (ADM) induction and maintenance therapy in patients with VEOIBD. Methods This was a retrospective study involving 31 sites affiliated with the IBD Porto Group and IBD Interest Group of ESPGHAN, as well as centers in North America. Demographic, clinical and laboratory data were collected from patients diagnosed with VEOIBD who commenced ADM therapy before 6 years of age between 2014 to 2023. Results We identified 77 VEOIBD patients with a median age at diagnosis of 2.6 years (interquartile range [IQR] 1.3–4.1), of whom 29 (38%) were diagnosed at age <2 years (infantile-onset IBD). Thirty-seven (48%) patients were diagnosed with Crohn’s disease, 25 (32%) with ulcerative colitis and 15 (20%) with IBD-unclassified. Five (9%) from those genetically tested were diagnosed with monogenic disease. Median age at initiation of ADM was 4.2 (IQR 2.8-5.1) years. Forty-four patients (57%) were Infliximab experienced, discontinued mainly due to pharmacokinetic (20 [45%]) and pharmacodynamic (13 [30%]) failures. At initiation of ADM, concomitant corticosteroids and immunomodulators were given in 37 (48%) and 29 (37%) patients, respectively. The median wPCDAI and PUCAI scores at baseline were 45 [37.5-60] and 45 [27.5-57.5], respectively. Median follow-up time was 85.4 (IQR 40.4-139.2) weeks. While patients with CD showed significant clinical improvement after 26 and 52 weeks (PCDAI decreased to 10 [0-33.4], p<0.001, and 10 [0-25], p<0.05, respectively), No significant improvement in PUCAI score was observed among patients with UC (Figure 1). Inflammatory markers and calprotectin showed a gradual decrease over time (Figure 1). Weight and Height Z scores did not differ significantly throughout the follow-up period. ADM discontinuation rates after 1 and 3 years were 40% and 65%, respectively, mainly due to primary non-response (14, 29.8%) and loss of response (19, 40.4%). Drug discontinuation rates were not dependent on concomitant immunomodulator treatment or ADM initiation or on age (less or above 3 years). Four patients (5.2%) developed severe infections, including a patient with TTC7A mutation who died following septic shock. Conclusion Adalimumab therapy was relatively safe and seemed more effective in young patients with Crohn’s disease, but not in those with ulcerative colitis. Durability was relatively low due to high rates of primary non-response and secondary loss of response.

Abstract Background Renal manifestations may occur in children with inflammatory bowel disease (IBD). The cause of renal manifestations is often unclear, but may occur as an extra-intestinal manifestation or due to IBD treatment. Renal complications can lead to acute renal failure, a severe complication and associated with a risk of developing chronic kidney disease (CKD). Current paediatric ECCO/ESPGHAN guidelines recommended to regular monitor renal function with calcineurin inhibitors. However, these recommendations are based on limited knowledge of renal manifestations in paediatric IBD. The aim of this study was to investigate the diagnosis and underlying causes of renal failure in children with IBD. Methods Cases of renal failure in children <19 years with IBD were collected from the international, prospective PIBDSETQuality Safety Registry1. A monthly survey was sent to participating paediatric gastroenterologists throughout the world asking to report cases of renal failure within their clinical practice. Renal failure was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 based on the Schwartz formula. Upon reporting a case of renal failure, a follow-up form was automatically sent to obtain more information about renal failure, IBD characteristics and outcomes (including CKD, defined as an eGFR <60 for >3 months). Results From November 2016 until August 2023, 220 gastroenterologists from 36 countries participated in the Safety Registry and 38 cases of renal failure were included. Characteristics at time of renal failure are reported in Table 1. Reported causes and diagnoses of renal failure are represented in Figure 1. Most frequently reported causes were IBD medication (n=12) and IBD itself (n=10). IBD medication included 5-ASA (n=5), tacrolimus (n=2) and one case of azathioprine or ibuprofen, vedolizumab, adalimumab, cyclosporine A and ciprofloxacin. Of the cases most likely caused by IBD itself, disease activity was remission (n=4), mild (n=2), moderate (n=3) or severe (n=1). In the majority of cases (n=26, 68%) creatinine was measured during routine follow-up, and not due to kidney-related symptoms. In 13/37 patients creatinine remained elevated after a median follow-up of 82 weeks [41-136 weeks]. Nine patients developed CKD, two patients required renal replacement therapy. Conclusion This is the first prospective study to report cases of renal failure in children with IBD. Renal failure can occur without symptoms, and may lead to CKD. Timely identification of cases of renal failure is important to adequately treat and monitor patients. We recommend to monitor creatinine in all children with IBD, independent of drug use, every 6 months. References 1. Aardoom et al. BMJ Open. 2020

Abstract Background The application of -omics technology offers important opportunities for biomarker discovery to personalise management of patients with inflammatory bowel disease (IBD). In previous work, we reported a characteristic profile of genome-wide DNA methylation in peripheral blood leucocytes from children with paediatric IBD (pIBD) at diagnosis defining the IBD methylome. This characteristic pattern of genome-wide alterations was replicated in inception cohorts of adult patients in UK and Scandinavia. Methods Whole blood DNA methylation profiling was performed using the Illumina EPIC array on 86 pIBD patients and 30 non-IBD controls. Patients had a median age of 12 y and were prospectively recruited from gastroenterology clinics in Oxford and Cambridge, UK. In modelling, we utilised the paediatric BISCUIT and PICTS study cohorts from Scotland as our training data. Publicly available data from the RISK paediatric CD cohort from North America was accessed (GSE11261) to further assess accuracy of the model. The model was then subjected to further testing in an Oxford-based paediatric coeliac cohort and adult cohorts with IBD, and rheumatoid arthritis (RA)(Table 1). Results Genome-wide methylation changes in the Oxford/Cambridge cohort were highly consistent with the index BISCUIT and PICTS cohorts. Four single methylation sites were selected to make up a diagnostic model involving the genes, RPS6KA2, VMP1, CF1 and ARHGEF3 (Figure 1) in the index cohort and validated in the Oxford/Cambridge cohort. Following receiver operating characteristic (ROC) area under the curve (AUC) analyses the model demonstrated an AUC of 0.912 (95% CI: 0.86-0.96) (Table 1). To further validate our model, we compared pIBD who were CRP-positive (>5 mg/l) and CRP-negative (<5 mg/l) at presentation against non-IBD children. In the CRP-positive group, we found an AUC of 0.99 (95% CI: 0.99-1). Within the CRP-negative group an AUC of 0.90 was observed against controls (95% CI: 0.83-0.96). The model was further validated using methylation data at the baseline timepoint in the RISK cohort, with an AUC of 0.93 (95% CI: 0.90-0.96). In further analyses, we demonstrated specificity for IBD compared with paediatric coeliac disease; and accuracy higher in childhood-onset AUC than adult-onset disease AUC; the model is not accurate in diagnosis of RA. Conclusion We confirm a characteristic pattern of DNA methylation changes in childhood-onset IBD; and derive and validate a 4-probe model for diagnosis with high accuracy in both Europe and North America. The model is specific for pIBD compared with symptomatic children with no demonstrable pathology; and children with coeliac disease; and may provide an alternative to current markers in blood and stool, including calprotectin.

Ustekinumab is an effective therapy for adult Crohn’s disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn’s Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7–17.2) with a median follow-up of 7.4 months (IQR 5.6–11.8). Ninety-nine percent had received prior anti-TNF, 63