Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's Disease.

OBJECTIVE: Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis. DESIGN: We generated 312 intestinal epithelial organoids (IEOs) from mucosal biopsies of 168 patients with CD (n=72), UC (n=23) and healthy controls (n=73). We performed genome-wide molecular profiling including DNAm, bulk as well as single-cell RNA sequencing. Organoids were subjected to gene editing and the functional consequences of DNAm changes evaluated using an organoid-lymphocyte coculture and a nucleotide-binding oligomerisation domain, leucine-rich repeat and CARD domain containing 5 (NLRC5) dextran sulphate sodium (DSS) colitis knock-out mouse model. RESULTS: We identified highly stable, CD-associated loss of DNAm at major histocompatibility complex (MHC) class 1 loci including NLRC5 and cognate gene upregulation. Single-cell RNA sequencing of primary mucosal tissue and IEOs confirmed the role of NLRC5 as transcriptional transactivator in the intestinal epithelium. Increased mucosal MHC-I and NLRC5 expression in adult and paediatric patients with CD was validated in additional cohorts and the functional role of MHC-I highlighted by demonstrating a relative protection from DSS-mediated mucosal inflammation in NLRC5-deficient mice. MHC-I DNAm in IEOs showed a significant correlation with CD disease phenotype and outcomes. Application of machine learning approaches enabled the development of a disease prognostic epigenetic molecular signature. CONCLUSIONS: Our study has identified epigenetically regulated intestinal epithelial MHC-I as a novel mechanism in CD pathogenesis.

Top 10 research priorities for digital technology for adolescents and young persons with inflammatory bowel disease: Results of a James Lind Alliance Priority Setting Partnership.

OBJECTIVES: Priority Setting Partnerships (PSP's) using the James Lind Alliance (JLA) methodology, bring together health professionals, patients and parents/carers to identify and prioritise unanswered questions that can be addressed by future research projects. To identify and prioritise the top 10 unanswered research priorities in digital technology for adolescents and young people (AYP) with inflammatory bowel disease (IBD). METHODS: A steering group (SG) consisting of AYP with IBD, their parents/carers, representatives from two charities (Crohn's & Colitis UK, Crohn's in Childhood Research Association), patient information forum and paediatric and adult and primary care healthcare professionals was established in 2021. The SG agreed the protocol, and scope of the PSP and oversaw all aspects. SG meetings were chaired by a JLA advisor and followed the established JLA methodology. RESULTS: The initial survey generated 414 in-scope questions from 156 respondents, thematically categorised into 10 themes and consolidated into 92 summary questions by the SG. A comprehensive literature review followed by SG deliberation narrowed the unanswered summary questions to 45, for the interim prioritising survey. One hundred and two respondents ranked their top 10 research questions. Outputs generated top 18 research priorities presented at a final virtual prioritisation workshop, facilitated by JLA advisors and attended by key stakeholders, ranked into top 10 research priorities. DISCUSSION: The top 10 research priorities will encourage researchers to undertake research that addresses these areas of unmet need for AYP living with IBD, their parents/carers and their healthcare professionals, thereby facilitating improved patient care.

Precision nutrition in pediatric IBD: A position paper from the ESPGHAN special interest group for basic science and translational research, the IBD Porto group, and allied health professionals.

Stratified and precision nutrition refers to disease management or prevention of disease onset, based on dietary interventions tailored to a person's characteristics, biology, gut microbiome, and environmental exposures. Such treatment models may lead to more effective management of inflammatory bowel disease (IBD) and reduce risk of disease development. This societal position paper aimed to report advances made in stratified and precision nutritional therapy in IBD. Following a structured literature search, limited to human studies, we identified four relevant themes: (a) nutritional epidemiology for risk prediction of IBD development, (b) food-based dietary interventions in IBD, (c) exclusive enteral nutrition (EEN) for Crohn's disease (CD) management, and (d) pre- and probiotics for IBD management. There is scarce literature upon which we can make recommendations for precision or stratified dietary therapy for IBD, both for risk of disease development and disease management. Certain single-nucleotide polymorphisms related to polyunsaturated fatty acid (PUFA) metabolism may modify the effect dietary PUFA have in increasing the risk of IBD development. Non-colonic CD, mild-to-moderate CD, and high microbiota richness may predict success of EEN and may be used both for prediction of treatment continuation, but also for early cessation in nonresponders. There is currently insufficient evidence to make recommendations for precision or stratified dietary therapy for patients with established IBD. Despite the great interest in stratified and precision nutrition, we currently lack data to support conclusive recommendations. Replication of early findings by independent research groups and within structured clinical interventions is required.

Ultrasound-guided distal transradial access for cardiac catheterization: Technical notes for the interventionalist.

Over the latest years, the use of distal radial access (dTRA), also called "snuffbox," has become more and more popular for cardiac catheterization. Indeed, dTRA has several advantages compared to the traditional proximal radial approach, such as a lower risk of hand ischemia, radial artery occlusion (RAO) and faster post-procedural hemostasis. However, due to the presence of different muscular-skeletal structures, as well as to the small diameter of the distal radial artery (dRA), an ultrasound-guided cannulation would be preferred since a blind puncture increases the risk of tendon damage and/or the irritation of the underlying periosteum. The present article is aimed to provide the key tips for performing US-guided access using the dRA in patients undergoing percutaneous cardiac procedures.

Novel pharmacological developments in the management of paediatric inflammatory bowel disease: Time for guideline update - A narrative review.

AIM: The incidence of paediatric inflammatory bowel disease (IBD) continues to increase in both adults and children across the globe, with more than one third of the patients not responding to anti-tumour necrosis factor biologics and immune modulators. This narrative review provides an overview of novel pharmacological developments in the management of paediatric IBD, including new biological therapies. METHODS: A PubMed Medline search was performed to include randomised controlled trials, retrospective and prospective observational studies, and relevant case reports of children with IBD published between 2018 and January 2023. Guidelines and protocols from relevant paediatric and adult gastroenterology societies, such as the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organisation, were also included. Non-pharmacological treatments including therapeutic diets and faecal microbiota transplantation were outside the scope of this work. RESULTS: Early real-world evidence suggests that newer biologics and small molecules, such as anti-integrins, interleukin-12 and/or interleukin-23 inhibitors, Janus kinase and signal transducer and activator of transcription proteins inhibitors, are safe and effective in adult patients with IBD, with promising growing evidence for paediatric IBD. CONCLUSION: While many developments have been achieved with novel pharmacological treatments to manage IBD, ongoing research is required to confirm their effectiveness and safety in the paediatric age. Extending the licence of novel treatments to children will be crucial to tackle the increasing loss of response to conventional treatments. International guidelines will require timely updating to incorporate novel treatments within the existing protocols.

Transcription and DNA Methylation Patterns of Blood-Derived CD8+ T Cells Are Associated With Age and Inflammatory Bowel Disease But Do Not Predict Prognosis.

BACKGROUND & AIMS: Gene expression patterns of CD8+ T cells have been reported to correlate with clinical outcomes of adults with inflammatory bowel diseases (IBD). We aimed to validate these findings in independent patient cohorts. METHODS: We obtained peripheral blood samples from 112 children with a new diagnosis of IBD (71 with Crohn's disease and 41 with ulcerative colitis) and 19 children without IBD (controls) and recorded medical information on disease activity and outcomes. CD8+ T cells were isolated from blood samples by magnetic bead sorting at the point of diagnosis and during the course of disease. Genome-wide transcription (n = 192) and DNA methylation (n = 66) profiles were generated using Affymetrix and Illumina arrays, respectively. Publicly available transcriptomes and DNA methylomes of CD8+ T cells from 3 adult patient cohorts with and without IBD were included in data analyses. RESULTS: Previously reported CD8+ T-cell prognostic expression and exhaustion signatures were only found in the original adult IBD patient cohort. These signatures could not be detected in either a pediatric or a second adult IBD cohort. In contrast, an association between CD8+ T-cell gene expression with age and sex was detected across all 3 cohorts. CD8+ gene transcription was clearly associated with IBD in the 2 cohorts that included non-IBD controls. Lastly, DNA methylation profiles of CD8+ T cells from children with Crohn's disease correlated with age but not with disease outcome. CONCLUSIONS: We were unable to validate previously reported findings of an association between CD8+ T-cell gene transcription and disease outcome in IBD. Our findings reveal the challenges of developing prognostic biomarkers for patients with IBD and the importance of their validation in large, independent cohorts before clinical application.

Advantages of Proactive Therapeutic Drug Monitoring in a Prospective Cohort of Children With Inflammatory Bowel Disease Treated With Anti-Tumour Necrosis Factor.

ABSTRACT: Few studies have addressed whether proactive therapeutic drug monitoring (TDM) results in improved clinical outcomes in children with inflammatory bowel disease (IBD) treated with anti-tumour necrosis factor. The aim of this study was to investigate the impact of using proactive TDM in this patient group.Pilot single-centre observational study to accrue data on patients managed with proactive TDM.More patients in the proactive TDM cohort were managed by escalating the infliximab (IFX) regime (P < 0.001). The need for switching to different biologics was significantly lower in this patient group (P < 0.001).The introduction of proactive TDM resulted in a significant reduction of patients requiring switch of their primary biologic. The results of this study are indicators that proactive TDM offers a better method of managing children with IBD on IFX therapy.

Making Research Flourish Through ESPGHAN: A Position Paper From the ESPGHAN Special Interest Group for Basic and Translational Research.

ABSTRACT: Recent research breakthroughs have emerged from applied basic research throughout all scientific areas, including adult and paediatric gastroenterology, hepatology and nutrition (PGHAN). The research landscape within the European Society of Paediatric Gastroenterology and Nutrition (ESPGHAN) is also inevitably changing from clinical research to studies involving applied laboratory research. This position paper aims to depict the current status quo of basic science and translational research within ESPGHAN, and to delineate how the society could invest in research in the present and future time. The paper also explores which research areas in the field of PGHAN represent the current and future priorities, and what type of support is needed across the ESPGHAN working groups (WGs) and special interest groups (SIGs) to fulfil their research goals.

Clinical Features and Outcomes of Paediatric Patients With Isolated Colonic Crohn Disease.

OBJECTIVES: Adult studies suggest that patients with isolated colonic Crohn disease (L2 CD) exhibit unique characteristics differentiating them from patients with ileo-caecal (L1) CD and ulcerative colitis (UC). We aimed to characterize clinical features and outcomes of paediatric patients with L2. METHODS: Retrospective data was collected through the Porto Inflammatory Bowel Disease group of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) on Paediatric patients with L2, L1 or UC at different time-points. Outcome measures included time to first flare, hospital admissions, initiation of anti-tumor necrosis factor-alpha (TNFα) drug, stricture and surgery. RESULTS: Three hundred patients were included: 102 L1, 94 L2 and 104 UC. Rates of hematochezia at presentation were 14.7%, 44.7% and 95.2%, while rates of fever were 12.7%, 26.6% and 2.9%, for patients with L1, L2 and UC, respectively (P < 0.001 for all comparisons). Skip lesions were identified in 65% of patients with L2, and granulomas in 36%, similar to L1 patients. Rates of anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic (pANCA) positivity significantly differed between the three groups: 25.4% and 16.7% for patients with L2, compared with 55.2% and 2.3%, and 1.8% and 52.9% for patients with L1 and UC, respectively. Response rates to exclusive enteral nutrition were comparable between L1 and L2 (78.3-82.4%), as was the response to oral steroids (70.4-76.5%) in the three groups. While times to first flare and admission were similar between groups, patients with L1 were commenced on anti-TNFα earlier. Moreover, stricturing phenotype and need for colectomy were very rare in patients with L2. CONCLUSIONS: Significant differences are observed in the clinical presentation and outcomes of Paediatric patients with L2, compared to patients with L1 and UC.

Sclerosing Cholangitis in Pediatric Inflammatory Bowel Disease: Early Diagnosis and Management Affect Clinical Outcome.

OBJECTIVE: To describe the characteristics and clinical course of children and young persons with inflammatory bowel disease (IBD) and sclerosing cholangitis (SC). STUDY DESIGN: Retrospective analysis of clinical characteristics, management, and outcome of two separate cohorts of children and young persons with IBD-SC managed in a tertiary pediatric gastroenterology center and in a tertiary pediatric hepatology center in the UK. RESULTS: Eighty-two pediatric patients (31% female) with IBD-SC and a mean age at diagnosis of 11.9 ± 2.8 years were followed up for a mean of 6.8 ± 3.3 years. The most common type of IBD was ulcerative colitis (55%), followed by unclassified IBD (30%) and Crohn's disease (15%). Autoimmune SC (ASC) was diagnosed in 72%, and small duct SC was diagnosed in 28%. Complication-free and native liver survival were 96% and 100%, respectively, at 5 years after diagnosis and 75% and 88%, respectively, at 10 years after diagnosis. Patients in the gastroenterology center, who were diagnosed with liver disease sooner after diagnosis of IBD compared with the hepatology center cohort (mean, 2.7 ± 6.1 months vs 9.3 ± 19.4 months; P = .03), did not develop liver-related complications during follow-up. CONCLUSIONS: Our data suggest that children with IBD-SC have better clinical outcomes than have been reported previously, particularly if diagnosed early. We recommend prompt assessment for SC, including liver biopsy and biliary imaging, when liver function abnormalities are detected in a children diagnosed with IBD.

Interventions for the management of abdominal pain in Crohn's disease and inflammatory bowel disease.

BACKGROUND: Crohn's disease is a remitting and relapsing disorder that can affect the whole gastrointestinal tract. Active disease symptoms include abdominal pain, fatigue, weight loss, and diarrhoea. There is no known cure; however, the disease can be managed, and therefore places a huge financial burden on healthcare systems. Abdominal pain is a common and debilitating symptom of Crohn's and other inflammatory bowel diseases (IBDs), and is multifaceted. Abdominal pain in Crohn's disease could be a symptom of disease relapse or related to medication adverse effects, surgical complications and strictures or adhesions secondary to IBD. In the absence of these factors, around 20 to 50% of people with Crohn's in remission still experience pain. OBJECTIVES: To assess the efficacy and safety of interventions for managing abdominal pain in people with Crohn's disease and IBD (where data on ulcerative colitis and Crohn's disease could not be separated). SEARCH METHODS: We searched CENTRAL, MEDLINE, three other databases, and clinical trials registries on 29 April 2021. We also searched the references of trials and systematic reviews for any additional trials. SELECTION CRITERIA: All published, unpublished, and ongoing randomised trials that compared interventions for the management of abdominal pain in the setting of Crohn's disease and IBD, with other active interventions or standard therapy, placebo, or no therapy were included. We excluded studies that did not report on any abdominal pain outcomes. DATA COLLECTION AND ANALYSIS: Five review authors independently conducted data extraction and 'Risk of bias' assessment of the included studies. We analysed data using Review Manager 5. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using GRADE methodology. MAIN RESULTS: We included 14 studies (743 randomised participants). Five studies evaluated participants with Crohn's disease; seven studies evaluated participants with IBD where the data on ulcerative colitis and Crohn's disease could not be separated; and two studies provided separate results for Crohn's disease participants. Studies considered a range of disease activity states. Two studies provided intervention success definitions, whilst the remaining studies measured pain as a continuous outcome on a rating scale. All studies except one measured pain intensity, whilst three studies measured pain frequency. Withdrawals due to adverse events were directly or indirectly reported in 10 studies. No conclusions could be drawn about the efficacy of the majority of the interventions on pain intensity, pain frequency, and treatment success, except for the comparison of transcranial direct current stimulation to sham stimulation. The certainty of the evidence was very low in all but one comparison because of imprecision due to sparse data and risk of bias assessed as unclear or high risk. Two studies compared a low FODMAP diet (n=37) to a sham diet (n=45) in IBD patients. The evidence on pain intensity was of very low certainty (MD -12.00, 95% CI -114.55 to 90.55). One study reported pain intensity separately for CD participants in the low FODMAP group [n=14, mean(SD)=24 (82.3)] and the sham group [n=12, mean(SD)=32 (69.3)]. The same study also reported pain frequency for IBD participants in the low FODMAP group [n=27, mean(SD)=36 (26)] and sham group [n=25, mean(SD)=38(25)] and CD participants in the low FODMAP group [n=14, mean(SD)=36 (138.4)] and sham group [n=12, mean(SD)=48 (128.2)]. Treatment success was not reported. One study compared a low FODMAP diet (n=25) to high FODMAP/normal diet (n=25) in IBD patients. The data reported on pain intensity was unclear. Treatment success and pain frequency were not reported. One study compared medicine-separated moxibustion combined with acupuncture (n=51) versus wheat bran-separated moxibustion combined with shallow acupuncture (n=51) in CD patients. The data reported on pain intensity and frequency were unclear. Treatment success was not reported. One study compared mindfulness with CBT (n=33) versus no treatment (n=33) in IBD patients. The evidence is very uncertain about the effect of this treatment on pain intensity and frequency (MD -37.00, 95% CI -87.29 to 13.29). Treatment success was not reported. One study compared soft non-manipulative osteopathic treatment (n=16) with no treatment besides doctor advice (n=14) in CD patients. The evidence is very uncertain about the effect of this treatment on pain intensity (MD 0.01, 95% CI -1.81 to 1.83). Treatment success and pain frequency were not reported. One study compared stress management (n=15) to self-directed stress management(n=15) and to standard treatment (n=15) in CD patients. The evidence is very uncertain about the effect of these treatments on pain intensity (MD -30.50, 95% CI -58.45 to -2.55 and MD -34.30, 95% CI -61.99 to -6.61). Treatment success and pain frequency were not reported. One study compared enteric-release glyceryl trinitrate (n=34) with placebo (n=36) in CD patients. The data reported on pain intensity was unclear. Treatment success and pain frequency were not reported.  One study compared 100 mg olorinab three times per day (n=8) with 25 mg olorinab three times per day (n=6) in CD patients. Pain intensity was measured as a 30% reduction in weekly average abdominal pain intensity score for the 100mg group (n=5) and the 25mg group (n=6). The evidence is very uncertain about the effect of this treatment on pain intensity (RR 0.66, 95% CI 0.38 to 1.15). Treatment success and pain frequency were not reported. One study compared relaxation training (n=28) to a waitlist (n=28) in IBD patients. The evidence is very uncertain about the effect of this treatment on pain intensity (MD -0.72, 95% CI -1.85 to 0.41). Treatment success and pain frequency were not reported. One study compared web-based education (n=30) with a book-based education (n=30) in IBD patients. The evidence is very uncertain about the effect of this treatment on pain intensity (MD -0.13, 95% CI -1.25 to 0.99). Treatment success and pain frequency were not reported. One study compared yoga (n=50) with no treatment (n=50) in IBD patients. The data reported on treatment success were unclear. Pain frequency and intensity were not reported. One study compared transcranial direct current stimulation (n = 10) to sham stimulation (n = 10) in IBD patients. There may be an improvement in pain intensity when transcranial direct current is compared to sham stimulation (MD -1.65, 95% CI -3.29 to -0.01, low-certainty evidence). Treatment success and pain frequency were not reported. One study compared a kefir diet (Lactobacillus bacteria) to no intervention in IBD patients and provided separate data for their CD participants. The evidence is very uncertain about the effect of this treatment on pain intensity in IBD (MD 0.62, 95% CI 0.17 to 1.07) and CD (MD -1.10, 95% CI -1.67 to -0.53). Treatment success and pain frequency were not reported. Reporting of our secondary outcomes was inconsistent. The most adverse events were reported in the enteric-release glyceryl trinitrate and olorinab studies.  In the enteric-release glyceryl trinitrate study, the adverse events were higher in the intervention arm. In the olorinab study, more adverse events were observed in the higher dose arm of the intervention.  In the studies on non-drug interventions, adverse events tended to be very low or zero. However, no clear judgements regarding adverse events can be drawn for any interventions due to the low number of events. Anxiety and depression were measured and reported at the end of intervention in only one study; therefore, no meaningful conclusions can be drawn for this outcome. AUTHORS' CONCLUSIONS: We found low certainty evidence that transcranial direct current stimulation may improve pain intensity compared to sham stimulation. We could not reach any conclusions on the efficacy of any other interventions on pain intensity, pain frequency, and treatment success. The certainty of the evidence was very low due to the low numbers of studies and participants in each comparison and clinical heterogeneity amongst the studies. While no serious or total adverse events were elicited explicitly with any of the treatments studied, the reported events were very low. The certainty of the evidence for all comparisons was very low, so no conclusions can be drawn.

DNA Methylation and Transcription Patterns in Intestinal Epithelial Cells From Pediatric Patients With Inflammatory Bowel Diseases Differentiate Disease Subtypes and Associate With Outcome.

BACKGROUND & AIMS: We analyzed DNA methylation patterns and transcriptomes of primary intestinal epithelial cells (IEC) of children newly diagnosed with inflammatory bowel diseases (IBD) to learn more about pathogenesis. METHODS: We obtained mucosal biopsies (N = 236) collected from terminal ileum and ascending and sigmoid colons of children (median age 13 years) newly diagnosed with IBD (43 with Crohn's disease [CD], 23 with ulcerative colitis [UC]), and 30 children without IBD (controls). Patients were recruited and managed at a hospital in the United Kingdom from 2013 through 2016. We also obtained biopsies collected at later stages from a subset of patients. IECs were purified and analyzed for genome-wide DNA methylation patterns and gene expression profiles. Adjacent microbiota were isolated from biopsies and analyzed by 16S gene sequencing. We generated intestinal organoid cultures from a subset of samples and genome-wide DNA methylation analysis was performed. RESULTS: We found gut segment-specific differences in DNA methylation and transcription profiles of IECs from children with IBD vs controls; some were independent of mucosal inflammation. Changes in gut microbiota between IBD and control groups were not as large and were difficult to assess because of large amounts of intra-individual variation. Only IECs from patients with CD had changes in DNA methylation and transcription patterns in terminal ileum epithelium, compared with controls. Colon epithelium from patients with CD and from patients with ulcerative colitis had distinct changes in DNA methylation and transcription patterns, compared with controls. In IECs from patients with IBD, changes in DNA methylation, compared with controls, were stable over time and were partially retained in ex-vivo organoid cultures. Statistical analyses of epithelial cell profiles allowed us to distinguish children with CD or UC from controls; profiles correlated with disease outcome parameters, such as the requirement for treatment with biologic agents. CONCLUSIONS: We identified specific changes in DNA methylation and transcriptome patterns in IECs from pediatric patients with IBD compared with controls. These data indicate that IECs undergo changes during IBD development and could be involved in pathogenesis. Further analyses of primary IECs from patients with IBD could improve our understanding of the large variations in disease progression and outcomes.

Early Treatment Response Predicts Outcome in Paediatric Ulcerative Colitis: GASTROENTEROLOGY: INFLAMMATORY BOWEL DISEASE.

The disease course of children with ulcerative colitis (UC) varies substantially. Published data on predictors of disease outcomes in children remain scarce. We validate clinical predictors of outcomes in 93 children with UC in a single centre (age range: 2-18 years, minimum follow-up: 18 months). We stratified children into 3 groups according to their disease course, that is, 1 = mild (38/93, 40.9%), 2 = moderate (38/93, 40.9%), 3 = severe (17, 18.2%). Comparison of clinical and biochemical parameters was performed between groups using Chi-square, Mann-Whitney, and log-rank tests. Predictors of a severe disease course included pancolitis (P 0.01), low albumin (P 0.005), low haemoglobin at diagnosis (P 0.04), paediatric ulcerative colitis activity index (PUCAI) at 3 months, and nonresponse to steroids at 3 months (P 0.0001). In our cohort, failure to achieve remission at 3 months implied an 80% likelihood to require biologics or major surgery within 18 months. A specific 3-month review point is recommended to guide future management.

Assessing pediatric ileocolonic Crohn's disease activity based on global MR enterography scores.

OBJECTIVES: This study was aimed at correlating a magnetic resonance index of activity (MaRIA) and a magnetic resonance enterography global score (MEGS) with activity indexes in a paediatric population with Crohn's disease (CD). METHODS: This retrospective study included 32 paediatric patients (median age 14.5 years, 18 male) with proven CD who underwent magnetic resonance enterography (MRE). A correlation analysis was performed on the MRE-based scores, the simplified endoscopic score for CD (SES-CD), the paediatric Crohn's disease activity index (PCDAI), and C-reactive protein (CRP) levels. Based on PCDAI, comparison of both global MaRIA and MEGS was made between patients with mild and moderate/severe disease activity. RESULTS: Global MaRIA correlated with SES-CD (r = 0.70, p = 0.001) and PCDAI (r = 0.42, p = 0.016). MEGS correlated with PCDAI (r = 0.46, p = 0.007) and CRP levels (r = 0.35, p = 0.046). MEGS differed significantly (p = 0.027) between patients grouped by clinical disease severity. CONCLUSIONS: MRE-based global scores correlated with clinical indexes of CD activity. Therefore, they represent a potential useful tool to predict CD activity and severity, as well as a possible promising alternative to endoscopy, to monitor paediatric patients with CD during their follow-up. KEY POINTS: • MRE is widely used to for accurate assessment of CD. • Global MaRIA and MEGS have been suggested as indicators of CD activity. • Paediatric studies comparing MRE-based global scores with clinical CD activity are lacking. • Such scores can serve as predictors of CD activity/severity in paediatric patients. • MRE offers an alternative to clinical score/endoscopy for paediatric CD monitoring.

Clinical course and outcomes of diagnosing Inflammatory Bowel Disease in children 10 years and under: retrospective cohort study from two tertiary centres in the United Kingdom and in Italy.

BACKGROUND: Most children with Inflammatory Bowel Disease (IBD) are diagnosed between 11 and 16 years of age, commonly presenting with features of typical IBD. Children with onset of gut inflammation under 5 years of age often have a different underlying pathophysiology, one that is genetically and phenotypically distinct from other children with IBD. We therefore set out to assess whether children diagnosed after the age of 5 years, but before the age of 11, have a different clinical presentation and outcome when compared to those presenting later. METHODS: Retrospective cohort study conducted at two European Paediatric Gastroenterology Units. Two cohorts of children with IBD (total number = 160) were compared: 80 children diagnosed between 5 and 10 years (Group A), versus 80 children diagnosed between 11 and 16 (Group B). Statistical analysis included multiple logistic regression. RESULTS: Group A presented with a greater disease activity (p = 0.05 for Crohn's disease (CD), p = 0.03 for Ulcerative Colitis (UC); Odds Ratio 1.09, 95 % Confidence Interval: 1.02-1.1), and disease extent (L2 location more frequent amongst Group A children with CD (p = 0.05)). No significant differences were observed between age groups in terms of gastro-intestinal and extra-intestinal signs and symptoms at disease presentation, nor was there a difference in the number of hospitalisations due to relapsing IBD during follow-up. However, children in Group A were treated earlier with immunosuppressants and had more frequent endoscopic assessments. CONCLUSION: While clinicians feel children between 5 and 10 years of age have a more severe disease course than adolescents, our analysis also suggests a greater disease burden in this age group. Nevertheless, randomized trials to document longer-term clinical outcomes are urgently needed, in order to address the question whether a younger age at disease onset should prompt per se a more "aggressive" treatment. We speculate that non-clinical factors (e.g. genetics, epigenetics) may have more potential to predict longer term outcome than simple clinical measures such as age at diagnosis.

Epigenetics in Paediatric Gastroenterology, Hepatology, and Nutrition: Present Trends and Future Perspectives.

Epigenetics can be defined as stable, potentially heritable changes in the cellular phenotype caused by mechanisms other than alterations to the underlying DNA sequence. As such, any observed phenotypic changes including organ development, aging, and the occurrence of disease could be driven by epigenetic mechanisms in the presence of stable cellular DNA sequences. Indeed, with the exception of rare mutations, the human genome-sequence has remained remarkably stable over the past centuries. In contrast, substantial changes to our environment as part of our modern life style have not only led to a significant reduction of certain infectious diseases but also seen the exponential increase in complex traits including obesity and multifactorial diseases such as autoimmune disorders. It is becoming increasingly clear that epigenetic mechanisms operate at the interface between the genetic code and our environment, and a large body of existing evidence supports the importance of environmental factors such as diet and nutrition, infections, and exposure to toxins on human health. This seems to be particularly the case during vulnerable periods of human development such as pregnancy and early life. Importantly, as the first point of contact for many of such environmental factors including nutrition, the digestive system is being increasingly linked to a number of "modern" pathologies. In this review article, we aim to give a brief introduction to the basic molecular principals of epigenetics and provide a concise summary of the existing evidence for the role of epigenetic mechanisms in gastrointestinal health and disease, hepatology, and nutrition.

Clinical Features and Risk Factors of Autoimmune Liver Involvement in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Autoimmune liver disease is reported in up to 7.8% of children with inflammatory bowel disease. A distinct inflammatory bowel disease phenotype has been suggested in adults and in small pediatric cohorts. The aim of the study was to evaluate the features of inflammatory bowel disease associated with autoimmune liver diseases and to analyze the characteristics of the liver disease. METHODS: Information on patients was obtained from the Italian Pediatric Inflammatory Bowel Disease Registry. Data of patients with and without autoimmune liver disease were compared. RESULTS: Autoimmune liver disease was detected in 6.8% of the 677 patients enrolled and was significantly associated with the diagnosis of ulcerative colitis (83%), with pancolonic involvement (84%), and with perinuclear antineutrophil cytoplasmic antibody positivity (41%) (all Ps < 0.05). Autoimmune liver disease was defined as sclerosing cholangitis in 61% of the patients and as an overlap syndrome in 33%. Concomitant intra- and extrahepatic biliary involvement was reported in 61% of cases, whereas exclusive extrahepatic lesions were reported in 21%. Hepatobiliary complications were observed in 9% of the patients during follow-up. CONCLUSIONS: Autoimmune liver disease, especially sclerosing cholangitis, was significantly more common in patients with extensive ulcerative colitis. Although complications are relatively rare in the pediatric age, monitoring is recommended.

The impact of age, disease severity, and BMI on bone health and growth in children and young people with Crohn's disease.

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.