Onset Inflammatory Bowel Disease Research Articles

Clinical features and genetic analysis of three patients with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome due to variants of FOXP3 gene

To analyze the clinical characteristics of three patients with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Three patients with IPEX syndrome diagnosed at the Children's Hospital of Fudan University from January 24, 2013 to July 29, 2019 were selected as the study subjects. Their clinical features, laboratory investigations and results of genetic testing were summarized. Treatment and prognosis were also explored. All of the three children had developed the disorder during infancy. One child had initial features including diabetes and diabetic ketoacidosis, whilst the other two had initiated by diarrhea. All patients had gastrointestinal involvement, and one was diagnosed as very early onset inflammatory bowel disease by colonoscopy and biopsy. Two children also had endocrine glands involvement. One child had manifested type 1 diabetes and positivity for thyroglobulin and thyroid peroxidase antibodies, though his thyroid function had remained normal. Another one had hypothyroidism and was treated by levothyroxine. Genetic testing revealed that all children had harbored missense variants of the FOXP3 gene, including c.1222G>A (p.V408M), c.767T>C (p.M256T) and c.1021A>G (p.T341A). The clinical symptoms of one patient were alleviated following allogeneic hematopoietic stem cell transplantation. One patient was stable after treatment with infliximab plus insulin, and one child had died of refractory septic shock and multiple organ dysfunction syndrome at 3 months old. FOXP3 gene variant-associated IPEX syndrome may have very early onset and diverse clinical manifestations. For male patients with infantile onset chronic diarrhea, multiple endocrine or multiple system involvement, genetic testing is recommended, which may facilitate early diagnosis, treatment and genetic counseling.

Potential effects of nutrition-induced alteration of gut microbiota on inflammatory bowel disease: A review.

Inflammatory bowel disease (IBD), mainly comprising ulcerative colitis and Crohn's disease, is a group of gradually progressive diseases bringing significant mental anguish and imposes serious economic burdens. Interplay of genetic, environmental, and immunological factors have been implicated in its pathogenesis. Nutrients, as crucial environmental determinants, mainly encompassing carbohydrates, fats, proteins, and micronutrients, are closely related to the pathogenesis and development of IBD. Nutrition is essential for maintaining the dynamic balance of intestinal eco-environments to ensure intestinal barrier and immune homeostasis, while this balance can be disrupted easily by maladjusted nutrition. Research has firmly established that nutrition has the potential to shape the composition and function of gut microbiota to affect the disease course. Unhealthy diet and eating disorders lead to gut microbiota dysbiosis and further destroy the function of intestinal barrier such as the disruption of membrane integrity and increased permeability, thereby triggering intestinal inflammation. Notably, appropriate nutritional interventions, such as the Mediterranean diet, can positively modulate intestinal microecology, which may provide a promising strategy for future IBD prevention. In this review, we provide insights into the interplay between nutrition and gut microbiota and its effects on IBD and present some previously overlooked lines of evidence regarding the role of derived metabolites in IBD processes, such as trimethylamine N-oxide and imidazole propionate. Furthermore, we provide some insights into reducing the risk of onset and exacerbation of IBD by modifying nutrition and discuss several outstanding challenges and opportunities for future study.

CLINICAL OUTCOMES OF INFLAMMATORY BOWEL DISEASE AFTER ORTHOTOPIC HEART TRANSPLANT

Abstract BACKGROUND Limited data are available on outcomes of patients with pre-existing inflammatory bowel disease (IBD) who undergo orthotopic heart transplantation (OHT) or develop de novo IBD post-OHT. We aimed to assess the incidence and disease outcomes of pre-existing and de novo IBD in OHT patients while evaluating the effect of IBD on OHT outcomes. METHODS A retrospective review of records was performed from a tri-site tertiary care system between July 2000 and July 2022. A total of 83 OHT receipients were concomitantly diagnosed with colitis of infectious or inflammatory etiology. Only patients with a diagnosis of IBD were included. Sub-analyses of the outcomes and immunosuppressive regimens of OHT recepients were done relative to those with pre-existing or de novo IBD. RESULTS A total of 8 OHT patients with concomitant IBD were identified. The median patient age (IQR) was 54 (23) with OHT and IBD onset at 50 (21.2) and 32.5 (15.7), respectively. Six patients were diagnosed with ulcerative colitis (UC) and 2 were diagnosed with Crohn’s disease. Five of the patients were female. All patients developed IBD within 11.5 (8) years within OHT. Only 1 patient developed de novo IBD 15 years after the first OHT and 7 years prior to a second OHT. OHT immunosuppressive regimens included a combination of tacrolimus (TAC) and prednisone (n=2), TAC and mycophenolate mofetil (MMF) (n=2), TAC, MMF, and sirolimus (n=2), TAC and sirolimus (n=1), and MMF with sirolimus (n=1). Therapy for pre-existing IBD included maintenance of 5-aminosalicylic (5-ASA) (n=3), escalation to vedolizumab (VD) (n=2), and discontinuation of IBD therapy (5-ASA and azathioprine) (n=3). De novo IBD consistent with UC (15 years post-OHT) was managed with 5-ASA (n=1). Six patients (including de novo IBD case) maintained clinical and endoscopic remission of IBD with no flares post-OHT while 2 patients (1 UC and 1 CD) with active disease flares responded clinically and endoscopically to VD escalation from 5-ASA and azathioprine. Among two UC patients with ileal J-pouch pre-OHT, 1 developed refractory pouchitis requiring diverting ileostomy (while on TAC and prednisone) with no pouchitis in the other (maintained on TAC and MMF). Good graft tolerance limited to mild acute cellular rejection episodes was noted in 6 patients, while multiple or no rejection episodes were noted in the remaining two. None of the patients developed CMV or MMF-induced colitis. One patient died due to progressive functional decline unrelated to graft failure or IBD. DISCUSSION The clinical course and treatment of IBD preceding OHT or de novo (though rare) is not significantly worsened or altered post-OHT. The majority of patients achieve clinical and endoscopic remission while on heart transplant-related immunosuppression. Biologic therapy escalation to VD resulted in clinical remission with no effect on graft tolerance. Table 1 Clinical outcomes of OHT patients with concomitant IBD

UNIQUE MONOCYTE EXPRESSION SIGNATURE IN A STXBP2 MUTATION CAUSING INFANTILE ONSET VEO-IBD AND HLH

Abstract Mutations in syntaxin-binding-protein-2 (STXBP2) can result in NK cell dysfunction leading to a hyperinflammatory state including familial HLH and infantile onset inflammatory bowel disease (IBD). While the function of STXBP2 in NK cells and cytotoxic T cells has been well described, it is highly expressed in monocytes with unclear relevance. We report the case of an infant who presented with severe infantile onset diarrhea with an identified pathogenic mutation in STXBP2. We sought to utilize scRNA-Seq to study the impact of STXBP2 deficiency on monocyte transcription, with the goal of generating insight into the pathogenesis of disease. METHODS: Trio whole exome sequencing was performed. PBMCs were collected from the described patient (case), and two control groups: 3 patients with VEO-IBD, and 3 age matched healthy controls. Single cell RNA-Seq was performed using the 10x platform and data analysis was done using Seurat in R. RESULTS: A male infant presented at 1 week of age with diarrhea and metabolic acidosis. Endoscopic evaluation at 4 weeks of age showed histologic findings of colitis and marked epithelial cell changes, including cell rounding. WES identified a homozygous pathogenic mutation in STXBP2. Due to significant risk of HLH, he underwent evaluation for stem cell transplant. However, in the interim he developed severe HLH requiring ICU level care. He recovered following aggressive treatment and underwent HSCT at 4 months of age and retransplant for graft failure at 11 months of age. He is currently in endoscopic remission off therapy. We analyzed PBMCs from the case patient using single cell RNA-Seq, as compared to patients with VEO-IBD and age-matched controls. STXBP2 expression was most enriched in monocyte populations and reduced in the case patient compared to controls. 231 and 187 genes were differentially expressed in the case monocytes as compared to both controls. The case patient had a paucity of non-classical monocytes. Within the classical monocytes, differentially expressed genes showed enrichment of host defense, cytokine processes, and apoptotic processes. Within the intermediate monocytes, differentially expressed genes showed enrichment of chemotaxis pathways, antigen presentation and T cell activation processes. CONCLUSIONS: Mutations in STXBP2 are a life-threatening cause of fHLH and infantile onset IBD. We report a case of infantile onset IBD due to a homozygous mutation in STXBP2 with resolution of disease post HSCT. Transcriptional analysis of PBMCs from this patient reveals a paucity of non-classical monocytes in the peripheral blood, and differential regulation of genes implicated in host defenses, antigen presentation, chemotaxis and apoptosis. These results may suggest the role of monocyte function in pathogenesis of STXBP2 and in other forms of IBD.

BIOACTIVE INTERLEUKIN-1 DETECTED IN IBD PATIENT INTESTINAL BIOPSIES IS A HALLMARK OF ULCERS AND CORRELATES WITH TRANSCRIPTOMIC ASSESSMENTS, INCLUDING AN ULCER-ASSOCIATED GENE MODULE

Abstract BACKGROUND Interleukin (IL)-1 and its post-translationally modified and released forms, IL-1α and IL-1β, have been identified as key molecules to maintain mucosal homeostasis and to drive inflammatory bowel disease (IBD). Deep cellular phenotypic, transcriptional, and in vitro data highlight the importance of IL-1-associated cytokine networks and IL-1 producing cells in severe and anti-TNF non-responsive IBD. Nevertheless, little is known about the presence of bioactive IL-1 proteins within the cell-free gastrointestinal (GI) mucosal environment and associated function in severe IBD and ulceration. METHODS We established a highly sensitive functional assay (~500-fold greater than ELISA) to assess bioactive extracellular IL-1 protein from previously cryopreserved GI biopsies. We performed an ex vivo study in a cohort of Crohn’s disease (CD, n=23), ulcerative colitis (UC, n=18) and non-IBD (n=17) patients, with biopsies from paired inflamed and uninflamed intestinal regions per patient (primarily colon but also ileal). We assessed differential IL-1 bioactivity, including IL-1α vs IL-1β contributions, and performed RNA-seq of the matched cellular compartments of the samples. An ulcer-associated gene signature derived from RNA-seq analysis was evaluated in a single-cell RNA-seq cohort (n=42) of very early onset IBD including monogenic disorders. RESULTS The extent of bioactive intestinal mucosal IL-1α and IL-1β corresponded with disease and ulcer severity in both CD and UC. The most extreme signals were seen in select CD patients with deep ulceration. Bioactive IL-1α was the predominant contributor to total IL-1 signal in most patients although several with ulcers displayed an IL-1β-predominant signal. Matched RNA-seq analysis demonstrated enhanced IL-1 transcripts, correlating with IL-1 bioactivity, and a weighted gene co-expression network analysis (WGCNA) revealed a compelling ulcer-specific module enriched in IL-1 signaling genes and wound repair. We validated our findings in several published (e.g., RISK cohort of ileal CD) as well as unpublished independent adult and pediatric datasets from our group. Deconvolution of the ulcer-specific gene module and projection onto an unpublished single-cell RNA-seq cohort of very early onset IBD patients (including IBD-causative mutations such as IL-10R deficiency characterized by deep ulceration) implicated specific stromal and myeloid populations in ulcer biology. CONCLUSION Mucosal ulceration in IBD is associated with bioactive IL-1α and IL-1β proteins, and transcriptomic evaluation of the same correlates with bioactive signal. An ulcer-associated gene module, validated in other datasets, sheds light on IL-1 biology in intestinal epithelial repair. Results strongly suggest the IL-1 signaling pathway being an attractive and precision-based therapeutic target in subsets of IBD patients.

P071 Neonatal levels of inflammatory markers in individuals who later develop early onset Inflammatory Bowel Disease

Abstract Background The early life period is suggested to be important in development of Inflammatory Bowel Disease (IBD). Studies in babies from mothers with IBD observed increased faecal calprotectin and changes in the microbial compartments compared to babies from healthy mothers1,2, which suggests that changes in early life might be associated with later disease development. Prospective studies of IBD risk following early life changes at the molecular level are sparse. We aimed to investigate if individuals with early onset (EO) IBD had changes in systemic inflammatory markers shortly after birth. Methods We measured the concentration of 9 cytokines in a cohort of 464 neonatal dried blood spot samples stored at the Danish National Biobank from individuals who later developed EO IBD (median age of diagnosis 11 years), as well as matched controls. Individuals who developed IBD were identified through the use of the Danish National Patient Registry. Uni- and multivariate logistic regression with adjustment for birth year, sex, and gestational age was conducted to assess the association between 6 of the inflammatory markers with later disease development (INF-γ, TNF-α, IL-1β, IL-4, IL-6 and IL-17a). Further exploratory analyses were performed investigating risk of very early onset (VEO) IBD (onset from 0-5 years) in 88 cases and their matched controls. Results No significant association with EO IBD was observed for any of the cytokines in uni- and multivariate models when adjusting for multiple testing. In the exploratory analysis of VEO IBD, increased IL-4 was associated with significantly reduced risk of IBD (OR=0.992, p-value=0.023) and increased IL-17a was borderline-significantly associated with increased risk of IBD (OR=1.002, p-value=0.063) in a multivariate logistic model including all 6 cytokines. This association did not remain significant when adjusting for multiple testing, which may reflect limited power. Conclusion In our unique study of 464 dried blood spots from later IBD patients and controls, we could not find an association between measured cytokines and EO IBD. In contrast, patients with VEO IBD had decreased levels of IL-4 and increased levels of IL-17a. This sub-cohort was small, and significance disappeared after adjusting for multiple testing. Still, we find it important to report these findings, as they are novel and may inspire future studies into the aetiology of VEO IBD. 1. Kim, E. S. et al. Longitudinal Changes in Fecal Calprotectin Levels Among Pregnant Women With and Without Inflammatory Bowel Disease and Their Babies. Gastroenterology (2021) 2. Torres, J. et al. Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice. Gut (2020)

P1003 Dietary pattern can influence the level of fatigue in patients with Inflammatory Bowel Disease in remission

Abstract Background It is well known that dietary pattern can play an important role in the onset of inflammatory bowel diseases (IBD). In patients with established disease, they can influence the risk of relapse and the disease course. The aim of the study is to explore the impact of dietary patterns on health-related quality of life (HR-QoL), fatigue, anxiety and depression in patients with IBD in corticosteroid-free clinical remission. Methods A total of 96 consecutive patients diagnosed with IBD that were in corticosteroid-free remission for at least 12 weeks were enrolled in this observational, cross-sectional study. During an interview, patients were asked about their dietary patterns. Twelve categories of foods were identified, 6 of them being considered "healthy" (vegetables and fruits >4 portions/day, cereals >3 portions/day, seeds >4 portions/week, cheese >1 portion/day, yoghurt >1 portion/day, fish >2 portions/week) and the other 6 "unhealthy" (fatty red meat >1 portion/day, sweetened beverages >1L/day, cured meat >2 portions/day, fried food >1 portion/day, chips >1 portion/day, mayonnaise >1 portion/day) (see Figure 1). An "unhealthy" dietary pattern was considered if the proportion of "unhealthy" food categories from the total food categories consumed by the patient exceeded 50%. HR-QoL, fatigue, anxiety and depression were evaluated using the following self-administered questionnaires: IBDQ-32, FACIT-Fatigue and HADS. Results Out of the 96 patients included, 60 (62.5%) were men. The median patient age was 38 years (IQR 31.5 – 45.5). Sixty patients (62.5%) were diagnosed with CD, and 36 (37.5%) with UC. Most of the patients were treated with biologics (93.8%). An unhealthy dietary pattern was identified in 58 (60.4%) patients. Patients with an "unhealthy" dietary pattern experienced significantly more fatigue compared to patients with a "healthy" dietary pattern (mean FACIT-F score 40.3 vs. 44.4 points, p=0.02). Even though not statistically significant, patients with "unhealthy" dietary pattern had a trend towards a lower HR-QoL (mean IBDQ score 187.3 vs. 192.8, p=0.24). Anxiety and depression were less frequent among patients with "unhealthy" dietary pattern, but the differences were not statistically significant (anxiety: 24.1% vs. 31.6%, p=0.57; depression: 13.8% vs. 21.2%, p=0.51). Conclusion Patients with an "unhealthy" dietary pattern experience significantly higher levels of fatigue compared to patients that are eating "healthier" food. There is also a trend towards lower HR-QoL in this category of patients.

P1120 New-onset Inflammatory Bowel Disease is uncommon in patients with psoriasis, psoriatic arthritis and spondylarthritis treated with secukinumab: a retrospective cohort study in a tertiary centre

Abstract Background Secukinumab (SEC) is an IL-17A inhibitor prescribed in patients with immune mediated inflammatory diseases like psoriasis (PsO), psoriatic arthritis (PsA) and spondylarthritis (SpA). Conflicting data are available on the onset of inflammatory bowel disease (IBD) among patients after the start of SEC. We aimed to provide data evaluating pre-existing and newly diagnosed IBD in patients being treated with SEC. Methods All patients receiving SEC at a single tertiary centre in The Netherlands between 2012-2022 were identified through the pharmacy registry. Data from electronic medical records were retrospectively collected: baseline (i.e. at initiation of SEC) characteristics, medical history (including pre-existing IBD), use of (disease modifying) concurrent medication, clinical symptoms, biochemistry (C-reactive protein, faecal calprotectin), endoscopy with pathology and cross-sectional imaging (CT, MRI, intestinal ultrasound). Patients were excluded if they received ≤3 doses of SEC. Results A total of 351 patients were included with one or more of the following indications for SEC treatment: PsO in 166/351 (47%), PsA in 130/351 (37%), axial SpA in 130/351 (37%), peripheral SpA in 31/351 (9%) and juvenile idiopathic arthritis in 1/351 (0.3%). Frequently used co-medication were NSAIDs (44%), topical corticosteroids (37%) and methotrexate (16%). Median follow-up time was 48 months (IQR 22,74). In total, ten patients with IBD were identified: 5/351 (1.4%) patients had pre-existing IBD (2/5 Crohn’s disease, 3/5 ulcerative colitis) and 5/351 (1.4%) patients developed IBD after SEC initiation (3/5 Crohn’s disease, 1/5 ulcerative colitis, 1/5 IBD-unclassified) (Table 1). All new-onset IBD cases were confirmed with endoscopy and pathology. Predominant clinical symptoms were diarrhoea, abdominal pain and haematochezia. In patients with new-onset IBD median time from initiation of SEC to development of clinical symptoms was 1.3 months (range 0-12) and median time to diagnosis was 7.5 months (range 3-16). Out of patients with pre-existing IBD in remission 2/5 developed clinical symptoms after start of SEC with a median time to development of 9 months (range 6-12); 3/5 patients sustained remission. After starting SEC 25% of patients reported gastrointestinal symptoms, however diagnostic work-up took place in only 52% of these patients revealing no signs of IBD. Conclusion In our cohort new-onset IBD after SEC initiation was uncommon (<2%) with a short median time to onset. IBD seemed equally distributed among indications. Caution and monitoring of gastrointestinal symptoms during SEC treatment is warranted in patients with pre-existing IBD, considering the possibility of an exacerbation.

P1089 Disease characteristics at time of diagnosis of adult onset inflammatory bowel disease and the risk of venous thromboembolism in the modern era – A Swedish nationwide cohort study 2007-2021

Abstract Background Studies from mainly before the wide use of targeted therapies and guidelines for thromboprophylaxis indicate that patients with inflammatory bowel disease (IBD) are at a doubled risk of venous thromboembolism (VTE). We studied the risk of VTE in a modern-day cohort of patients with IBD, overall and in subgroups of disease characteristics. Methods Using Swedish healthcare registers, we identified a nationwide population-based cohort of 55,252 patients with incident IBD between 2007 and 2021 with a median follow-up time of 6.5 years. Patients were matched by age, sex, calendar year and county of residence with up to ten reference individuals from the general population (N=536,067). The primary outcome was VTE, including pulmonary embolism and deep vein thrombosis. Incidence rates per 1,000 person-years and hazard ratios (HR) were calculated for IBD in general and according to disease subtype, sex, age and disease characteristics at diagnosis. HRs stratified by matching variables (model 1) and additionally adjusted for comorbidities and socioeconomic factors (model 2) were estimated by using Cox regression. Results The incidence rate of VTE among patients with IBD was 5.03 per 1,000 person-years compared with 2.34 per 1,000 person-years among reference individuals (Table 1). This corresponded to a doubled incidence of VTE (HR=2.18, 95% confidence interval (CI)=2.07-2.29, model 1). Adjusting further for covariates in model 2 had only minor effects on the HR. The HR was consistent across IBD subtypes and sex. The relative risk was higher for those with younger age (18-39 years) at IBD diagnosis (HR 2.52, 95% CI: 2.22-2.83) with a risk difference of 1.25 per 1,000 person-years. The IR, 10.64 per 1,000 person-years, and risk difference, 5.42 per 1,000 person-years, was the highest for those with elderly onset (≥60 years) IBD. There was a stronger association for those with extensive ulcerative colitis (E3), primary sclerosing cholangitis, extraintestinal manifestations and perianal disease. HRs for VTE were persistently elevated across follow-up time, but was higher during the first year of follow-up (Figure 1). Conclusion The risk of VTE was doubled in these modern-day data and remained elevated across follow-up time. Disease characteristics associated with higher inflammatory burden at diagnosis and older age are markers of increased risk. This underscores the importance of continuous vigilance and individual assessment of risk factors for VTE in patients with IBD.

P391 A not so innocent bystander: The prevalence and burden of anaemia at IBD onset

Abstract Background Anaemia is the most common systemic complication of Inflammatory Bowel Disease (IBD). Contemporary studies linking its prevalence with symptom burden at disease onset are limited. We present the prevalence and disability associated with anaemia in a large new onset adult IBD cohort. Methods Demographic, clinical and biochemical indices were collected prospectively in patients referred with suspected IBD between January 2021 - April 2023. Anaemia was defined as haemoglobin (Hb) of <115g/L in women and <130g/L in men. Iron deficiency was defined as Ferritin <30ug/L (<100ug/L if active inflammation – CRP >5mg/L, Faecal Calprotectin [FCP] >200ug/g) or Iron saturations <15%. IBD disk scores were collected in a subgroup of patients. For two groups, non-parametric Mann-Whitney U tests were utilised, with a pairwise Dunn test and holm corrected p values for more than two. Results Hb results were available for 586 patients (182 CD, 170 UC, 234 non-IBD). Of these, an IBD disk score was available for 245 (84 CD, 71 UC, 90 non-IBD). Hb levels were significantly lower in CD than non-IBD (Table 1). Overall, a significantly larger proportion of patients with CD were anaemic than UC (X2 10.2 p=0.001, odds ratio 2.4 [95% CI 1.39-4.16]). Whilst most anaemic patients in both groups were iron deficient, many without anaemia also had demonstrable iron deficiency (Figure 1). In CD, Hb levels were significantly lower in ileocolonic disease than either isolated ileal (median Hb 125vs135.5g/L, p=0.002) or isolated colonic (125vs139g/L, p=0.002). Across IBD, Hb significantly correlated with Harvey Bradshaw Index (n=142, Spearman’s Rho [SR] -0.23 p=0.007), Partial Mayo (n=143, SR -0.23 p=0.006), Simple endoscopic score for CD (n=130, SR -0.29 p<0.001) and FCP (n=314, SR -0.23 p<0.001). Regarding overall disease burden, Hb correlated with overall disability as determined by the IBD disk (n=155, -0.23 p=0.004). Anaemic patients had higher overall disability (total disk score 62.5vs49 p=0.007). Using individual disk domains, those with anaemia had higher fatigue (median 9vs8, p=0.012), disruption of education or work (7vs4, p<0.001), impairment of body image (7vs4, p=0.019) and reduced sexual function (5.5vs1, p=0.004). When compared in a linear regression alongside age, body mass index, ethnicity, IBD type and baseline FCP, Hb was the second strongest predictor of overall disk score (Model fit R=0.515, BMI t=3.05 p=0.003, Hb t=-2.41 p=0.019). Conclusion Anaemia is frequently present at IBD onset, particularly in CD. Nearly half of those without anaemia have demonstrable iron deficiency. Severity of anaemia is associated with overall disease activity but influences symptom burden and disability beyond that which is attributable to mucosal inflammation alone.

D-ECCO Grant Personalizing the dietetic strategy in children with IBD: exploring an antioxidant approach

Abstract Background and Aims Diet is a key element in the pathogenesis and treatment of Inflammatory Bowel Disease (IBD). Also, oxidative stress (OS) is involved in IBD onset and evolution. Our group is conducting a multicenter trial (the OxIBDiet study, NCT0451301) to explore the OS imbalance in both children and adults with IBD, compared to matched controls, the genetic variants of genes implicated in OS and the effects of an Antioxidant diet (AoD) on these patients. Preliminary results have shown a great imbalance in the total antioxidant capacity in IBD compared to healthy matched controls, particularly in IBD children, and a clear improvement of the antioxidant capacity and oxidant parameters after 3 months of AoD. Aims of this study are: 1. To identify IBD subjects’ responders to a specific dietetic treatment (on the basis of clinical, biochemical and genetic characteristics); 2. To evaluate the effect of antioxidant compounds on stem cell derived 3D models of the intestinal epithelium by organ-on-a-chip technology; 3. To characterize the effect of AoD and Mediterranean diet in terms of inflammatory pattern. Methods A machine-learning algorithm that integrates clinical parameters, anthropometrics, blood parameters and genetic data measured in OxIBDiet cohort will be generated and validated in a new cohort of 30 IBD children (15 CD and 15 UC). Human intestinal organoids will be generated from 10 patients, in which an endoscopy is planned for disease reassessment, and levels of interleukins and TNF-alfa will be measured, after stimulation with antioxidant compounds. Thirdly, cytokine analysis in serum from OxIBDiet cohort who performed dietetic sub-study will be evaluated. Anticipated Impact Results of this study will provide useful indications on factors that influence redox imbalance in IBD and will permit to identify patients who may benefit from a personalized dietetic approach, especially an AoD.

P757 Patient attitudes, perceptions, and beliefs on the role of diet and nutrition in inflammatory bowel diseases. A scoping review

Abstract Background Despite substantial evidence implicating diet in the development and management of inflammatory bowel disease (IBD), we still lack widely agreeable recommendations for dietary therapy. As a result, patients often self-manage their disease symptoms following a range of dietary regimes, including elimination diets and specific nutrient supplementation. The aim of this in-depth scoping review is to characterise the perception of patients in the role of diet in IBD. Methods An extensive literature search was undertaken on PubMed (inception to August ‘23), including MeSH terms ("Inflammatory Bowel Disease" OR IBD OR Crohn's OR Colitis) AND (belief OR perception OR opinion OR views OR attitude) AND (diet OR food OR nutrition). Eligible studies included primary research exploring attitudes, perceptions, or beliefs of adults and children with IBD and/or their carers towards the role of diet in IBD onset, progression or management. We excluded animal, in vitro and non-English articles (Table 1). Results 1,649 records were identified. After full-text review of 162, 42 papers fulfilled eligibility criteria. Another 6 papers were identified after cross-checking reference lists from included papers, resulting in final inclusion of 48 articles. All articles described that diet perceptions relate with behaviour. In 17 studies a significant percentage of participants considered diet an initiating factor for their IBD diagnosis (Median,IQR: 32%,28%-45%). In 39 studies, patients listed foods they perceived to trigger or benefit their symptoms or inflammation. Most of these studies listed foods affecting the disease for IBD in general (n=29), while fewer studies described trigger and beneficial foods for Crohn’s disease (n=13) and ulcerative colitis (n=16), separately. Spicy food, dairy, alcohol, and coffee were the most perceived as disease-trigger foods, whereas rice, chicken, gluten free products and fish were perceived as beneficial (Fig 1A). Interestingly, 23 studies described patients’ most frequent sources of diet and nutrition information for IBD management (Fig 1B). The top-ranked being patient’s own experience with diet(82%), gastroenterologists(40%), other physicians(35%) and internet(35%). Only 25% of participants reported dietitians as their source of information. Conclusion There is a strong belief among patients with IBD that diet is important in disease development and management. It is possible that such beliefs translate to disease management practices, hence increasing restrictive eating, diminish quality or life, including food related quality of life. Until further evidence is produced to pinpoint the exact role of diet in IBD management, it is imperative that HCPs initiate such discussions and advise their patients accordingly.

OP17 IBD ulcers are characterized by bioactive interleukin-1 and transcriptomic hallmarks of stromal cell state reprogramming

Abstract Background The programs that perpetuate the inflammation and prevent epithelial repair in Inflammatory Bowel Disease (IBD) remain unclear. Interleukin (IL)-1 plays a role in the maintenance of mucosal homeostasis but also in IBD. Expansion of IL-1 expressing myeloid cells is a hallmark of IBD tissue, including severe and anti-TNF unresponsive disease, and IL-1 expression is highly localized to ulcer beds. However, little is known about the presence of bioactive IL-1 proteins in the cell-free mucosal environment of IBD, nor whether IL-1-driven programs affect epithelial regeneration in IBD ulcers. Methods We established a highly sensitive assay (~500-fold greater than ELISA) to assess bioactive extracellular IL-1 from previously cryopreserved IBD biopsies. We assessed a cohort of Crohn’s Disease (CD, n=23), Ulcerative Colitis (UC, n=18) and non-IBD (n=17) patients, with biopsies from paired inflamed/uninflamed regions (primarily colon but also ileal). We assessed IL-1 bioactivity, including IL-1α vs IL-1β contributions, and performed RNA-seq of samples’ matched cellular compartments. An ulcer-associated gene signature was interrogated in a single-cell (sc)RNA-seq cohort (n=42) of very early onset (VEO)IBD including monogenic disorders, as well as publicly available IBD bulk RNA-seq datasets and scRNA-seq of mouse models of colitis. Results IL-1α and IL-1β bioactivity corresponded with disease and ulcer severity in CD and UC. The most extreme signals were seen in select CD patients with deep ulceration. IL-1α was the predominant contributor to total IL-1 bioactivity in most patients although several with ulcers displayed IL-1β predominance. IL-1 bioactivity correlated with IL-1 transcripts in matched RNA-seq, and weighted gene co-expression network analysis revealed a compelling ulcer-specific module. This module contained transcription factors and genes related to cell state, validated in publicly available datasets (e.g. RISK cohort of ileal CD and scRNA-seq of murine DSS colitis), that when interrogated in a scRNA-seq dataset of VEOIBD (including patients with IL-10RA mutations characterized by deep ulcers), suggests an orchestrated IL-1-driven myeloid/stromal response to epithelial ulceration involving cell state reprogramming and loss of key myofibroblast populations. Conclusion Mucosal ulceration in IBD is associated with bioactive IL-1α and IL-1β proteins, and transcriptomic evaluation of the same correlates with bioactive signal. An ulcer-associated gene module, validated in other datasets, sheds light on IL-1 biology in intestinal epithelial repair. Results strongly suggest the IL-1 signaling pathway being an attractive and precision-based therapeutic target in subsets of IBD patients.

P910 Salivary calprotectin as a prognostic biomarker in Early Onset Inflammatory Bowel Disease: a cohort study

Abstract Background Inflammatory Bowel Disease (IBD), including Ulcerative Colitis (UC) and Crohn’s Disease (CD) affects children in 25% of cases. In Early Onset IBD (EOIBD) oral involvement is common and oral manifestations (OM) are frequently the first presenting sign of disease. This study compared salivary calprotectin (SCp) between EOIBD and healthy controls (HC), differentiating patients based on their history of OM. Furthermore, this report correlated salivary and faecal calprotectin (FCp) in EOIBD and assessed the prognostic accuracy of SCp in predicting disease relapses. Methods A cohort study was conducted; 9 HC and 27 EOIBD (18 UC and 9 CD) were recruited at the University of Naples Federico II. EOIBD were divided in two subgroups based on the history of OM. A sample of stimulated whole saliva was collected by each participant by spitting. The samples were then processed by ELISA for determining SCp. For each patient clinical disease activity was measured through Paediatric Ulcerative Colitis Activity Index (PUCAI) and Paediatric Crohn’s Disease Activity Index (PCDAI), at baseline and during follow-up (4/8/12 weeks). At baseline, patients provided a stool specimen for FCp determination. SCp levels were compared between groups. In EOIBD SCp was correlated to clinical data and to FCp. Results At baseline all the patients were in treatment with immunosuppressive drugs; 19 were in clinical remission (PUCAI/PCDAI <10) and 8 had mild disease (PUCAI/PCDAI<35). 13 EOIBD had an history of OM: 12 suffered from aphthous-like manifestations while 3 reported granulomatous lesions; 10 experienced oral involvement before IBD diagnosis. OM were more prevalent in CD than in UC and were associated to ileocolic, perianal and upper gastrointestinal tract involvement. EOIBD with OM reported significantly higher SCp than EOIBD without OM and HC: 155,79±60,08 pg/mL in EOBD with OM vs 82,95±51,58 pg/mL in EOIBD without OM (P<0,01**) and 98,21±39,67 pg/mL in HC (P=0,21). Despite the systemic therapy and the clinical remission, in 7 EOIBD with OM oral lesions persisted. These patients had higher SCp compared to those who experienced OM remission (P<0,05*). In EOIBD with OM higher SCp was associated to higher FCp (P<0,05*) while in EOIBD without OM this correlation was not described. No correlation was found between SCp values and PUCAI/PCDAI at baseline. EOIBD with OM who reported higher SCp were found to have increased risk of relapse (P<0,05*) while no association was reported in EOIBD without OM. Conclusion In EOIBD with OM SCp is significantly higher, mirrors intestinal inflammation and predicts relapses. Our results suggest the use of SCp as a prognostic biomarker in EOIBD with OM although more studies are needed.

P570 Efficacy and safety of Adalimumab in Very Early-onset IBD- A Multicentre Study from the Paediatric IBD Porto Group of ESPGHAN

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.

OP28 Defective STAT3 signaling in refractory Very Early Onset Inflammatory Bowel Disease is associated with a transcriptional signature which predicts response to anti-IL23-based therapies

Abstract Background Very early onset inflammatory bowel disease (VEOIBD) has a monogenic cause in >5% of cases. IL10R deficiency is among the more common causes of monogenic IBD and presents with severe disease refractory to conventional therapies. For most VEOIBD patients, the molecular basis of disease is unknown. We employed flow cytometry and bulk RNA-sequencing to localize pathway-level dysfunction in VEOIBD patients with unknown molecular basis. Methods VEOIBD patients prospectively enrolled in a biorepository were screened for IL10R deficiency using a flow cytometry assay. Patient peripheral blood mononuclear cells (PBMCs) were stimulated with IL10 and control cytokine IL21 and pSTAT3 activation was measured. RNA-sequencing was performed on 115 whole blood samples, comprising VEOIBD patients with either confirmed (n=35, IL10R deficient n=4), or unknown monogenic causes (n=70), and controls (n=10). Transcriptome analysis focused on patients with abnormal STAT3 activation as determined by flow cytometry. Results We identified 6 patients with refractory VEOIBD and defective phosphorylation of STAT3 upon stimulation with both IL10 and IL21 by flow cytometry (Fig 1A), a result confirmed by Western blot (Fig 1B). All six "STAT3-defective" (STAT3-def) patients lacked deleterious mutations in known VEOIBD genes as determined by whole exome sequencing. Principal component analysis of blood transcriptome data showed the STAT3-def and IL10R deficient patients generally clustered together (Fig 1C). Cell-type de-convolution analysis of the blood transcriptomes was used to infer cell-type abundance and cell-type specific differentially expressed genes (DEGs) for the STAT3-def and IL10R deficient groups relative to the rest. Genes downregulated in estimated M1 macrophages from the STAT3-def group were enriched in the Hallmark pathway "IL6-JAK-STAT3 signaling." STAT3-def M1 macrophage DEGs were then projected on an adult colonic Crohn’s disease Bayesian network and extended out a path length of 1. The resulting STAT3-def subnetwork of 440 genes included the known VEOIBD genes STAT3, STAT1, TYMP, and TRIM22 (Fig 1D) and the top enriched signaling pathways included IL23, IL6, and IL12. This is of significant interest given three STAT3-def patients with disease refractory to anti-TNF and vedolizumab achieved remission with anti-IL23-based therapies (Table 1). Conclusion We identified 6 patients with refractory VEOIBD and a shared biochemical phenotype and blood transcriptional signature. Network analysis revealed signaling pathways targeted by existing IBD medications, including anti-IL23-based therapies. Molecular analysis of IBD patient blood has exciting potential to localize pathway-level dysfunction and guide precision medicine approaches.

P293 Safety and diagnostic yield of wireless video capsule endoscopy in early onset inflammatory bowel disease (EOIBD) in children under the age of 6 years in a tertiary paediatric IBD centre

Abstract Background Wireless video capsule endoscopy (VCE) is a well-established diagnostic tool used in the evaluation of small bowel disease in paediatric IBD. Patients usually swallow the capsule. Young children are rarely able to swallow the capsule and these therefore need to be placed with the help of an OGD and an ACORN device. 2 capsule systems were used: PillCam and MiroCam. The aim of this study was to look at the safety of capsule insertion in children less than 6 years of age and to also look at the diagnostic yield. Methods We conducted a retrospective review of our VCE data base over a 7 year period from April 2016 to August 2023. Results We conducted a retrospective review of our VCE data base over a 7 year period from April 2016 to August 2023. 22 patients (14 male) and 27 capsule episodes were included into the study with a an age range at point of capsule insertion between 2 years and 5 months and 5 years and 8 months (median 5 years). All capsules were inserted with an ACORN device. All patients had a histologically proven diagnosis of EOIBD; during this period 4 patients had 2 VCEs and 1 patient 3 VCEs placed. All patient had genetic tests performed, only 1/24 patients had a monogenic mutation confirmed. 15/27 (56%) of all capsules were normal, 8/27 (30%) showed small bowel ulcerations only, 2/27 (7%) showed both small bowel and colonic ulcerations and 5/27 (19%) showed colitis only. We were able to insert the capsule in all 27 capsule episodes without any complications. All studies were complete with the capsule entering the colon and no capsule got stuck. Conclusion Wireless video capsule endoscopy in early onset inflammatory bowel disease in children under the age of 6 years is safe with a diagnostic yield of around 50%. This modality should be used in the diagnostic pathway of EOIBD.

P607 Increased rates of fractures and malignancy in elderly onset IBD in Singapore

Abstract Background Elderly onset inflammatory bowel disease (EOIBD) has variable characteristics in the published literature. We performed this study to report the disease characteristics, treatment exposure, and clinical outcomes of EOIBD compared to adult onset IBD (AOIBD) in Singapore. Methods This is a retrospective study involving IBD patients seen at two tertiary hospitals in Singapore from January 2020 to September 2023. Patients were identified from the Singapore National IBD registry. Those with missing data on age of IBD diagnosis were excluded. Data on baseline demographics, disease characteristics, treatment and disease-related complications were collected. EOIBD is defined as age of diagnosis ≥ 60 years old and AOIBD as those diagnosed from age 18 to 59 years old. The characteristics was compared between these two groups. Data was analysed using SPSS version 27.0. Results 1116 patients were included in the final analysis, 10.6% (n =118) were EOIBD as shown in Figure 1. 50% were male with a mean age of diagnosis at 68 years old. The comparison between EOIBD and AOIBD are shown in Figure 1 and Table 1. There is a higher proportion of Crohn’s disease (CD) (45.7% vs 37.4%) in EOIBD. In terms of treatment, there is significantly lower use of thiopurines amongst EOIBD (34.5% vs 46.8%, p = 0.012). There was a trend of higher use of methotrexate among EIOBD (19.6% vs 10.6%, p = 0.067) although this was not statistically significant and this is similarly observed in the use of biologics (32.8% in EOIBD vs 27.1% in AOIBD, p = 0.205). There were no significant differences in corticosteroids (CS) exposure, CS dependence and mean number of CS courses used. There was a lower proportion of IBD-related surgery in EOIBD (12.1 vs 18.5%, p = 0.094) with EOID having a significantly lower mean number of IBD-related surgery (1.1 vs 1.6, p <0.001). Among EOIBD, there were significantly higher rates of malignancy (17% vs 6%, p <0.001) and fractures (18.1% vs 9.2%, p = 0.02); the latter despite a statistically higher mean level of vitamin D (20.9 ng/ml vs 18.3 ng/ml, p = 0.026). There were no differences in IBD-related hospitalization. Conclusion EOIBD is associated with increased rates of fractures and malignancy compared to AOIBD. Therefore, bone health and malignancy screening should be regularly performed in this group of patients to clinical outcomes.

P1122 Comorbidities Associated with Pediatric Onset Inflammatory Bowel Diseases: A Population-Based Study

Abstract Background Inflammatory bowel disease (IBD) can be associated with various disorders, including dermatological, rheumatological, or psychiatric conditions. However, little is known about the incidence of these co-morbidities in paediatric-onset IBD at the population-based level. Methods All patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) before the age of 17 between 1988 and 2011, and included in the EPIMAD population-based registry, were followed retrospectively until 2013. In this population, we collected information on comorbidities present at diagnosis, as well as events related to the development of a new chronic condition, hospitalization, or an infectious event of interest (as pneumopathy, meningitis, or pyelonephritis) reported in the medical records during the follow-up period. Results A total of 1,344 patients were included, comprising 1,007 (74.9%) with CD and 337 (25.1%) with UC. The median age at diagnosis was 14.3 years (IQR [11.7; 16.0]). During a median follow-up of 8.3 years ([4.3-13.9]), 361 (26.9%) patients exhibited at least one comorbidity. At diagnosis, 9.4% (95% CI [7.8% - 11.0%]) of patients had at least one comorbidity. The cumulative incidence of comorbidity was 13% (95% CI [11% - 14%]) at 1 year after diagnosis and 20% (95% CI [17% - 22%]) at 5 years. No association was found between the risk of comorbidity and the clinical characteristics at IBD diagnosis. However, the cumulative incidence of comorbidity was higher in the diagnosis period 2001-2011 than in the period 1988-1993 (HR=1.7 [1.2-2.2]; p<0.001). The most frequent comorbidities were infectious (5.6%), dermatological (5.5%), and pulmonary (5.3%) (Figure 1). The most common infectious events included bacteraemia, digestive tract infection with Clostridioides difficile, and viral infection with Herpesviridae or parvovirus B19, with a cumulative incidence during follow-up of 1.2%, 1.0%, and 0.9%, respectively. During follow-up, viral infections with HBV, HCV, or HIV were observed in 0.2% of patients, and pneumopathy was diagnosed in 0.7% of patients. Eczema and asthma were the predominant dermatological and pulmonary comorbidities, affecting 2.6% and 5.1% of patients, respectively. Conclusion In this paediatric-onset IBD population-based cohort, the most common comorbidities were infectious, dermatological, and pulmonary. Bacteraemia emerged as the most prevalent severe infectious event during follow-up, affecting 1.2% of patients.

P494 Efficacy and safety of Upadacitinib in moderate to severe paediatric Crohn’s disease and ulcerative colitis in a tertiary Paediatric IBD (PIBD) centre – A case series

Abstract Background Upadacitinib is a selective Janus kinase 1 inhibitor approved for the treatment of patients 18 years and older with the diagnosis of Crohn’s disease and ulcerative colitis. Although there is promising data for its use in adult inflammatory bowel disease (IBD), limited data are currently available on its use in paediatric IBD. We present our experience in this case series of patients ≤ 18 years on Upadacitinib. Methods We identified patients under the age of ≤ 18 years, started on Upadacitinib for the indication of IBD. Data on demographics, disease subtype, duration on Upadacitinib, number of biologic failures, tofacitinib use, concomitant biologic use, adverse events and clinical remission were gathered. Results 12 patients with paediatric IBD (median age at Upadacitinib start 15.5 years, range 13.9 to 17.8 years, 8 (67%) males, were identified. 7 patients had Crohn’s disease, 3 patients had ulcerative colitis and 2 patients had IBD unclassified. 4 patients (33%) were diagnosed under the age of 6 years with early onset IBD (EOIBD), 1 was 3.5 years old, 1 was 4 years old and 2 were 5 years old. 11/12 (92%) patients had failed 3 or more biologics. Upadacitinib was used as monotherapy in all patients and previous biologic treatments were stopped. 1 patient with a partial response to tofacitinib was switched to Upadacitinib. All patients had active disease at commencement of Upadacitinib. All 12 (100%) patients were started on 45 mg of Upadacitinib. 8/12 (67%) patients have been followed up for at least 8 weeks. Out of the 8 patients, 5/8 (63%) patients were in clinical remission between 8-16 weeks of therapy, 2/8 (25%) had partial response and 1/8 (13%) has been refractory to treatment. Relapse of symptoms was noted in 1 patient after dose was dropped to 30 mg; this patient had achieved remission on 45 mg. No serious adverse events occurred; 2 patients noted to have increased triglycerides (max 5.75mmol/L; range 0.38-1.58mmol/L). 1 of them had previous exposure to tofacitinib and the triglycerides were already raised prior to starting Upadacitinib. 1 patient developed headaches, as a result, Upadacitinib dose was decreased. There were no incidences of shingles or other serious infections. Abbreviations CD, Crohn's disease; UC, ulcerative colitis; IBD-U; inflammatory bowel disease unclassified; Upa, upadacitinib; AEs; adverse events Conclusion The patients in this case series, started on Upadacitinib, are a heterogeneous group with refractory disease. In these paediatric and adolescent patients Upadacitinib seemed safe and efficacious with a low side effect profile. Further national and international collaborative studies are needed to confirm our findings. Table 1. Patient Characteristics