Onset Inflammatory Bowel Disease Research Articles

Characterization of a L136P mutation in Formin-like 2 (FMNL2) from a patient with chronic inflammatory bowel disease.

Diaphanous related formins are highly conserved proteins regulated by Rho-GTPases that act as actin nucleation and assembly factors. Here we report the functional characterization of a non-inherited heterozygous FMNL2 p.L136P mutation carried by a patient who presented with severe very early onset inflammatory bowel disease (IBD). We found that the FMNL2 L136P protein displayed subcellular mislocalization and deregulated protein autoinhibition indicating gain-of-function mechanism. Expression of FMNL2 L136P impaired cell spreading as well as filopodia formation. THP-1 macrophages expressing FMNL2 L136P revealed dysregulated podosome formation and a defect in matrix degradation. Our data indicate that the L136P mutation affects cellular actin dynamics in fibroblasts and immune cells such as macrophages.

DOP71 Fungal and bacterial gut microbiota in paediatric onset Inflammatory Bowel Disease introduced to infliximab

Abstract Background Paediatric Inflammatory Bowel Disease (PIBD), including Crohn’s Disease (CD), Ulcerative Colitis (UC) and IBD undefined (IBDU) is increasing worldwide and is characterized by an onset inflammation in the gastrointestinal tract. The patients may present severe symptoms such as abdominal pain, diarrhoea and bloody stool. No defined pathogenesis has been established for PIBD, but an imbalanced intestinal microbiota is strongly associated to the disease. Anti-tumour necrosis factor alpha (TNF-α) is an effective drug to treat inflammation in IBD, but up to half of the patients do not have a long-term response to the drug. Presently, there are no methods available to predict the TNF-α response. Here we have investigated the biomarkers of the gut fungal and bacterial microbiota, which are largely unexplored in paediatric patients, particularly for the fungal microbiota, with the aim to find possible predictors of drug response. Methods The gut microbiota composition of 30 PIBD (25 CD, 2 UC and 3 IBDU) patients at the Children′s Hospital, University of Helsinki receiving the anti-TNF-α drug infliximab (IFX) was studied by MiSeq sequencing targeting the bacterial 16S rRNA gene and fungal ITS region separately from faecal samples collected before the start of treatment and two and six weeks after treatment initiation. The response to IFX was evaluated by a faecal calprotectin value below 100 µg/g at week six after treatment initiation. The fungal MiSeq sequencing data was processed by using the DADA2 pipeline, annotated to the BLAST database and analysed using the package mare. The bacterial MiSeq sequencing data was analysed using mare and annotated to the SILVA database. Results Both the fungal and bacterial microbiota differed significantly between responders compared to non-responders to IFX, further validated by high predictive power (area under curve > 0.8) for therapy response. This difference was characterized by an increase in short-chain fatty acid producing bacteria, such as bacteria in the class Clostridia in the responders at baseline. This was observed as elevated Faecalibacterium and Subdoligranulum genera in particular of responders at baseline. Additionally, Candida was increased while Saccharomyces was decreased in non-responders at the end of the study. Finally, we observed that the interkingdom correlations differed between response groups to IFX. Conclusion Our results strengthen the proposal that the gut microbiota composition of PIBD patients could predict the response to anti-TNF-α treatment in the future.

P501 Incidence and therapeutic management/treatment of very early onset inflammatory bowel disease during 2015–2020

Abstract Background To investigate the incidence of very early onset inflammatory bowel disease (VEO-IBD) in a cohort representing two regions in Denmark during the period 2015–2019 and to assess the medical and surgical treatment. Methods All patients diagnosed with VEO-IBD within The Capital Region and The Zealand Region from January 1, 2015 to July 1, 2020 were included. Demographic and clinical data and medical and surgical treatment were extracted from the files. Results Forty patients with VEO-IBD were identified. The incidence rate was 2.0/100,000 (CI 95% 0.8–5.9) during the 2015–2019. Totally 35 patients (87.5%) received immunomodulatory therapy during follow-up. The cumulative risk of receiving immunomodulatory therapy after 1 year, 3 years and 5 years was 58% (95% CI 39–71), 88% (95% CI 70–95) and 91% (95% CI 73–97) respectively. Totally 23 patients (57.5%) received biological therapy. The cumulative risk of receiving biological therapy after 1 year, 3 years and 5 years was 37% (95% CI 19–50), 46% (95% CI 27–60) and 57% (95% CI 36–71) respectively. Six patients (15%) received vedolizumab. Four patients (10%) with VEO-IBD underwent a colectomy during the follow-up period of which two patients received vedolizumab. Conclusion The incidence of VEO-IBD was 2.0/100,000. Medical treatment with immunomodulators and biological therapy was used extensively, possibly reducing surgery. However, medical treatment remains a complicated balancing of the effect (anti-inflammatory), side effect (cancer risk) and surgery in VEO-IBD.

P640 Characteristics of elderly onset Inflammatory Bowel Disease in a cohort of Hispanics

Abstract Background The incidence and prevalence of elderly-onset Inflammatory Bowel Disease (EO-IBD), defined as diagnosed >60 y/o, is increasing. The natural history of this cohort is unclear. Disease behavior in elderly patients may differ between adult onset IBD (AO-IBD) and EO-IBD. Comorbidities, age-related frailty and side effects of medications are challenges. We compare a cohort of Hispanic EO-IBD and elderly AO-IBD patients in the IBD Registry, a database collecting demographic and medical data of patients since 1995. Methods Of 1345 subjects,122 were ≥60 y/o at recruitment, including AO and EO subjects. Variables included age at diagnosis, gender, IBD type, family history of ulcerative colitis (UC) and Crohn’s disease (CD), disease extent, extraintestinal manifestations (EIM), surgery, and medications. Descriptive statistics were calculated for interval and ratio variables. Frequencies and percentages were calculated for nominal variables cross-tabulated by age of diagnosis. The study is approved by the IRB. Results Of the 122 subjects, 59 (48.4%) had AO-IBD and 63 (51.6%) EO-IBD. Mean age of diagnosis was 49.6 y/o for the AO group and 66.4 y/o for the EO group, disease duration was 15.37 yr for AO and 3.73 yr for EO (P<.001). Female gender was more frequent (52.5%: AO, 55.6%: EO-IBD). Most were non-smokers (AO: 57.6%, EO:54%). UC was more common (AO: 62.7%, EO: 60.3%). Family history of CD was low (AO: 6.8%, EO: 6.4%), while family history of UC was more frequent in AO-IBD (18.6% vs 12.7 % in EO-IBD). Small bowel CD was the most frequent (48%) in both groups. UC extension was most commonly pancolitis (AO:58%, EO: 41%. Corticosteroid and biologic use were higher in AO-IBD (see table). EIMs were reported by 41% of AO and 27% of EO, the most frequent was joint involvement (17% AO and 16% EO). Cancer was reported in 3.4% of AO-IBD and 1.6% of EO-IBD. Osteoporosis was reported on 14% of AO-IBD and only 2% in EO-IBD. Surgery was more frequent in the AO group, 41% (n = 24) vs 24% (n = 15) in EO. Conclusion Baseline characteristics, disease location and behavior were similar in AO and EO IBD groups. Use of corticosteroids, biologics and surgery were less frequent in the EO-IBD group (not significant). Whether these findings are related to a shorter disease duration, less severe disease or a more conservative management dictated by age and co-morbidities needs to be explored. Selecting the appropriate treatment option for elderly individuals is an important clinical issue.

P360 Aggressive Inflammatory Bowel Disease is associated to Hermansky-Pudlak Syndrome: Characterization of a Puerto Rican Cohort

Abstract Background Hermansky-Pudlak Syndrome (HPS), a rare autosomal recessive disorder, is the most common single-gene disorder in Puerto Rico. It is characterized by an aberrant biogenesis of lysosome-related organelles inducing oculocutaneous albinism, bleeding diathesis, and damage to other organs. Around 30% of patients with HPS develop granulomatous enterocolitis, a Crohn’s-like inflammatory bowel disease (IBD). The mutant HPS1 gene is associated with a more severe Early Onset IBD (EO-IBD). We wish to describe a group of patients with HPS-associated IBD. Methods Puerto Ricans with HPS and concomitant IBD were recruited in our IBD clinic for a prospective cohort study. After informed consent, demographic and medical data were collected from the patient and the medical record. Variables included sex, HPS genotype, age at the time of IBD diagnosis, IBD location and behavior according to Montreal and Paris Classification, surgical interventions, medications, and extra-intestinal manifestations (EIM). Descriptive analysis was performed calculating mean and standard deviations. This study is approved by the MSC IRB. Results 13 patients with HPS and IBD, 9 with confirmed genotype 1, were identified: 8 males and 5 females. The mean age at the time of IBD diagnosis was 22 ± 11 years. 6 were diagnosed at ≤ 16 y/o (A1), 6 were diagnosed between 17-40 years (A2) and 1 patient was in the range of EO-IBD (7 y/o). 9 patients had advanced penetrating behavior (B3) of which 7 had concomitant perianal involvement. Most patients (9) had a surgical intervention; 8 have an ostomy. The majority (10) are using biologics (4 with concurrent immunomodulators). The most frequent EIM was peripheral arthropathy seen in 45%. Conclusion HPS patients had a severe course of IBD, as shown by age at diagnosis, phenotype, the prevalence of perianal disease, surgery and use of biologics. In comparison to a database of 836 Puerto Ricans with non HPS Crohn’s Disease, those with HPS were more likely to have surgeries (69% vs 55%, P=.303) and use biologics (77% vs 43%, P=.015). Gastrointestinal symptoms including bleeding may be overlooked by the primary physician. Proactive vigilance in patients with HPS to make an early diagnosis of IBD and aggressive medical treatment may result in better outcomes for these patients.

The Growing Need to Understand Very Early Onset Inflammatory Bowel Disease.

Very Early Onset Inflammatory Bowel Disease (VEO-IBD) represents a cohort of inflammatory bowel disease (IBD) patients diagnosed before 6 years of age. Unlike IBD diagnosed at older ages, VEO-IBD can be associated with underlying primary immunodeficiencies. VEO-IBD has been linked to monogenic variations in over 70 genes involved in multiple pathways of immunity. As sequencing technologies and platforms evolve and become readily available, an increasing number of genes linked to VEO-IBD have emerged. Although monogenic defects are rare in VEO-IBD, diagnosis of these variants can often dictate specific treatment. In this mini-review, we set out to describe monogenic variants previously characterized in multiple patients in the literature that contribute to VEO-IBD, diagnostic tools, unique treatment modalities for specific genetic diagnoses, and future directions in the field of VEO-IBD. Although this mini-review is by no means comprehensive of all the novel monogenic variants linked to VEO-IBD, we hope to provide relevant information that is readily accessible to clinicians and educators.

Metformin Affects Gut Microbiota Composition and Diversity Associated with Amelioration of Dextran Sulfate Sodium-Induced Colitis in Mice.

Background: Inflammatory bowel disease (IBD) is an increasingly common and globally emergent immune-mediated disorder. The etiology of IBD is complex, involving multiple factors such as immune dysregulation, environmental factors, genetic mutations, and microbiota dysbiosis, exacerbated by a lack of effective clinical therapies. Recently, studies hypothesized that dysbiosis of intestinal flora might participate in the onset of IBD. Metformin is widely used to treat type 2 diabetes and has shown beneficial effects in mouse models of IBD, although its underlying mechanisms remain poorly understood. Accumulating studies found that metformin shows beneficial effects for diabetes by affecting microbiota composition. This study explores possible regulatory effects of metformin on intestinal microecology during treatment for IBD. Methods: Inflammation was induced using 3% Dextran Sulfate Sodium (DSS) solution to generate mice models of IBD. Metformin treatments were assayed by measuring body weights and colon lengths of mice and H&E staining to observe histological effects on colon tissue structures. Changes in bacterial community composition and diversity-related to IBD and metformin treatment were assessed by high-throughput metagenomic sequencing analysis. Results: Metformin administration significantly ameliorated body weight loss, inhibited colon shrinking, and contributed to preserving the integrity of colon histological structures. The gut microbiota profiles revealed that the biodiversity of intestinal flora lost during inflammation was restored under metformin treatment. Metformin administration was also associated with decreased pathogenic Escherichia shigella and increased abundance of Lactobacillus and Akkermansia. Conclusion: Metformin appears to induce anti-inflammatory effects, thus ameliorating colitis symptoms, concurrent with enrichment for beneficial taxa and restored microbial diversity, suggesting a viable strategy against IBD.

Correlation Between Sleep, Life, Mood, and Diet and Severity of Inflammatory Bowel Disease in China: A Retrospective Study.

BackgroundThe aim of the present study was to assess the relationship between inflammatory bowel disease (IBD) and quality of sleep, quality of life (QoL), mental health, and dietary intake to identify potential risk factors for IBD.Material/MethodsThis was a retrospective analysis from September 2019 to August 2020. We enrolled 71 patients with IBD aged 14 to 69 years who completed the IBD-Life Habits Questionnaire, which included data on demographics, environmental factors, and dietary habits; the Pittsburgh Sleep Quality Index (PSQI); Patient Health Questionnaire (PHQ-9); Generalized Anxiety Disorder-7 (GAD-7); and the Inflammatory Bowel Disease Questionnaire (IBDQ). Of the patients, 46 had IBD that was in remission and in 25 the disease was active, based on scores used to assess clinical symptoms. The Crohn’s Disease Activity Index (CDAI) and the Partial Mayo Score were used for Crohn disease (CD) and ulcerative colitis (UC), respectively.The patients were divided into 2 groups, based on disease status: remission (CDAI <150 or Mayo Score=0) and active (CDAI ≥150 or Mayo Score >0). Because sleep and dietary habits in the patients with UC and CD were not significantly different, the 2 groups of patients were eventually combined into a single IBD group. The IBD-Life Habits Questionnaire, except for IBDQ, was completed by 68 age- and sex-matched healthy controls.ResultsScores for PSQI (P=.001), PHQ-9 (P=.003), GAD-7 (P=.007), and IBDQ (P=.001) were significantly higher in the patients with active IBD. An IBDQ score >168.0 (PSQI score >7.5) indicates a clinically active state of IBD with a sensitivity of 84.8% (72.0%) and a specificity of 88.0% (82.6%). Diet composition was not related to disease activity. An analysis of patients and controls showed that lack of siblings could be a protective factor for onset of IBD (OR 0.300, 95% CI 0.119–0.785), while not being breastfed (OR 2.753, 95% CI 1.025–7.396) and consuming spicy foods could be risk factors for onset of IBD (OR 2.186, 95% CI 1.370–3.488).ConclusionsIn patients with IBD, poor sleep quality, poor QoL, depression, and anxiety were related to having active disease, whereas diet was not. Attempting to control dietary composition in patients with IBD may not be effective in preventing disease flare, but attention should be paid to intake of spicy foods.

Systematic Review: The Gut Microbiome and Its Potential Clinical Application in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic relapsing–remitting systemic disease of the gastrointestinal tract. It is well established that the gut microbiome has a profound impact on IBD pathogenesis. Our aim was to systematically review the literature on the IBD gut microbiome and its usefulness to provide microbiome-based biomarkers. A systematic search of the online bibliographic database PubMed from inception to August 2020 with screening in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. One-hundred and forty-four papers were eligible for inclusion. There was a wide heterogeneity in microbiome analysis methods or experimental design. The IBD intestinal microbiome was generally characterized by reduced species richness and diversity, and lower temporal stability, while changes in the gut microbiome seemed to play a pivotal role in determining the onset of IBD. Multiple studies have identified certain microbial taxa that are enriched or depleted in IBD, including bacteria, fungi, viruses, and archaea. The two main features in this sense are the decrease in beneficial bacteria and the increase in pathogenic bacteria. Significant differences were also present between remission and relapse IBD status. Shifts in gut microbial community composition and abundance have proven to be valuable as diagnostic biomarkers. The gut microbiome plays a major role in IBD, yet studies need to go from casualty to causality. Longitudinal designs including newly diagnosed treatment-naïve patients are needed to provide insights into the role of microbes in the onset of intestinal inflammation. A better understanding of the human gut microbiome could provide innovative targets for diagnosis, prognosis, treatment and even cure of this relevant disease.

Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.

Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed. In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.

Children With Inflammatory Bowel Disease in the COVID-19 Main Endemic Focus: The Lombardy Experience.

Objectives: In the era of Coronavirus 2019 (COVID-19), concern has been raised for immunosuppressed patients, including children with inflammatory bowel diseases (IBD). We aimed to collect data from IBD tertiary centers of Lombardy during pandemic.Methods: A cross-sectional survey enrolling IBD children has been completed by seven major IBD centers in Lombardy during lockdown. The clinical form included questions on any symptom consistent with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the IBD adherence treatment. Furthermore, we have reviewed all IBD medical records including new IBD diagnoses and flares in known IBD patients after the lockdown.Results: Questionnaires of 290 IBD children were returned during lockdown. Out of them, 24 children (8%) complained of mild symptoms suspicious of SARS-CoV-2 infection without needing hospitalization or changing IBD treatment. During the lockdown, one patient presented with IBD flare and one had infectious colitis, with no new IBD cases. Conversely, after lockdown, 12/290 (4%) children relapsed and 15 children were newly diagnosed with IBD. Last year, in the same timeframe, 20/300 (7%) children presented with IBD flare, while 17 children had IBD onset with no statistical difference.Conclusions: Our data on children with IBD in a high COVID-19 prevalence region are reassuring. Only a minority of IBD children had mild symptoms, and no hospitalization or treatment modification was needed. Standard IBD treatments including biologics were safely continued. New IBD diagnoses and flares in known IBD children occurred after the lockdown phase, although no significant difference was found compared with the previous year.

Characterization of novel and large fragment deletions in exon 1 of the IL10RA gene in Chinese children with very early onset inflammatory bowel diseases

BackgroundDefects in interleukin 10 (IL10) and its receptors are particularly involved in very early onset inflammatory bowel disease (VEOIBD). However, large fragment deletions of IL10 receptor A (IL10RA) are rare.MethodsVEOIBD patients with confirmed mutations in the IL10RA gene were enrolled from January 1, 2019 to June 30, 2020. The clinical features and endoscopic-radiological findings of the patients with large fragment deletions of the IL10RA gene were determined and followed up.ResultsThirty-five patients with IL10RA gene mutations, namely, 28 compound heterozygous mutations and 7 homozygote mutations, were enrolled in this study. Six patients carried the reported point mutation c.301C > T (p. R101RW) or c.537 G > A (p. T179T) in one locus and a large fragment deletion in exon 1 in another locus, which were novel mutations in this gene. A 333-bp deletion of exon 1 (117857034–11857366 del) was the main mutation in this locus in 85.7% of the patients with large fragment deletions. The time of disease onset ranged from birth to 4 years, and diarrhea was the main initial symptom. In total, 6/7 patients had perianal complications, including perianal abscess, fistula and skin tags. Six patients accepted thalidomide treatment, 5/7 accepted mesalamine, 3/7 accepted hematopoietic stem cell transplantation (HSCT), and 3/7 were waiting for HSCT.ConclusionsWe identified a novel large deletion of exon 1 involving the IL10RA gene for the first time and showed the characteristics of VEOIBD patients. This study expands the spectrum of Chinese VEOIBD patients with IL0RA gene mutations.

Intestinal Intussusception as Crohn’s Disease Debut

Intussusception is a rare cause of intestinal obstruction in adults, occurring only in 5% of cases. Clinical case: a 22-year-old male patient with intestinal obstruction secondary to ileocolic intussusception as the onset of inflammatory bowel disease, who underwent en bloc resection of the affected segment. Keywords: Intussusception; Crohn’s disease

Study on interleukin-10 receptor A gene mutations-induced neonatal very early onset inflammatory bowel disease in 2 infants

Study on interleukin-10 receptor A gene mutations-induced neonatal very early onset inflammatory bowel disease in 2 infants

Food and Food Groups in Inflammatory Bowel Disease (IBD): The Design of the Groningen Anti-Inflammatory Diet (GrAID).

Diet plays a pivotal role in the onset and course of inflammatory bowel disease (IBD). Patients are keen to know what to eat to reduce symptoms and flares, but dietary guidelines are lacking. To advice patients, an overview of the current evidence on food (group) level is needed. This narrative review studies the effects of food (groups) on the onset and course of IBD and if not available the effects in healthy subjects or animal and in vitro IBD models. Based on this evidence the Groningen anti-inflammatory diet (GrAID) was designed and compared on food (group) level to other existing IBD diets. Although on several foods conflicting results were found, this review provides patients a good overview. Based on this evidence, the GrAID consists of lean meat, eggs, fish, plain dairy (such as milk, yoghurt, kefir and hard cheeses), fruit, vegetables, legumes, wheat, coffee, tea and honey. Red meat, other dairy products and sugar should be limited. Canned and processed foods, alcohol and sweetened beverages should be avoided. This comprehensive review focuses on anti-inflammatory properties of foods providing IBD patients with the best evidence on which foods they should eat or avoid to reduce flares. This was used to design the GrAID.

Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease

CARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD.

Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn\u2019s Disease

Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.

A191 TEN YEARS FOLLOW UP OF EARLY ONSET INFLAMMATORY BOWEL DISEASE PATIENTS- A SINGLE CENTER RETROSPECTIVE COHORT STUDY

Abstract Background Early onset inflammatory bowel disease (EOIBD) and Very early onset inflammatory bowel disease (VEOIBD) prevalence has been increasing over the last decades. These young patients have been known to have special disease characteristics and disease location. Although it is known that only a low percentage of these patients require biologic treatment after diagnosis, there is only scarce evidence about their long- term outcome and biologic requirements. Aims To assess the ten year outcome of early onset and very early onset IBD patients. Methods We retrospectively reviewed IBD patients diagnosed under 10 years of age, between January 2005 and December 2009, from the British Columbia (BC) Pediatric IBD database. Disease characteristics and symptoms at diagnosis were documented. The disease location and severity at diagnosis were documented according to the Paris classification. Data collected retrospectively included a ten year treatment follow up period, number of hospitalizations, corticosteroid courses and surgeries. These parameters were documented at three time points: after the first year, after five years and ten years. Results 68 patients under the age of 10 were diagnosed with IBD during the study period. 2 patients failed to meet inclusion criteria and were excluded. Median age at diagnosis was 6.06 (IQR 4.5–8.6). 47.7% of patients had Crohn’s disease and 71.2% were males. 63 patients completed the 5 year follow up, and 52 the 10-year period due to lack of follow up or transfer to adult care. After the first year of follow up 0% patients in the VEOIBD group and 5% patients in the EOIBD group were treated with biologic treatment, whereas after the 10-year period 42.3% and 29.6% of patients were treated with biologic therapy respectively (p=0.282). Overall, 4 patients underwent colectomy and 2 a small bowel resection. Conclusions Although the percentage of VEIBD and EOIBD patients receiving biologic treatment after ten years is higher than after the first year, it is still lower than what is reported in the literature in older pediatric IBD patients and adults. Funding Agencies None

A26 A SYSTEMTIC REVIEW OF MONOGENIC INFLAMMATORY BOWEL DISEASE: CLINICAL PHENOTYPE AND GENOTYPE

Abstract Background Advances in genomic technologies have led to an increase in reports of monogenic inflammatory bowel disease (IBD). The majority of the studies on monogenic IBD have focused only on young children aged &amp;lt;6 years. There are no detailed reports containing a comprehensive picture of monogenic IBD with specific numbers on the clinical features, genetic profiles and disease course. Since each gene-specific cause of monogenic IBD is rare, it is difficult to collect cases in a single study even with international cohort studies. Aims To elucidate a comprehensive picture of monogenic IBD, we conducted a systematic review of all reported cases of monogenic IBD. Methods A systematic review of MEDLINE articles published between January 2000 and December 2019 was conducted. 662 monogenic IBD cases were identified from 273 eligible articles. Data on clinical manifestation, genotype, and management were collected. Results The most frequently reported genes causative of monogenic IBD patients were IL10RA, CYBB, IL10RB, and TTC7A (Figure). In total, 64.8% of patients developed IBD before six years old, 15.6% between ages 10 and 17.9 years, and 11.6% at age 18 years or older. Only 32.7% had any history of extra-intestinal manifestation (EIM) before IBD onset. There was substantial difference in the onset age groups and the underlying monogenic disorders. 74.4% developed at least one EIM during their clinical course. The most common EIMs were atypical infection (44.1%), dermatologic abnormality (39.2%), autoimmunity (22.7%) and lymphoid organ abnormality (11.5%). Autosomal recessive (62.8%) was the most common inheritance pattern, and missense-variants (44.3%) were the most identified type of genetic variants. Deletions including CNVs, intronic, synonymous and inversion, which have the possibility to be overlooked by whole exome sequencing were shown in some cases. Bowel surgery, biologics, and hematopoietic stem cell transplantation were performed in 28.3%, 32.8%, and 24.4% of patients, respectively. Conclusions Monogenic IBD diagnosis and management is a challenging clinical problem across age groups; the EIMs are more diverse and the management is evidently more difficult compared to non-monogenic IBD. An improved understanding of the characteristics of the genes and underlying disease processes in monogenic IBD is necessary for effective management. Funding Agencies CAG, CIHRUehara Memorial Foundation Fellowship

A25 THE RISING GLOBAL INCIDENCE OF PEDIATRIC INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW OF POPULATION-BASED STUDIES

Abstract Background The incidence of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is increasing internationally, particularly in developing nations where rates were historically low. Previous reports of the incidence and prevalence of pediatric-onset IBD have identified a paucity of population-based studies. Aims We reviewed the global trends in incidence of pediatric IBD using evidence from population-based studies. Methods (PROSPERO CRD42019125193) We systematically reviewed studies indexed in MEDLINE, EMBASE, Airiti Library, and SciELO from 01/2010-02/2020 to identify population-based studies reporting the incidence of pediatric-onset IBD, CD, and UC. Included studies combined childhood and adolescent-onset IBD (onset &amp;lt;21y). Changes in incidence since 2000 were plotted by continent, with data from 2000–09 provided by our previous systematic review1. To depict trends, multiple times points reported in single studies were connected on graphs. When incidence was reported as an aggregated estimate over a range of years, data was plotted using the midpoint of the interval. Results Of 8096 abstracts screened, 74 studies described the incidence of IBD, CD, or UC in 33 countries (Figure panel A). The incidence of pediatric-onset IBD is highest in Northern Europe and North America, and lowest in Southern Europe, Asia, and the Middle East. This geographical distribution is similar in UC, while incidence of pediatric-onset CD is highest in North America and Northern Europe, followed by Australia. Trends in incidence over time, stratified by continent, are reported in Figure, panel B. Significantly increasing incidence of IBD, CD, and/or UC was reported in China, Bahrain, Canada, New Zealand, Australia, Singapore, Saudi Arabia, and most European countries. Very Early Onset (VEO) IBD significantly increased in Canada, however Saudi Arabia reported decreasing incidence of VEO-CD but stable incidence of VEO-UC. Conclusions Conclusion: Incidence of pediatric-onset IBD are highest in Northern Europe and North American and are increasing globally. There remains a paucity of studies from many parts of the world on the incidence pediatric IBD. Further research is needed to understand the pathogenesis of the rising incidence of pediatric IBD, including work to understand the genetic, environmental, immunological and microbiome alterations leading to the increasing rates in children.