Phenotype Of Crohn’s Disease Research Articles

NOVEL GENETIC SUSCEPTIBILITY CANDIDATES IN GRANULOMATOUS AND NON-GRANULOMATOUS PEDIATRIC CROHN’S DISEASE

Abstract Background Non-caseating granulomas are a hallmark histopathological finding of Crohn’s disease (CD). Studies have suggested that the presence of granulomas may indicate a more aggressive CD phenotype associated with a complicated clinical course, including stricturing and/or penetrating disease, need for biologic therapy, and need for surgery. As such, identification of genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis, which in turn may optimize treatments and guide novel therapeutics to combat CD complications. There is relatively sparse genetic information known about CD subtypes, especially GCD. The aim of this study was to determine the extent of genetic variation between pediatric CD patients with and without a pathognomonic sub-mucosal granuloma detected at the time of diagnosis. Methods Whole-exome next-generation sequencing (WES) was performed on peripheral blood derived DNA from patients with GCD and non-GCD (NGCD). PLINK analysis was used to identify single nucleotide polymorphisms (SNPs) that were overrepresented in comparisons between groups, and subgroup allele frequencies were also compared to publically available, large population-based genomic data in gnomAD. The potential deleteriousness of single nucleotide variants was determined by the CADD scoring tool. Results WES was completed for 17 patients with GCD and 19 with NGCD. There were no significant differences in baseline clinical characteristics, treatments, nor 1-year outcomes between the groups. Overlap analyses between PLINK- and gnomAD-generated SNPs revealed significant enrichment in those associated with HLA-DQA1, LILRA1, SAA2, PCDHB, HLA-B, NOD2, and IGH shared by GCD and NGCD groups. In the meantime, GCD-specific (top candidates linked with HLA-B and MUC4) and NGCD-specific (top candidates linked with HLA-B and ACOT9) SNPs were sparse. Conclusions We are the first to examine WES-based genetic variation between treatment-naïve pediatric CD patients purely separated by the presence of a sub-mucosal epithelioid granuloma. While there were very few SNPs consistently differentiating between GCD and NGCD patients in our cohort using two distinct methodologies, we were able to identify several novel SNPs that were significantly enriched in pediatric CD patients compared to the control human genome. Our findings will require subsequent confirmation in larger but similarly scrutinized cohorts of patients.

Systematic review and meta-analysis: the impact of co-occurring immune-mediated inflammatory diseases on the disease localization and behavior of Crohn's disease.

Background:Patients with Crohn’s disease (CD) are at increased risk of co-occurring immune-mediated inflammatory diseases (IMIDs). As discrepancy exists regarding the phenotypic presentation of CD among patients with such co-occurring IMIDs, we aimed to conduct a systematic review with meta-analysis characterizing the phenotype of CD among this subgroup of patients.Methods:PubMed, Embase, and Scopus were searched from their earliest records to October 2019 for studies reporting the behavior and localization of CD according to the Vienna or Montreal Classifications and CD-related surgery in patients with co-occurring IMIDs. These studies were the subject of a random effect meta-analysis.Results:After reviewing 24,413 studies, we identified a total of 23 studies comprising 1572 and 35,043 CD patients with and without co-occurring IMIDs, respectively, that fulfilled our inclusion criteria. Overall, patients with co-occurring IMIDs were more likely to have upper gastrointestinal inflammation than were patients without co-occurring IMIDs [relative risk (RR) = 1.49 (95% confidence interval (CI) 1.09–2.04), p = 0.01, I2 = 7%]. In addition, presence of primary sclerosing cholangitis (PSC) was associated with a lower occurrence of ileal affection [RR = 0.44 (95% CI 0.24–0.81), p < 0.01, I2 = 32%], increased occurrence of colonic affection [RR = 1.78 (95% CI 1.33–2.38), p < 0.01, I2 = 32%] and an increased likelihood of non-stricturing and non-penetrating behavior [RR = 1.43 (95% CI 0.97–2.11), p = 0.07, I2 = 86%]. The latter reached significance when cumulating different IMIDs [RR = 1.30 (95% CI 1.09–1.55), p < 0.01, I2 = 88%]. CD patients with PSC also underwent fewer CD-related surgeries [RR = 0.55 (95% CI 0.34–0.88), p = 0.01, I2 = 0%], irrespective of CD location or behavior.Conclusion:This study emphasizes that CD patients with co-existing PSC are likely to have a unique inflammatory distribution primarily confined to the colon, while patients with IMIDs in general have higher likelihood of affection of upper gastrointestinal tract and a non-stricturing and non-penetrating behavior. As such a phenotype of CD is typically associated with a milder disease course; future studies are needed to confirm these results.

Body weight, serum albumin and food intolerance were linked to upper gastrointestinal Crohn's disease: a 7-year retrospective analysis.

BackgroundThe clinical features of upper gastrointestinal (L4) Crohn’s disease (CD) and its subtypes, along with the associated and nutritional status, remain poorly described. Our aim was to evaluate the clinical characteristics of L4 CD phenotype and its subtypes at diagnosis, and their relationship with the nutritional status.MethodsA retrospective study was conducted on 869 CD patients diagnosed between 2013 and 2019, and the association between the clinical characteristics and nutritional status of L4 patients was determined using Random forest importance ranking and logistic regression.ResultsThe majority of the patients (59.72%) presented L4 lesions, of which 335, 158 and 26 had proximal ileal, jejunal and esophago-gastroduodenal (EGD) lesions respectively. L4 patients were predominantly male (OR 2.07), smoker (OR 1.80), and had higher body weight and BMI, longer disease course, and stricturing disease (OR 1.88). Furthermore, the serum albumin level, body weight and disease course showed higher MDG in the random forest importance ranking test for L4 CD and L4-proximal ileal types. According to logistic regression, body weight (OR 1.054), disease course (OR 1.010), stricturing behavior (OR 4.998) and tomato intolerance (OR 1.313) were the independent risk factors for L4. In addition, body weight (OR 1.042) and stricturing behavior (OR 3.152) were the relevant factors for proximal ileal subtype, and stricturing behavior (OR 4.206) and perianal disease (OR 0.339) for jejunal subtype.ConclusionsL4 disease has a higher incidence rate compared to the non-L4 CD, and mainly affects males, and those with prolonged disease course, stricturing behavior, higher weight, BMI, albumin levels and food intolerance (FI).

S0884 A Retrospective Review of Factors Associated With Recurrent Ileocolonic Resection in Patients With Crohn's Disease

INTRODUCTION: Additional ileocolonic resection(s) (ICR) in Crohn’s Disease (CD) patients undergoing the first ICR represents an important source of morbidity and complications. The factors that predict time to recurrent ICR are not well defined. Here we reviewed patients with stricturing CD who have had at least two ICRs to inquire if any clinical factors are associated with a short period of time between ICRs. METHODS: A cohort was designed using surgical billing codes for patients with CD who had an ICR between 2007 and 2018 at one institution and validated by manual chart review. Independent variables included age, sex, race, smoking, family history of IBD, duration of disease, Montreal phenotype, perianal involvement, biologic medications, total number of resections, and indication for surgery. The variables were tested independently for association with time between the first and second ICR (T1-2) using a multivariate linear regression model. Rutgeerts score between first and second ICR was tested using one-way ANOVA (using i0 and >=i1, compared to T1-2) for the 29 patients with endoscopic data. RESULTS: From the initial cohort of 365 patients, 294 patients were excluded due to surgical indication other than stricture, location not ileocecum, only one ICR, extreme outlier results (n = 2) and incomplete charts. Demographic data is shown in Table 1. A total of 14 patients used biologic medications prior to index ICR, and an additional 42 patients were started on biologics between first and second ICR. Taking biologics before the first resection was associated with a shorter T1-2 (5.2 vs 10.8 years, P = 0.0009). Starting biologics after index surgery did not impact T1-2. The remainder of the variables tested did not show a significant association with T1-2. The average amount of time for T1-2 was 9.5 years. CONCLUSION: In patients who underwent recurrent ICR, being prescribed biologics before index resection is significantly associated with a shorter time from index to subsequent resection (P < 0.001). However, this variable only explains 12% of the variability, suggesting additional variables affect T1-2. This association may be explained by a confounding factor such as disease activity/more aggressive CD phenotype. It is also possible that in a substrata of CD patients, taking biologics before index ICR accelerates pro-fibrogenic mechanisms. Future studies are needed to identify more clinical and/or molecular factors that would further explain and predict need for subsequent ICRs in CD patients.Table 1.: Demographics

The New Proactive Approach and Precision Medicine in Crohn's Disease.

The proactive approach to Crohn’s disease (CD) management advocates moving toward algorithmic tight-control scenarios that are designed for each CD phenotype to guide remission induction, maintenance therapy, active monitoring, and multidisciplinary care to manage the complexities of each inflammatory bowel disease (IBD) patient. This requires accurate initial clinical, laboratory, radiological, endoscopic, and/or tissue diagnosis for proper phenotypic stratification of each CD patient. A substantial proportion of patients in symptomatic remission have been reported to demonstrate evidence of active disease, with elevated fecal calprotectin(FC) and C-reactive protein (CRP) levels as a hallmark for mucosal inflammation. Active mucosal inflammation, and elevated CRP and fecal calprotectin (FC) have been shown to be good predictors of clinical relapse, disease progression, and complications in IBD patients. The next frontier of treatment is personalized medicine or precision medicine to help solve the problem of IBD heterogeneity and variable responses to treatment. Personalized medicine has the potential to increase the efficacy and/or reduce potential adverse effects of treatment for each CD phenotype. However, there is currently an unmet need for better elucidation of the inflammatory biopathways and genetic signatures of each IBD phenotype, so personalized medicine can specifically target the underlying cause of the disease and provide maximal efficacy to each patient.

P105 PREDICTIVE FACTORS FOR DEVELOPING SMALL BOWEL OBSTRUCTIONS AFTER ILEAL RESECTION IN PATIENTS WITH CROHN’S DISEASE

Abstract Background and Aims Patients with Crohn’s disease (CD) may require small bowel resections. Unfortunately, some of these patients may develop post-operative small bowel obstructions (SBO). Many clinicians perceive ileal resections dramatically increase the risk of developing SBO in the future, but the incidence and risk factors to developing SBO are poorly described. The primary aim of this study is to document the incidence and factors associated with the development of SBO not related to recurrence of disease in CD patients that undergo ileal resection. We also sought to assess long-term outcomes of this complication. Methods We performed a retrospective cohort study including patients aged 18 years or older with CD, who have had ileocecal resection with ileocolonic anastomosis or segmental small bowel resection. Data abstracted included demographics, phenotype and therapies of CD, disease recurrence post-ileal resection and multiple surgical variables. The primary outcome was the development of SBO within 5 years post-surgery not including obstructions secondary to recurrence of CD. Results 92 total patients were included in the analysis. All had a colonoscopy within a year of the surgery. The mean Rutgeerts score was 0 (interquartile range [IQR] 0 to 2) and the mean short endoscopic score was 0 (IQR 0 to 4). The remainder of baseline characteristics are shown in Table 1. At 6 months, 1 year, and 5 years, the rate of SBO was 4/92 (4%), 6/92 (6.5%), and 15/92 (16%), respectively. Throughout follow-up, only 5 patients had an SBO attributed to intra-abdominal adhesions and only 2 patients required surgical lysis of adhesions. Patients that were found to have histologic inflammation in the margins of the resected bowel specimen had a significantly higher chance of developing an SBO within 5 years of the initial surgery (OR: 4.5 [95%CI: 1.3–15.3], p=0.02 - Table 2). Conversely, patients with either active endoscopic and/or radiologic inflammation on post surgical surveillance colonoscopy did not have a higher risk of developing an SBO within 5 years of the initial surgery (p=0.37). Finally the length of bowel resected at the index surgery was not associated with the development of an SBO (AUC: 0.62, p=0.18). Conclusions The incidence of SBO after ileal resection in CD is low and resolves with medical management on most cases. Inflammation in the margins of the resected bowel and previous bowel resections were associated with new SBO within 5 years. These results must take into account the study population were monitored and cannot be extrapolated to those patients that lost follow-up.

P652 Underweight patients with Crohn’s disease and without vitamin D supplementation are at high risk of vitamin D deficiency

Abstract Background Vitamin D deficiency is frequently present in inflammatory bowel disease (IBD) with a higher incidence in Crohn’s disease (CD) than in ulcerative colitis (UC). Given the involvement of the alimentary tract, many factors can contribute to vitamin D deficiency. The aim of the study was to investigate the association of vitamin D deficiency according to body mass index (BMI) in adult patients with IBD. Methods A cross-sectional study was conducted on a cohort of 152 IBD patients, 68.1% (n = 104) CD and 31.9% (n = 48) UC. The mean age of the total study population was 37.3±11.8 years and 57.3% (n = 87) were male. All patients were adult, Caucasian and without vitamin D supplementation. Patients were recruited during one year period. Results Out of all IBD patients, 60.5% (n = 92) had vitamin D deficiency, 32.2%, (n = 49) insufficiency and 7.2% (n = 11) sufficiency. According to BMI categories there were 12.5% (n = 19) obese patients, 27.6% (n = 42) overweight, 51.3% (n = 78) with normal body weight, and 8.6% (n = 13) underweight. There was a significant difference in vitamin D levels according to different BMI categories in terms of underweight patients having the lowest vitamin D levels; underweight 29.84±11.94 mmol/l, normal 46 ± 20.7 mmol/l, overweight 48±20.1 mmol/l, obese 51±15.3 mmol/l. In addition, there was a significant correlation of vitamin D levels and BMI values (Rho = 0.212, 95% CI 0.069–0.345, p = 0.004), which was more clearly observed in the lower range of BMI values (Figure 1). Male underweight patients had lower levels of vitamin D compared with female patients (26.6 ± 9 vs. 34.7 ± 5.6, p &amp;lt; 0.05). Both patients with CD and UC had significant positive correlation of vitamin D levels and BMI values (UC Rho=0.40, 95% CI 0.16–0.59, p = 0.001, UC Rho = 0.27, 95% CI 0.01–0.05, p = 0.044). However, when comparing vitamin D levels according to phenotype, a significant difference in vitamin D levels was observed in underweight CD (28.4 ± 11.1) comparing to underweight UC patients (40.6 ± 10.6), p &amp;lt; 0.05. In logistic regression analysis, CD phenotype was risk factor for vitamin D deficiency (OR 2.18 95% CI 1.01–4.72, β = 1.22, p = 0.04). Conclusion Our results on untreated IBD patients show a high proportion of vitamin D deficiency both in CD and UC, and significant correlation of vitamin D levels and BMI values, especially in the lower range of BMI values. Moreover, underweight CD patients have lower vitamin D levels comparing to UC. This suggests the need for regular vitamin D monitoring and supplementation especially in IBD patients at risk.

N30 Experience of living with intestinal failure: a systematic review of qualitative studies

Abstract Background Intestinal failure (IF) affects about 2000 people with Crohn’s disease (CD) in the UK. It is a result of the most severe phenotype of CD where an individual can no longer obtain sufficient nutrients from their gut to sustain life without supplementation in the form of parenteral nutrition (PN) or fluids intravenously and most have a stoma. Many cannot tolerate any food and very little drink by mouth. Such individuals usually need a permanent central venous catheter and must have an infusion of PN overnight, all or most nights in the week, often for 10–12 h at the time. Complications such as infection or thrombosis of the central line are a constant risk. This treatment must often continue for life. This systematic review aimed to explore the experience of people living with IF and the impact of the condition on their daily lives. Methods The following databases were searched in July 2019: MEDLINE, PubMed, PsychINFO, Web of Science and Global Health Scopus. Search terms included ‘intestinal failure’, ‘short bowel syndrome’, ‘quality of life’ (QoL) and terms relating to psychosocial functioning. English language articles were retrieved and screened by one reviewer at title and abstract, ratified by a second reviewer. The resulting articles selected at abstract were screened at full text by 3 reviewers. Results Eight papers, based on 7 studies, were included with a total of 97 participants: 36 male, 61 female. The age range of adults was 28–83. One study was conducted in children, with age range of 7–17. In 5 studies, all participants were on HPN. In 2 studies, 4/6 and 7/10 participants were on HPN respectively. There was one overarching theme: ‘Complications and challenges of living with IF’, with three specific themes that reflect the patients’ experience: (1) ‘Eating for survival’ encompasses the perpetual need to eat in order to make up for the large quantities of nutrients lost due to malabsorption (2) ‘Life with HPN: nutritional safety net at a price’ describes relief from the pressure to eat for survival but with drawbacks such as restrictions on social activities and risk of catheter line infections. (3) ‘Benefits and pitfalls of having a stoma’ relates to benefits of having a stoma, such as reduced frequency of toilet visits, and the accompanying inconvenience of leaks, high output and negative body image. Conclusion Living with IF has many challenges. Patients struggle with retaining enough nutrients and the physical and technical difficulties with having HPN and/or a stoma. The psychosocial well-being in these patients is affected by these challenges, as a result. Overall, QoL is poor and currently very little is being done to improve this.

N31 What factors affect quality of life and psychological well-being in patients with intestinal failure? A systematic review of quantitative studies

Abstract Background The most common cause of intestinal failure (IF) is Crohn’s disease (CD). The definition of IF is ‘the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth’. It is a result of the most severe phenotype of CD, where an individual can no longer obtain sufficient nutrients and fluids from their gut to sustain life without supplementation in the form of parenteral nutrition (PN) or intravenous fluids. Home PN (HPN) allows people to receive infusion at home and increases survival rates (65% after 6 years). Whilst HPN improves length of life, studies have demonstrated this treatment can severely negatively affect an individuals’ quality of life (QoL) and employment. The aim of this systematic review was to identify factors affecting QoL in people with IF. Methods A search of databases MEDLINE, PubMed, PsycINFO, Web of Science, Global Health, and Scopus was conducted in July 2019. Search terms included ‘Crohn’s disease’, ‘short bowel syndrome’, ‘intestinal failure’, ‘quality of life’, and ‘health-related quality of life’. Titles and abstracts were screened by one reviewer. Any uncertainties about inclusion of the papers were discussed with two reviewers. Full texts were screened by 3 reviewers. Quantitative studies that measured QoL as an outcome in people with IF were included. Results Nineteen studies including a total of 924 participants met the inclusion criteria. Six key themes of factors affecting QoL were identified: (1) Practicalities of IF and HPN, e.g. sleep disturbances from the noise of the pump; managing a high output stoma. (2) Impact of medical interventions, e.g. blood tests. (3) Social impact/physical activity/personal relationships, e.g. restricted ability to travel, socialise and eat with friends. (4) Personal and sexual impact, e.g. lack of sexual desire. (5) Impact of symptoms, e.g. fatigue. (6) Patient characteristics, e.g. age. Some studies also reported positive effects on health (such as more energy), improved symptoms and QoL with HPN, especially for those who had been very unwell previously. Conclusion People with IF often have poor QoL that is affected by many factors, from their symptoms to practical aspects of HPN. However, themes related to the ‘social’ and ‘personal’ impact of IF dominated in the literature. While there is considerable evidence on what affects QoL in people with IF, there appears to very little research on attempting to improve QoL in this patient group.

P164 HLA G expression is differentially expressed in infiltrating cells in inflammatory bowel disease and in healthy specimens

Abstract Background Since HLA-G is an immune checkpoint molecule and since Crohn’s disease (CD) and ulcerative colitis (UC) exhibit immune-mediated mechanism deregulation, we aimed to evaluate HLA-G intestinal expression and soluble (sHLA-G) levels in CD/UC patients, stratified according to CD phenotype/localisation and UC extension. Methods HLA-G tissue expression was assessed by immunohistochemistry in biopsies collected from 151 patients (90 CD, 61 UC) and 24 healthy controls, and in surgical resections (28 CD, 12 UC). Plasma sHLA-G levels (97 CD, 81 UC and 120 controls) were evaluated using ELISA Results HLA-G expression was observed in intestinal epithelial cells of controls and CD/UC specimens, exhibiting closely similar profiles, and in lamina propria infiltrating cells, exhibiting differential patterns. In biopsies, CD/UC lamina propria plasma cells/lymphocytes presented: i) increased HLA-G expression compared with controls (p &amp;lt; 0.0001), ii) irrespective of the extent, UC cell staining was greater compared with CD cells (p = 0.0011), and iii) the inflammatory CD phenotype presented increased number of infiltrating cells compared with stenosing and fistulizing phenotypes (p = 0.0407). In surgical resections, CD/UC patients exhibited increased infiltrating cell HLA-G expression in lesion areas compared with margins. sHLA-G levels were increased in UC/CD patients (p &amp;lt; 0.0001) when compared with controls, but no difference was observed between patients. Conclusion Increased infiltrating cell HLA-G expression associated with increased sHLA-G levels in CD/UC patients may reflect host on-going strategies to suppress chronic inflammation. References

Geographic Distribution, Phenotype and Epidemiological Tendency in Inflammatory Bowel Disease Patients in Romania.

Background and objective: The incidence of inflammatory bowel disease (IBD) over the past years in Romania has been on the rise, but epidemiologic data are lacking. The aim of this study was to define the characteristics of IBD, the trends and phenotype among IBD patients in Romania. Material and methods: We conducted a prospective study over a period of 12 years, from 2006 to 2017. All patients diagnosed with IBD on clinical, radiological, endoscopic and histological features were included. We divided the country into eight regions: west (W), north-east (NE), north-west (NW), south-east (SE), south-west (SW), south (S), central (C) and Bucharest-Ilfov (B), and data were analyzed accordingly. Results: A total of 2724 patients were included in this database, but only 2248 were included in the final analysis, with all data available. Of the 2248 patients, 935 were Crohn’s disease (CD), 1263 were ulcerative colitis (UC) and 50 were IBD-undetermined. In UC phenotypes we observed more frequent left-sided colitis (50.5%, p < 0.0001), and in CD phenotype we observed more frequent colonic and ileo-colonic localization (37.8% and 37.6%, p < 0.0001). The region with the most IBD cases was NE (25.1%) and with the least IBD cases was SW (4.9%). UC was found more frequently in NE (32%), while CD was found more frequently in Bucharest (28.6%). Conclusions: In Romania, ulcerative colitis is more frequent than CD. UC is predominant in the northern part of Romania, while CD has become predominant in the southern part of the country. IBD occurs more in the male population, and in urban and industrialized areas. There are differences between the regions in Romania regarding IBD phenotypes, gender distributions, age distribution, treatment, smoking status and complications.

801 Phenotypic Characteristics of Crohn’s Disease in Latin Americans Versus U.S. Hispanics: A Systematic Review With Meta-Analysis

INTRODUCTION: Latin America is experiencing a rise in the prevalence and incidence of inflammatory bowel disease (IBD). Environmental and dietary changes may be contributing factors. In Latin America, Crohn’s disease (CD) is less common than ulcerative colitis (UC), but the predominant phenotype of CD is not established. Also, it is unknown whether there are regional differences in phenotype across Latin America. This systematic review aims to describe the phenotype of CD in Latin Americans as compared with U.S. Hispanics. METHODS: We conducted a systematic review with meta-analysis of population-based studies to compare the phenotype of CD across Latin America with U.S. Hispanics. Phenotype was defined according to the Montreal classification. A systematic search was conducted using MEDLINE and EMBASE. Inclusion criteria: (i) studies describing the phenotype of CD in Latin America and Hispanics in the U.S. (ii) age &gt;18. Exclusion criteria: (i) prevalence or incidence studies not describing the phenotype. A random effects model was chosen “a priori” for analysis of pooled proportions. RESULTS: A total of 4,627 studies were screened. 34 studies from Latin America and 7 studies from the U.S met inclusion criteria. 2,877 Latin Americans and 233 U.S. Hispanics had the diagnosis of CD. The predominant phenotype in Latin America was ileo-colonic disease (L3) with a pooled proportion of 0.37 (95% CI 0.32-0.41, I2 82%), and for U.S. Hispanics, 0.46 (95% CI 0.31-0.61, I2 82.5%), P = 0.88. Inflammatory behavior (B1) was predominant for Latin America and U.S. Hispanics, 0.51 (95% CI 0.41-0.60, I2 94.3%) vs. 0.64 (95% CI 0.42-0.87, I2 91.7%), P = 0.24, respectively. Perianal involvement was similar between Latin Americans and U.S Hispanics with nearly one-third of patients showing this phenotype, P = 0.82. Phenotype across Latin America was similar except in Cuba, where ileal disease was present in nearly one-half of patients. Colonic CD (L2) was less frequently seen in Cuba, 0.15 (95% CI 0.10-0.21), P = 0.002. Disease behavior and perianal involvement were similar across Latin Americans, Table 1. CONCLUSION: The phenotype of Crohn's disease was similar between Latin Americans and U.S. Hispanics. This goes in line with current knowledge that ileo-colonic disease is the predominant disease location in Caucasians. Disease behavior and perianal involvement were similar between Latin Americans and U.S. Hispanics. In Latin America, the phenotype was homogeneous, except in Cuba where ileal disease was the predominant location.

Relationship between the IL23R SNPs and Crohn's Disease Susceptibility and Phenotype in the Polish and Bosnian Populations: A Case-Control Study.

It is suggested that IL-23/IL-17 axis and single nucleotide polymorphisms (SNPs) of IL23R may have crucial role in pathogenesis of Crohn’s disease (CD). Thus, we sought to assess the IL23R SNPs contribution to susceptibility and phenotype of CD. We recruited 117 CD subjects and 117 controls from Poland and 30 CD subjects and 30 controls from Bosnia and Herzegovina (B&H). Two common IL23R SNPs: rs1004819, rs7517847 were genotyped using TaqMan SNP assays. In the Polish population it was found that allele rs1004819: A increases the risk of CD, while allele rs7517847: A is protective against disease development. In Poles the co-carriage of two IL23R risk genotypes was associated with increased risk of CD. A significantly increased risk of CD early onset was observed in Poles carrying at least one rs7517847: G allele. It was also found that IL23R SNPs may be associated with structuring/penetrating CD behavior, as alleles rs1004819: A and rs7517847: G were significantly less frequent in patients without complications, from Poland and B&H, respectively. Allele rs1004819: A was also significantly more frequent in Poles with penetrating CD. These results confirm IL23R SNPs contribution to CD susceptibility in the Polish population and suggest their impact on early age of onset and more severe disease course.

P093 COMPARATIVE INCIDENCE OF INFLAMMATORY BOWEL DISEASE IN DIFFERENT AGE GROUPS: A COMMERCIALLY-INSURED, POPULATION-BASED US STUDY

Data on the incidence of inflammatory bowel disease (IBD) by age groups are available in countries outside of the United States (US) or localized populations within the US. We aimed to estimate the incidence rates (IRs) of IBD by age groups using a US multiregional dataset. We used the Optum® Research Database to identify incident IBD patients with a disease-free interval of 1.5 years between 2005-2015. Overall and age-specific IRs were calculated for 4 different age groups: pediatric (0-17 years), young adult (18-25 years), adult (26-59 years), elderly (>60 years). Time trends of incidence were evaluated in each age group. Disease extent and phenotype were also compared. The mean IR for the cohort (n=60,247) from 2005-2015 was 37.5/100,000. The IR was highest in adult and elderly cohorts (36.4 and 36.7/100,000 respectively), with predominance of ulcerative colitis (UC) over Crohn’s disease (CD). The IR increased over the 10-year study period for all age groups (time trends p-value <0.001). The elderly group had more colonic and more stricturing CD phenotype but less perianal disease. In pediatric and young adult cohorts, the incidence for CD (5.2 and 11.8/100,000 respectively) was higher than UC (2.4 and 9.6/100,000 respectively), with a higher rate of penetrating CD. In one of the most comprehensive evaluations of the incidence of IBD in the US, we found a similar incidence rate to other national populations. We also confirmed differences of IBD phenotypes based on age groups, with less aggressive and lower rates of perianal disease in the elderly. Figure 1. Distribution of IRs for IBD in four different age cohorts.

P093 COMPARATIVE INCIDENCE OF INFLAMMATORY BOWEL DISEASE IN DIFFERENT AGE GROUPS: A COMMERCIALLY-INSURED, POPULATION-BASED US STUDY

Data on the incidence of inflammatory bowel disease (IBD) by age groups are available in countries outside of the United States (US) or localized populations within the US. We aimed to estimate the incidence rates (IRs) of IBD by age groups using a US multiregional dataset. We used the Optum® Research Database to identify incident IBD patients with a disease-free interval of 1.5 years between 2005-2015. Overall and age-specific IRs were calculated for 4 different age groups: pediatric (0-17 years), young adult (18-25 years), adult (26-59 years), elderly (>60 years). Time trends of incidence were evaluated in each age group. Disease extent and phenotype were also compared. The mean IR for the cohort (n=60,247) from 2005-2015 was 37.5/100,000. The IR was highest in adult and elderly cohorts (36.4 and 36.7/100,000 respectively), with predominance of ulcerative colitis (UC) over Crohn’s disease (CD). The IR increased over the 10-year study period for all age groups (time trends p-value <0.001). The elderly group had more colonic and more stricturing CD phenotype but less perianal disease. In pediatric and young adult cohorts, the incidence for CD (5.2 and 11.8/100,000 respectively) was higher than UC (2.4 and 9.6/100,000 respectively), with a higher rate of penetrating CD. In one of the most comprehensive evaluations of the incidence of IBD in the US, we found a similar incidence rate to other national populations. We also confirmed differences of IBD phenotypes based on age groups, with less aggressive and lower rates of perianal disease in the elderly.Figure 1Distribution of IRs for IBD in four different age cohorts.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

P176 COMPLICATED CROHN’S DISEASE IS ASSOCIATED WITH PERIANAL INVOLVEMENT, IBD-ASSOCIATED SEROLOGIES, AND POLYGENIC RISK SCORES DERIVED FROM IBD-ASSOCIATED VARIANTS

In Crohn’s disease (CD), disease severity is categorized by the Montreal classification. More complicated (stricturing and/or penetrating) disease is associated with poor quality of life. Our aim was to identify clinical, serological, and genetic factors associated with complicated CD. For each disease location, we performed case-control univariate analyses comparing stricturing (B2), stricturing and penetrating (B2/B3), or penetrating (B3) to non-stricturing/non-penetrating (B1) CD. Demographics and clinical features were obtained by chart review. ELISA was used to determine IBD-related serologies. Genotyping was performed using Illumina Immunochip array. Polygenic risk scores (PRS) were calculated using known IBD-associated variants weighted for effect sizes. We included 1919 caucasian CD patients from a single center. Summary statistics for disease phenotype by disease location can be seen in Table 1. In small bowel (L1), colonic (L2), and ileocolonic (L3) disease, all three complicated disease phenotypes (B2, B2/B3, and B3) were associated with positive serology for ASCA IgA (OR 2.09-5.62, adj p < 2.84e-6). B2 (in L2 and L3) was associated with perianal involvement (OR 1.74-4.14, adj p < 0.01413). More complicated disease phenotype was associated with PRS for CD (OR 1.24-2.15, adj p < 0.0423) and B1 phenotype was associated with PRS for UC (Ulcerative Colitis) (OR 0.477-0.82, adj p < 0.0386). We have identified association of perianal involvement, ASCA IgA, and CD PRS to complicated disease behavior. In addition, we discovered a UC PRS association with B1 phenotype even in colonic disease. These findings can help identify patients at risk of developing more severe disease and help individualize management decisions.

Complex interaction between HNRNPD mutations and risk polymorphisms is associated with discordant Crohn’s disease in monozygotic twins

Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) affecting the lining of digestive tracts of the colon and ileum. To investigate the reasons behind the presence of CD phenotype in one of the monozygotic (MZ) twins, we utilized the whole exome sequence (WES) datasets of CD tissue biopsy and CD blood of affected twin and the exome dataset of blood from healthy twin. We report the presence of discordant and rare damaging mutation in HNRNPD and other risk polymorphisms such as, rs12103, rs2241880, rs3810936, rs7076156, rs1042058 and rs1292053. HNRNPD was found carrying two novel heterozygous mutations – a stop gain mutation that truncated the protein at 249th and 268th amino acid position and a single base missense mutation replacing Aspartate with Valine at 300th amino acid. The identified risk polymorphisms were found conferring susceptibility to CD and IBD. Discordant deleterious and damaging mutation was detected in HNRNPD that have been implicated in inflammatory pathways. Integrating these variants led to the elucidation of pathophysiology of CD in the affected twin involving the causal processes of macrophage activation, tissue death, autophagy, immune response, cell-migration and T-cell activation.

A Novel Strategy to Identify mRNA 3′ UTR and mRNA Level Difference in Crohn’s Disease

Abstract Background and Aims: Crohn’s disease (CD) is a chronic and refractory intestinal inflammatory disease. The 3′ untranslated region (3′ UTR) of mRNA transcript can regulate its own translational process post-transciptionally, and its role in CD remains unclear. The aim of this study was to identify the critical genes influencing CD phenotype via the regulation of mRNA 3′ UTR. Methods: Isoform Structural Change Model (IsoSCM) was used to evaluate the length of 3′ UTR of the whole transciptome from a RNA-seq based online CD database. Correlations between 3′ UTR length status and mRNA level were analyzed by Spearman coefficients. Correlated genes list was overlapped with published critical CD related gene list. Univariate and multivariate analysis were performed to identify the genes associated with CD phenotype. Results: Compared with normal control, 3′ UTR of 34192 genes were shortened and 57389 were lengthened among 432784 genes in CD patients. The 3′ UTR changes of 255 genes were found significantly correlated with their mRNA level. Furthermore, 8 overlapped genes were shared by above 255 correlated genes and known CD related gene list (ABCB1, FAF1, TUT2, IL27, JAK2, LTB, NAGLU and PTPN2). The mRNA level of ABCB1 and JAK2, and shortened 3′ UTR length of JAK2 transcript were found to be correlated with deep ulcer in CD patients by univariate and multivariate analysis. Conclusions: The 3′ UTR changes of CD related genes were confirmed to be related to the phenotype of CD. Our findings may provide further insight into the epigenetic mechanisms and therapeutic strategies for CD.

Evolution of disease phenotype in pediatric-onset Crohn’s disease after more than 10 years follow up—Cohort study

BackgroundPediatric-onset Crohn’s disease (CD) is a heterogeneous disorder which is subjected to progression and complications in a substantial proportion of patients. AimsWe aimed to assess the progression in pediatric-onset CD phenotype on long term follow up. MethodsMedical charts of pediatric onset CD patients with at least 10 years follow-up were analyzed retrospectively. Disease phenotype was determined at diagnosis and during follow up at different time points. Phenotype was determined according to the Paris classification. The impact of possible predictors on phenotype progression was assessed as well as the association between different therapeutic regimens during disease course and phenotype progression. ResultsProgression of disease location, behavior, and perianal involvement was observed in 20%, 38% and 20% of patients, respectively, after a median follow-up of 16.4 (±4.4) years. Microscopic ileocolonic disease at diagnosis was significant predictors for progression of disease extent. Treatment with anti tumor necrosis factor-ɑ agents and number of flares per years of follow-up were associated with progression of disease extent, behavior and perianal involvement. ConclusionDisease extent, behavior and prevalence of perianal disease change significantly over time in pediatric-onset CD. In our cohort, most clinical, laboratory and endoscopic parameters do not serve as predictors for long-term disease progression.

IL23R and ATG16L1 variants in Moroccan patients with inflammatory bowel disease.

BackgroundInflammatory bowel diseases (IBD) are chronic diseases of the gastrointestinal tract. Although their pathogenesis is unclear, the combination of genetic predisposition and environmental components are believed to be the main cause of these diseases. Recently, many variants in interleukin 23 receptor (IL23R) and autophagy-related 16-like 1 (ATG16L1) genes have been associated with the disease. Our objective was to assess the frequency of ATG16L1 (T300A) and IL23R (L310P) variants in Moroccan IBD (Crohn’s disease and Ulcerative Colitis) patients and to evaluate a possible effect of these variants on disease’s phenotype and clinical course.Methods96 Moroccan IBD patients and 114 unrelated volunteers were genotyped for ATG16L1 (T300A) and IL23R (L310P) variants by PCR-restriction fragment length polymorphism.ResultsThis is the first report on the prevalence of ATG16L1 (T300A) and IL23R (L310P) variants in a Moroccan group. We found that IL23R (L310P) variant conferred a protective effect for crohn’s disease (CD) but not ulcerative colitis (UC) patients. The presence of ATG16L1 (T300A) mutated alleles was associated with CD type but not with disease onset. In addition, the carriage of T300A variant alleles conferred a protective effect in UC.ConclusionOur results showed that the prevalence of ATG16L1 and IL23R variants was not significantly different between patients and controls. However a possible role of ATG16L1 (T300A) on CD phenotype was suggested.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-0500-7-570) contains supplementary material, which is available to authorized users.