Stricturing Behavior Research Articles

Clinical Phenotype and Disease Course of Inflammatory Bowel Disease in Iran: Results of the Iranian Registry of Crohn's and Colitis (IRCC).

Data on the epidemiology of inflammatory bowel disease (IBD) in the Middle East are scarce. We aimed to describe the clinical phenotype, disease course, and medication usage of IBD cases from Iran in the Middle East. We conducted a cross-sectional study of registered IBD patients in the Iranian Registry of Crohn's and Colitis (IRCC) from 2017 until 2022. We collected information on demographic characteristics, past medical history, family history, disease extent and location, extra-intestinal manifestations, IBD medications, and activity using the IBD-control-8 questionnaire and the Manitoba IBD index, admissions history, history of colon cancer, and IBD-related surgeries. In total, 9746 patients with ulcerative colitis (UC) (n=7793), and Crohn's disease (CD) (n=1953) were reported. The UC to CD ratio was 3.99. The median age at diagnosis was 29.2 (IQR: 22.6,37.6) and 27.6 (IQR: 20.6,37.6) for patients with UC and CD, respectively. The male-to-female ratio was 1.28 in CD patients. A positive family history was observed in 17.9% of UC patients. The majority of UC patients had pancolitis (47%). Ileocolonic involvement was the most common type of involvement in CD patients (43.7%), and the prevalence of stricturing behavior was 4.6%. A prevalence of 0.3% was observed for colorectal cancer among patients with UC. Moreover,15.2% of UC patients and 38.4% of CD patients had been treated with anti-tumor necrosis factor (anti-TNF). In this national registry-based study, there are significant differences in some clinical phenotypes such as the prevalence of extra-intestinal manifestations and treatment strategies such as biological use in different geographical locations.

MRI AND BLOOD-BASED BIOMARKERS ASSOCIATED WITH SURGICAL MANAGEMENT IN CHILDREN AND ADULTS WITH SMALL BOWEL CROHN'S DISEASE

Abstract BACKGROUND Despite advances in medical therapy, many children and adults with ileal Crohn’s Disease (CD) progress to fibrostenosis requiring surgery. Prior studies have identified circulating and imaging biomarkers associated with strictures, although their associations with need for surgery are not well-established. PURPOSE We aimed to identify MRI and circulating biomarkers associated with the need for surgical management in chidlren and adults with ileal CD. METHODS This prospective, multi-center study included pediatric and adult CD cases undergoing ileal resection (n=50), and CD controls receiving medical therapy (n=83). Noncontrast research MRI examinations measured bowel wall three-dimensional magnetization transfer ratio normalized to skeletal muscle (normalized 3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, intravoxel incoherent motion (IVIM) diffusion-weighted imaging metrics, and the simplified magnetic resonance index of activity (sMaRIA) (Figure 1). Circulating biomarkers included CD64, ECM1, and GM-CSF autoantibodies (Ab). Clinical variables, including demographics, anthropometrics, and routine clinical laboratory data (e.g., CRP, fecal calprotectin), also were obtained at the research visit. Associations between MRI and circulating biomarkers and need for ileal resection were tested using univariate and multivariable LASSO regression. RESULTS Mean participant age was 23.9±13.1 years. Disease duration and treatment exposures did not vary between the groups. Univariate biomarker associations with ileal resection included log GM-CSF Ab (odds ratio [OR]=2.87; p=0.0009), normalized 3D MTR (OR=1.05; p=0.002), log MOLLI T1 (OR=0.01; p=0.02), log IVIM perfusion fraction (f) (OR=0.38; p=0.04), and IVIM apparent diffusion coefficient (ADC) (OR=0.3; p=0.001). MRI and circulating biomarker Tukey box plots are presented in Figure 2. The multivariable model for surgery based upon AICc criteria included age (OR=1.03; p=0.29), BMI (OR=0.91; p=0.09), log GM-CSF Ab (OR=3.37; p=0.01), normalized 3D MTR (OR=1.07; p=0.007), sMaRIA (OR=1.14; p=0.61), luminal narrowing (OR=10.19; p=0.003), log CRP (normalized) (OR=2.75; p=0.10), and hematocrit (OR=0.90; p=0.13). CONCLUSION After accounting for clinical and MRI measures of severity, normalized 3D MTR and GM-CSF Ab are associated with need for surgery in ileal CD. GM-CSF autoantibodies and MRI biomarker sequences may be useful for guiding management decisions in CD patients. Figure 1 Research MRI images from a surgical Crohn’s disease patient with stricturing behavior involving the terminal ileum. A and B. Coronal and axial fat-saturated T2-weighted single-shot fast spin-echo (SSFSE) images show wall thickening and luminal narrowing of the terminal ileum (arrows) with more proximal bowel dilation measuring greater than 3 cm. C. Axial 3D magnetization transfer images – MT pulse on (bottom image, arrow), MT pulse off (top image, arrow). D. Axial modified Look-Locker inversion recovery (MOLLI) T1 relaxation image (arrow). E. Representative axial intravoxel incoherent motion diffusion-weighted images with increasing b-values (left to right, arrows). Figure 2 Variation in circulating and imaging biomarkers in Crohn’s disease patients with medical and surgical management. Ctrl: non-IBD healthy controls; Med: CD patients with nonsurgical medical management; Surg: CD patients with surgical management.

P1170 Long-term outcomes of newly diagnosed Inflammatory Bowel Disease (IBD) patients: results from the nationwide EpidemIBD study of GETECCU

Abstract Background Aims: 1) To describe the main epidemiological and clinical characteristics of patients at IBD diagnosis and the long-term outcomes; 2) to analyse the use of drugs for IBD, and the need of hospitalisations and surgeries; 3) to compare IBD management based on the type of disease and the resources of the hospitals. Methods Prospective, population-based nationwide registry. Adult patients diagnosed with IBD, Crohn’s Disease (CD), Ulcerative Colitis (UC) or IBD unclassified, during 2017 in the 17 Spanish regions were included. Patients who consented were followed-up for 5 years (yr) after diagnosis. Treatment was grouped into 5 categories: mesalamine (oral or topical), steroids (intravenous, oral, or topical), immunomodulators (thiopurines, methotrexate or cyclosporine), biologics (anti-TNF, vedolizumab, ustekinumab) or JAK inhibitors (JAKi), and surgery. Hospitals were classified into high resources and low resources ones. Cumulative incidence of exposure to each of the studied treatments was estimated by Kaplan-Meier curves; curves were compared with log-rank test. Results 3,301 incident cases of IBD diagnosed during 2017 in 108 hospitals, covering over 22 million inhabitants in Spain (about 50% of the population), were enrolled into the follow-up study. Main characteristics of the cohort are summarised in table 1. Median diagnosis delayed was 3.5 months (5.6 in CD and 2.7 in UC, p<0.001). During the 5-yr follow-up, 25% of UC patients progressed to more extensive involvement, while 8% of CD patients with inflammatory behaviour progressed to either stricturing or fistulising behaviour. Most of the patients who received mesalamine, corticosteroids, or immunomodulators initiated treatment within the first 2 years after diagnosis (figure 1). However, the cumulative incidence of biologics/JAKi usage steadily increased over time, reaching 49% by the 5-yr timepoint in CD. In terms of surgeries, a progressive increase in cumulative incidence was observed in CD; the incidence of colectomy remained stable in UC from the 2nd year post-diagnosis. A higher cumulative incidence of biologics/JAKi usage, hospitalisations, and surgeries was observed in CD at high resources hospitals; no differences were observed in the use of other therapeutic resources or the management of UC. Conclusion In the EpidemIBD large-scale epidemiological study, we have observed that the delay in diagnosing IBD is shorter than previously described. Approximately 50% of patients with CD and 20% of patients with UC ended up receiving biologics/JAKi in the first 5 yrs following diagnosis. The percentage of patients undergoing surgery was lower than previously reported; in the case of UC, the majority of colectomies occurred within the first 2 yrs after diagnosis.

DOP05 Bowel damage and its correlation with the disability index in patients with recently diagnosed Crohn´s Disease

Abstract Background Crohn’s disease (CD) progression can lead to bowel damage (BD) and disability. However, the longitudinal characterization of BD and disability in early CD patients remains limited. Methods The Crohn´s Disease Cohort (CROCO) is a multicentre, European cohort study of newly diagnosed CD patients (<12 months following diagnosis) intended to prospectively characterize BD progression and disability. At one year following inclusion (Y1), BD progression was evaluated using the Lémann Index (LI). Magnetic resonance enterography was completed by all patients, with additional endoscopy and/or pelvic MRI based on disease location. Absence of BD was defined as a LI=0, and any presence of bowel damage was indicated by LI>0. Disability was assessed using the validated IBD-disability index (IBD-DI) encompassing various domains. We report the LI at Y1 and its association with significant disease features and with the IBD-DI. Results Among the 261 included patients, 135 have completed the Y1 visit, with 100 having their LI calculated [57% male, median age at diagnosis of 36 years old (IQR 26-48)]. Most patients (90%) had ileal or ileocolonic involvement, 68% had inflammatory phenotype, and 11% had perianal disease. At inclusion, 7% of patients had undergone surgery (5 intestinal and 2 perianal), and 53% had initiated biological therapy within the first year of disease, primarily anti-TNF in mono or combination therapy. Of those with stricturing (B2) or penetrating (B3) behaviour, 77% and 79%, respectively, were on anti-TNF therapy. Overall, 61% of the patients exhibited some degree of BD (LI>0), yet the median LI at Y1 was low [0.6 (IQR 0-2)]. Univariate analysis revealed an association between the presence of any bowel damage at Y1 and disease behaviour at inclusion (B2 OR 3.33, 95%CI 0.84-13.18 and B3 OR 8.5, 95%CI 1.82, 39.66; p<0.01). Additionally, there was a significant association with anti-TNF therapy (OR 2.88, 95%CI 1.24-6.66, p=0.012). In a multivariate logistic model, only older age at diagnosis appeared protective against any BD (Table 1). Among those evaluated for the LI, 84 completed the IBD-DI at Y1. The median IBD-DI was 17.3 (IQR 10.7-32.6) and 30% experienced moderate-to-severe disability (IBD-DI>35). No association was observed between LI and IBD-DI at Y1 (OR 1.09, 95%CI 0.39-3.04, p=0.86) and there were no differences in the median LI across disability categories (p=0.67) (Figure 1). Conclusion In a cohort of newly diagnosed CD patients, one-third exhibited no bowel damage as per the LI evaluation. For those presenting any degree of damage, the global LI remained low. No association was found with disability assessed by the IBD-DI. These data add to the growing concept that early disease represents a window of opportunity.

Diagnosis and Clinical Features of Perianal Lesions in Newly Diagnosed Crohn's Disease: Subgroup Analysis from Inception Cohort Registry Study of Patients with Crohn's Disease (iCREST-CD).

Perianal lesion is a refractory phenotype of Crohn's disease [CD] with significantly diminished quality of life. We evaluated the clinical characteristics of perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the quality of life in Japanese patients with CD. Patients newly diagnosed with CD after June 2016 were included between December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD [iCREST-CD]. Perianal lesions were present in 324 [48.2%] of 672 patients with newly diagnosed CD; 71.9% [233/324] were male. The prevalence of perianal lesions was higher in patients aged <40 years vs ≥40 years, and it decreased with age. Perianal fistula [59.9%] and abscess [30.6%] were the most common perianal lesions. In multivariate analyses, male sex, age <40 years and ileocolonic disease location were significantly associated with a high prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were associated with low prevalence. Fatigue was more frequent [33.3% vs 21.6%] while work productivity and activity impairment-work time missed [36.3% vs 29.5%] and activity impairment [51.9% vs 41.1%] were numerically higher in patients with than those without perianal lesions. At the time of CD diagnosis, approximately half of the patients had perianal lesions; perianal abscesses and perianal fistulas were the most common. Young age, male sex, disease location and behaviour were significantly associated with the presence of perianal lesions. The presence of perianal lesion was associated with fatigue and impairment of daily activities. University Hospital Medical Information Network Clinical Trials Registry System [UMIN-CTR, UMIN000032237].

Preclinical Serological Signatures are Associated With Complicated Crohn’s Disease Phenotype at Diagnosis

At diagnosis, up to one-third of patients with Crohn's disease (CD) have a complicated phenotype with stricturing (B2) or penetrating (B3) behavior or require early surgery. We evaluated protein biomarkers and antimicrobial antibodies in serum archived years before CD diagnosis to assess whether complicated diagnoses were associated with a specific serological signature. Prediagnosis serum was obtained from 201 patients with CD and 201 healthy controls. Samples were evaluated with a comprehensive panel of 1129 proteomic markers (SomaLogic) and antimicrobial antibodies. CD diagnosis and complications were defined by the International Classification of Diseases-Ninth Revision and Current Procedural Terminology codes. Cox regression models were utilized to assess the association between markers and the subsequent risk of being diagnosed with complicated CD. In addition, biological pathway and network analyses were performed. Forty-seven CD subjects (24%) had a B2 (n= 36) or B3 (n= 9) phenotype or CD-related surgery (n= 2) at diagnosis. Subjects presenting with complicated CD at diagnosis had higher levels of antimicrobial antibodies six years before diagnosis as compared with those diagnosed with noncomplicated CD. Twenty-two protein biomarkers (reflecting inflammatory, fibrosis, and tissue protection markers) were found to be associated with complicated CD. Pathway analysis of the altered protein biomarkers identified higher activation of the innate immune system and complement or coagulation cascades up to six years before diagnosis in complicated CD. Proteins and antimicrobial antibodies associated with dysregulated innate immunity, excessive adaptive response to microbial antigens, and fibrosis precede and predict a complicated phenotype at the time of diagnosis in CD patients.

P634 Ustekinumab and vedolizumab as first-line biological therapy for inflammatory bowel disease. A multicenter study based on the ENEIDA registry.

Abstract Background The use of ustekinumab (UST) and vedolizumab (VDZ) as first line therapy for inflammatory bowel disease (IBD) is increasing due to safety reasons and contraindications of anti-TNFs. However, there are no studies evaluating their efficacy and safety in clinical practice under these circumstances. Thus, our aims were to describe bionaïve patients’ characteristics starting VDZ or UST and to evaluate treatment persistence of these drugs and their safety profile in this scenario. Methods Descriptive, retrospective and multicenter study based on the ENEIDA registry (a large, prospectively maintained database of the Spanish Working Group in IBD –GETECCU). All IBD patients never exposed to biological agents who started VDZ or UST as first-line biological treatment were identified. Results Out of 29,450 IBD patients ever exposed to biological drugs included in the ENEIDA registry, 924 patients met the inclusion criteria. Of these, 366 (40%) started UST and 558 (60%) VDZ as first line biological therapy. UST group: 48% women, 90% Crohn’s disease (43% ileal; 13% colic; 43.5% ileocolic; 31% upper gastrointestinal involvement; 25% stricturing behaviour; 12% penetrating, 18% perianal disease), 10% ulcerative colitis (74% extensive, 17% left-sided, 9% proctitis), 27% had extraintestinal manifestations (EIM). Median age at the beginning of UST was 57 years (IQR 57-70), 17% patients had a past history of malignancy and, 34% had associated comorbidities. UST indication was luminal activity except in 2% for perianal disease and 5% for EIM. At the end of follow-up (median 14 months [IQR 6-30]), 12 patients (3.3%) developed adverse effects (AEs) that led to treatment discontinuation in the majority of them (92%). VDZ group: 44% women, 42% Crohn’s disease (44% ileal; 18% colic; 38% ileocolic; 25% upper gastrointestinal involvement; 28% stricturing behaviour; 13% penetrating; 7% perianal disease), 58% ulcerative colitis (50% extensive, 42% left-sided, 8% proctitis), 17% had EIM. The median age at the beginning was 61 years (IQR 48-71), 24% had past history of malignancy and, 34% associated comorbidities. The indication was exclusively luminal activity. At the end of follow-up (median 21 months [IQR 8-36]), 36 patients (6.5%) had AEs, that lead to treatment withdrawal in 67% of them (24 patients). Cumulative treatment persistence rates were 78%, 60% and 50% for VDZ and 85%, 75% and 66% for UST at 12, 24 and 36 months, respectively (P&amp;lt;0.001). Conclusion In clinical practice, VDZ and UST are used first-line particularly in elderly patients with comorbidities. Both treatments have a good safety profile and a high persistence of treatment, being superior for ustekinumab.

P846 Epidemiological and Clinical Characteristics of Inflammatory Bowel Diseases in Patients from Greece

Abstract Background There are few reports from Greece about the epidemiological and clinical features of inflammatory bowel diseases (IBD), which were mainly evaluated in retrospective studies with data collection from hospital registries. We aimed to determine the epidemiological profile and clinical features as well as to detect any differences between patients with Crohn’s disease (CD) and ulcerative colitis (UC), based on retrospectively-prospectively collected data from a cohort of IBD patients followed in daily clinical practice. Methods Patients with biopsy-confirmed IBD aged 10–90 years old were included in the study. A comprehensive questionnaire was used to collect data on each site visit from July 2018 until March 2022. Logistic regression analysis and chi-squared test were used to compare the frequency of epidemiological and clinical characteristics between patients with UC and CD. Results We collected 300 patients diagnosed with IBD (180 with CD, 113 with UC, and 7 with indeterminate colitis). The median age of IBD patients was 42 years. The onset of disease in CD group was observed between 17 and 40 years of age in the majority of patients (58%). Ileocolonic location of CD was present in 70% of CD patients; 39% had stricturing behavior and 29% had perianal disease (abscesses and fistulas). CD patients developed more often aphthous stomatitis (34%) than patients with UC (13%, OR 3.45; 95% CI: 1.76-6.78; P&amp;lt; .001). Patients with CD had a 20-fold increased risk to undergo a surgical procedure (OR 19.87; 95% CI: 6.03-65.48; P&amp;lt; .001), mainly enterectomy (26%), as shown in table 1. At study entry, C-reactive protein (CRP) elevation was more frequently present in CD compared to UC patients (OR 1.93; 95% CI: 1.04-3.59; P&amp;lt; .05). Most patients with UC had extensive colitis (56%). Mesalamine was predominantly used in UC patients (81% vs 46% in CD, P&amp;lt; .005), and sulfasalazine and thiopurines in CD patients (60-70% vs 9-13% in UC, P&amp;lt; .005), as shown in table 2. The most commonly used anti-TNF agent was Infliximab, mainly in CD patients (24% vs 4% in UC, OR 0.12; 95% CI: 0.04-0.34; P&amp;lt; .001). Adalimumab was used in 12% of IBD patients and Vedolizumab in 8%. Around 4% of patients with complicated CD received Ustekinumab. Tofacitinib was used in 2% of patients with severe complicated UC and extraintestinal manifestations. Enteral diet (Modulen®) was used in 6% of CD patients and in only 2% of UC patients with severe UC pancolitis. Conclusion In this retrospective-prospective cohort study of 300 patients with IBD, CD patients had a significantly higher risk of developing aphthous stomatitis and increased levels of CRP. CD patients also required more often treatment with anti-TNF agents and immunosuppressants, and a surgical procedure, mainly enterectomy.

DOP64 Utilising genomics to predict outcomes and delineate novel subgroups in inflammatory bowel disease

Abstract Background The rise of ‘big data’ in inflammatory bowel disease (IBD) presents an opportunity to improve understanding of pathogenesis and unpick the molecular complexity of this heterogenous condition. Personalisation of IBD management relies on predicting outcomes, response to therapy and prevention of complications. Here, we present results outlining subgrouping of patients and outcome prediction using multiomic/clinical data. Methods Using whole exome sequencing from 1100 patients in the Southampton IBD cohort, including 650 paediatric cases, we have performed iterative studies focused on 1) Impact of genomic variation across the NOD-signaling pathway measured by perturbation of transcription across multiple genes, 2) Development of NOD2 as a genomic biomarker of stricturing Crohn’s disease (CD), 3) Utilising machine learning and genomic data to develop disease classification models. These data utilise GenePy, a tool developed in house that summarises genomic variation to give a per individual, per gene deleteriousness metric. Results Within the NOD-signaling pathway patients harbouring deleterious variation in NOD2 had reduced NOD2 expression and increased NFKBIA expression, reflecting reduced NFKB signaling, figure 1A. We report deleterious variation in several key complexes including NOD2-RIPK2 and TAK1-TAB, resulted in reduced transcription of NFKB activators and alternative inflammatory pathway activation, figure 1C-D. Utilising genomic data we constructed a NOD2 prediction model for stricturing disease in Crohn’s disease; 56.7% of patients in the ‘high-risk group’ had stricturing behaviour, whilst in the low-risk group only 21.4% had strictures. Addition of terminal ileal (TI) disease to the NOD2 risk groups significantly improved prediction, figure 2A. Using survival modelling, high-risk group paediatric patients presenting with TI disease had a HR of 4.89 (P = 2.3×10-5) compared with the low-risk group patients without TI disease, figure 2B. Finally, we used supervised machine learning of genomic data to classify patients with CD or ulcerative colitis. We employed different gene lists and assessed how accurately we could assign patients to their diagnosis. An autoimmune gene panel produced the best model (AUROC 0.68), compared to an IBD panel (AUCROC 0.61). NOD2 was the most discriminating gene in all the gene panels. Conclusion These iterative projects demonstrate the utility of integrating genomic and clinical data to improve the subtyping of patients with IBD and provide disease prediction models. Future work will include analyses of additional inflammatory pathways and targeting different clinical outcomes. We hope clinical translation of these findings will be a step-change in precision medicine for IBD.

P424 Do antiTNF through levels correlate with joint extraintestinal manifestations (EIM) activity in Inflammatory bowel disease (IBD) patients?

Abstract Background Inflammatory arthropathies are the most common EIM associated to IBD with a prevalence of 20-50% for axial inflammation and 5-20% for peripheral arthritis. AntiTNF is the preferred treatment in patients with axial spondiloarthritis (AxSp) intolerant or refractory to NSAIDs and has shown efficacy in peripheral arthritis (pSp) as well. Nevertheless, an optimal antiTNF through level has not been yet stablished in this clinical setting. Thus, our aims were to evaluate the correlation between antiTNF through levels and joint EIM activity in IBD patients. Methods We conducted a prospective, multicenter cohort study. IBD patients diagnosed with articular EIM (AxSp, pSp or both) under antiTNF treatment at least 6 months were included. Anti-TNF concentrations were measured using ELISA. Blood samples were obtained just before the administration of the drug (trough levels), and an simultaneous evaluation by a reumatologist was performed. Definitions: inactive AxSp = ASDAS-CRP &amp;lt;1,3 and BASDAI&amp;lt;2 , low active AxSp: ASDAS-CRP &amp;lt;2,1 and BASDAI&amp;lt;4; inactive pSp=arthritis, enthesitis and dactylitis=0, low active pSp: arthritis, enthesitis and dactylitis ≤1. IBD activity was based on partial Mayo score for ulcerative colitis (UC) patients and on Harvey-Bradshaw score for Crohn′s disease (CD) patients. Results A total of 78 patients were included: Median age 52 ±15, 45% women, 82% CD (56% ileal; 18% colic; 24% ileocolic; 2% upper gastrointestinal involvement; 22% stricturing behaviour; 16% penetrating; 14% perianal disease), 18% UC (61% extensive, 15% left-sided, 23% proctitis), 11% had another EIM. HLA B-27 was present in 26% patients. Distribution of spondiloartrhopaties was: AxSp 42%, pSp 37%, or both 20%. Among CD patients, 18,9% presented clinical activity (n=14). Mean IBD disease duration was 11± 9,7 years. Fourteen patients (18%) were also under immunosupressive treatment .Through levels distributed by joint activity are shown in table 1.Figure 1 shows distribution of adalimumab through levels by AxSp activity. Conclusion No correlation between antiTNF through levels and joint EIM activity was found in these preliminary results. However, patients with active axial Sp treated with adalimumab had lower through levels than those with inactive axial Sp.

P141 Risk Factors of Atherosclerotic Cardiovascular Disease (Ischemic Heart Disease and Cerebrovascular Accident) in Patients With Inflammatory Bowel Disease: a hospital-based cohort

Abstract Background Immune-mediated inflammatory diseases (IMIDs) involve an increased risk of developing atherosclerotic cardiovascular disease (ASCVD). However, the association between inflammatory bowel disease (IBD) and ASCVD is not well established. Our aims were to evaluate the frequency of ASCVD [ischemic heart disease (IHD) and cerebrovascular accident (CVA)] after IBD diagnosis and to identify the risk factors associated with its development. Methods Observational, single-centre study which included all patients seen at the IBD Unit of the Hospital Universitario Central de Asturias (Spain) between May 2010 and April 2022. Cardiovascular risk factors and the development of ASCVD were prospectively assessed; in addition, this information was sought selectively prior to IBD diagnosis and patients’ first visit to the unit. Regarding classical risk factors, we analysed hypertension, dyslipidaemia and diabetes mellitus. As possible risk factors related to IBD, we analysed the presence of complex IBD which, in the case of Crohn’s disease (CD), we defined as the presence of stricturing or penetrating behaviour or the need for bowel resection surgery, and, in the case of ulcerative colitis (UC), as an E3 extension or the need for colectomy. Finally, we analysed the coexistence of other IMIDs as a risk factor. Results A total of 2,153 patients were included (52% CD, 45% UC and 3% IBD-unclassified). Forty-nine percent were women and mean age at IBD diagnosis was 39 years. Twenty-four percent had hypertension, 14% dyslipidaemia and 8.6% diabetes; 59% were current or former smokers; 37% had an associated IMID (12% cutaneous and 7.9% joint). Prior to IBD diagnosis, 62 patients had presented with ASCVD (41 IHD and 21 CVA). After IBD diagnosis, 95 patients had at least one ASCVD (49 IHD and 46 CVA); after 31,516 patient-years of follow-up, the incidence of a first ASCVD was 0.31 per 100 patient-years (0.16 IHD and 0.15 CVA). The incidence of ASCVD was stable over time after IBD diagnosis. In the multivariate analysis (Table 1), age at IBD diagnosis &amp;gt;50 years (p&amp;lt;0.001), hypertension (p=0.006), dyslipidaemia (p=0.032), male sex (p=0.004) and a history of ASCVD prior to IBD diagnosis (p=0.011) were associated with an increased risk of ASCVD. With these variables, a Cox regression survival analysis was performed (Figure 1 and 2). Neither the type of IBD, the existence of complex IBD nor the coexistence of other IMIDs was associated with an increased risk of ASCVD. Table 1. Figure 1. Figure 2. Conclusion The development of ASCVD in patients with IBD is associated with classical risk factors (hypertension and dyslipidaemia), as well as older age at diagnosis and male sex. The coexistence of other IMIDs does not increase the risk of ASCVD in these patients.

SUBCUTANEOUS INFLIXIMAB IN REFRACTORY CROHN'S DISEASE PATIENTS AFTER THE MULTIPLE TREATMENT FAILURES - SHORT TREATMENT OUTCOMES

Abstract BACKGROUND Subcutaneous administration of infliximab shows an increased benefit in terms of pharmacokinetics and pharmacodynamics effects compared to the intravenous infliximab. The practical question arises whether routine administration in refractory CD patients who have failed prior biological therapy will provide "biobetter" clinical efficacy. AIMS We propose a single center study designed to evaluate SC-IFX treatment outcomes in patients with active CD after the previous failures of other biologicals (TMAbs). Such a refractory CD cohort was chosen because there is currently insufficient appropriate medication therapy available for these patients and the identification of parameters predicting response to SC-IFX treatment could be of great benefit to some of them. PATIENTS &amp; METHODS A total of 32 CD patients were included, with the median age of 34.5 years and median CD duration of 11 years; &amp;gt;90% of them with stricturing and/or penetrating disease behavior, &amp;gt;80% with ileocolic involvement, and about 40% with the active perianal disease. Eighteen of 32 patients (56%) have failed on ≥3 previous TMAbs, the rest on 2 previous TMAbs. Twenty (62.5%) of n = 32 have had IV-IFX in past; in this sub-cohort, 85% of patients have positive anti-IFX antibodies (ATI). In ATI-positive sub-cohort, induction of SC-IFX was realized with four 120 mg SC doses weekly. Two induction IV infusions of 5 mg/kg IFX were administered in 2-week intervals in ATI-negative sub-cohort. Maintenance treatment in whole cohort consisted of 120 mg SC IFX bi-weekly. RESULTS Of the 32 patients, 7 individuals have failed the treatment during the induction phase: one because of heart disease progression, and 6 patients due to delayed hypersensitivity reactions with systemic manifestation. In 25/32 patients who continued their treatment up to W14, the initial median Harvey-Bradshaw index (HBI) of 6 (min 1, max 28) did not decrease significantly within the 14 weeks of treatment (p=0.067). However, both the serum CRP level (p=0.039) and fecal calprotectin level (p=0.027) have shown significant decrease. Median trough IFX levels have increased from 6 μg/mL at W2 to 10 μg/mL at W14 (p&amp;lt;0.001), and median ATI levels dropped from median of 38 ng/mL to 5 ng/mL (p= 0.0004). None of the patients with initial zero ATI levels have shown new ATI formation. Moreover, in 10 of 17 patients (59%) with the initial ATI positivity, ATI serum levels have decreased significantly even to the cut-off levels. The only risk factor for SC-IFX discontinuation before W14 was a high serum levels of ATIs (p &amp;lt; 0.001). CONCLUSIONS Our short-term experience with SC-IFX shows the treatment efficacy and tolerability in complicated CD patients after multiple TMAbs failures.The research gap in information about biobetters in patients with IBD must be filled and predictive factors for the response to SC-IFX must be found.

Oncological outcomes of Crohn's disease-associated cancers focusing on disease behavior.

The overall risk of colorectal cancer in Crohn's disease (CD) is higher than in the general population, and CD-associated cancer (CDAC) has poorer prognosis than sporadic cancer. Developing treatment strategies for improving the prognosis of CDAC, we evaluated the characteristics of CDAC according to the underlying disease behavior, namely stricturing and penetrating. This multicenter retrospective study comprises 316 CDAC patients who underwent surgery between 1985 and 2019. Clinicopathological findings including disease behavior and oncological outcomes were investigated. There was no association between the preoperative course of CDAC patients and disease behavior; however, postoperative information revealed distinctly different characteristics between CDAC patients with stricturing behavior and those with penetrating behavior (stricturing with lymphatic invasion and peritoneal dissemination recurrence, and penetrating with histologically poorly differentiated and local recurrence). Oncological outcome of patients with CDAC was distinctly different according to disease behavior, as penetrating provided a poor outcome (overall survival [OS]: p=0.02; relapse-free survival [RFS]: p=0.002) whereas stricturing had no effect. Furthermore, penetrating behavior was identified as one of the independent risk factors for poor OS and RFS (OS: hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.16-3.09, p=0.01; RFS: HR 2.15, 95% CI 1.28-3.63, p=0.004). Our study highlights the different characteristics of CDAC according to the underlying disease behavior and substantiates the poor prognosis of CDAC patients with penetrating behavior. Treatment planning including screening, surgical procedures, and postoperative treatment, with awareness of these findings, may contribute to improved prognosis for CDAC patients.

Prediction of Crohn's Disease Stricturing Phenotype Using a NOD2-derived Genomic Biomarker.

Crohn's disease (CD) is highly heterogenous and may be complicated by stricturing behavior. Personalized prediction of stricturing will inform management. We aimed to create a stricturing risk stratification model using genomic/clinical data. Exome sequencing was performed on CD patients, and phenotype data retrieved. Biallelic variants in NOD2 were identified. NOD2 was converted into a per-patient deleteriousness metric ("GenePy"). Using training data, patients were stratified into risk groups for fibrotic stricturing using NOD2. Findings were validated in a testing data set. Models were modified to include disease location at diagnosis. Cox proportional hazards assessed performance. Six hundred forty-five patients were included (373 children and 272 adults); 48 patients fulfilled criteria for monogenic NOD2-related disease (7.4%), 24 of whom had strictures. NOD2 GenePy scores stratified patients in training data into 2 risk groups. Within testing data, 30 of 161 patients (18.6%) were classified as high-risk based on the NOD2 biomarker, with stricturing in 17 of 30 (56.7%). In the low-risk group, 28 of 131 (21.4%) had stricturing behavior. Cox proportional hazards using the NOD2 risk groups demonstrated a hazard ratio (HR) of 2.092 (P = 2.4 × 10-5), between risk groups. Limiting analysis to patients diagnosed aged < 18-years improved performance (HR-3.164, P = 1 × 10-6). Models were modified to include disease location, such as terminal ileal (TI) disease or not. Inclusion of NOD2 risk groups added significant additional utility to prediction models. High-risk group pediatric patients presenting with TI disease had a HR of 4.89 (P = 2.3 × 10-5) compared with the low-risk group patients without TI disease. A NOD2 genomic biomarker predicts stricturing risk, with prognostic power improved in pediatric-onset CD. Implementation into a clinical setting can help personalize management.

The first association study of Protein Tyrosine Phosphatase, Non-Receptor Type 2 (PTPN2) gene polymorphisms in Malaysian patients with Crohn’s disease

Crohn’s disease (CD) is one of the sub-entities of Inflammatory Bowel Disease which causes chronic inflammation in the gastrointestinal tract. The development of CD has shown to have a strong genetic association. Therefore, the present study aimed to investigate the association between genetic polymorphisms in a susceptible locus of CD, the protein tyrosine phosphatase, non-receptor type 2 (PTPN2) gene and the development of CD in Malaysian patients. A total of 137 CD patients and 274 matched healthy controls were recruited in the present study. Genomic DNA was extracted from the venous blood of participants and five targeted single nucleotide polymorphisms (SNPs) in the PTPN2 gene were genotyped using polymerase chain reaction. Associations between the SNPs and CD were determined using Fisher’s exact test and odds ratio. Findings showed that all five selected SNPs were not significantly associated with the development of CD in Malaysian patients, which was in contrast to studies among the European populations. Malaysian Chinese with rs487273 heterozygous G/T genotype was found to have a lower occurrence of CD (P-value = 0.0253; OR = 0.4396). Patients with rs2542152 homozygous T genotype were associated with stricturing behaviour (P-value = 0.0302, OR = 2.9944). The rs16939895 A/G genotype was associated with inflammation at the ileum site (P-value = 0.0387, OR = 2.2105)while homozygous G genotype was associated with colonic CD (P-value = 0.0164, OR = 2.3917). Functional studies of these SNPs are needed to evaluate their potential use as a biomarker for disease phenotypes among Asian patients.

Surgical Planning in Penetrating Abdominal Crohn's Disease.

Crohn's disease (CD) is increasing globally, and the disease location and behavior are changing toward more colonic as well as inflammatory behavior. Surgery was previously mainly performed due to ileal/ileocaecal location and stricturing behavior, why many anticipate the surgical load to decrease. There are, however, the same time data showing an increasing complexity among patients at the time of surgery with an increasing number of patients with the abdominal perforating disease, induced by the disease itself, at the time of surgery and thus a more complex surgery as well as the post-operative outcome. The other major cause of abdominal penetrating CD is secondary to surgical complications, e.g., anastomotic dehiscence or inadvertent enterotomies. To improve the care for patients with penetrating abdominal CD in general, and in the peri-operative phase in particular, the use of multidisciplinary team discussions is essential. In this study, we will try to give an overview of penetrating abdominal CD today and how this situation may be handled. Proper surgical planning will decrease the risk of surgically induced penetrating disease and improve the outcome when penetrating disease is already established. It is important to evaluate patients prior to surgery and optimize them with enteral nutrition (or parenteral if enteral nutrition is ineffective) and treat abdominal sepsis with drainage and antibiotics.

ILEAL ENTEROCYTE BRUSH BORDER ABNORMALITIES ASSOCIATE WITH PROGRESSIVE DISEASE COURSE IN PEDIATRICS CROHN’S DISEASE

Abstract BACKGROUND Biomarkers are needed to identify the subset of Crohn’s disease (CD) patients at-risk for severe, treatment-refractory disease. Short ileal microvillus length (MVL) is an epithelial biomarker that predicted non-response to treatment in adult CD. Here, we hypothesized that short MVL phenotype would occur in pediatric CD and associate with more severe disease. METHODS H&amp;E-stained ileal tissue sections were obtained from 3 pediatric cohorts: WashU, CCHMC, and RISK (n=58 controls, n=377 CD). MVL was measured in regions not involved in acute inflammation. RISK had baseline “pre-treatment” and follow-up “post-treatment” sampling, clinical phenotyping, and transcriptomic data. Transmission electron microscopy (TEM) and immunofluorescence was performed on paired samples from 6 CD and 6 controls. RESULTS Ileal MVL was shorter in pediatric CD (mean: 1.44 μm) vs. controls (mean: 1.64 μm; P&amp;lt;0.0001). MVL did not associate with body mass index, disease location, endoscopic deep ulcers, or disease activity index scores. Histological inflammation scores were greater in baseline CD vs. controls, but similar between CD with short (defined as &amp;lt;1.46 μm, 10th percentile of controls) or normal MVL. Progression from B1 inflammatory disease behavior to B2 stricturing or B3 internal penetrating disease behavior was more likely to occur in patients with shorter MVL (n=91 follow-up samples collected prior to disease progression event; B2: P=0.0077, B3: P=0.0186). Additionally, progression to B2 occurred sooner in those with short follow-up MVL (P=0.0206). In contrast, associations with disease behavior progression based on baseline MVL were not observed. RNA-seq analysis identified 92 genes differentially expressed between CD and controls and correlated with MVL. Gene function analysis showed enrichment (P&amp;lt;0.001) for actin cytoskeleton, transporter activity, and plasma membrane among the 43 genes positively associated with MVL, and enrichment for myeloid cell, response to bacterium, and extracellular matrix among the 49 genes negatively associated with MVL. TEM showed thinning of the terminal web in CD, with diminished microvillus rootlet length and organelle-free zones, features associated with shortened or disorganized microvilli in mouse models. We next assessed terminal web-associated proteins, PLS1 and MYH14, and found that both were altered in CD samples; PLS1 was abnormally enhanced at the brush border, and MYH14 was aberrantly localized in the cytoplasm. Misexpression of MYH14 was associated with terminal web thinning and shorter MVL. CONCLUSIONS This study supports short ileal MVL phenotype in follow-up CD samples as an epithelial biomarker for more severe disease prognosis, particularly for progression to stricturing disease. Our data suggest that terminal web alterations underlie the short MVL phenotype.

Can Enteric Fistulae in Patients with Crohn’s Disease Occur in Isolation: Findings from 500 Consecutive Operative Cases

Background or PurposeEnteric Crohn’s disease (CD) is characterized by transmural inflammation resulting in inflammatory, stricturing, or penetrating phenotypes. However, data regarding the relationship between stricturing and penetrating behavior is lacking. The incidence of penetrating CD in the absence of a stricture is unclear. The aim of this study is to assess if enteric fistulae in adult patients undergoing abdominal surgery for symptomatic CD occur in isolation. MethodsResection or repair of enteric CD fistulae performed in a quaternary care referral center (2009–2017) was analyzed. Fistulae associated with pelvic or continent pouch, rectal stump, or ano-vagina were excluded. Fistulae were stratified based on origin, tract, target, and relationship to stricture. Strictures were stratified as inflammatory or fibrostenotic. ResultsFive hundred consecutive operative reports were reviewed. A total of 490 fistulae were evaluated. Two hundred ninety-nine fistulae were in patients undergoing index surgery. Incidence of CD fistulae not associated with stricture was 14.9% in total, but only 8% in the index surgery cohort. The majority of fistulae originated from the ileum (95%). CD fistulae originating from the stomach or duodenum were not identified in the index cohort. Fistulae within an inflammatory stricture were likely to include an intra-abdominal abscess (p < 0.001). Fistulae associated with a fibrostenotic stricture were more likely to originate proximal to the stricture (p < 0.001). The incidence of fistula-associated adenocarcinoma was 0.6%. ConclusionsSymptomatic CD fistulae in the absence of stricture are uncommon. Caution should be exercised when making a diagnosis of CD in the presence of enteric fistulae, but an absence of stricture, particularly in patients with prior abdominal surgery.

Systematic Review and Meta-Analysis: Risk of Hospitalization in Patients with Ulcerative Colitis and Crohn's Disease in Population-Based Cohort Studies.

Inflammatory bowel diseases (IBD) lead to high morbidity and unplanned healthcare utilization. We conducted a systematic review with meta-analysis to estimate the cumulative incidence of IBD-related (and all-cause) hospitalization in patients with ulcerative colitis (UC) and Crohn's disease (CD). Through a systematic review to September 3, 2019, we identified population-based inception cohort studies in patients with IBD that reported patient-level cumulative incidence of hospitalization at 1, 3 and 5 years after diagnosis. Hospitalization risk was pooled using random effects meta-analysis, and risk factors analyzed through mixed-effects meta-regression and qualitative synthesis. In patients with UC (6 cohorts), 1-, 3- and 5-year risk of UC-related hospitalization was 10.4% (95% CI 8.2-13.2), 17.0% (95% CI 14.0-20.4) and 21.5% (95% CI 18.0-25.4), respectively, with considerable heterogeneity. In patients with CD (6 cohorts), 1-, 3- and 5-year risk of CD-related hospitalization was 29.3% (95% CI 20.0-40.8), 38.5% (95% CI 26.8-51.7) and 44.3% (95% CI 32.7-56.5), respectively, with considerable heterogeneity. On meta-regression, steady decline in risk of hospitalization was observed in patients diagnosed in a more contemporary era. Younger age at onset (both UC and CD), extensive colitis (UC), ileal-dominant CD, perianal CD and penetrating and/or stricturing behavior (CD) and early need for corticosteroids and immunosuppressive therapy (both UC and CD) were associated with increased risk of hospitalization. Approximately one in five and one in two patients with UC and CD are hospitalized within 5years of diagnosis, respectively. Population health management strategies are required to mitigate unplanned healthcare utilization.

Changes in the Long-term Prognosis of Crohn's Disease between 1986 and 2015: The Population-Based Songpa-Kangdong Inflammatory Bowel Disease Cohort Study.

Background/AimsThe long-term course of Crohn’s disease (CD) has never been evaluated in non-Caucasian population-based cohorts. The aim of the present study was to evaluate the long-term prognosis of Korean CD patients in the well-defined population-based Songpa-Kangdong inflammatory bowel disease cohort.MethodsOutcomes of disease and their predictors were evaluated for 418 patients diagnosed with CD between 1986 and 2015.ResultsDuring a median of 123 months, systemic corticosteroids, thiopurines, and anti-tumor necrosis factor (TNF) agents were administered to 58.6%, 81.3%, and 37.1% of patients, respectively. Over time, the cumulative probability of starting corticosteroids significantly decreased (p=0.001), whereas that of starting thiopurines and anti-TNFs significantly increased (both p<0.001). The cumulative probability of behavioral progression was 54.5% at 20 years, and it significantly decreased during the anti-TNF era. Intestinal resection was required for 113 patients (27.0%). The cumulative probabilities of intestinal resection at 1, 5, 10, 20, and 25 years after CD diagnosis were 12.7%, 16.5%, 23.8%, 45.1%, and 51.2%, respectively. Multivariable Cox regression analysis identified stricturing behavior at diagnosis (adjusted hazard ratio [aHR], 2.70; 95% confidence interval [CI], 1.55 to 4.71), penetrating behavior at diagnosis (aHR, 11.15; 95% CI, 6.91 to 17.97), and diagnosis of CD during the anti-TNF era (aHR, 0.51; 95% CI, 0.35 to 0.76) as independently associated with intestinal resection. The standardized mortality ratio among CD patients was 1.36 (95% CI, 0.59 to 2.68).ConclusionsThe long-term prognosis of Korean patients with CD is at least as good as that of Western CD patients, as indicated by the low intestinal resection rate. Moreover, behavioral progression and intestinal resection rates have decreased over the past 3 decades.