Consecutive Crohn's Disease Patients Research Articles

P646 Utilisation of indocyanine green fluorescence imaging for Crohn’s disease following intestinal resection

Abstract Background Growing evidences have shown that there are important advantages related to the utilisation of indocyanine green fluorescence imaging (ICG-FI) to reduce the risk of postoperative anastomotic leakage (AL) in colorectal surgery. However, the impact of ICG-FI on postoperative AL of Crohn’s disease (CD) following intestinal resection has not been investigated. Methods This is a retrospective study of consecutive CD patients who were treated with intestinal resection and anastomosis at a single institution between January 2017 and August 2019. The cohort was divided into 2 groups, those with ICG-FI compared with those without ICG-FI for intestinal resection. ICG was administered intravenously with a bolus of 5 mg, and the intestinal perfusion was evaluated by a SPY Elite system. Their baseline characteristics and perioperative outcomes were further analysed. Results No adverse reactions were recorded. Of the 88 CD patients who underwent intestinal resection, 36 patients underwent ICG-FI during intestinal resection, while 52 CD patients who underwent routine intestinal resection were from a prospectively maintained database. The 2 groups were similar in terms of patient demographics, immunosuppressive medication use, and the procedural factors. In patients with ICG-FI, poor perfusion of the bowel judged by ICG-FI led to additional intestinal resection in 25% (9/36). ICG-FI reduces the AL rate from 13.5% (7 leaks) of non-ICF-FI group to 8.3% (3 leaks) in ICG-FI group (p = 0.456). Forty-four (50%) patients had previous intestinal resection. Overall, 10 anastomotic leaks were identified (11.4% leak rate). There were 2 leaks (4.5%) detected in patients with no previous intestinal resection, compared with 8 leaks (18.2%) identified in patients with a history of previous intestinal resection (p = 0.044). The number of previous resections correlated with increasing risk for AL (correlation coefficient = 0.998). In univariate analysis, steroid use, CRP level and preoperative weight loss >10% in 6 months were independently associated with AL. Conclusion ICG-FI is applicable to intestinal resection for CD and may play a role in perfusion-related AL. A large prospective randomised trial should be warranted.

P066 Azathioprine linked with impaired intestinal epithelial regeneration in Crohn’s disease

Abstract Background In patients operated due to active Crohn’s disease (CD), the negative effect of steroids and biologics on septic complications is known. Until now, azathioprine (AZA) is considered to be safe. The aim of our study was to assess the impact of AZA on intestinal epithelial cells damage in patients with active CD as a surrogate marker of healing. Methods Intestinal specimens taken from macroscopically healthy surgical margins of all consecutive CD patients operated due to active isolated ileocecal disease during the study period (2014–2016) were evaluated. Expression of caspase-3, p-53 and Ki-67 as markers of cell apoptosis, DNA damage and proliferation were immunohistochemically tested and assessed using a confocal microscope and microimage for in-tissue-cytometry analysis. Western-blot analysis was performed for the evaluation of cellular integrity using ZO-1 and E-cadherin as a markers. 30-day clinical outcomes were assessed. The study was approved by the institutional Ethics Committee. Results From 61 operated due to active CD patients, 35 met the inclusion criteria. Patients were divided accordingly to preoperative treatment: treated with no immunomodulators (N-9 patients), on steroids (S-14 patients), on AZA (A-6 patients), and on combination therapy, AZA + steroids (AS-6 patients). There were no substantial differences between groups. We found statistically significant increase of apoptosis in A group compared with N (5.33 ± 1.05 vs. 1.29 ± 0.51, p = 0.011), but also S group (1.58 ± 0.68, p = 0.014) and increase of DNA damage in A, AS and S groups compared with N group (p =0.01; p = 0.032; p = 0.035, respectively) (Figure 1a–c). P53-mediated cell cycle arrest and apoptosis through a caspase-3-dependent pathway in response to DNA damage was the most intensive in A group (Figure 2a). Reduction of cell proliferative activity in group A did not reach statistical significance (p = 0,057). A reduction of ZO-1 in A group and increased level of E-cadherin in S group were found. The effect of the decreased number of tight junctions and disintegration of the mucosa layer was observed in A group (Figure 2b). Clinically, in 30-day postoperative follow-up, six wound healing complications and one anastomotic leak were found, all in patients treated with immunomodulators. Conclusion We found that in epithelial cells of the small and large intestine of patients treated with AZA, apoptotic activity and DNA damage processes are increased when regeneration processes and mucosal integrity are significantly disturbed. These abnormalities of intestinal epithelial regeneration may be a surrogate marker of impaired mucosal healing.

Magnetisation transfer imaging adds information to conventional MRIs to differentiate inflammatory from fibrotic components of small intestinal strictures in Crohn's disease.

Identifying inflammation- or fibrosis-predominant strictures in Crohn's disease (CD) is crucial for treatment strategies. We evaluated the additive value of magnetisation transfer (MT) to conventional MRI for differentiating CD strictures using surgical histopathology as a reference standard. Twenty-eight consecutive CD patients who underwent MRI preoperatively were recruited. MRI parameters included T2-weighted imaging (T2WI) hyperintensity, bowel wall thickness, enhancement pattern changes over time, enhancement pattern and gain ratio in dynamic contrast-enhanced phases, and MT ratio. Correlation analysis was performed using Spearman's rank test. Receiver operating characteristic curve analysis and Cohen's κ were used. A model with combined MRI variables characterising intestinal strictures was proposed and validated in 14 additional CD patients. Significant correlations with histological inflammation scores were shown for wall thickness (r = 0.361, p = 0.001) and T2WI hyperintensity (r = 0.396, p < 0.001), whereas histological fibrosis scores were significantly correlated with MT ratio (r = 0.681, p < 0.001) and wall thickness (r = 0.461, p < 0.001). T2WI hyperintensity could differentiate mild from moderate-to-severe inflammation with a sensitivity of 0.871 and a specificity of 0.800. MT ratio could discriminate mild from moderate-to-severe fibrosis with a sensitivity and a specificity of 0.913 and 0.923, respectively. Combining MT ratio and T2WI hyperintensity, the MRI classification moderately agreed with the pathological stricture classification (p < 0.01, κ = 0.549). In the validation set, the diagnostic accuracy of T2WI hyperintensity and MT ratio were 86% and 89%, with good agreement between MRI and histopathological classification (p < 0.01, κ = 0.665). MT ratio combined with conventional MRI improves the differentiation of fibrotic from inflammatory components of small-bowel strictures in CD patients. • MT ratio from magnetisation transfer imaging combined with T2WI from conventional MRI can simultaneously characterise bowel fibrosis and inflammation in adult Crohn's disease.

Endoscopic activity, tissue factor and Crohn's disease: findings in clinical remission patients.

Background:As Crohn’s disease (CD) is associated with a high risk of thromboembolic events (TE), including patients with subclinical inflammation, we aim to evaluate the correlation between the impact of endoscopic activity (EA) in the coagulation profiling of CD patients while in clinical remission.Methods:From 164 consecutive CD patients included in clinical remission [Crohn’s disease activity index (CDAI) < 150], 75 were in the EA group [Simplified Endoscopic Score for CD (SES-CD) ⩾ 7], 89 were in the endoscopic remission (ER) group (SES-CD ⩽ 2), and 50 were included as healthy controls in the study. Blood samples were analyzed for tissue factor (TF), factor VIII (FVIII), thrombomodulin (TM), ADAMTS-13, von Willebrand factor (VWF), and endogenous thrombin potential (ETP), as well as collecting data regarding risk factors for TE and CD profile.Results:Mean plasma TF activity showed significantly higher levels in the EA group when compared with the ER and control groups (127 pM versus 103 pM versus 84 pM; p = 0.001), although the VWF:Ag (160% versus 168% versus 110%; p = 0.001), VWF/ADAMTS-13 (191 versus 219 versus 138; p = 0.003), FVIII (150% versus 144% versus 90%; p = 0.001) and TM (5.13 ng/ml versus 4.91 ng/mL versus 3.81 ng/ml; p < 0.001) were only increased in CD regardless of EA status when compared with controls. Lastly, ETP with and without TM remained the same in all three groups.Conclusions:CD patients in clinical remission with EA present endothelial lesion inducing TF exposure and subsequent coagulation cascade activation. Recommended thromboprophylaxis for EA outpatient subgroups will require additional investigation in order to be validated.

Comparison of Three Magnetization Transfer Ratio Parameters for Assessment of Intestinal Fibrosis in Patients with Crohn's Disease.

ObjectiveTo establish a novel standardized magnetization transfer ratio (MTR) parameter which considers the element of the normal bowel wall and to compare the efficacy of the MTR, normalized MTR, and standardized MTR in evaluating intestinal fibrosis in Crohn's disease (CD).Materials and MethodsAbdominal magnetization transfer imaging from 20 consecutive CD patients were analyzed before performing elective operations. MTR parameters were calculated by delineating regions of interest in specified segments on MTR maps. Specimens with pathologically confirmed bowel fibrosis were classified into one of four severity grades. The correlation between MTR parameters and fibrosis score was tested by Spearman's rank correlation. Differences in MTR, normalized MTR, and standardized MTR across diverse histologic fibrosis scores were analyzed using the independent sample t test or the Mann-Whitney U test. The area under the receiver operating characteristic curve (AUC) was computed to test the efficacies of the MTR parameters in differentiating severe intestinal fibrosis from mild-to-moderate fibrosis.ResultsNormalized (r = 0.700; p < 0.001) and standardized MTR (r = 0.695; p < 0.001) showed a strong correlation with bowel fibrosis scores, followed by MTR (r = 0.590; p < 0.001). Significant differences in MTR (t = −4.470; p < 0.001), normalized MTR (Z = −5.003; p < 0.001), and standardized MTR (Z = −5.133; p < 0.001) were found between mild-to-moderate and severe bowel fibrosis. Standardized MTR (AUC = 0.895; p < 0.001) had the highest accuracy in differentiating severe bowel fibrosis from mild-to-moderate bowel wall fibrosis, followed by normalized MTR (AUC = 0.885; p < 0.001) and MTR (AUC = 0.798; p < 0.001).ConclusionStandardized MTR is slightly superior to MTR and normalized MTR and therefore may be an optimal parameter for evaluating the severity of intestinal fibrosis in CD.

Implementation of infliximab standardized doses after pharmacokinetic modelization in a cohort of patients with Crohn’s disease

BackgroundAccording to infliximab (IFX) license in Crohn’s disease (CD), infusion doses are based on patient’s body-weight. Dose banding providing standardized doses (SD) has been implemented in parenteral chemotherapy in order to optimize aseptic unit capacity and reduce drug expenditure, duration of hospital stay and costs without decreasing efficacy. Material and methodThe first part was a single-center retrospective analysis of consecutive CD patients receiving IFX maintenance therapy to determine standardized doses covering more than 50% of infusions. The second part was a prospective cohort study assessing the impact of SD compared to body-weight doses (BWD) on admission duration and costs. ResultsSix IFX SD covering more than 90% of infusion doses were implemented for dose banding. According to the Monte-Carlo simulation, there was no significant difference between IFX SD and BWD maintenance regimens. When assessed prospectively in 116 patients (75 patients treated with SD and 41 with BWD) corresponding to 128 infusions, hospitalization duration was shortened by 70 min per patient (p < 0.001). ConclusionAccording to a pharmacokinetic model, IFX SD has a pharmacokinetic profile close to BWD and is associated with reduced length of hospitalization in a cohort of patients with CD. IFX SD implementation could optimize infusion units functioning and, save time and costs without decreasing efficacy.

P061 Perianal Involvement in Crohn's Disease: Are There Always Two Sides to Every Coin?

BACKGROUND: Crohn's disease (CD) is complicated with perianal disease in 21-23% of patients. Presence of perianal disease has been associated with a disabling course of CD and dreadful impact on quality of life. We aim to identify if perianal disease has negative implication on CD remission rates, after one-year infliximab therapy course. METHODS: Cohort, retrospective, single center study, including consecutive CD patients on Infliximab perfusion. Patients were followed one year, since the beginning of biological therapy. Co-variables were chosen bearing in mind clinical relevance and literature evidence. We split our outcome variable into clinical remission; analytical remission; endoscopic remission and deep remission (including all three mentioned before). The correlation towards the outcome variable was assessed with univariate and multivariate analysis, and a survival assessment, using SPSS – P value < 0.05 was considered statistically significant. RESULTS: We assessed 74 patients with CD, of whom 41 (55,4%) were female, with a mean age of 36 years old, all Caucasian. From our cohort, 36.5% of the patients presented perianal disease at diagnosis. After one year of treatment course, we documented 31.5% of deep remission, 47.2% endoscopic remissions, 55.4% analytical remission and 70.3% of clinical remission. Sixty-six patients (89.2%) presented any type of initial response to the treatment, from whom, 20 presented disease relapses (clinical or/and analytical or/and endoscopic). Patients with perianal disease, on the first year of Infliximab therapy, have a higher probability of disease relapse, displaying statistically significant difference on Kaplan-Meyer curves (Breslow P-value 0.043). Several variables had statistical significance towards the outcomes on the univariate analysis (age at diagnosis; disease behavior at diagnosis; smoking; hospital admission; days of hospital stay; corticoid cycle; biological naïve patients; blood infliximab levels; calprotectin, protein c reactive, erythrocyte sedimentation rate levels before and after one year of follow up). Adjusting for confoundment, patients with perianal disease have an odd 7.6 times higher of achieving endoscopic remission (P-value 0.038) and 17 times higher of achieving clinical remission (P-value 0.019) with infliximab therapy. CONCLUSION(S): In CD patients on infliximab therapy, perianal disease involvement is associated with higher endoscopic, analytical and clinical remission rates, after one year follow up. However, they are more prone to disease relapse, in the first year of biological therapeutic.

Pathophysiology and risk factors for cholelithiasis in patients with Crohn's disease.

Cholelithiasis is more common in patients with Crohn's disease (CD) than in the healthy population. The aim here was to examine risk factors for cholelithiasis in a cohort of CD patients and to compare the prevalence of cholelithiasis in a cohort of CD patients with that in a control group. This was a single-center retrospective case-control study. The cohort comprised all consecutive CD patients who underwent abdominal ultrasound from January 2007 to January 2018. The control group comprised age- and gender-matched non-CD patients referred for upper gastrointestinal tract dyspepsia. The study included 238 CD patients and 238 controls. The prevalence of cholelithiasis in the CD and control groups was 12.6 % and 9.2 %, respectively (risk ratio (RR), 1.36; p=0.24). Univariate analysis revealed that cholelithiasis was associated with multiple risk factors. Multivariate analysis identified age (OR, 1.077; 95 % CI, 1.043-1.112; p<0.001) and receipt of parenteral nutrition (OR, 1.812; 95 % CI, 1.131-2.903; p=0.013) as independent risk factors for cholelithiasis in CD patients. The prevalence of cholelithiasis in CD patients was higher than that in the control group; however, the difference was not statistically significant. Age and receipt of parenteral nutrition were independent risk factors for cholelithiasis in CD patients.

Opioid Analgesics Do Not Improve Abdominal Pain or Quality of Life in Crohn's Disease.

Abdominal pain and opioid analgesic use are common in Crohn's disease (CD). We sought to identify factors associated with abdominal pain in CD and evaluate the impact of opioid analgesics on pain and quality-of-life scores in this setting. We performed a longitudinal cohort study using a prospective, consented IBD natural history registry from a single academic center between 2009 and 2013. Consecutive CD patients were followed for at least 1year after an index visit. Data were abstracted regarding pain experience (from validated surveys), inflammatory activity (using endoscopic/histologic findings), laboratory studies, coexistent psychiatric disorders, medical therapy, opioid analgesic, and tobacco use. Of 542 CD patients (56.6% women), 232 (42.8%) described abdominal pain. Individuals with pain were more likely to undergo surgery and were more frequently prescribed analgesics and/or antidepressants/anxiolytics. Elevated ESR (OR 1.79; 95%CI 1.11-2.87), coexistent anxiety/depression (OR 1.87; 95%CI 1.13-3.09), smoking (OR 2.08; 95%CI 1.27-3.40), and opioid use (OR 2.46; 95%CI 1.33-4.57) were independently associated with abdominal pain. Eighty patients (14.8%) were prescribed opioids, while 31 began taking them at or after the index visit. Patients started on opioids demonstrated no improvement in abdominal pain or quality-of-life scores on follow-up compared to patients not taking opioids. Abdominal pain is common in CD and is associated with significant opioid analgesic utilization and increased incidence of anxiety/depression, smoking, and elevated inflammatory markers. Importantly, opioid use in CD was not associated with improvement in pain or quality-of-life scores. These findings reinforce the limitations of currently available analgesics in IBD and support exploration of alternative therapies.

Stopping anti-tumour necrosis factor therapy in patients with perianal Crohn's disease.

Little is known of the outcome of patients with perianal Crohn's disease after stopping anti-tumour necrosis factor (TNF) therapy. To evaluate the rate of relapse in perianal Crohn's disease (CD) after stopping anti-TNF therapy. Consecutive perianal CD patients treated with anti-TNF therapy with subsequent discontinuation were retrieved from prospective inflammatory bowel disease database of institutes in Hong Kong, Shanghai, Taiwan, Malaysia, Thailand and Singapore from 1997 to June 2019. Cumulative probability of perianal CD relapse was estimated using Kaplan-Meier method. After a median follow-up of 89months (interquartile range [IQR]: 65-173months), 44 of the 78 perianal CD patients (56.4%) relapsed after stopping anti-TNF, defined as increased fistula drainage or recurrence of previously healed fistula, after stopping anti-TNF therapy. Cumulative probabilities of perianal CD relapse were 50.8%, 72.6% and 78.0% at 12, 36 and 60months, respectively. Younger age at diagnosis of CD [adjusted hazard ratio (HR): 1.04; 95% CI 1.01-1.09; P=.04] was associated with a higher chance of perianal CD relapse. Among those with perianal CD relapse (n=44), retreatment with anti-TNF induced remission in 24 of 29 patients (82.8%). Twelve (27.3%) patients required defunctioning surgery and one (2.3%) required proctectomy. Maintenance with thiopurine was not associated with a reduced likelihood of relapse [HR=1.10; 95% CI: 0.58-2.12; P=.77]. Among the 17 patients who achieved radiological remission of perianal CD, five (35.3%) developed relapse after stopping anti-TNF therapy after a median of 6months. More than half of the perianal CD patients developed relapse after stopping anti-TNF therapy. Most regained response after resuming anti-TNF. However, more than one-fourth of the perianal CD patients with relapse required defunctioning surgery. Radiological assessment before stopping anti-TNF is crucial in perianal CD.

699 Role of C-Reactive Protein as a Marker for Disease Course in Obese Patients With Inflammatory Bowel Disease

INTRODUCTION: Currently, the disease course and clinical outcomes of obese patients with inflammatory bowel disease (IBD) have been mixed. This study aims to compare biomarkers of inflammation such as erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) in both obese and non-obese African American (AA) and Caucasian populations. METHODS: We conducted a prospective observational study of consecutive Crohn's disease (CD) and ulcerative colitis (UC) patients in the outpatient setting at a tertiary referral center between 2014-2017. Body mass index (BMI), ESR, CRP, hemoglobin (Hgb) were measured at 2 consecutive visits. Obesity was defined as a BMI ≥30. The Wilcox signed rank test was used to compare continuous variables, and the Chi square test for categorical variables. A multivariate logistic regression model was created to look at change in CRP (no change, increase by half, decrease by half) from initial to follow-up visit. The regression model analysis included ethnicity, gender, BMI, type of IBD (CD versus UC), age, alcohol use, tobacco use, hypertension, kidney disease, heart disease, and treatment as covariates. RESULTS: The study included 92 subjects, 65% had CD and 30% were AA (Table 1). The average time between visits was 136 days. In the obese group, 33% were AA and 70% were female. Also, a larger portion of CD patients were obese compared to UC patients (37% and 11% respectively with P = 0.03). There was a significant decrease in the CRP in the obese group (P = 0.029) whereas non-obese individuals had an increase in CRP (Table 2). There was no significant difference in ESR and hemoglobin (Hgb) between obese and non-obese individuals. 63 patients where included in the regression model, which showed that a decrease in CRP was significantly associated with obesity (P = 0.0081) when adjusted for the above covariates. Overall, obese individuals were more likely to experience no change in CRP or a decrease in CRP while non-obese individuals were more likely to have a rise in CRP. There was no difference in clinical disease activity indices (HBI/SCCAI) between obese and non-obese patients. CONCLUSION: In our study, the obese patients were more likely to be female, have CD, and be Caucasian. While there was no difference in Hgb or ESR in obese versus non-obese, there is a difference in CRP. CRP could have importance as a sensitive marker for disease course in patients whose BMI ≥30. A larger cohort may provide further insight into this observation.

Assessment of bioelectrical phase angle as a predictor of nutritional status in patients with Crohn's disease: A cross sectional study

The assessment of body composition (BC) can be used to identify malnutrition in patients with Crohn's disease (CD). The aim of this study was to evaluate the nutritional status of CD patients by assessing BC, phase angle (PhA) and muscle strength. Differences in disease duration and medications were also considered. Consecutive adult CD patients aged 18-65 years were enrolled in this cross-sectional study. Disease activity was clinically defined by the Crohn's Disease Activity Index (CDAI) in the active and quiescent phases. All participants underwent anthropometry, BC and handgrip-strength (HGS) measurements; additionally, blood samples were taken. Data from CD patients were also compared with age-, sex- and BMI-matched healthy people. A total of 140 CD patients with a mean age of 38.8±13.9 years and a mean body weight of 64.9±12kg were recruited and compared to controls. The findings showed that all nutritional parameters, especially PhA and HGS, were lower in CD patients than in controls, and these parameters were substantially impaired as disease activity increased. Active CD patients had a lower body weight and fat mass than both the quiescent and control groups. PhA was negatively correlated with age (r=-0.362; p=0.000) and CDAI (r=-0.135; p=0.001) but was positively associated with fat free mass (FFM) (r=0.443; p=0.000) and HGS (r=0.539; p=0.000). Similarly, serum protein markers were lower in the active CD group than in the quiescent group (p<0.05). Disease duration and medications did not significantly affect nutritional status. BIA-derived PhA is a valid indicator of nutritional status in CD patients, and its values decreased with increasing disease activity. Additionally, small alterations in BC, such as low FFM, and reduced HGS values can be considered markers of nutritional deficiency. Therefore, the assessment of BC should be recommended in clinical practice for screening and monitoring the nutritional status of CD patients.

836 – Immunologic Predictors of Response to Vedolizumab Treatment in Patients with Inflammatory Bowel Disease: Results of a Phase Iv Prospective Interventional Trial

Objective: Vedolizumab (VDZ) is a monoclonal antibody directed against α4β7 integrin heterodimer, approved for patients with inflammatory bowel disease (IBD). This study aimed at identifying circulating and mucosal immunologic predictors of response in patients with active ulcerative colitis (UC) and Crohn’s disease (CD). Design: This is an explorative, prospective, phase IV interventional trial (Eudract n. 2015- 003270-32). Consecutive CD and UC patients received open-label VDZ at weeks 0, 2, 6 and 14. A week 10 infusion was performed in CD patients. Patients with clinical response at week 14 were maintained with VDZ every 8 weeks up to 54 weeks. At week 0 and 14 peripheral blood was obtained and endoscopy with biopsies was performed. The expression of surface markers, chemokine receptors and α4β7 heterodimer on peripheral blood and lamina propria lymphocytes was assessed by flow cytometry. Results: 38 IBD patients (20 UC, 18 CD) were included in the study. At week 14, clinical response and remission rates were 87% and 66%, respectively. Endoscopic response rate was 47%. Among week 14 responders, clinical remission rate at week 54 was 69%. No clinical variables were found to predict either clinical or endoscopic outcomes. On the contrary, higher baseline levels of circulating memory CXCR3+CCR6- CD4+ T cells (Th1 cells) were strongly associated with week 14 clinical response (P=0.0001). Reduced baseline levels of lamina propria memory CXCR3-CCR6+ CD4+ T cells (Th17 cells) and CXCR3+CCR6+ CD4+ T cells (Th1/17 cells) were predictive of endoscopic response (P=0.012 and P=0.005 respectively). Circulating levels of Th1 memory T cells predicted clinical remission in IBD patients at week 54. Conclusions: The results of this exploratory study uncovered a panel of circulating and mucosal immunological predictors of response to vedolizumab treatment. These data provide further insights on the mechanism of action of vedolizumab in IBD patients.

Mucosal Healing Is Associated With the Reduced Disabling Disease in Crohn's Disease.

OBJECTIVES:Mucosal healing (MH) is the goal of the “treat to target” strategy in Crohn's disease (CD), which seeks to prevent disability. However, evidence is limited regarding whether achieving MH can reduce disability in CD. We aimed to estimate the probability of disabling disease and to investigate the association between MH and disabling disease in CD.METHODS:This was a retrospective case-control study of 319 consecutive CD patients. The primary outcome was disabling disease occurrence (defined as surgery, hospitalizations, steroid dependency, or disease complications). The secondary endpoint was disabling disease recurrence. The Kaplan-Meier method and Cox proportional hazards model were used to calculate cumulative rates and for multivariate analysis, respectively.RESULTS:Of 319 CD patients (median follow-up time: 42.4 months, interquartile range: 24.7–60.0 months), 105 (32.9%) progressed to disabling disease and 20 (6.3%) had the recurrence of disabling disease. The cumulative rates of disabling disease were 11.3%, 30.2%, and 44.9% at 1, 3, and 5 years, respectively, after diagnosis. MH was associated with a significantly lower frequency of surgery, new penetrating event, and new stenosis (P = 0.004, P = 0.001, P = 0.002, respectively). Univariate and multivariate analyses revealed that MH was an independent protective factor of disabling disease occurrence (hazard ratio: 0.166, 95% confidence interval: 0.084–0.329).CONCLUSIONS:Disabling disease was common in Chinese CD patients and increased during follow-up. Moreover, MH was significantly associated with a reduced occurrence of disabling disease in CD.

30 ELEVATION OF PLASMA ONCOSTATIN M IS ASSOCIATED WITH PRIMARY BIOCHEMICAL NONRESPONSE AND SECONDARY CLINICAL NONRESPONSE TO INFLIXIMAB IN PEDIATRIC CROHN’S DISEASE PATIENTS

Oncostatin M (OSM) and OSM receptor (OSMR) were found to be highly expressed in inflamed intestinal tissue in patients with Crohn’s disease (CD) and ulcerative colitis (UC).1 West et al. also found elevations of mucosal OSM was strongly associated with treatment nonresponse to tumor necrosis factor-α inhibitors (anti-TNF).1 We hypothesized that increased abundance of plasma OSM would also be associated with anti-TNF nonresponse with our primary aim to identify an OSM cut-point for early anti-TNF nonresponse. We enrolled anti-TNF naïve children with CD starting infliximab into this prospective, observational study. The primary outcome was biochemical response and defined by a fecal calprotectin <400 µg/ml prior to the first maintenance dose (infusion 4). This outcome was restricted to patients with both a pre-infliximab fecal calprotectin >400 µg/ml and a stool sample collected at infusion 4. Clinical remission at 12 months was defined as a weighted pediatric CD activity index <12.5, off steroids, and on infliximab without surgery in the first year. The ideal OSM cut-point was identified using the Youden index from the receiver operating characteristic curve analysis of biochemical responders and nonresponders. OSM was measured using ELISA (ThermoFisher, Frederick, MD) with an intra-assay CV<10%. Fecal calprotectin was measured with ELISA (Buhlmann, Switzerland). Infliximab concentrations were measured with ELISA (Immundiagnostik, Germany). We measured pre-infliximab OSM in 40 consecutive CD patients. The cohort was 35% female, 90% white race with a mean age of 13 (SD 4) years at the start of infliximab. One patient remained on methotrexate during induction and 50% of the cohort received prednisone prior to the first induction dose. 33/40 met criteria for evaluation for the primary aim with 16/33 (49%) in biochemical remission at infusion 4. The median (IQR) OSM in biochemical nonresponders was 96 (69-198) pg/ml compared to 166 (84-1766) pg/ml in nonresponders (p=0.035, Figure1). Using the Youden index, we identified plasma OSM >143 pg/ml was 71% sensitive and 75% specific for biochemical nonresponse (Figure 2). The median infusion 4 fecal calprotectin in the OSMhigh (>143 pg/ml) group was 985 (382-2501) µg/g compared to 317 (141-676) µg/g in OSMlow group (p=0.04). We found only 25% of the OSMhigh patients achieved biochemical response compared to 71% with OSMlow (p=0.015). Thirty-five percent of OSMhigh patients achieved steroid-free clinical remission at month 12 (odd’s ratio of 0.21, 95% CI 0.05-0.77, p=0.023). We found no differences in infliximab concentration at infusions 2, 3 and 4 between OSMhigh and OSMlow patients. In a small pediatric CD cohort, we identified a pre-infliximab cut-point of >143 pg/ml was predictive of early biochemical nonresponse and secondary clinical nonresponse at year 1. Figure 1. Oncostatin M (OSM) was measured with ELISA prior to the first infliximab infusion. Fecal calprotectin was measured prior to infusion 1 and 4. Groups compared by Mann-Whitney test. Figure 2. Oncostatin M (OSM) was measured prior to the first infliximab infusion. Area under the curve (AUC) was determined by the receiver operating characteristic curve for biochemical nonresponse at infusion 4 (defined by a fecal calprotectin ≥400 µg/g). The ideal cut-point for OSM was determined by the Youden index.

Endoscopic stricturotomy versus ileocolonic resection in the treatment of ileocolonic anastomotic strictures in Crohn’s disease

Endoscopic stricturotomy (ESt) is a novel technique in the treatment of anastomotic strictures in Crohn's disease (CD). The aim of this study was to compare the outcome of patients with ileocolonic anastomotic stricture treated with ESt versus ileocolonic resection (ICR). This historical cohort study included consecutive CD patients with ileocolonic anastomotic stricture treated with ESt or ICR from 2010 to 2017. The primary outcomes were surgery-free survival and postprocedural adverse events. Thirty-five patients treated with ESt and 147 patients treated with ICR were analyzed. Median follow-up was .8 years (interquartile range [IQR], .2-1.7) and 2.2 years (IQR, 1.2-4.4) in the ESt and ICR groups, respectively (P< .001). Subsequent stricture-related surgery was needed in 4 patients (11.3%) receiving ESt and in 15 patients (10.2%) receiving ICR (P= .83). Kaplan-Meier analysis also showed no statistical difference regarding surgery-free survival between the 2 groups (P= .24). Procedure-related major adverse events were documented in 5 of 49 patients (10.2% per procedure) undergoing ESt and 47 patients (31.9%) undergoing ICR (P= .003). Risk factors for decreased surgery-free survival on multivariate analysis included preprocedural corticosteroids (hazard ratio [HR], 2.8; 95% confidence interval [CI], 1.0-8.1), multiple strictures (HR, 4.9; 95% CI, 1.7-14.2), and increased disease-related hospitalizations (HR, 4.0; 95% CI, 1.2-13.0). With the limitation of a shorter follow-up, ESt achieved comparable surgery-free survival with a decreased morbidity when compared with ICR.

Functional rare variants influence the clinical response to anti-TNF therapy in Crohn's disease.

Background:The effect of low-frequency functional variation on anti-tumor necrosis factor alpha (TNF) response in Crohn’s disease (CD) patients remains unexplored. The objective of this study was to investigate the impact of functional rare variants in clinical response to anti-TNF therapy in CD.Methods:CD anti-TNF naïve patients starting anti-TNF treatment due to active disease [Crohn’s Disease Activity Index (CDAI > 150)] were included. The whole genome was sequenced using the Illumina Hiseq4000 platform. Clinical response was defined as a CDAI score <150 at week 14 of anti-TNF treatment. Low-frequency variants were annotated and classified according to their damaging potential. The whole genome of CD patients was screened to identify homozygous loss-of-function (LoF) variants. The TNF signaling pathway was tested for overabundance of damaging variants using the SKAT-O method. Functional implication of the associated rare variation was evaluated using cell-type epigenetic enrichment analyses.Results:A total of 41 consecutive CD patients were included; 3250 functional rare variants were identified (2682 damaging and 568 LoF variants). Two homozygous LoF mutations were found in HLA-B and HLA-DRB1 genes associated with lack of response and remission, respectively. Genome-wide LoF variants were enriched in epigenetic marks specific for the gastrointestinal tissue (colon, p = 4.11e–4; duodenum, p = 0.011). The burden of damaging variation in the TNF signaling pathway was associated with response to anti-TNF therapy (p = 0.016); damaging variants were enriched in epigenetic marks from CD8+ (p = 6.01e–4) and CD4+ (p = 0.032) T cells.Conclusions:Functional rare variants are involved in the response to anti-TNF therapy in CD. Cell-type enrichment analysis suggests that the gut mucosa and CD8+ T cells are the main mediators of this response.

Ustekinumab Dose Intensification Can Be Effective in Crohnʼs Disease Patients Not Responding to Induction

Introduction: Ustekinumab, an IL-12/23 inhibitor is used for the treatment of Crohn's Disease (CD). Patients receive an IV infusion followed by subcutaneous injections every 8 weeks. There is limited data about the efficacy of dose intensification. This study aimed to analyze the response of ustekinumab dose escalation based on clinical and laboratory parameters. Methods: This is a retrospective cohort study from a large metropolitan IBD center. We analyzed data of all CD patients who had ustekinumab induction between September 26, 2016 and October 1, 2017 and required dose intensification. Data collected included demographics, prior immunosuppressant use, concomitant immunosuppressants, regimen of dose intensification, and response to therapy based on clinical and lab evaluation. Results: Among 122 consecutive CD patients on ustekinumab with a median follow-up of 146 days, 21(17%) required dose intensification. 4 patients (19%) had inflammatory, 7(33%) stricturing and 10(48%) penetrating disease. 20 patients (95%) had failed previously at least one anti-TNF. Dose escalation utilized was: increase in injection frequency to every 6 weeks (q6w, n=5), every 4 weeks (q4w, n=11), or a combination of IV booster and frequency change to q6w or q4w (n=5). 7 patients required dose escalation due to primary non-response, 4 due to secondary loss of response, and 10 due to poor initial response. Median follow-up after dose intensification was 177 days. Overall, 11 patients (52%) had clinical response after dose escalation. In this group, 2 patients (18%) were primary non-responders to induction while 9(82%) had poor initial clinical response. None of 4 patients with secondary loss of response were able to regain response. 5 of 11 (45%) patients on q4w regimen, 4 of 5 (80%) on q6w, and 2 of 5 (40%) on combination regimen achieved clinical response. Among 6 (27%) patients who were on steroids at baseline, one was weaned off and one was on a lower dose at the follow-up evaluation. Lab data before and after dose intensification are shown on the table below. Side effects reported were dizziness, fatigue, nausea, abdominal pain, dehydration, diarrhea, arthritis, and a perianal abscess. Conclusion: This retrospective cohort study reveals that dose intensification can be beneficial in patients who do not achieve clinical response on the q8w dosing regimen of ustekinumab. Further studies are needed to evaluate efficacy and safety of dose escalation.617 Figure 1 No Caption available.

Diffusion-weighted magnetic resonance enterography for prediction of response to tumor necrosis factor inhibitors in stricturing Crohn's disease.

Distinguishing between fibrotic and inflammatory strictures in Crohn's disease (CD) is still challenging. The capacity of diffusion-weighted (DWI) magnetic resonance (MRE) to identify intestinal fibrosis was recently demonstrated; however, the therapeutic implications of this association have never been evaluated. The aim of the current study was to identify imaging features, including DWI, which can predict response to anti-inflammatory treatment in patients with stricturing CD. Consecutive CD patients with intestinal strictures that initiated treatment with anti-tumor necrosis alpha (anti-TNF) between June 2012 and April 2017 with MRE adjacent to treatment onset were retrospectively collected. The primary outcome was treatment failure, defined as drug discontinuation, CD-related surgery, or endoscopic dilatation of the stricture. Clinical, demographic, and imaging data were compared between patients who did and did not develop treatment failure within 12 months of anti-TNF treatment initiation. A total of 21 patients were included in the study; 9/21 (42.8%) developed treatment failure. None of the clinical/demographic parameters were associated with the risk of treatment failure. Among imaging parameters, only ADC value (< 1 × 10-3mm2/s) was significantly associated with the risk of treatment failure (AUC = 0.81, 66% vs. 0%, p = 0.015). Our results suggest that ADC value on DWI MRE may predict the risk of treatment failure in stricturing CD. If replicated in larger studies, these results may guide therapeutic decisions and suggest avoiding anti-TNF treatment.

Association Between Serum Infliximab Trough Concentrations During Maintenance Therapy and Biochemical, Endoscopic, and Histologic Remission in Crohn's Disease.

Objective and more rigorous therapeutic outcomes are emerging as novel targets in Crohn's disease (CD). We investigated the association between maintenance serum infliximab trough concentrations and biochemical, endoscopic, or histologic remission in CD. This retrospective multicenter study involved consecutive CD patients treated with infliximab who had a serum C-reactive protein (CRP) measured within 1 week or endoscopic evaluation within 12 weeks of therapeutic drug monitoring between January 2010 and June 2016. Biochemical remission was defined as a normal CRP (≤5 mg/L). Endoscopic remission was defined as absence of any mucosal break (ulceration or erosion) or for patients with an ileocolonic resection, a Rutgeerts score of ≤i1. Histologic remission was defined as absence of active inflammation. Seventy-one CRP levels and 96 colonoscopies from 110 CD patients were evaluated. Based on ROC analyses, infliximab concentration thresholds of 2.2, 9.7, and 9.8 μg/mL were found to be related with biochemical, endoscopic, and histologic remission, respectively. Multiple logistic regression analyses identified infliximab concentration ≥2.2 (OR 6.4; 95% CI, 1.5-27.1; P = 0.011), ≥9.7 (OR 3.6; 95% CI, 1.4-9; P = 0.006) and ≥9.8 μg/mL (OR 3.2; 95% CI, 1.3-7.9; P = 0.011) as variables independently associated with biochemical, endoscopic, and histologic remission, respectively. This study showed that higher maintenance infliximab trough concentrations are associated with more favorable rates of biochemical, endoscopic, or histologic remission in CD patients and that infliximab concentrations may differ based on the treatment goal.