Adult Crohn's Disease Research Articles

Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn's Disease.

Paneth cell defects in Crohn’s disease (CD) patients (called the Type I phenotype) are associated with worse clinical outcomes. Recent studies have implicated mitochondrial dysfunction in Paneth cells as a mediator of ileitis in mice. We hypothesized that CD Paneth cells exhibit impaired mitochondrial health and that mitochondrial-targeted therapeutics may provide a novel strategy for ileal CD. Terminal ileal mucosal biopsies from adult CD and non-IBD patients were characterized for Paneth cell phenotyping and mitochondrial damage. To demonstrate the response of mitochondrial-targeted therapeutics in CD, biopsies were treated with vehicle or Mito-Tempo, a mitochondrial-targeted antioxidant, and RNA transcriptome was analyzed. During active CD inflammation, the epithelium exhibited mitochondrial damage evident in Paneth cells, goblet cells, and enterocytes. Independent of inflammation, Paneth cells in Type I CD patients exhibited mitochondrial damage. Mito-Tempo normalized the expression of interleukin (IL)-17/IL-23, lipid metabolism, and apoptotic gene signatures in CD patients to non-IBD levels. When stratified by Paneth cell phenotype, the global tissue response to Mito-Tempo in Type I patients was associated with innate immune, lipid metabolism, and G protein-coupled receptor (GPCR) gene signatures. Targeting impaired mitochondria as an underlying contributor to inflammation provides a novel treatment approach for CD.

P267 Sequencing of anti-TNF agents and gut-selective anti-lymphocyte trafficking (GSALT) therapy in the treatment of Crohn’s disease (CD)

Abstract Background Anti-TNF agents and GSALT therapy (MAdCAM α4β7 blocker) are available treatment options for patients (pts) with moderate-to-severe CD. There are limited data on the optimal sequencing of these two mechanisms of action (MOAs) from the first line (1L) to second line (2L) biologic treatment of CD to inform clinician’s decision making. Methods This retrospective study used the Truven Health MarketScan administrative claims database to assess treatment pathways in a large U.S. insured population. Biologic naïve adult CD pts (identified using ICD-9 and 10 codes) who initiated (date of initiation defined as an index date) 1L biologic treatment (adalimumab [ADA], infliximab [IFX], certolizumab pegol [CTZ], or vedolizumab [VDZ] between 09/2016 and 09/2019) with at least 6 months of continuous health benefits enrolment post biologics initiation were included. Pts treated with biologics of different MOAs in 1L and 2L setting were identified to evaluate the treatment sequencing of either VDZ to anti-TNF or anti-TNF to VDZ. Treatment persistence was defined as time to index drug discontinuation with a pre-defined gap or switch to other biologic drugs. Results In the 1L, 474 VDZ and 4173 anti-TNF (2648 ADA, 1446 IFX, and 79 CTZ) pts were included. Among the 1L VDZ pts, only 33 switched to anti-TNF as 2L biologic treatment (VDZ to anti-TNF). Among the 1L anti-TNF pts, 221 switched to VDZ as 2L biologic therapy (anti-TNF to VDZ). In the VDZ to anti-TNF group, only proportion of 6 months treatment persistence was assessed due to the small number of pts in 2L. Median 1L treatment persistence was 842 days in VDZ pts and 557 days in anti-TNF pts (log rank p=0.041). The median treatment persistence in 2L VDZ post anti-TNF was 625 days (anti-TNF to VDZ). The 6 months treatment persistence to 2L was estimated as 85.1% (95% CI 59.1–95.2) in VDZ to anti-TNF group and 80.1% (95% CI 73.8–85.1) in anti-TNF to VDZ group. The 6 months treatment persistence was estimated as 74.8% (95% CI 73.4–76.1) in 1L anti-TNF and 85.1% (95% CI 59.1–95.2) in 2L anti-TNF post VDZ (VDZ to anti-TNF). Conclusion VDZ in 1L biologic treatment of CD was associated with significantly improved treatment persistence compared with anti-TNF agents. The sequencing of VDZ to anti-TNF had higher treatment persistence in both 1L and the first 6 months of 2L compared with the sequencing of anti-TNF to VDZ. The use of VDZ before anti-TNF agents led to higher persistence to anti-TNF in 2L than if anti-TNF was used in 1L during 6 months period of time. VDZ used in 2L post anti-TNF showed lower treatment persistence than if VDZ was used in 1L. This real-world evidence from U.S. large database suggests the use of GSALT prior to anti-TNF agents in biologic naïve pts with CD.

DOP48 Use of biologic therapies with different mechanisms of action (MOA) in the first-line (1L) treatment of Crohn’s Disease (CD) in the U.S

Abstract Background Anti-cytokine biologics (anti-TNF agents, anti-IL-12/23 agent) and gut-selective anti-lymphocyte trafficking agent (MAdCAM α4β7 blocker) are available treatment options for patients (pts) with moderate-to-severe CD. There are limited data on treatment persistence of these different MOA as 1L biologic treatment of CD in real-world setting. Methods This retrospective study used the Truven Health MarketScan administrative claims database to assess treatment patterns in a large U.S. insured population. Biologic naïve adult CD pts (CD diagnosed by using ICD 9 and 10 codes) who initiated (date of initiation defined as index date) 1L biologic treatment (adalimumab [ADA], infliximab [IFX], vedolizumab [VDZ] or ustekinumab [UST] between 09/2016 and 09/2019) with ≥6 months of continuous health benefits enrolment post biologics initiation were included. Treatment persistence was defined as time to index drug discontinuation with a pre-defined gap or switch to other biologic drugs. Results Overall, 2648 ADA, 1446 IFX, 474 VDZ, and 415 UST treated CD pts were identified. The mean age was highest for VDZ pts (45.5 y), followed by UST (42.2 y), ADA (40.1 y) and IFX (38.8 y). The use of corticosteroid in 12 months prior to 1L biologics was highest for ADA pts (74.3%), then UST (68.2%), VDZ (65.2%), and IFX (64.9%). Disease duration (time from the first observed CD diagnosis to 1L biologics initiation date) ≤ 2 yrs was found lowest in VDZ pts (48.1%), then UST (54.7%), ADA (59.6%), and IFX (67.6%). Fistulising condition in 12 months before 1L biologics was highest in IFX pts (11.9%), then UST (9.4%), ADA (7.7%), and VDZ (5.3%). Continuation on 1L biologics was highest in VDZ pts (59.1%), followed by IFX (58.0%), UST (57.6%), and ADA (50.8%). Treatment discontinuation was highest in UST pts (35.7%), then ADA (35.4%), VDZ (30.2%), and IFX (28.2%). Switch to 2L biologics was highest in IFX pts (13.9%), then ADA (13.8%), VDZ (10.8%) and UST (6.8%). Median treatment persistence was highest for VDZ pts (842 days), followed by IFX (770 days), UST (566 days) and ADA (507 days). VDZ pts showed higher treatment persistence than ADA pts (log-rank p-value=0.005) or UST pts (p=0.14). IFX pts had higher persistence than ADA pts (p<0.0001) or UST pts (p=0.07). The adjusted hazard ratio of treatment discontinuation, with VDZ as the reference group, was highest for ADA (1.36, p<0.0001), then UST (1.27, p=0.023) and IFX (1.07, p=0.45). Conclusion In biologic naïve CD pts, real-world evidence shows that VDZ is associated with longer treatment persistence when compared with any of the currently approved anti-cytokine biologics. With >2 years of treatment persistence, VDZ and IFX were significantly superior to both ADA and UST.

P571 Optimal biologic management of endoscopic postoperative recurrence following ileocecal resection in Crohn’s disease

Abstract Background Endoscopic postoperative recurrence (POR) of Crohn’s Disease (CD) following ileocolonic resection (ICR) is common; however, optimal treatment strategies of identified POR are unknown. We assessed the role of biologic therapy to treat endoscopic POR in a real-world cohort. Methods Retrospective cohort study of adult CD patients who underwent ICR from 2009–2020 at a tertiary center. Patients with endoscopic POR detected on postoperative colonoscopy and a subsequent follow-up colonoscopy were included. Patients were categorized by biologic therapy at time of POR and further sub-grouped by therapy modification after POR detection (no change, therapy optimization, or change in biologic class). Therapy optimization included: starting or modifying immunomodulator therapy, corticosteroids, or budesonide. POR was defined by Rutgeerts’ ≥ i2b. Results 203 CD patients (49.8% female, 15.4% > 1 prior ICR, 49.0% pre-operative biologic exposure) were included. Of these, 137 (67%) patients were not on biologic therapy at POR detection: 43% subsequently started a biologic, 23% optimized therapy, and 34% had no change. 66 (33%) patients were on anti-TNF at POR identification: 24% subsequently changed biologic class, 48% optimized anti-TNF, and 27% had no change (Figure 1). There was no difference in median time from ICR to POR detection (483 days, p=0.08) or inter-colonoscopy interval (483 days, p=0.25) between groups. In patients not on biologics at POR detection, those who started a biologic saw a 21% increase in subsequent endoscopic remission compared to those who optimized therapy (49.2% vs 28.1%, p=0.09) and a 12% increase compared to those who received no change (49.2% vs 37%). In patients not on biologics with severe POR (i3/i4, n=62), there was significantly higher remission rate by starting biologic therapy compared to optimizing existing therapy (53.3% vs 16.7%) or no change (53.3% vs 35.7%), p=0.04. In individuals receiving anti-TNF at time of POR, there was a 25% increase in endoscopic remission in patients who switched biologic class compared to those who optimized therapy (56.2% vs 31.2%) and a 34% increase compared to those with no change (56.2% vs 22.2%), p=0.1. Furthermore, significantly higher rates of improved Rutgeerts’ score were observed in switching biologic class compared to therapy optimization (68.8% vs 43.8%) or no change (68.8% vs 27.8%), p=0.04. Conclusion After endoscopic POR detection following ICR, initiating biologic therapy in individuals not previously receiving it, and changing mechanism of action in those already receiving anti-TNF, may improve clinical outcomes compared to alternative management strategies. If confirmed, these findings may inform optimal management strategies for endoscopic POR.

P199 Analysis of clinical features of asymptomatic perianal fistulizing Crohn’s disease

Abstract Background Perianal fistula represents an aggressive phenotype of Crohn’s disease (CD), and is detected in CD patients without perianal complains. Data of CD patients with asymptomatic perianal fistula is scarce. Our study targets to assess the clinical characteristics of adult CD patients with asymptomatic perianal fistulas in adults with CD. Methods This retrospectively study collected data from Sir Run Run Shaw Hospital. Newly diagnosed CD patients undergoing magnetic resonance imaging examinations during 2014–2019 were enrolled. The perianal fistulizing CD patients were divided into two groups: 1) symptomatic perianal fistula group, 2) asymptomatic perianal fistula group, then we analyze the features of clinical features, medication and prognosis of each group. Results Among 437 CD patients, 346 (79.2%) had perianal fistulas whereas 91 (20.8%) did not. In patients with perianal fistulas, 89 (25.7%) did not have perianal symptoms. Comparing to symptomatic perianal fistula group, asymptomatic perianal fistula group combined with lower perianal abscess incidence (73.9% vs. 25.8%, p < 0.001). According to Park’s classification, the most common type of fistula in these two groups was intersphincteric fistula (73.2% vs. 53.2% p=0.094). Patients with asymptomatic perianal fistulas were described by the following features when compared with patients with symptomatic perianal fistulas: higher rate of female sex (38.2% vs. 17.9%, p < 0.001), shorter disease duration at enrolment (0.8 vs. 1.0 years, p = 0.001), higher rate of stricturing behavior (32.6% vs. 18.7%, p < 0.01), worse outcomes of laboratory examinations at diagnosis, including hemoglobin (119.0 vs. 131.0 g/dL, p < 0.001), platelet (333.0 vs. 283.0 *10^9, p < 0.001), ESR (20.0 vs. 14.0 mm/H, p < 0.01), albumin (35.6 vs. 37.5 g/L, p = 0.001), C-reactive protein (27.3 vs. 15.7 mg/L, p = 0.001). The age at diagnosis and disease locations were not different. For asymptomatic perianal fistula patients, antibiotics (57.3%) and surgery (6.7%) were taken at diagnosis. The usage of biologics at diagnosis showed no difference (59.6% vs. 40.4% p=0.108). Regarding clinical outcomes, the cumulative probabilities for bowel surgery (p < 0.05) and bowel obstruction (p < 0.01) in asymptomatic perianal fistula group were higher than symptomatic perianal fistula group. Conclusion Asymptomatic perianal fistulas account for a certain proportion. Female sex, shorter disease duration, stricturing behavior and poor outcomes of laboratory examinations at diagnosis are associated with detection of asymptomatic perianal fistulas. We should pay more attention to CD patients with asymptomatic perianal fistulas because they may have poor prognosis or even worse as patients with symptomatic perianal fistulas.

P327 Long-term effectiveness of ustekinumab in refractory Crohn’s disease: an Italian multicenter real-life study

Abstract Background Ustekinumab (UST) is increasingly used in Italy for the treatment of refractory Crohn’s disease (CD), however very few data concerning real-life experience has been reported. Therefore, the aim of this study was to assess the long-term effectiveness of UST in refractory CD patients treated in a large Italian cohort. Methods A retrospective study was conducted in 5 Italian tertiary centers. All adult CD patients who started UST because of anti-tumor necrosis factor (TNF) failure were included. The co-primary outcomes were steroid-free clinical remission (defined as Harvey Bradshaw Index, HBI ≤4) at weeks 26 and 52. Secondary outcomes were changes in HBI score, changes in C-reactive protein (CRP) values, normalization of CRP (≤0.5 mg/dl) at weeks 8, 26, and 52, and adverse events. Categorical variables were expressed as frequency and percentage. Unpaired t-test was used to compare variables. A p-value <0.05 indicated statistical significance. Continuous variables were expressed as mean and standard deviation (SD), and median with interquartile range (IQR). Results Between Nov 2018 and Feb 2020,140 patients (51.4% male; median age 45.0 years, IQR 36.3-54.0; median disease duration 16.0 years, IQR 8.0-22.0) were included. The majority of patients had ileocolonic disease (L1, 38.6%; L2, 11.4%; L3, 50.0%) and an inflammatory phenotype (B1, 50.7%; B2, 31.0%; B3, 18.3%). All patients had previously been exposed to at least one anti-TNF agent, 27.1% to 2 anti-TNF agents, and 20.0% to vedolizumab . At inclusion 15.7% of patients received corticosteroids and 8.6% immunomodulators. All patients received an intravenous dose of 6 mg/kg, followed by subcutaneous administration of 90 mg every 8 (90%) or 12 weeks (10%) according to clinical judgment. The proportion of patients achieving steroid-free clinical remission was 61.0% and 64.2% at weeks 26 and 52 respectively. A significant decrease in the mean HBI was reported from baseline to week 8 (6.8 ± 3.6 vs 4.5 ± 3.1; p <0.001), week 26 (3.5 ± 2.9; p <0.001), and week 52 (3.1 ± 2.4; p <0.001). The mean CRP values was also significantly decreased from baseline to week 8 (4.6 ± 7.3 vs 2.8 ± 7.1; p <0.001), week 26 (1.7 ± 3.8; p <0.001), and week 52 (1.1 ± 2.2; p<0.001). At baseline 93 of 119 patients had high CRP value: a normal CRP value was observed in 34.9%, 37.8%, and 49.3% of patients at weeks 8, 26, and 52 respectively. Overall, 11 patients (7.9%) discontinued UST within 1 year: primary failure (n=2), secondary failure (n=6), adverse events (n=3: 2 allergic reactions, and 1 arthralgia). Conclusion To our knowledge this is one of the largest Italian cohort followed up to 1 year, and the results confirm that UST is an effective and safe treatment in refractory CD patients.

DOP31 Management and outcome of postoperative Crohn’s Disease in the elderly as compared to young adults: Data from Eneida registry

Abstract Background A less aggressive phenotype of Crohn’s disease (CD) has been reported in patients with elderly onset CD. Despite this, similar surgical rates among younger and older CD patients have been reported. However, scarce data are available about the risk of postoperative recurrence (POR) regarding the age, and no data are available about the use of immunosuppressants and biological agents for prevention of POR in elderly patients. Our aim was to evaluate the management of CD in the postoperative setting and the rate of surgical POR in CD patients according to the age at surgery. Methods Cohort study including all adult CD patients in the ENEIDA registry (a prospectively-maintained database of the Spanish Working Group in IBD –GETECCU-) who underwent a first intestinal resection with ileo-colonic anastomosis. Patients were grouped regarding their age at the moment of the first surgery: over 60 years (elderly) and between 18 and 60 years of age (controls). Preventive treatment for POR, surgical POR (need for a further intestinal resection) and postoperative morbidity were compared between both groups. Results Out of the 69,740 IBD patients included in the ENEIDA database, 3,982 had a first intestinal resection for Crohn’s disease with an ileo-colonic anastomosis between 2005 and 2020. Of them, 535 were elderly and 3,454 controls. Time from IBD diagnosis to surgery was significantly longer in the elderly (114±128 vs. 93±97 months; p<0.001). Regarding baseline characteristics, the elderly had a lower proportion of penetrating behaviour (25% vs. 39%; p<0.0001) and perianal disease (14% vs. 25%; p<0.0001). No differences were observed in the rate of postoperative morbidity (16% vs 15%; p=0.18). Time of follow-up after surgery was significantly lower in the elderly (63±57.5 vs. 81.2±56 months; p<0.0001). A significantly lower proportion of elderly patients started preventive therapies for POR (immunosuppressants or biological agents) as compared to controls (26% vs. 43%, respectively; p<0.0001). In spite of this, the rates of surgical POR were similar in elderly and controls (19.8% vs. 17.6%, respectively; p=0.169). In the multivariate logistic regression analysis only the inflammatory pattern of the disease was associated with surgical POR (HR 1.27; 95%IC (1.011–1.602)). Conclusion The elderly patients show similar rates of surgical POR as compared to younger patients. Given the high risk of thiopurine and anti-TNF-related adverse events, elderly patients with inflammatory pattern would benefit from preventive therapy with safer biologicals.

P111 Cross-sectional imaging is highly sensitive in detecting endoscopic post-operative recurrence in Crohn’s disease patients

Abstract Background Postoperative Crohn’s disease (CD) surveillance relies on endoscopic monitoring. The role of cross-sectional imaging in post-operative CD surveillance is less clear. We aimed to evaluate radiographic characteristics, endoscopic concordance, and the predictive ability of imaging for postoperative recurrence (POR). Methods Multi-institution retrospective cohort study of adult CD patients who underwent ileocolonic resection (ICR) between 2009–2020. Patients with a CT or MR enterography within 90 days of a postoperative surveillance colonoscopy were included. Imaging studies were interpreted by blinded expert CD radiologists. Endoscopic activity was assessed by Rutgeerts’ scoring (POR ≥ i2b). Patients were categorized by presence of endoscopic POR (E+ or E-) or radiographic disease activity (R+ or R-) and grouped by endoscopic and radiographic concordance. Results 201 CD patients (57.7% female, mean age 31 years, 81.2% stricturing CD, 17.9% >1 prior ICR, 22.5%) with paired colonoscopy and imaging were included. Median time from ICR to paired endoscopy was 23.2 months. Imaging was highly sensitive for detecting POR (84.2%), but poorly specific (32.8%). The plurality (41.8%, N=84) were discordant E-/R+, 32.8% concordant positive (E+/R+), 20.4% concordant negative (E-/R-), and 5% discordant E+/R-. In patients with endoscopic POR, imaging detected intestinal wall thickening (86.8%; p=0.004) and hyper-enhancement (84.2%; p=0.003) at higher rates and corresponded with endoscopic severity (Figure 1). Multiple correspondence analysis showed association between severe endoscopic (i3/i4) disease and advanced radiographic disease. The majority (58.3 %) of E+/R- patients (N=12) had a Rutgeerts’ score of i2b. Majority of E-/R+ (N=84) had minimal/mild radiographic disease (81%). Differences in characteristics between the E-/R+ and E+/R+ was most pronounced in length of disease >10 cm (26.1%, 45.3%). Subsequent colonoscopies were performed in 74 E-/R+ (i0=28, i1=12, i2a=34) and 35 E-/R- (i0=20, i1=9, i2a=6) patients with 18 E-/R+ (24.3%; i0=8, i1=3, i2a=7) and 4 E-/R- (11.4%; i0=1, i1=2, i2a=1) patients developing POR (p=0.09). However, survival analysis between E-/R+ and E-/R- showed no difference to time to subsequent POR (p=0.24) (Figure 2). Imaging features at time of paired negative endoscopy did not predict subsequent endoscopic POR. Conclusion Cross-sectional imaging is highly sensitive to detect endoscopic POR; advanced radiographic disease correlates with increased endoscopic severity. Patients with no endoscopic recurrence in the presence of radiographic activity may require increased surveillance, though larger study cohorts are needed. Imaging compliments, but should not supplant, endoscopic POR surveillance paradigms.

DOP17 In high-risk Crohn’s Disease patients, anastomosis configuration types have similar rates of endoscopic recurrence

Abstract Background There is conflicting data on the influence of surgical anastomosis configuration on endoscopic postoperative recurrence (POR) of Crohn’s disease (CD) following ileocolonic resection (ICR). Furthermore, whether this relationship differs by preoperative risk factors for POR has not been studied. We aimed to assess the role of ileocolonic anastomosis type on the rate and time to POR by preoperative POR risk. Methods Retrospective cohort study of adult CD patients who underwent ICR between 2009–2020 at a quaternary IBD referral center. Patients with a primary or secondary anastomosis and ≥1 postoperative colonoscopy were included. Endoscopic activity was assessed by modified Rutgeerts’ scoring. POR was defined as Rutgeerts’ ≥ i2b. Patients were categorized by anastomosis type: end-to-end (ETE), end-to-side (ETS), or side-to-side (STS). High-risk CD patients were defined by ≥1: age ≤ 30 years, active smoker, or ≥2 ICR for penetrating disease. Results 548 CD patients (52.6% female, age 35 y, 15.5% > 1 prior ICR, 19.7% on biologic prophylaxis, 74.8% high-risk for POR) were included in the study (Figure 1). The majority received a STS (52.0%, N=285), 27.2% ETS, and 20.8% ETE. Patients with an ETE were diagnosed with CD at a younger age (p=0.04), had more penetrating disease (p=0.01), hand-sewn anastomoses (p <0.001), and diverting loop ileostomies (p=0.02). There were no differences in prior ICR, smoking, biologic prophylaxis, or in median time from ICR to first post-operative colonoscopy (388.5 days, p=0.41) or POR detection (905 days, p=0.8) by anastomosis type. ETS patients had a shorter median follow-up time (3.9 y, p=0.02). The majority (55.7%) of all patients experienced POR (57% ETS; 55.4% STS; 54.4% ETE). Overall, there was no significant association between anastomosis type and POR rate (p=0.91) or time to POR (p=0.32). However, in high-risk CD patients, ETS was significantly associated with more rapid time to POR on log-rank (p=0.03) and multivariable Cox modeling (HR=1.51; p=0.04). Postoperative prophylactic biologic therapy initiated within 3 months of ICR significantly delayed POR in the overall cohort (HR=0.64; p=0.012) and the high-risk CD subgroup (HR=0.67; p=0.047). High-risk CD patients on prophylactic biologics had no difference in time to POR by anastomosis type (p=0.66). Conclusion In post-operative CD patients, there is no difference in rates of endoscopic recurrence by anastomosis configuration regardless of risk stratification. In high-risk patients, ETS was associated with more rapid endoscopic recurrence compared to other configurations, however prophylactic postoperative biologics may protect against this effect. Figure 2: KM Survival analysis of time (days) to POR

P563 Comparison of long-term outcomes of infliximab with adalimumab in biologic naïve patients with Crohn’s disease: a tertiary referral center 13-year experience

Abstract Background The comparative efficacy and safety of infliximab (IFX) and adalimumab (ADA) have shown variable results in biologic-naïve patients with Crohn’s disease (CD). Thus, long-term comparisons between IFX and ADA with or without immunomodulator therapies are still needed. The purpose of this study was to evaluate the long-term clinical effectiveness and safety profile of IFX compared to ADA in biologic-naïve patients with CD. Methods Data of all adult CD patients treated with IFX or ADA as their first biologic agent was collected retrospectively between December 2007 and February 2021. We compared CD-related hospitalization, CD-related major abdominal surgery, steroid use and serious infections leading to treatment cessation. Results Out of 224 biologic-naïve patients with CD, 101 started IFX first (median age at onset: 38.12 years, 61.4% male) and 123 started ADA first (median age at onset: 30.2 years, 64.2% male). Median disease duration was 6.94 years (IQR: 3.82–12.17) and 6.91 years (IQR: 3.94–10.95) for IFX and ADA, respectively, of whom 33% and 37.4% had active smokers, 10.9% and 13.4% had family history of inflammatory bowel disease (IBD) 22.8% and 19.5% had perianal disease, 43.6% and 43.9 had prior major abdominal surgery and 52.6% and 49.6% had extraintestinal manifestations. There were no significant differences between the two groups with respect to the age at onset of tumor necrosis factor antagonist, gender, smoking status, family history of IBD, perianal disease, prior major abdominal surgery, extraintestinal manifestations, prior immunomodulator (Thiopurine or Methotrexate) or steroid usage, all laboratory test results and Crohn’s Disease Activity Index (CDAI) score at baseline (p>0.05). Overall, the median follow-up time was 2.81 and 3.55 years after starting the first IFX and ADA group, respectively. There were no significant differences in the rate of steroid use (4% IFX vs. 10.6% ADA p=0.109), CD-related hospitalization (13.9% IFX vs. 22.8% ADA p=0.127), CD-related major abdominal surgery (9.9% IFX vs. 13% ADA p=0.608) and serious infections leading to treatment cessation (1% IFX vs 0.8% ADA p>0.999) between IFX and ADA. These outcomes were similar in patients treated with IFX or ADA monotherapy or in combination with an immunomodulator. Conclusion In this retrospective observational tertiary referral center study, we observed that there was no significant difference in long-term effectiveness and safety of infliximab and adalimumab in biologic-naïve patients with CD.

P196 Colon-involving versus non-colon-involving Crohn’s disease classification: is the Montreal classification outdated?

Abstract Background An appropriate disease classification is essential for the management of Crohn’s disease (CD) patients. Recently, a new classification of colon-involving versus non-colon-involving disease extension was considered to be more predictive of adverse outcomes than the Montreal classification (MRC). We aimed to investigate the association of a colon-based classification with clinically relevant outcomes in patients with CD compared with the MRC. Methods Retrospective cohort-study which consecutively included adult CD patients with at least 1 year of follow-up. Patients were categorized into colon-involving and non-colon-involving disease and according to the MRC. Patients’ demographic, clinical, biochemical, and imaging data were recorded and compared between the two classifications. The primary outcome was the need for treatment with steroids or biologics, hospitalization and major abdominal surgery. Results Of 327 patients, 52.3% were female with a mean age of 43.3±13.1 years. The most common disease location according to MRC was L1 (48.9%), followed by L3 (41.3%) and L2 (9.8%). Overall, 51.1% of patients had colon-involving disease. Although patients with colon-involvement at diagnosis had higher frequency of perianal lesions (27.5% vs 16.9%, P<0.05) and serum inflammatory biomarkers (lower hemoglobin, and higher leucocyte and platelet counts, c-reactive protein and erythrocyte sedimentation rate), this classification was not predictive of relevant outcomes. Considering the two types of colon-involving disease (L2, L3), patients with L2 disease had higher extraintestinal manifestations (43.8% vs 20.7%, respectively, P<0.05), higher B1 disease behavior (87.5% vs 58.5%, respectively, P<0.05) and lower B2 disease behavior (6.25% vs 22.2%, respectively, P<0.05). Disease location according to MRC was predictive of the need for treatment with biologics, hospitalization and major abdominal surgery in univariate analysis, but not in multivariate analysis. Conclusion Although simpler, defining Crohn’s disease extension by colon-involving versus non-colon-involving is not more predictive of adverse outcomes than the Montreal classification. Therefore, the use of Montreal Classification should still be considered essential in the adequate management of IBD patients.

A nationwide real-world study on dynamic ustekinumab dosing and concomitant medication use among Crohn’s disease patients in Finland

Background Real-world evidence to support optimal ustekinumab dosing for refractory Crohn’s disease (CD) patients remains limited. Data from a retrospective nationwide chart review study was utilized to explore ustekinumab dosing dynamics and optimization, identify possible clinical predictors of dose intensification, and to evaluate ustekinumab trough concentrations (TCs) and concomitant medication use in Finland. Methods Information gathered from17 Finnish hospitals included clinical chart data from 155 adult CD patients who received intravenous ustekinumab induction during 2017–2018. Data on ustekinumab dosing and TCs, concomitant corticosteroid and immunosuppressant use, and antiustekinumab antibodies were analyzed in a two-year follow-up, subject to availability. Results Among 140 patients onustekinumab maintenance therapy, dose optimization was required in 55(39%) of the patients, and 41/47 dose-intensified patients (87%) persisted on ustekinumab. At baseline, dose-intensified patient group had significantly higher C-reactive protein (CRP) levels, and at week 16, significantly lower ustekinumab TCs than in patients without dose intensification. Irrespective of dose optimization, a statistically significant reduction in the use of corticosteroids was observed at both 16 weeks and one year, coupled with an increased proportion of patients on ustekinumab monotherapy. Antiustekinumab antibodies were undetectable in all 28 samples from 25 patients collected throughout the study period. Conclusions Nearly a third of all CD patients on ustekinumab maintenance therapy, with a history of treatment-refractory and long-standing disease, required dose intensification. These patients persisted on ustekinumab and had significant reduction of corticosteroid use. Increased baseline CRP was identified as the sole indicator of dose intensification. Trial registration EUPAS30920

Prospective observational study on Stelara (ustekinumab) assessing effectiveness in Crohn’s disease (PROSE): a 16-week follow-up

Background Prospectively and systematically collected real-world data on the effectiveness of ustekinumab (anti-interleukin-12/23) for treating Crohn’s disease (CD) are still limited. Aim To assess the short-term real-world effectiveness of ustekinumab in Swedish patients with active CD. Methods Prospective multicentre study of adult CD patients initiating ustekinumab according to recommended doses at 20 hospitals, between January 2017 and November 2018. Data were collected through an electronic case report form (eCRF) linked to the Swedish Inflammatory Bowel Disease Registry (SWIBREG). The primary outcomes were clinical response (≥3-point-decrease of Harvey–Bradshaw index (HBI)) and remission (HBI ≤4 points) at week 16. Secondary outcomes included C-reactive protein (CRP) and haemoglobin (Hb) at baseline compared to week 16. Results Of 114 included patients, 107 (94%) had failed ≥ 1 and 58 (51%) ≥ 2 biological agents (anti-tumour necrosis factor [aTNF] agents or vedolizumab). The 16-week ustekinumab retention rate was 105 (92%). Data on HBI at baseline were available for 96 patients. At week 16, response or remission was achieved in 38/96 (40%) patients (25/96 (26%) achieving clinical remission and 23/96 (24%) showing a clinical response). The median CRP concentration (N = 65) decreased from 6 to 4 mg/l (p = .006). No significant changes in Hb were observed. No incident malignancies or infections, requiring antibiotic treatment, were reported. Conclusions In this nation-wide prospective real-world study of adult patients with CD, ustekinumab was associated with clinical effectiveness when administered according to clinical practice and seemed to represent a safe treatment option.

Single-cell analyses of Crohn\u2019s disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions

Crohn’s disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we profile, via multiple single-cell technologies, T cells purified from the intestinal epithelium and lamina propria (LP) from terminal ileum resections of adult severe CD cases. We find that intraepithelial lymphocytes (IEL) contain several unique T cell subsets, including NKp30+γδT cells expressing RORγt and producing IL-26 upon NKp30 engagement. Further analyses comparing tissues from non-inflamed and inflamed regions of patients with CD versus healthy controls show increased activated TH17 but decreased CD8+T, γδT, TFH and Treg cells in inflamed tissues. Similar analyses of LP find increased CD8+, as well as reduced CD4+T cells with an elevated TH17 over Treg/TFH ratio. Our analyses of CD tissues thus suggest a potential link, pending additional validations, between transmural inflammation, reduced IEL γδT cells and altered spatial distribution of IEL and LP T cell subsets.

Ultrasonography Tight Control and Monitoring in Crohn’s Disease During Different Biological Therapies: A Multicenter Study

Bowel ultrasonography (BUS) is a noninvasive tool for evaluating bowel activity in Crohn's disease (CD) patients. Aim of our multicenter study was to assess whether BUS helps to monitor intestinal activity improvement/resolution following different biological therapies. Adult CD patients were prospectively enrolled at 16 sites in Italy. Changes in BUS parameters [i.e. bowel wall thickening (BWT), lesion length, echo pattern, blood flow changes and transmural healing (TH: normalization of all BUS parameters)] were analyzed at baseline and after 3, 6 and 12 months of different biological therapies. One hundred eighty-eight out of 201 CD patients were enrolled and analyzed (116 males [62%]; median age 36 years). Fifty-five percent of patients were treated with adalimumab, 16% with infliximab, 13% with vedolizumab and 16% with ustekinumab. TH rates at 12 months were 27.5% with an NNT of 3.6. TH at 12 months after adalimumab was 26.8%, 37% after infliximab, 27.2% after vedolizumab and 20% after ustekinumab. Mean BWT improvement from baseline was statistically significant at 3 and 12 months (P < .0001). Median Harvey-Bradshaw index, C-reactive protein and fecal calprotectin decreased after 12 months from baseline (P < .0001). Logistic regression analysis showed colonic lesion was associated with a higher risk of TH at 3 months and a greater BWT at baseline was associated with a lower risk of TH at 3 months [P= .03 (OR 0.70, 95% CI 0.50-0.97)] and 12 months [P= .01 (OR 0.58, 95% CI 0.38-0.89)]. At 3 months therapy optimization during the study was the only independent factor associated with a higher risk of no ultrasonographic response [P= .02 (OR 3.34, 95% CI 1.18-9.47)] and at 12 months disease duration [P= .02 (OR 3.03, 95% CI 1.15-7.94)]. Data indicate that BUS is useful to monitor biologics-induced bowel activity improvement/resolution in CD.

Can Conventional and Diffusion-Weighted MR Enterography Biomarkers Differentiate Inflammatory from Fibrotic Strictures in Crohn's Disease?

Background and Objectives: To retrospectively assess the value of magnetic resonance enterography (MRE) parameters derived from conventional and diffusion weighted imaging (DWI) sequences to differentiate fibrotic strictures from inflammatory ones in adult patients with Crohn’s disease (CD), using surgical specimens as the histopathological reference standard. Material and Methods: Twenty-three patients with CD who had undergone surgical resection of ileal strictures with full-thickness histopathologic analysis within 3 months from preoperative MRE were included. Two radiologists blinded to histopathology in consensus evaluated the following biomarkers on MRE images matched to resected pathological specimens: T1 ratio, T2 ratio, enhancement pattern, mural thickness, pre-stenotic luminal diameter, and apparent diffusion coefficient (ADC). A blinded pathologist graded stricture histological specimens with acute inflammation score (AIS) and fibrosis score (FS). MRE measurements were correlated with the reference standard. Results: Inflammation and fibrosis coexisted in 78.3% of patients. T2 ratio was reduced in patients with severe fibrosis (p = 0.01). Pre-stenotic bowel dilatation positively correlated with FS (p = 0.002). The ADC value negatively correlated with FS (p < 0.001) and was different between FS grades (p < 0.05). The area under the receiver operating characteristic curve for discriminating between none and mild/moderate–severe bowel wall fibrosis was 0.75 for pre-stenotic bowel dilatation (sensitivity 100%, specificity 44.4%) and 0.97 for ADC (sensitivity 80%, specificity 100%). Conclusions: Inflammation and fibrosis often coexist in CD bowel strictures needing surgery. The combination of parameters derived from conventional MR sequences (T2 ratio, pre-stenotic dilatation) and from DWI (ADC) may provide a contribution to detect and grade bowel fibrosis in adult CD patients.

Skeletal muscle anabolic and insulin sensitivity responses to a mixed meal in adult patients with active Crohn's disease.

We have previously shown reduced protein balance in response to nutrition in paediatric Crohn's disease (CD) in remission, associated with reduced lean mass (sarcopenia) and reduced protein intake in males. We aim to compare skeletal muscle metabolic response to feeding in adult active CD and healthy volunteers. Eight CD participants with active disease (41.3±4.5yrs; BMI 26.9±1.5kg/m2) and eight matched healthy volunteers (Con) (41.2±4.3yrs; BMI 25.1±1.1kg/m2) were recruited. Participants had a dual energy X-ray absorptiometry scan, handgrip dynamometer test, wore a pedometer and completed a food diary. Arterialized hand and venous forearm blood samples were collected concurrently and brachial artery blood flow measured at baseline and every 20mins for 2hrs after the ingestion of a standardized mixed liquid meal. Net balance of branched chain amino acids (BCAA), glucose and free fatty acids across the forearm were derived. No differences in muscle BCAA, glucose or FFA net balance were found between CD and Con. Neither were differences in muscle mass and function, physical activity or diet found. CD did not differ from Con in whole body insulin and lipid responses, or in energy expenditure and fuel oxidation. Skeletal muscle mass, function, dietary protein intake and response to a test meal in an adult CD cohort with active disease is similar to that seen in healthy volunteers. Combining these results with our previous findings in paediatric patients suggests that age of onset and/or disease burden over time, as well as daily protein intake, may be significant in the development of sarcopenia in CD. Longitudinal studies investigating these factors are required.

Effect of Originator Infliximab Treatment on Disease-Related Hospitalizations, Work Productivity and Activity Impairment, and Health Resource Utilization in Patients with Crohn’s Disease in a Real-Life Setting: Results of a Prospective Multicenter Study in Germany

Introduction: Infliximab (IFX) therapy is efficacious for inducing and maintaining symptomatic remission in patients with Crohn’s disease (CD), but whether this benefit results in reduced hospitalization rates and therefore may improve patients’ quality of life in an economically sensible way is conflicting so far. Methods: We conducted a noninterventional, multicenter, open-label, prospective study to evaluate the effect of originator IFX treatment on patient-reported outcomes and disease-related hospitalizations in adult CD patients in Germany treated for the first time with IFX according to label. Results: Two hundred and ninety-four patients were included in the study. We observed a statistically significant reduction in the number of CD-related hospitalizations from the year before baseline (mean 1.00 per patient, SD ± 0.93) to the mean value of the 1st (0.62, SD ± 0.95) and 2nd year (0.32, SD ± 0.75) of the observation period (p < 0.0001). After 3 months of IFX therapy, work productivity and activity increased by an average of 12.6 and 17.1%, respectively. Patient’s clinical outcome was markedly improved as the total CD activity index (CDAI) sum score continuously decreased from baseline to month 24 and the mean score of the total inflammatory bowel disease questionnaire (IBDQ) changed substantially from 141 at baseline to 172 after 24 months of IFX treatment. Additionally, the number of work incapacity days declined. Recently, no new safety issues of IFX have been identified. Conclusion: In this large, prospective, multicenter study on disease-related hospitalization rates, work productivity, capacity for daily activities, and HRQoL in patients with CD, IFX significantly reduces their hospitalization rates and improves work productivity, daily activity, and quality of life over 24 months.

IPAA in Known Preoperative Crohn's Disease: A Systematic Review.

Crohn's disease is a relative contraindication to IPAA due to perceived increased rates of pouch failure. This study aimed to determine pouch functional outcomes and failure rates in patients with a known preoperative diagnosis of Crohn's disease. A database search was performed in Ovid Medline In-Process & Other NonIndexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, and Ovid Cochrane Database of Systematic Reviews. The published human studies that reported short-term postoperative outcomes and/or long-term outcomes following IPAA in adult (≥18 years of age) Crohn's disease populations were selected. Ileal pouch anal anastomoses were constructed in patients who had Crohn's disease diagnosed preoperatively or through proctocolectomy pathology. The primary outcomes measured were long-term functional outcomes (to maximal date of follow-up) and the pouch failure rate. Of 7019 records reviewed, 6 full articles were included in the analysis. Rates of pelvic sepsis, small-bowel obstruction, pouchitis, anal stricture, and chronic sinus tract were 13%, 3%, 31%, 18%, and 28%. Rates of incontinence, urgency, pad usage in the day, pad usage at night, and need for antidiarrheals were 24%, 21%, 19%, 20%, and 28%, and mean 24-hour stool frequency was 6.3 bowel movements at a mean 69 months of follow-up. The overall pouch failure rate was 15%; no risk factors for pouch failure were identified. This investigation was limited by the small number of studies with significant study heterogeneity. In patients with known preoperative Crohn's disease, IPAA construction is feasible with functional outcomes equivalent to patients with ulcerative colitis, but, even in highly selected patients with Crohn's disease, pouch failure rates remain higher than in patients with ulcerative colitis.

Inflammatory bowel disease patients provide reliable self-reported medical information: A multicentre prospective pharmacovigilance monitoring system.

PurposeTo assess the agreement between patient‐reported and health care provider‐reported medical information in inflammatory bowel disease (IBD).MethodsThis multicentre, prospective, event monitoring study enrolled adult Crohn's disease (CD) and ulcerative colitis (UC) patients treated with a biological in four medical centers in the Netherlands. At two‐monthly intervals, patients completed questionnaires on biological use, combination therapy and indication. The patient‐reported information was compared with their electronic health records (EHRs) and analysed for percentage agreement and Cohen's kappa. A reference population from a prospective IBD registry was used to assess the representativeness of the study population.ResultsIn total, 182 patients (female 50.5%, mean age 42.2 years, CD 76.9%) were included in the analysis. At baseline, 51.0% of the patients were prescribed an immunomodulator (43.9% thiopurines, 7.1% methotrexate), and patients were prescribed biologicals as follows: 59.3% infliximab, 30.2% adalimumab, 9.3% vedolizumab, and 1.1% ustekinumab. Agreement on patient‐reported indication and biological use was almost perfect (κ = 0.878 and κ = 1.000, respectively); substantial for combination therapy (κ = 0.672). Gender, age, type of IBD, biological use and combination therapy were comparable with the reference population.ConclusionSystematic patient‐reporting by questionnaires was reliable in retrieving indication and treatment specific information from IBD patients. These results indicate that the use of patient‐reporting outcomes in daily IBD practice can ensure reliable information collection.