Mo1687 Efficacy of Anti-TNF on Severe Postoperative Endoscopic Recurrence in Crohn's Disease

Mo1688 Interobserver and Intraobserver Agreement of the Mayo Score of Endoscopic Activity in Ulcerative Colitis

Infliximab treatment of postoperative ulcers in Crohn's disease: to inject or not to inject—that is the question

Postoperative Crohn's Disease Recurrence: Time to Adapt Endoscopic Recurrence Scores to the Leading Surgical Techniques

Background Recently, a new antimesenteric, functional, end-to-end, hand-sewn ileocolic anastomosis (Kono-S) has shown a significant reduction in endoscopic recurrence (ER) and surgical recurrence (SR) rate in Crohn’s disease (CD). This trial aimed to provide randomized controlled data comparing Kono-S anastomosis and conventional stapled ileocolic side-to-side anastomosis. Methods Randomized controlled trial (RCT) at a tertiary referral centre. The primary endpoint is ER rate (Rutgeerts score ≥ i2) after 6 months and surgical recurrence at 60 months. Secondary endpoints are clinical recurrence (CR) rate after 24 and 36 months, and SR after 24 and 36 months. Statistics was performed by using standard analyses. Furthermore, a sample size able to consent the detection of a reduction >30% in total endoscopic recurrence (when assuming a 60% to 65% ER expected rate in the control group and a 30% in the case group) was calculated; to allow a 10% drop-out of patients, 36 patients per group were needed (72 patients in the entire population). Results A total of 119 CD patients were included in the study. In all, 51 ileocolic CD patients were randomized in the Kono group and 68 in the conventional side-to-side group. At 6 months, 17 (33.3%) patients in the Kono group and 51 (75%) patients in the conventional group presented an ER (Rutgeerts score≥i2) at colonoscopy (p<0.001). A severe post-operative ER (Rutgeerts score≥i3) was found in 8 (15.7%) patients in the Kono group versus 23 (33.8%) patients in the conventional group (p=0.03). At 24 months, CR rate was 19.6% in the Kono group versus 30.9% in the conventional group (p=0.2), while SR rate was 0% in the Kono group versus 4.4% (3 patients) in the standard group (p=0.2). At 36 months, CR rate was 19.6% in the Kono-s group versus 33.8% in the conventional group (p=0.1). At 36 months, no patients (0%) in the Kono group experienced SR, while 6 patients (8.8%) in the conventional group did (p=0.03). Furthermore, when considering a median follow-up of 54 (42-60) months at interim analysis of SR, the difference between the two groups was confirmed to be significant (0% vs 8.8%; p=0.02). Conclusion This is the first RCT comparing Kono-S anastomosis and conventional side-to-side anastomosis in CD. The results demonstrate a significant reduction in postoperative endoscopic and surgical recurrence rates, no safety issues, and a favourable trend for lower clinical recurrence rate in patients who underwent Kono-S anastomosis compared to the conventional side-to-side anastomosis.

Risk Prediction and Comparative Efficacy of Anti-TNF vs Thiopurines, for Preventing Postoperative Recurrence in Crohn's Disease: A Pooled Analysis of 6 Trials

The Value of Myenteric Plexitis to Predict Early Postoperative Crohn’s Disease Recurrence

Sa1237 Long-Term Evaluation of Preoperative Wireless Capsule Endoscopy As a Predictor of Outcome After Ileal Pouch-Anal Anastomosis

To determine the difference in clinical outcome between ulcerative colitis (UC) patients with Mayo endoscopic subscore (MES) 0 and those with MES 1. UC patients with sustained clinical remission of 6 mo or more at the time of colonoscopy were examined for clinical outcomes and the hazard ratios of clinical relapse according to MES. Parameters, including blood tests, to identify predictive factors for MES 0 and slight endoscopic recurrence in clinically stable patients were assessed. Moreover, a receiver operating characteristic curve was generated, and the area under the curve was calculated to indicate the utility of the parameters for the division between complete and partial mucosal healing. All P values were two-sided and considered significant when less than 0.05. A total of 183 patients with clinical remission were examined. Patients with MES 0 (complete mucosal healing: n = 80, 44%) were much less likely to relapse than those with MES 1 (partial mucosal healing: n = 89, 48%) (P < 0.0001, log-rank test), and the hazard ratio of risk of relapse in patients with MES 1 vs MES 0 was 8.17 (95%CI: 4.19-17.96, P < 0.0001). The platelet count (PLT) < 26 × 10(4)/μL was an independent predictive factor for complete mucosal healing (OR = 4.1, 95%CI: 2.15-7.99). Among patients with MES 0 at the initial colonoscopy, patients of whom colonoscopy findings shifted to MES 1 showed significant increases in PLT compared to those who maintained MES 0 (3.8 × 10(4)/μL vs -0.6 × 10(4)/μL, P < 0.0001). The relapse rate differed greatly between patients with complete and partial mucosal healing. A shift from complete to partial healing in clinically stable UC patients can be predicted by monitoring PLT.

Introduction: Endoscopic recurrence of Crohn's disease (CD) after curative ileocecal resection, which is reported in up to 70% of patients within 1 year, precedes clinical relapse. Azathioprine (AZA) reduces the risk of both clinical and endoscopic recurrence. Aim: To evaluate the association between thiopurine metabolite levels and endoscopic improvement in CD patients with moderate to severe postoperative endoscopic recurrence. Methods: Patients treated with AZA within the AZT-2 study, a prospective double-blinded trial comparing 2.0–2.5mg/kg/d AZA versus 4.0g/d mesalamine for prevention of clinical relapse in patients with postoperative moderate to severe endoscopic recurrence, were included. Ileocolonoscopy was performed at baseline and at week 52 or at premature discontinuation (median 364 days, range: 176–381). Red blood cell concentrations (RBC) of 6-thioguanine nucleotides (6-TGN), 6-methyl-mercaptopurine ribonucleotides (6-MMPR), and 6-methyl-thioguanine nucleotides (6-MTGN) were measured by high-performance liquid chromatography assay. A cut-off value of 6-TGN of ≥235pmol/8×108 RBC was used as established in literature. 6-MMPR and 6-MTGN levels below and above the median were considered low and high, respectively. Endoscopic improvement was defined as a reduction of the endoscopic score according to Rutgeerts by at least one point, and mucosal healing as endoscopic score of i0 (=no lesions). Results: Endoscopic data were available on 31 patients treated with azathioprine (f/m=13/18, median age: 32 years, median AZA dose: 2.24mg/kg/d) for median 358 days. At last observation, the median levels of 6-TGN (n=26), 6-MMPR (n=27), and 6-MTGN (n=26) were 139.7, 1696.1 and 70.1pmol/8×108 RBC, respectively. Overall, endoscopic score improved from i3-i4 to i0-i2 (p=0.004). Mucosal healing was achieved in 6/31 (19.4%) of patients. High 6-TGN levels (n=8) were associated with a significantly higher drop in the Rutgeerts score than low 6-TGN (n=18) levels (median drop of 3 vs. 1, p=0.023). There was no difference concerning mucosal healing (p=0.33). Furthermore, there was no correlation between 6-MMPR and 6-MTGN levels and endoscopic improvement. Conclusion: Our data suggest that high 6-TGN levels may linked to endoscopic improvement in patients with postoperative endoscopic recurrence of CD.

The recurrence of Crohn's Disease after ileo-colonic resection is a crucial issue. Severe endoscopic lesions increase the risk of developing early symptoms. Prevention and treatment of post-operative Endoscopic Recurrence (ER) have been studied with conflicting results. We compare effi cacy of azathioprine (AZA) vs. high-dose 5-aminosalicylic acid (5-ASA) in preventing clinical recurrence and treating severe post-operative ER. We performed a 1-year multicenter randomized double-blind double-dummy trial. Primary end-points were endoscopic improvement and therapeutic failure (clinical recurrence or drug discontinuation due to lack of efficacy or adverse events) 12 months after randomization. We also performed a post-trial analysis on symptomatic and endoscopic outcomes 10 years after the beginning of the trial, with a median follow-up of 60 months. Therapeutic failure occurred in 8 patients (17.4%) within 12 months from randomization, with no significant difference between patients treated with 5-ASA (20.8%, 5 patients) and those with AZA (13.6%, 3 patients). Therapeutic failure was due to clinical recurrence in the 5-ASA group and to adverse events in the AZA group. Endoscopic improvement at 12 months was observed in 8 patients, 2 (11.8%) in the 5-ASA group and 6 (30%) in the AZA group. No serious adverse event was recorded. At the post-trial analysis (median follow-up 60 months), 47.8% (22/46) of patients experienced clinical recurrence: 54.2% (13/24) in the 5-ASA group and 40.9% (9/22) in the AZA group, p=0.546. Patients treated with AZA had lower risk of drug escalation. Clinical recurrence was associated with smoking (p=0.031) and previous surgery (p=0.003). Our trial indicates that there was no difference in terms of treatment failure between 5-ASA and AZA in patients with severe ER. The main limit of AZA is its less favorable safety profile.

Crohn's disease (CD) patients who undergo ileocolonic resection frequently have disease recurrence. The aim of this preliminary study was to identify urinary metabolomic profiles associated with disease recurrence in order to identify underlying mechanisms of recurrence and possible disease biomarkers. Biopsies from the neoterminal ileum were collected from CD patients (n = 38) after ileocolonic resection in order to assess mucosa-associated microbiota using 16S rRNA multitag pyrosequencing. Urine samples were collected, and metabolomic profiling was done using high-resolution nuclear magnetic resolution spectroscopy and a combined direct infusion liquid chromatography tandem mass spectrometry. The Rutgeerts scoring system was used to assess endoscopic postoperative recurrence of CD. There were 28 (73.7%) patients with endoscopic CD recurrence. CD patients who were in endoscopic remission had a higher abundance of Bacteroidetes and lower abundance of Fusobacteria and Proteobacteria in comparison with CD patients who had endoscopic recurrence. In addition, metabolomic profiling could also discriminate between these 2 groups of patients. Endoscopic recurrence was associated with increased concentration of urinary levoglucosan. Rutgeerts score was positively correlated with levoglucosan and propylene glycol levels. CD patients who present with endoscopic disease recurrence after surgery have a unique urinary metabolomic fingerprint that can differentiate them from CD patients who are in endoscopic remission after ileocolonic resection. In addition, mucosal-associated microbiota in CD patients with or without disease recurrence after surgery differs and correlates with some urinary metabolites.

MUC1-glycoprotein is expressed at low levels and in fully glycosylated form on epithelial cells. Inflammation causes MUC1 overexpression and hypoglycosylation. We hypothesized that overexpression of hypoglycosylated MUC1 would be found in postoperative Crohn's disease (CD) recurrence and could be considered an additional biomarker of recurrence severity. We examined archived neo-terminal ileum biopsies from patients with prior ileocecal resection who had postoperative endoscopic assessment of CD recurrence and given a Rutgeerts ileal recurrence score. Consecutive tissue sections were stained using 2 different anti-MUC1 antibodies, HMPV that recognizes all forms of MUC1 and 4H5 that recognizes only inflammation-associated hypoglycosylated MUC1. A total of 71 postoperative CD patients were evaluated. There was significant increase in MUC1 expression of both glycosylated/normal (P<0.0001) and hypoglycosylated/abnormal (P<0.0001) forms in patients with severe endoscopic CD recurrence (i3+i4), ileal score i2, compared with patients in endoscopic remission (i0+i1). Results were similar regardless of anti-TNF-α use. Although MUC1 expression and Rutgeerts scores were in agreement when characterizing the majority of cases, there were a few exceptions where MUC1 expression was characteristic of more severe recurrence than implied by Rutgeerts score. MUC1 is overexpressed and hypoglycosylated in neo-terminal ileum tissue of patients with postoperative CD recurrence. Increased levels are associated with more severe endoscopic recurrence scores, and this is not influenced by anti-TNF-α use. Discrepancies found between Rutgeerts scores and MUC1 expression suggest that addition of MUC1 as a biomarker of severity of postoperative CD recurrence may improve categorization of recurrence status and consequently treatment decisions.

This trial aimed to provide randomized controlled data comparing Kono-S anastomosis and stapled ileocolic side-to-side anastomosis. Recently, a new antimesenteric, functional, end-to-end, hand-sewn ileocolic anastomosis (Kono-S) has shown a significant reduction in endoscopic recurrence score and surgical recurrence rate in Crohn disease (CD). Randomized controlled trial (RCT) at a tertiary referral institution. Primary endpoint: endoscopic recurrence (ER) (Rutgeerts score ≥i2) after 6 months. Secondary endpoints: clinical recurrence (CR) after 12 and 24 months, ER after 18 months, and surgical recurrence (SR) after 24 months. In all, 79 ileocolic CD patients were randomized in Kono group (36) and Conventional group (43). After 6 months, 22.2% in the Kono group and 62.8% in the Conventional group presented an ER [P < 0.001, odds ratio (OR) 5.91]. A severe postoperative ER (Rutgeerts score ≥i3) was found in 13.8% of Kono versus 34.8% of Conventional group patients (P = 0.03, OR 3.32). CR rate was 8% in the Kono group versus 18% in the Conventional group after 12 months (P = 0.2), and 18% versus 30.2% after 24 months (P = 0.04, OR 3.47). SR rate after 24 months was 0% in the Kono group versus 4.6% in the Conventional group (P = 0.3). Patients with Kono-S anastomosis presented a longer time until CR than patients with side-to-side anastomosis (hazard ratio 0.36, P = 0.037). On binary logistic regression analysis, the Kono-S anastomosis was the only variable significantly associated with a reduced risk of ER (OR 0.19, P < 0.001). There were no differences in postoperative outcomes. This is the first RCT comparing Kono-S anastomosis and standard anastomosis in CD. The results demonstrate a significant reduction in postoperative endoscopic and clinical recurrence rate for patients who underwent Kono-S anastomosis, and no safety issues.ClinicalTrials.gov ID NCT02631967.

After ileocaecal resection for Crohn's disease (CD), inflammatory lesions frequently recur on the anastomosis and/or on the neo-terminal ileum. To identify predictors of early post-operative endoscopic recurrence. From September 2010 to September 2017, the REMIND group conducted a prospective nationwide study in nine French academic centres. Data were collected at the time of surgery and endoscopy, performed 6-12months after surgery. Endoscopic recurrence was defined as a Rutgeerts score ≥i2. Baseline factors associated with endoscopic recurrence were searched by univariate and multivariate regression analysis. Two hundred and eighty-nine CD patients were included. Endoscopy within 1year following surgery was performed in 225 (78%) patients (104M/121F). Mean age and disease duration were 35 (12.2) and 8.8 (8.9) years respectively. Seventy (32%) patients were active smokers at surgery. One hundred and forty-two (63%) patients received at least one anti-TNF therapy before surgery. After surgery, 40 (18%) patients received thiopurines and 66 (29%) received an anti-TNF agent. Endoscopic recurrence occurred in 107 (47%) patients. In multivariate analysis, male gender (OR=2.48 [IC 95% 1.40-4.46]), active smoking at surgery (OR=2.65 [IC 95% 1.44-4.97]) and previous resection (OR=3.03 [IC 95% 1.36-7.12]) were associated with a higher risk of endoscopic recurrence. Inversely, post-operative anti-TNF treatment decreased the risk of endoscopic recurrence (OR=0.50 [IC 95% 0.25-0.96]). Male gender, active smoking at surgery and previous intestinal resection are associated with a higher risk of endoscopic post-operative recurrence, while post-operative anti-TNF treatment is associated with a lower risk.

To evaluate the efficacy and safety of purine analogs (azathioprine, 6-mercaptopurine (6-MP)) in the prevention of postoperative recurrence in Crohn's disease (CD). We searched MEDLINE, the Cochrane Library, and EMBASE. The primary end points, clinical and endoscopic recurrence at 1 and 2 years, and safety were analyzed by the methods of Peto and Der Simonian and Laird. Four controlled trials enrolled 433 patients and compared azathioprine (n=3) or (6-MP) (n=1) with control arms (placebo with or without antibiotic induction therapy or mesalamine). In the overall analysis, purine analogs were more effective than control arms in preventing clinical recurrence at 1 year (mean difference, 95% confidence interval (CI): 8, 1-15%, P=0.021, number needed to treat (NNT)=13) and 2 years (mean difference, 95% CI: 13%, 2-24%, P=0.018, NNT=8). In sensitivity analyses, the efficacy of purine analogs was superior to that of placebo for the prevention of clinical and endoscopic recurrence at 1 year (mean differences, 95% CI: 13, 1.8-25%, P=0.025, NNT=7, and 23%, 9-37%, P=0.0016, NNT=4, respectively). At 1 year, in the overall analysis, purine analogs were more effective than control arms were in preventing severe (i2-4) endoscopic recurrence (mean difference, CI 95%: 15, 1.8-29%, P=0.026, NNT=7), but they were not effective in the prevention of very severe (i3-4) recurrence. The rate of adverse events leading to drug withdrawal was higher in thiopurine-treated patients than in control arms (17.2 vs. 9.8%, respectively, P=0.021). Purine analogs are more effective than placebo in preventing both clinical and endoscopic postoperative recurrence in CD, but they are associated with a higher rate of adverse events leading to drug withdrawal.