Oral Curcumin No More Effective Than Placebo in Preventing Recurrence of Crohn's Disease After Surgery in a Randomized Controlled Trial.

BACKGROUND AND AIMS: Recurrence of Crohn's disease (CD) after surgery is a major concern. Curcumin has anti-inflammatory properties and induces endoscopic remission in patients with ulcerative colitis. We investigated the efficacy of curcumin vs placebo in preventing post-operative recurrence of CD, based on endoscopic and clinical indices, in patients receiving concomitant thiopurine therapy. METHODS: We conducted a double-blind randomized controlled trial at 8 referral centers in France, from October 2014 through January 2018, of 62 consecutive patients with CD undergoing bowel resection. Patients received azathioprine (2.5 mg/kg) and were randomly assigned to groups given oral curcumin (3 g/day; n = 31) or an identical placebo (n = 31) for 6 months, and were then evaluated by colonoscopy. We also collected data on CD activity index, results from laboratory tests, and answers to quality of life questionnaires during this 6-month period. The primary endpoint was postoperative recurrence of CD in each group (Rutgeerts' index score ≥i2) at month 6 (determined by central reading). An interim analysis (intent to treat) was scheduled after 50% of the patients were enrolled. RESULTS: At month 6, postoperative recurrence (Rutgeerts' index score ≥i2) occurred in 18 patients (58%) receiving curcumin and 21 patients (68%) receiving placebo (P = .60). A significantly higher proportion of patients receiving curcumin (55%) had a severe recurrence of CD (Rutgeerts' index score ≥i3) than patients receiving placebo (26%) (P = .034). We observed a clinical recurrence of CD (CD activity index score >150) at month 6 in 45% of patients receiving placebo and 30% of patients receiving curcumin (P = .80). Quality of life scores at month 6 did not differ significantly between groups (P = .80). Severe adverse events developed in 6% of patients receiving placebo and 16% of patients receiving curcumin (P = .42). CONCLUSIONS: In a randomized controlled trial of patients who underwent surgery for CD and received thiopurine treatment, we found that curcumin was no more effective than placebo in preventing CD recurrence. There were no significant differences between groups in quality of life or severe adverse events. The study was discontinued after interim analysis due to futility. ClinicalTrials.gov no: NCT 02255370.

Efficacy of adalimumab in patients with Crohn's disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study.

OBJECTIVE: The efficacy of anti-tumour necrosis factors (anti-TNFs) in patients with Crohn's disease (CD) and symptomatic small bowel stricture (SSBS) is controversial. The aim of this study was to estimate the efficacy of adalimumab in these patients and to identify the factors predicting success. DESIGN: We performed a multicentre, prospective, observational cohort study in patients with CD and SSBS. The included patients underwent magnetic resonance enterography at baseline and subsequently received adalimumab. The primary endpoint was success at week 24, defined as adalimumab continuation without prohibited treatment (corticosteroids after the eight week following inclusion, other anti-TNFs), endoscopic dilation or bowel resection. The baseline factors independently associated with success were identified using a logistic regression model, leading to a simple prognostic score. Secondary endpoints were prolonged success after week 24 (still on adalimumab, without dilation nor surgery) and time to bowel resection in the whole cohort. RESULTS: From January 2010 to December 2011, 105 patients were screened and 97 were included. At week 24, 62/97 (64%) patients had achieved success. The prognostic score defined a good prognosis group with 43/49 successes, an intermediate prognosis group with 17/28 successes and a poor prognosis group with 1/16 successes. After a median follow-up time of 3.8 years, 45.7%±6.6% (proportion±SE) of patients who were in success at week 24 (ie, 29% of the whole cohort) were still in prolonged success at 4 years. Among the whole cohort, 50.7%±5.3% of patients did not undergo bowel resection 4 years after inclusion. CONCLUSIONS: A successful response to adalimumab was observed in about two-thirds of CD patients with SSBS and was prolonged in nearly half of them till the end of follow-up. More than half of the patients were free of surgery 4 years after treatment initiation. CLINICAL TRIAL REGISTRATION NUMBER: NCT01183403; Results.

Fecal Matrix Metalloprotease-9 and Lipocalin-2 as Biomarkers in Detecting Endoscopic Activity in Patients With Inflammatory Bowel Diseases.

BACKGROUND: Fecal biomarkers are emerging tools in the assessment of mucosal healing in inflammatory bowel diseases (IBD). GOALS: We aimed to evaluate the accuracy of fecal matrix metalloprotease-9 (MMP-9) and fecal lipocalin-2 (LCN-2) compared with calprotectin in detecting endoscopic activity in IBD STUDY:: Overall, 86 IBD adults underwent colonoscopy consecutively and prospectively, with Crohn's disease Endoscopic Index of Severity (CDEIS) in Crohn's disease (CD) patients or Mayo endoscopic subscore calculation for ulcerative colitis (UC) patients, and stool collection. Fecal calprotectin was measured using quantitative immunochromatographic testing. Fecal MMP-9 and LCN-2 was quantified by enzyme-linked immunosorbent assay. MMP-9 and LCN-2 thresholds were determined using receiver operating curves. RESULTS: In 54 CD patients, fecal calprotectin, MMP-9 and LCN-2 correlated with CDEIS and were significantly increased in patients with endoscopic ulcerations. MMP-9 >350 ng/g detected endoscopic ulceration in CD with a sensitivity of 90.0% and a specificity of 63.6%, compared with fecal calprotectin >250 µg/g (sensitivity=90.5% and specificity=59.1%). Fecal LCN-2 demonstrated lower performances than the 2 other biomarkers (sensitivity=85.7% and specificity=45.5%).In 32 UC patients, fecal MMP-9, LCN-2, and calprotectin levels were significantly increased in patients with endoscopic activity. In UC patients, fecal MMP-9 >900 ng/g had the best efficacy to detect endoscopic activity (sensitivity=91.0% and specificity=80.0%, compared with fecal calprotectin >250 µg/g (sensitivity=86.4% and specificity=80.0%) and LCN-2 >6700 ng/g (sensitivity=82.0% and specificity=80.0%). CONCLUSIONS: Fecal MMP-9 is a reliable biomarker in detecting endoscopic activity in both UC and CD patients.

Granulocyte/monocyte adsorptive apheresis for the treatment of therapy-refractory chronic active ulcerative colitis.

OBJECTIVES: Current options for patients with steroid-dependent, chronic-active ulcerative colitis (UC) with insufficient response/intolerance to immunosuppressants (ISs) and/or biologics are limited. The aim of this study was to assess the long-term outcome of granulocyte/monocyte adsorptive (GMA) apheresis (Adacolumn®) in this population. MATERIALS AND METHODS: Ninety five adults with steroid-dependent active UC and insufficient response/intolerance to IS and/or TNF inhibitors received 5-8 aphereses in a single induction series of ≤10 weeks. Endpoints included rates of remission (clinical activity index [CAI] ≤ 4) at weeks 24 and 48. RESULTS: Of 94 patients (ITT population), remission and response rates were 34.0% and 44.7% at week 24, and 33.0% and 39.4% at week 48. Among 30 patients with prior failure of IS and biologics, 33.3% and 20.0% were in remission at weeks 24 and 48. At both weeks, 19.2% of patients achieved steroid-free remission. Sustained remission or response occurred in 27.7% of patients at 48 weeks. The cumulative colectomy rate at week 96 was 23.4%. Safety was consistent with previous findings. CONCLUSIONS: This study confirms findings of the 12-week interim analysis and demonstrates that GMA apheresis provides a safe and beneficial long-term outcome for patients with chronic active UC resistant/intolerant to IS and/or TNF inhibitors.

Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.

Medical Therapies for Stricturing Crohn's Disease: Efficacy and Cross-Sectional Imaging Predictors of Therapeutic Failure.

BACKGROUND: Medical therapy efficacy remains controversial in stricturing Crohn's disease. Cross-sectional imaging, especially magnetic resonance imaging, has been suggested as very helpful to guide therapeutic decision making. AIM: To assess efficacy and predictors of therapeutic failure in patients receiving medical treatments for stricturing Crohn's disease. METHODS: In this retrospective study, therapeutic failure was defined as symptomatic stricture leading to surgical or endoscopic therapeutics, hospitalization, treatment discontinuation or additional therapy and short-term clinical response as clinical improvement assessed by two physicians. The 55 cross-sectional imaging examinations (33 magnetic resonance imaging and 22 CT scan) before starting medical therapy were analyzed independently by two radiologists. Results were expressed as hazard ratio (HR) or odds ratio (OR) with 95% confidence intervals (95% CI). RESULTS: Among 84 patients, therapeutic failure rate within 60 months was 66.6%. In multivariate analysis, Crohn's disease diagnosis after 40 years old (HR 3.9, 95% CI [1.37-11.2], p = 0.011), small stricture luminal diameter (HR 1.34, 95% CI [1.01-1.80], p = 0.046), increased stricture wall thickness (HR 1.23, 95% CI [1.04-1.46], p = 0.013) and fistula with abscess (HR 5.63, 95% CI [1.64-19.35], p = 0.006) were associated with therapeutic failure, while anti-TNF combotherapy (HR 0.17, 95% CI [0.40-0.71], p = 0.015) prevented it. Considering 108 therapeutic sequences, the short-term clinical response rate was 65.7%. In multivariate analysis, male gender (OR 0.15, 95% CI [0.03-0.64], p = 0.011), fistula with abscess (OR 0.09, 95% CI [0.01-0.77], p = 0.028) and comb sign (OR 0.23, 95% CI [0.005-0.97], p = 0.047) were associated with short-term clinical failure. CONCLUSION: Anti-TNF combotherapy seemed to prevent therapeutic failure, and cross-sectional imaging should be systematically performed to help medical management in stricturing Crohn's disease.

The Clinical Outcome in Patients Treated With a Newly Designed SEMS in Cervical Esophageal Strictures and Fistulas.

BACKGROUND AND GOALS: Using a self-expandable metallic stent (SEMS) in the cervical esophagus is controversial due to an increased risk of complications. Here we assessed a new type of SEMS purpose-designed for the cervical esophagus area. STUDY: Patients with malignant or benign stenosis within 4 cm distance of the upper esophageal sphincter who underwent placement of a SEMS with a shorter proximal head (Niti-S Esophageal Covered Stent-Cervical-type, NSECSC), were included. Main outcome measures were the functional outcome, tolerance, complications, recurrent dysphagia, and survival. RESULTS: About 37 patients had an NSECSC placed between April 2008 and June 2013 for esophageal stenosis (malignant=20, benign=17), 5 with associated tracheoesophageal fistula. The mean stenosis-upper esophageal sphincter distance was 1.86±1.27 cm. The median follow-up was 150 days. Dysphagia improved in 27/37 cases (73%). Short-term and long-term tolerance without needing stent removal was 92% and 82%, respectively. The complication rate was 59% (22/37): 32% (n=14) major complications [fistula (3), perforation (3), aspiration pneumonia (5), laryngeal dyspnea (2), and bleeding (1)], and 27% (n=10) minor complications [pain (7) or dysphonia (3)]. A multivariate analysis confirmed a higher risk of major complications in cases of benign stenosis (odds ratio=5.2; 95% confidence interval, 1.05-25.90; P=0.04). Recurrent dysphagia occurred in 15 patients (obstruction=7, migration=8). CONCLUSIONS: The NSECSC does not appear less morbid than standard SEMS in the cervical esophageal area, but could be useful in malignant indications as it is well-tolerated and offers effective palliation of the dysphagia. However, this device should not be used in benign cervical esophageal strictures or fistulas.

Detection of Dysplasia or Cancer in 3.5% of Patients With Inflammatory Bowel Disease and Colonic Strictures.

BACKGROUND & AIMS: Colonic strictures complicate inflammatory bowel disease (IBD) and often lead to surgical resection to prevent dysplasia or cancer. We assessed the frequency of dysplasia and cancer among IBD patients undergoing resection of a colorectal stricture. METHODS: We analyzed data from the Groupe d'études et thérapeutiques des affections inflammatoires du tube digestif study. This was a nationwide retrospective study of 12,013 patients with IBD in France who underwent surgery for strictures at 16 centers from August 1992 through January 2014 (293 patients for a colonic stricture, 248 patients with Crohn's disease, 51% male, median age at stricture diagnosis of 38 years). Participants had no preoperative evidence of dysplasia or cancer. We collected clinical, endoscopic, surgical, and pathology data and information on outcomes. RESULTS: When patients were diagnosed with strictures, they had IBD for a median time of 8 years (3-14). The strictures were a median length of 6 cm (4-10) and caused symptoms in 70% of patients. Of patients with Crohn's disease, 3 (1%) were found to have low-grade dysplasia, 1 (0.4%) was found to have high-grade dysplasia, and 2 (0.8%) were found to have cancer. Of patients with ulcerative colitis, 1 (2%) had low-grade dysplasia, 1 (2%) had high-grade dysplasia, and 2 (5%) had cancer. All patients with dysplasia or cancer received curative surgery, except 1 who died of colorectal cancer during the follow-up period. No active disease at time of surgery was the only factor associated with dysplasia or cancer at the stricture site (odds ratio, 4.86; 95% confidence interval, 1.11-21.27; P = .036). CONCLUSIONS: In a retrospective study of patients with IBD undergoing surgery for colonic strictures, 3.5% were found to have dysplasia or cancer. These findings can be used to guide management of patients with IBD and colonic strictures.

Endoscopic ultrasound-guided biliary drainage after failed ERCP: cumulative experience of 101 procedures at a single center.

BACKGROUND AND STUDY AIM: Endoscopic ultrasound (EUS)-guided biliary access is an alternative to percutaneous access after failed endoscopic retrograde cholangiopancreatography (ERCP). This report presents 7 years' cumulative experience of EUS-guided biliary drainage for obstructive jaundice in patients with failed ERCP. PATIENTS AND METHODS: Between February 2006 and February 2013, 101 patients (malignant = 98, benign = 3) with previous failed ERCP underwent an EUS intra- or extrahepatic approach with transluminal stenting or an EUS-guided rendezvous procedure with transpapillary stent placement. A single endoscopist performed all procedures. RESULTS: A total of 71 patients underwent the intrahepatic approach (66 hepatogastrostomies and 5 EUS-guided rendezvous), and 30 underwent the extrahepatic approach (26 choledochoduodenostomies, 1 choledochojejunostomy, 1 choledochoantrostomy, and 2 EUS-guided cholangiographies). Technical and clinical success rates were 98.0 % and 92.1 %, respectively. There was no difference in efficacy between hepatogastrostomies and choledochoduodenostomies (94 % vs. 90 %; P = 0.69) or in major complications (10.6 % vs. 6.7 %; P = 1). Adverse events occurred in 12 patients (11.9 %): 10 in the hepatogastrostomy group (2 limited pneumoperitoneum, 1 hepatic hematoma, 5 bile leakage, 2 sepsis), and 2 in the choledochoduodenostomy group (1 arteriobiliary fistula and 1 sepsis). There were six procedure-related deaths, five among the first 50 patients and one among the last 51 patients. Hepatogastrostomy vs. choledochoduodenostomy, plastic vs. metal stenting, stent-in-stent vs. 1 stent, nasobiliary drain, or postoperative octreotide infusion were not prognostic of bile leakage. CONCLUSION: EUS-guided biliary drainage is an efficient technique, but is associated with significant morbidity that seems to decrease with the learning curve. It should be performed in tertiary care centers in selected patients. Prospective randomized studies are needed to compare EUS-guided biliary drainage with percutaneous transhepatic cholangiography drainage.

Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial.

BACKGROUND: Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication. METHODS: In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152). FINDINGS: 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI -7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. INTERPRETATION: Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. FUNDING: Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.

Large-balloon dilation of the sphincter of Oddi after sphincterotomy or infundibulotomy to extract large calculi or multiple common bile duct stones without using mechanical lithotripsy.

OBJECTIVE: Endoscopic sphincterotomy plus large-balloon dilatation (ESLBD) has an efficacy equal to or higher than that of endoscopic sphincterotomy alone for biliary lithiasis extractions. Our purpose was to evaluate the feasibility, efficacy and morbidity of large-balloon dilatation of the sphincter of Oddi after sphincterotomy or infundibulotomy for large or multiple common bile duct stones. MATERIAL AND METHODS: Retrospective analysis. RESULTS: A total of 64 ESLBD procedures were performed in 62 patients: 57 after sphincterotomy and 7 after infundibulotomy. The feasibility was 100%, and full clearance of the common bile duct was achieved in a single session without using mechanical lithotripsy in 95.3% of cases. Short-term complications were observed in 9 patients (14%). There were no perforations. The most frequent complication was delayed bleeding (7.8%). There was no significant difference of overall complications after sphincterotomy or after infundibulotomy (12.3% vs. 28.6%, p = 0.25). The incidence of acute pancreatitis was significantly higher after infundibulotomy than after sphincterotomy (28.6% vs. 0%, p = 0.01). CONCLUSIONS: ESLBD after endoscopic sphincterotomy or infundibulotomy is a simple, reproducible and effective technique, associated with a low morbidity rate and helps in avoiding mechanical lithotripsy in 95.3% of cases for the endoscopic extraction of large or multiple common bile duct stones.

Ustekinumab is more effective than azathioprine to prevent endoscopic postoperative recurrence in Crohn's disease.

BACKGROUND: Preventing postoperative recurrence (POR) is a major concern in Crohn's disease (CD). While azathioprine is an option, no data is available on ustekinumab efficacy in this situation. AIMS: We compared the effectiveness of ustekinumab versus azathioprine in preventing endoscopic POR in CD. METHODS: We retrospectively collected data from all consecutive CD patients treated with ustekinumab after intestinal resection in 9 centers. The control group (azathioprine alone) was composed of patients who participated in a randomized controlled trial conducted in the same centers comparing azathioprine alone or in combination with curcumin. Propensity score analyses (inversed probability of treatment weighting = IPTW) were applied to compare the two groups. The primary endpoint was endoscopic POR (Rutgeerts' index ≥ i2) at 6 months. RESULTS: Overall, 32 patients were included in the ustekinumab group and 31 in the azathioprine group. The propensity score analysis was adjusted on the main risk factors (smoking, fistulizing phenotype, prior bowel resection, resection length >30 cm and ≥2 biologics before surgery) and thiopurines or ustekinumab exposure prior to surgery making the two arms comparable (∣d∣ < 0.2). After IPTW, the rate of endoscopic POR at 6 months was lower in patients treated with ustekinumab compared to azathioprine (28.0% vs. 54.5%, p = 0.029). After IPTW, the rates of i2b-endoscopic POR (Rutgeerts' index ≥ i2b) and severe endoscopic POR (Rutgeerts' index ≥ i3) were 20.8% versus 42.5% (p = 0.066) and 16.9% versus 27.9% (p = 0.24), in the ustekinumab and azathioprine groups, respectively. CONCLUSION: Ustekinumab seemed to be more effective than azathioprine in preventing POR in this cohort of CD patients.

Faster and less invasive tools to identify patients with ileal colonization by adherent-invasive E. coli in Crohn's disease.

BACKGROUND AND AIMS: The identification of Crohn's disease (CD)-associated adherent and invasive Escherichia coli (AIEC) is time-consuming and requires ileal biopsies. We aimed to identify a faster and less invasive methods to detect ileal colonization by AIEC in CD patients. METHODS: CD patients requiring ileo-colonoscopy were consecutively enrolled in this prospective multicenter study. Samples from saliva, serum, stools, and ileal biopsies of CD patients were collected. RESULTS: Among 102 CD patients, the prevalence of AIEC on ileal biopsies was 24.5%. The abundance and global invasive ability of ileal-associated total E. coli were respectively ten-fold (p = 0.0065) and two-fold (p = 0.0007) higher in AIEC-positive (vs. AIEC-negative), while abundance of total E. coli in the feces was not correlated with AIEC status in the ileum. The best threshold of ileal total E. coli was 60 cfu/biopsy to detect AIEC-positive patients, with high negative predictive value (NPV) (94.1%[80.3-99.3]), while the global invasive ability (>9000 internalized bacteria) was able to detect the presence of AIEC with high positive predictive value (80.0% [55.2-100.0]). Overall, 78.1% of the AIEC + patients were colonized by two or less different AIEC strains. The level of serum anti-total E. coli antibodies (AEcAb) was higher in AIEC-positive patients (p = 0.038) with a very high negative predictive value (96.6% [89.9-100.0]) (p = 0.038) for a cut-off value > 1.9 × 10-3 . CONCLUSIONS: More than two thirds of AIEC-positive CD patients were colonized by two or less AIEC strains. While stools samples are not accurate to screen AIEC status, the AEcAb level appears to be an attractive, rapid and easier biomarker to identify patients with Crohn's disease harboring AIEC.

CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease.

The ileal mucosa of Crohn disease (CD) patients is abnormally colonized by adherent-invasive E. coli (AIEC) that are able to adhere to and invade intestinal epithelial cells. Here, we show that CD-associated AIEC strains adhere to the brush border of primary ileal enterocytes isolated from CD patients but not controls without inflammatory bowel disease. AIEC adhesion is dependent on type 1 pili expression on the bacterial surface and on carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) expression on the apical surface of ileal epithelial cells. We report also that CEACAM6 acts as a receptor for AIEC adhesion and is abnormally expressed by ileal epithelial cells in CD patients. In addition, our in vitro studies show that there is increased CEACAM6 expression in cultured intestinal epithelial cells after IFN-gamma or TNF-alpha stimulation and after infection with AIEC bacteria, indicating that AIEC can promote its own colonization in CD patients.

Variation of faecal calprotectin level within the first three months after bowel resection is predictive of endoscopic postoperative recurrence in Crohn's disease.

BACKGROUND: Early prediction of postoperative recurrence (POR) remains a major concern in Crohn's disease (CD). AIMS: To assess serial faecal calprotectin (Fcal) monitoring within the first three months to predict CD endoscopic POR. METHODS: In a multicenter randomized controlled trial, CD patients received azathioprine 2.5 mg/kg/day with oral curcumin (3 g/day) or placebo. Fcal was measured at baseline, one month (M1) and M3. Endoscopic POR at M6 was defined as Rutgeerts' index ≥ i2b (central reading). RESULTS: Among the 48 patients included, there was no significant difference of median Fcal levels at baseline (p = 0.15), M1 (p = 0.44) and M3 (p = 0.28) between patients with or without endoscopic POR at M6. Fcal kinetics during the first 3 months after surgery was significantly different between the patients with or without POR at M6 (p = 0.021). The median variation between Fcal level at baseline and M3 (ΔFcal M3-M0) was significantly higher in patients with endoscopic POR compared to those without POR (p = 0.01). ΔFcal M3-M0 >+10% demonstrated the best performances to predict endoscopic POR at M6 (AUC=0.73, sensitivity=64.7%[41.1-82.7], specificity=87.5%[68.0-96.3], negative predictive value=77.8%[57.5-91.4] and positive predictive value=78.6%[49.2-95.3]). CONCLUSION: Fcal variation within the first three months after ileocolonic resection is a promising predictor of early endoscopic POR in CD patients.

Bowel wall healing assessed using magnetic resonance imaging predicts sustained clinical remission and decreased risk of surgery in Crohn's disease.

BACKGROUND: Endoscopic mucosal healing is considered as the best therapeutic target in Crohn's disease (CD) as it is associated with better long-term outcomes. We investigated whether bowel wall healing (BWH) assessed using magnetic resonance imaging (MRI) could predict favorable outcomes and could be a potential therapeutic target. METHODS: We performed a post hoc analysis from two prospective studies (n = 174 patients). All the patients with previous objective signs of bowel inflammation and assessed by MRI for therapeutic efficacy had a standardized and blinded evaluation, and underwent MRI. Complete BWH was defined as no segmental MaRIA > 7 or no segmental Clermont score > 8.4 and BWH as no segmental MaRIA > 11 or no segmental Clermont score > 12.5. Clinical corticosteroid-free remission (CFREM) was defined as no reappearance or worsening of clinical manifestation leading to therapeutic modification, hospitalization or CD-related surgery. Multivariate analyses were performed including all the relevant parameters. RESULTS: Overall, 63 patients with CD were included (mean follow-up = 4.8 ± 3.1 semesters). In multivariate analysis (n = 303 semesters), complete BWH or BWH was associated with sustained CFREM according to MaRIA [OR = 4.42 (2.29-26.54); p = 0.042 and OR = 3.43 (1.02-27.02); p = 0.047, respectively] or Clermont score [OR = 3.09 (1.01-12.91); p = 0.049 and OR = 3.88 (1.40-13.80); p = 0.036, respectively]. In multivariate analysis (n = 63 patients), complete BWH or BWH was associated with decreased risk of surgery using MaRIA [HR = 0.16 (0.043-0.63); p = 0.008 and HR = 0.24 (0.07-0.77); p = 0.017, respectively] or Clermont score [HR = 0.24 (0.07-0.78); p = 0.016 and HR = 0.23 (0.07-0.76); p = 0.016, respectively]. CONCLUSIONS: MRI endpoints are predictive of favorable outcomes after medical therapy and could be used as therapeutic target in daily practice and clinical trials.

Combined evaluation of biomarkers as predictor of maintained remission in Crohn's disease.

BACKGROUND: The individual performances and the complementarity of Crohn's disease (CD) activity index (CDAI), C-reactive protein (CRP) and faecal calprotectin (Fcal) to monitor patients with CD remain poorly investigated in the era of "tight control" and "treat to target" strategies. AIM: To assess CDAI, CRP and Fcal variation, alone or combined, after 12 wk (W12) of anti-tumor necrosis factor (TNF) therapy to predict corticosteroids-free remission (CFREM = CDAI < 150, CRP < 2.9 mg/L and Fcal < 250 µg/g with no therapeutic intensification and no surgery) at W52. METHODS: CD adult patients needing anti-TNF therapy with CDAI > 150 and either CRP > 2.9 mg/L or Fcal > 250 µg/g were prospectively enrolled. RESULTS: Among the 40 included patients, 13 patients (32.5%) achieved CFREM at W52. In univariable analysis, CDAI < 150 at W12 (P = 0.012), CRP level < 2.9 mg/L at W12 (P = 0.001) and Fcal improvement at W12 (Fcal < 300 µg/g; or, for patients with initial Fcal < 300 µg/g, at least 50% decrease of Fcal or normalization of Fcal (< 100 µg/g) (P = 0.001) were predictive of CFREM at W52. Combined endpoint (CDAI < 150 and CRP ≤ 2.9 mg/L and FCal improvement) at W12 was the best predictor of CFREM at W52 with positive predictive value = 100.0% (100.0-100.0) and negative predictive value = 87.1% (75.3-98.9). In multivariable analysis, Fcal improvement at W12 [odd ratio (OR) = 45.1 (2.96-687.9); P = 0.03] was a better predictor of CFREM at W52 than CDAI < 150 [OR = 9.3 (0.36-237.1); P = 0.145] and CRP < 2.9 mg/L (0.77-278.0; P = 0.073). CONCLUSION: The combined monitoring of CDAI, CRP and Fcal after anti-TNF induction therapy is able to predict favorable outcome within one year in patients with CD.

Macrophages Inability to Mediate Adherent-Invasive E. coli Replication is Linked to Autophagy in Crohn's Disease Patients.

The macrophages from Crohn's Disease (CD) patients are defective to control the replication of CD-associated adherent-invasive E. coli (AIEC). We aimed to identify the host factors associated with AIEC replication focusing on polymorphisms related to autophagy. Peripheral blood monocyte-derived macrophages (MDM), obtained from 95 CD patient, 30 ulcerative colitis (UC) patients and 15 healthy subjects, were genotyped for several CD-associated polymorphisms. AIEC bacteria survival increased within MDM from CD patients compared to UC (p = 0.0019). AIEC bacteria survival increased in patients with CD-associated polymorphism IRGM (p = 0.05) and reduced in those with CD-associated polymorphisms XBP-1 (p = 0.026) and ULK-1 (p = 0.033). AIEC infection led to an increase of pro-inflammatory cytokines IL-1ß (p < 0.0001) and TNF-α (p < 0.0001) in CD macrophages. ULK-1 expression increased in AIEC-infected MDM from CD patients compared to MDM from UC patients or healthy subjects (p = 0.0056) and correlated with AIEC survival (p = 0.0013). Moreover, the expression of ULK-1 phosphorylation on Serine 757 decreased following to AIEC infection (p < 0.0001). Short-term silencing of ULK-1 and IRGM genes restricted and promote, respectively, AIEC survival within MDM (p = 0.0018 and p = 0.0291). In conclusion, the macrophage defect to mediate AIEC clearance in CD patients is linked to polymorphisms related to autophagy such as IRGM and ULK-1.

Systematic Review With Meta-Analysis: Anti-TNF Therapy in Refractory Pouchitis and Crohn's Disease-Like Complications of the Pouch After Ileal Pouch-Anal Anastomosis Following Colectomy for Ulcerative Colitis.

Background: Inflammatory complications including chronic refractory pouchitis and Crohn's disease (CD)-like complications of the pouch are common complications after ileal pouch-anal anastomosis (IPAA) following colectomy for ulcerative colitis (UC). We performed a systematic review and meta-analysis to evaluate the efficacy of anti-TNF therapy in distinguishing patients with chronic refractory pouchitis from those with CD-like complications of the pouch. Methods: We performed a systematic literature search to identify articles and abstracts reporting anti-TNF agents efficacy in treating inflammatory complications of the pouch after IPAA for UC. Short-term and long-term remissions were evaluated at 8 weeks 95%CI[5-10] and 12 months 95%CI[12-18.5], respectively. Results: We identified 21 articles and 3 abstracts including 313 patients treated either with infliximab (n = 194) or adalimumab (n = 119) for inflammatory complications of the pouch. The rates of short-term and long-term clinical remission were 0.50 (95%CI [0.37-0.63]; I2 = 0.57) and 0.52 (95%CI[0.39-0.65]; I2 = 0.59), respectively. The rate of remission after anti-TNF induction therapy seemed to be higher in CD-like complications of the pouch 0.64 (95%CI[0.5-0.77]; I2 = 0.18), compared to refractory pouchitis 0.10 (95%CI [0.00-0.35]; I2 = 0.00) (P = 0.06), whereas no such difference appeared after long-term maintenance therapy 0.57 (95%CI[0.43-0.71]; I2 = 0.32) and 0.37 (95%CI [0.14-0.62]; I2 = 0.47), respectively (P = 0.57). Sensitivity analyses suggested no difference in outcomes. No significant publication bias has been detected. Conclusion: Anti-TNF agents have a clear trend to have higher and faster efficacy in CD-like complications of the pouch compared to refractory pouchitis, highlighting the need to differentiate these two entities both in daily practice and clinical trials.