Endoscopic Recurrence Of Crohn's Disease Research Articles

Azathioprine plus exclusive enteral nutrition versus azathioprine monotherapy for the prevention of postoperative recurrence in patients with Crohn's disease: an open-label, single-centre, randomised controlled trial.

Azathioprine (AZA) effectively prevents postoperative endoscopic recurrence (ER) in Crohn's disease (CD). However, the efficacy of AZA emerge needs 3 months. Exclusive enteral nutrition (EEN) can maintain remission for CD. The trial investigates whether AZA plus postoperative 3-month EEN is superior to AZA alone in preventing ER of CD. Totally, 84 high-risk CD patients undergoing intestinal resection received AZA alone or AZA plus a 3-month EEN (AZA+EEN) postoperatively. The primary endpoint was the rate of ER at month 12. Secondary endpoint included the rate of ER at month 3, clinical recurrence (CR), CD activity index (CDAI) scores, fecal calprotectin (FC) and CRP. Quality of life were assessed using Short Form-36 (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ). The patients in the AZA+EEN group exhibited significantly lower rates of ER compared to the AZA group at both months 12 (33.3% [13/39] vs 63.2% [24/38], P=0.009) and months 3 (8.6% [3/35] vs 28.1% [9/32], P=0.037) post-surgery. The rates of CR between the two groups at month-3 and month-12 were similar. The CDAI scores, FC, albumin level and CRP were all comparable between the 2 groups. The quality of life was significantly higher in the AZA group than that of the AZA+EEN group at month 3 but became comparable from month 5 to 12 postoperatively. In high-risk CD patients, combining AZA with postoperative 3-month EEN reduces 1-year ER but may temporarily impact quality of life. Further large-scale, long-term studies are warranted.

Altered Expression of the Epithelial Mucin MUC1 Accompanies Endoscopic Recurrence of Postoperative Crohn's Disease.

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.

Enteral Nutrition Associated with Decreased Risk of Postoperative Recurrence of Crohnʼs Disease

Introduction: Crohn's disease (CD) is a chronic, relapsing-remitting disorder of the gastrointestinal tract. CD patients often undergo surgical resection for treatment of their disease, though are still at risk of postoperative recurrence. Enteral nutrition (EN) is frequently used in CD as adjunct to medical therapy to manage protein-calorie malnutrition. It has also been suggested that EN may help both induce and maintain remission and promote mucosal healing. While several studies have shown decreased rates of postoperative CD recurrence following EN treatment, this association has not been well established. Objective: Assess effect of EN on postoperative clinical and endoscopic recurrence in Crohn's disease patients. Methods: A thorough search of multiple databases, including Scopus, Cochrane, MEDLINE/PubMed, and CINAHL were performed (May 2018). Studies assessing the role of pre- or postoperative enteral nutrition in preventing postoperative clinical and endoscopic recurrence of CD were included. A metaanalysis was completed using the Mantel-Haenszel model. Results: In a complete analysis of five studies, there was a 5-fold decrease risk in developing clinical recurrence at one year (OR 5.04 95% CI 2.66, 9.952, p2=80%). Sensitivity analysis excluded one study with lowest rate of recurrence in non-EN group to minimize heterogeneity there remains a dramatic decrease in clinical recurrence among patients on EN relative to no EN (OR 16.68 95% CI 6.37,43.66 p2=0%). Similar results were noted for clinical recurrence with EN at 5 year postoperatively with decreased risk for recurrence more than 24-fold in the group receiving EN compared to no EN (OR 24.61 95% CI 11.52,52.57 p2=78%). Two studies, by Wang, et al, and Yamamoto, et al, also assessed for endoscopic recurrence. Risk of endoscopic recurrence at 1 year was decreased by nearly 3-fold in the EN group relative to no EN (OR 2.69 95% CI 1.22,5.92 p=0.01, I2=48%) with EN. Conclusion: Postoperative enteral nutrition is associated with decreased rates of clinical and endoscopic recurrence after surgical resection. Further studies are needed to assess optimal duration of EN and longer-term effects.

A Distinctive Urinary Metabolomic Fingerprint Is Linked With Endoscopic Postoperative Disease Recurrence in Crohn's Disease Patients.

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.

Effectiveness of Mesalazine, Thiopurines and Tumour Necrosis Factor Antagonists in Preventing Post-Operative Crohn's Disease Recurrence in a Real-Life Setting

Background: Most Crohn's disease (CD) patients develop endoscopic recurrence within one year of intestinal resection. The best treatment method to prevent post-operative CD recurrence remains uncertain. Methods: A total of 155 CD patients from 2 referral centres, who were undergoing intestinal resection with ileo-colonic anastomosis (January 2004-January 2015), were included. All subjects received preventive therapy with tumour necrosis factor antagonists (anti-TNFs), thiopurinesor mesalazine. The primary outcome was the rate of endoscopic recurrence (Rutgeerts score ≥i2) in the 3 treatment groups. Results: Patients treated with anti-TNFs were at significantly lower risk of endoscopic recurrence during the follow-up than those receiving thiopurines or mesalazine (incidence rates of 2.2, 3.0 and 4.8 per 100 person-months, respectively, log-rank, p = 0.011). The median time to recurrence was significantly longer in patients treated with anti-TNFs than in those who received thiopurines or mesalazine (37.0, 13.7, and 16.8 months, respectively, log-rank, p = 0.011). Anti-TNFs were more effective than mesalazine (univariable analysis, hazard ratio [HR] 0.45, 95% CI 0.26-0.77, p = 0.004; multivariable analysis, HR 0.45, 95% CI 0.26-0.77, p = 0.004), and non-significantly superior over thiopurines. Conclusion: Anti-TNF therapy was the most effective strategy for the prevention of endoscopic CD recurrence.

Predictive value of myenteric and submucosal plexitis for postoperative Crohn's disease recurrence

Objectives: To assess the predictive values of myenteric and submucosal plexitis for postoperative endoscopic recurrence of Crohn's disease (CD). Methods: A retrospective study of CD patients who underwent intestinal resection between 1995 and 2013 in the Department of Surgery 2, Tokyo Women's Medical University was performed. Proximal resection margins were analyzed and plexitis was evaluated by counting the number of inflammatory cells in myenteric and submucosal plexuses. The sizes of the most severely inflamed ganglion (MIG) were measured. Multiple regression analysis was used to identify independent risk factors for postoperative endoscopic recurrence. Results: Of the 51 included patients, 40 patients underwent colonoscopy after surgery. Endoscopic recurrence was observed in 21 patients (52.5%). Mean duration (±standard deviation) from surgery to recurrence was 49.7±34.7 months. Endoscopic recurrence rates at 1, 3, and 5 years were 5.0%, 24.1%, and 45.1%, respectively. Submucosal plexitis and myenteric plexitis were observed in 36 (90.0%) and 37 patients (92.5%), respectively. On multivariate analysis, initial intestinal resection, rate of plexitis <50%, size of the MIG in the myenteric plexus ≥867 μm2, and total number of inflammatory cells in the submucosal plexus ≥8 were independent risk factors for postoperative endoscopic recurrence. Conclusions: Pathological findings of proximal resection margins, especially submucosal plexitis and large sizes of myenteric plexus, are predictive of postoperative endoscopic recurrence in CD.

Infliximab Prevents Postsurgical Endoscopic Recurrence of Crohn Disease

Available data suggest that patients at high risk for recurrence after Crohn disease resection have a lower risk for recurrence after surgery by

Su1384 Medical Prophylaxis After Ileocolic Resection for Crohn's Disease – No Need to Rush

Background: Crohn's disease (CD) most commonly affects the terminal ileum, with a majority of patients ultimately requiring ileocolic resection. Histologic and immunologic evidence suggests that mucosal inflammation occurs early after exposure of the neoterminal ileum to autologous luminal contents. Therefore, early medical prophylaxis has been advocated to prevent endoscopic recurrence of CD. The purpose of this study was to evaluate whether the timing of medical prophylaxis after ileocolic resection affects endoscopic recurrence of CD. Methods: A single institution, prospectively maintained database was queried for CD patients undergoing ileocolic resection over a 13-year period ending January 2013. Patients were included if they underwent postoperative endoscopy within 12-months of surgery and were started on medical therapy using 5-aminosalicylates (5ASA), immunomodulators, or biologic agents prior to their first postoperative endoscopy. Patients were divided into two groups; those started on medical prophylaxis within 4 weeks of surgery (Early) and those who receivedmedical prophylaxis 4 weeks or more after surgery (Late). The primary endpoint was endoscopic recurrence (defined as a Rutgeerts' endoscopic score of i2, i3, or i4 at first postoperative endoscopy). Secondary endpoints included time to endoscopic recurrence, and any radiological, clinical and surgical recurrence. Results: The 165 study patients had a mean age (SD) of 32.2 (14.6) years and 91 (55%) were male (Table). Mean time to starting medical therapy was 3.8 (2) weeks. 99 patients (60%) were in the Early prophylaxis group and 65 (40%) were in the Late prophylaxis group. Compared to the Early prophylaxis group, the Late prophylaxis group was treated more commonly with biologics (p<0.001) and less commonly with 5-ASA (p=0.007) or immunomodulators (p=0.004). At a mean endoscopy time of 6.8 (2.4) months, 65 patients (39%) had endoscopic recurrence; 39 (39%) in the Early group and 26 (39%) in the Late group. There was also no significant difference in clinical or surgical recurrence between the Early versus Late prophylaxis patient groups. Subgroups analysis of patients treated postoperatively with non-biologic medical prophylaxis, biologic alone, or biologic with other agents, showed no significant difference in endoscopic recurrence between Early and Late prophylaxis patient groups. Conclusion: Althoughmedical prophylaxis after ileocolic resection for CD has been shown to reduce endoscopic recurrence, it may be safe to wait until patients are out of the initial perioperative period prior to initiating medical prophylaxis without any adverse effects on endoscopic recurrence.

Mucosal Improvement in Patients With Moderate to Severe Postoperative Endoscopic Recurrence of Crohn’s Disease and Azathioprine Metabolite Levels

The value of azathioprine metabolites (6-thioguanine nucleotides [6-TGN]) in monitoring clinical treatment response is still controversially discussed. Data regarding thiopurine metabolite levels and endoscopic improvement are lacking. Data were analyzed post hoc from a 1-year, multicenter, double-blind, double-dummy, randomized trial comparing azathioprine 2.0 to 2.5 mg/kg per day versus mesalamine 4 g/d in a subset of 23 postoperative patients with Crohn's disease (CD) treated with azathioprine and having moderate-to-severe endoscopic recurrence according to a modified 6-grade score. Red blood cell (RBC) concentrations of 6-TGN, 6-methyl-mercaptopurine ribonucleotides (6-MMPR), and 6-methyl-thioguanine nucleotides (6-MTGN) were indicated as follows: area under the concentration-time curve, average concentration (C av), and concentration at the final study visit. Overall, 74% of patients showed an improvement in the modified endoscopic score (P = 0.022). Median endoscopic score reduced from 4 at the baseline to 2 at the final visit. Patients with a high C av for 6-TGN (≥ 193 pmol/8 × 10(8) RBC; P = 0.017) or 6-MTGN (≥ 79.2 pmol/8 × 10(8) RBC; P = 0.035) significantly improved in endoscopic score, and the improvement in endoscopic score correlated with C av for 6-TGN (r = -0.51; P = 0.013). For concentration at the final visit, higher values for 6-TGN (≥ 142 pmol/8 × 10(8) RBC; P = 0.017) were associated with a better postoperative score. Sensitivity analysis revealed a significant correlation between 6-TGN (area under the concentration-time curve) and postoperative endoscopic improvement. Our post hoc analysis from a double-blind, randomized trial suggests that higher RBC 6-TGN levels are associated with endoscopic improvement in patients with severe postoperative endoscopic recurrence of CD. Thus, our study provides first evidence on the utility of monitoring of thiopurine metabolites to achieve mucosal response in CD.

Scheduled infliximab monotherapy to prevent recurrence of Crohnʼs disease following ileocolic or ileal resection: A 3-year prospective randomized open trial

Infliximab (IFX) is effective for remission induction and maintenance of Crohn's disease (CD). This trial assessed the efficacy of scheduled maintenance IFX monotherapy to prevent postoperative CD recurrence. Thirty-one CD patients who had ileocolic resection within the past 4 weeks were randomly assigned to scheduled IFX at 5 mg/kg intravenously every 8 weeks for 36 months (n = 15) or without IFX (control, n = 16). All patients were treated without immunomodulator or corticosteroid following surgery. The primary and secondary endpoints were remission rates at 12 and 36 months, defined as CD Activity Index (CDAI) ≤150, an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) score <2, and C-reactive protein (CRP) <0.3 mg/dL. Additionally, endoscopic recurrences at 12 and 36 months were evaluated. At 12 and 36 months, 100%, and 93.3% of patients in the IFX group were in remission (IOIBD <2), respectively vs. 68.8% and 56.3% in the control arm (P < 0.03). Similarly, 86.7% and 86.7% of patients in the IFX group maintained serological remission (CRP <0.3 mg/dL) vs. 37.5% and 37.5% in the control arm (P < 0.02). Further, the IFX group achieved higher endoscopic remission at 12 months, 78.6% vs. 18.8% (P = 0.004). However, in the Kaplan-Meier survival analysis the CDAI scores between the two arms were not significantly different either at 12 or at 36 months. No adverse event (AE) was observed. An early intervention with IFX monotherapy should prevent clinical, serological, and endoscopic CD recurrence following ileocolic resection. Thiopurine naivety and eliminating the initial loading dose of IFX might minimize serious AEs.

Relationship between Thiopurine metabolite levels and endoscopic improvement in patients with postoperative moderate to severe endoscopic recurrence of Crohn's disease

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.

P074 - Myenteric plexitis does not predict endoscopic Crohn's disease recurrence 12 months following ileo-colonic resection in district general hospital practice

P074 - Myenteric plexitis does not predict endoscopic Crohn's disease recurrence 12 months following ileo-colonic resection in district general hospital practice

A Meta-Analysis on the Efficacy of Probiotics for Maintenance of Remission and Prevention of Clinical and Endoscopic Relapse in Crohn’s Disease

To evaluate whether probiotics maintain remission in patients with Crohn's disease (CD). A meta-analysis of controlled clinical trials. PUBMED and Cochrane Central Register of Controlled Trials were searched for clinical trial studies investigated the efficacy of probiotics for the maintenance of remission in Crohn's disease. Clinical relapse and endoscopic relapse were the key outcomes of interest. Data were searched within the time period of 1966 through May 2007. Eight randomized placebo-controlled clinical trials met our criteria and were included in the analysis. Seven determined clinical relapse and three evaluated endoscopic relapse among patients with CD received probiotics for maintenance of remission. Pooling of seven trials for the outcome of clinical relapse yielded an odds ratio of 0.92 (95% confidence interval of 0.52-1.62, P = 0.8853), a nonsignificant odds ratio. The odds ratio for three studies for the outcome of endoscopic relapse was 0.97 (95% confidence interval of 0.54-1.78, P = 0.93), a nonsignificant odds ratio. This meta-analysis fails to demonstrate the efficacy of probiotics in maintaining remission and preventing clinical and endoscopic recurrence in CD. It is suggested to use probiotic preparations containing a mixture of lactobacillus with E. coli or Saccharomyces.

Azatioprina y mesalazina en la prevención de la recurrencia posquirúrgica en la enfermedad de Crohn: estudio retrospectivo

Surgical resection is still a mainstay of the treatment of Crohn's disease (CD). However, recurrence is the rule. The aim of the present study was to evaluate CD recurrence in a series of patients who underwent surgical resection with subsequent treatment with azathioprine (AZA) or mesalazine (5-ASA) and to identify the factors associated with recurrence.The medical records of patients with CD who underwent bowel resection during a 4-year period were reviewed. Only patients who received AZA or 5-ASA as prophylaxis for recurrence were included.Thirty-three patients treated with AZA and 16 treated with 5-ASA were included. Endoscopic recurrence was found in 8.6% of the AZA group and in 87.5% of the 5-ASA group (p <0.001). Clinical recurrence occurred in 31.2% of patients in the 5-ASA group and in none in the AZA group (p=0.004). The accumulated probability of both clinical and endoscopic recurrence was significantly lower in the AZA group (p=0.0025 and p=0.005, respectively). Factors associated with a greater risk of endoscopic recurrence were termino-terminal anastomosis and 5-ASA treatment. The only factor associated with clinical recurrence was 5-ASA treatment.AZA seems to be more effective than 5-ASA in the prevention of postsurgical endoscopic recurrence of CD. Prospective studies with long-term follow-up are required to establish the true utility of AZA in the prophylaxis of CD recurrence.