Postoperative Endoscopic Recurrence Research Articles

P205 Histologic image-based ensemble model to identify myenteric plexitis and predict endoscopic postoperative recurrence in Crohn’s disease: a multicentre, retrospective study

Abstract Background Myenteric plexitis is correlated with postoperative recurrence of Crohn’s disease (CD) when relying on traditional statistical methods. However, comprehensive assessment of the myenteric plexus remains challenging. This study aimed to develop and validate a deep learning system to predict postoperative recurrence through automatic screening and identification of features of the muscular layer and myenteric plexus. Methods In this study, we retrospectively reviewed 205 CD patients who underwent bowel resection surgery from 2 hospitals. Patients were divided into a training cohort (n=108), an internal validation cohort (n=47) and an external validation cohort (n=50). A total of 190960 patches from 278 whole-slide images of surgical specimens were analysed using ResNet50, and 6144 features were extracted after transfer learning. Spearman correlation analysis, LASSO logistic regression and the interclass correlation coefficient test were utilized for feature selection. We used five robust algorithms to construct classification models. The performances of the models were evaluated by the area under the receiver operating characteristic curve (AUC) in three cohorts. Results The stacking model achieved satisfactory accuracy in predicting postoperative recurrence of CD in the training cohort (AUC: 0.980; 95% CI 0.960-0.999), internal validation cohort (AUC: 0.908; 95% CI 0.823-0.992), and external validation cohort (AUC: 0.868; 95% CI 0.761-0.975). The accuracy for identifying the severity of myenteric plexitis was 0.833, 0.745, and 0.694 in the training cohort, internal validation cohort and external validation cohort, respectively. Conclusion Our work initially established an interpretable stacking model based on muscular layer and myenteric plexus features extracted from histologic images to identify the severity of myenteric plexitis and predict postoperative recurrence of CD.

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, Randomized Controlled Trial.

Azathioprine [AZA] effectively prevents postoperative endoscopic recurrence [ER] in Crohn's disease [CD]. However, the efficacy of AZA emerges after 3 months. Exclusive enteral nutrition [EEN] can maintain remission in CD. The present trial investigates whether AZA plus postoperative 3-month EEN is superior to AZA alone in preventing ER of CD. In total, 84 high-risk CD patients undergoing intestinal resection received AZA alone or AZA plus 3 months of EEN [AZA + EEN] postoperatively. The primary endpoint was the rate of ER at 12 months. Secondary endpoints included the rate of ER at 3 months, clinical recurrence [CR], CD activity index [CDAI] scores, faecal calprotectin [FC], and C-reactive protein [CRP]. Quality of life was assessed using Short Form-36 [SF-36] and the Inflammatory Bowel Disease Questionnaire [IBDQ]. Patients in the AZA + EEN group exhibited significantly lower rates of ER compared to the AZA group at both 12 months (33.3% [13/39] vs 63.2% [24/38], P = 0.009) and 3 months (8.6% [3/35] vs 28.1% [9/32], P = 0.037) post-surgery. The rates of CR between the two groups at 3 and 12 months were similar. CDAI scores, FC, albumin level, and CRP were all comparable between the two groups. Quality of life was significantly higher in the AZA group than in the AZA + EEN group at 3 months but became comparable from 5 to 12 months 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. NCT05214430.

Major Abdominal Surgery for Pediatric Crohn's Disease in the Anti-TNF Era: 10-Year Analysis of Data From the IBD Registry of Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition.

The natural history of Crohn's disease (CD) can result in complications requiring surgery. Pediatric data are scarce about major abdominal surgery. The IBD Registry from the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition has been active since 2008 and collects data from major pediatric IBD centers in Italy. The aim of the present report was to explore the prevalence of major abdominal surgery among children affected by CD in an era when antitumor necrosis factor (anti-TNF-α) agents were already used so that we might appraise the incidence of surgical-related complications and identify the factors associated with postoperative disease recurrence. We retrospectively analyzed data from patients enrolled in the registry from January 2009 to December 2018. Patients with monogenic IBD and patients undergoing surgery for perianal disease were excluded. In total, 135 of 1245 patients were identified. We report the prevalence of major abdominal surgery of 10.8%. Pediatric surgeons performed the procedure in 54.1% of cases, and a laparoscopic approach was used in 47.4% of surgical procedures. Seventeen patients (12.6%) experienced a total of 21 early postoperative complications, none of which was severe. A laparoscopic approach was the only factor negatively associated with the occurrence of postoperative complications (odds ratio, 0.22; 95% confidence interval, 0.06-0.8; P = .02). Fifty-four (40%) patients experienced postoperative endoscopic recurrence, and 33 (24.4%) of them experienced postoperative clinical recurrence. The postoperative treatment with anti-TNF-α drugs was significantly associated with a reduced risk of endoscopic recurrence (odds ratio, 0.19; 95% confidence interval, 0.05-0.79; P = .02). In our cohort, the overall prevalence of major abdominal surgery was low, as well as the rate of surgical-related complications. Postoperative anti-TNF-α therapy seems be protective against endoscopic recurrence.

Fecal microbiota related to postoperative endoscopic recurrence in patients with Crohn's disease.

Postoperative recurrence (POR) remains a major challenge for patients with Crohn's disease (CD). Gut microbial dysbiosis has been reported to be involved in the pathogenesis of POR. This study aims to investigate the relationship between fecal microbiome and endoscopic recurrence in patients with CD after ileocolonic resection. This is a cross-sectional study. Fecal samples were collected from 52 patients with CD after surgical intervention from 6 to 12 months before endoscopic examination. Endoscopic recurrence was defined as Rutgeerts score ≥ i2. The microbiome was analyzed by sequencing the V3-V4 hypervariable regions of the 16S rRNA gene. A total of 52 patients were included and classified into POR (n = 27) and non-POR (n = 25) groups. Compared with the non-POR group, the POR group had a significantly lower community richness (Chao1 index: 106.5 vs 124, P = 0.013) and separated microbial community (P = 0.007 for Adonis, P = 0.032 for Anosim), combined with different distribution of 16 gut microbiotas and decrease of 11 predicted metabolic pathways (P < 0.05). Lactobacillus and Streptococcus were identified to closely correlate to non-POR (P < 0.05) after controlling for confounding factors. Kaplan-Meier analysis indicated that the patients with higher abundance of Streptococcus experienced longer remission periods (P < 0.01), but this was not for Lactobacillus. The predicted ethylmalonyl-coA pathway related to increased amount of succinate was positively correlated with Streptococcus (r > 0.5, P < 0.05). The characteristic alterations of fecal microbiota are associated with postoperative endoscopic recurrence in patients with CD; particularly, high abundance of Streptococcus may be closely related to endoscopic remission.

Early Initiation of Adalimumab Significantly Diminishes Postoperative Crohn's Disease Endoscopic Recurrence and Is Superior to 6-Mercaptopurine Therapy: An Open-Label, Randomized Controlled Study.

Postoperative recurrence (POR) is the rule in patients with Crohn's disease (CD), mitigated with prophylactic therapy. The evidence for therapeutic choice and timing of intervention is lacking. We aimed to compare the rates of POR in patients treated early with prophylactic 6-mercaptopurine (6-MP) or adalimumab. We conducted a prospective single-center randomized open-label clinical study in which patients in surgical remission following their first ileocecectomy were randomized to receive early treatment with 6-MP or adalimumab. Patients were followed up clinically every 3 months and underwent endoscopy at weeks 32 and 58 postoperatively. The primary endpoint was endoscopic recurrence (ePOR) at 1 year (week 58), defined as a Rutgeerts score ≥ i2. We enrolled 35 patients (25 males, mean age 35 ± 1.4 years, median disease duration 5 ± 6.1 years) following ileocecectomy. Of these, seven (20%) were current smokers and nine (26%) biologics-experienced. Patients allocated to adalimumab had significantly less ePOR than patients treated with 6MP at week 32 (21% vs. 69%, p = 0.004) and 58 (47% vs. 75%), (p = 0.03, HR = 0.39, 95% CI = 0.16-0.93). POR was associated with an increased diameter of the resected small bowel surgical specimen, lower baseline body mass index (BMI), increased week 18 fecal calprotectin, increased week 18 serum alanine aminotransferase and decreased week 18 hemoglobin level. Adalimumab was more effective than 6-MP in preventing ePOR. Increased operative small bowel diameter and lower postoperative BMI were associated with ePOR. At eighteen weeks, serum hemoglobin, ALT and fecal calprotectin levels were predictive of endoscopic disease recurrence. (ClinicalTrials.gov ID NCT01629628).

Comparative Persistence of Non-tumor Necrosis Factor (TNF) vs. TNF Antagonists for Post-operative Prophylaxis in Crohn's Disease (CD).

The comparative safety and effectiveness of available biologics for post-operative prophylaxis in Crohn's disease (CD) is uncertain. Drug persistence may serve as a real-world proxy for tolerability and effectiveness. We evaluated the comparative persistence of non-TNF and TNF antagonists for post-operative prophylaxis and their comparative effectiveness for preventing early endoscopic post-operative recurrence (POR). We conducted a single-center, retrospective study of surgically naïve CD subjects undergoing ileocecal or small bowel resection between 1/1/2000 and 12/31/2021 and prescribed a biologic for post-operative prophylaxis. We compared the risk of prophylaxis failure (requiring recurrent surgery or discontinuation of therapy due to persistent POR despite optimized drug level or dose escalation, immunogenicity, and/or adverse event) and early endoscopic POR (Rutgeert's score≥i2 within 15months postoperatively) between non-TNF and TNF antagonist prophylaxis using Cox proportional hazard and logistic regression, respectively, adjusting for demographic and disease characteristics. The study included 291 subjects (81% TNF antagonists). After multivariable adjustment, non-TNF antagonist prophylaxis was associated with a significantly lower risk of prophylaxis failure than TNF antagonists (hazard ratio 0.26; 95% confidence interval (CI) [0.13-0.53]). Prophylaxis with non-TNF and TNF antagonists had similar risk of early endoscopic POR (odds ratio 0.66; 95% CI [0.32-1.36]). Stratifying the non-TNF antagonists by anti-integrin and anti-IL12/23 yielded similar results. In a cohort of surgically naïve CD subjects prescribed a biologic for post-operative prophylaxis, non-TNF antagonists had greater persistence than TNF antagonists with similar risk for early endoscopic POR. If confirmed by large, prospective studies, these findings can inform post-operative management strategies in CD.

Histological Image-based Ensemble Model to Identify Myenteric Plexitis and Predict Endoscopic Postoperative Recurrence in Crohn's Disease: A Multicentre, Retrospective Study.

Myenteric plexitis is correlated with postoperative recurrence of Crohn's disease when relying on traditional statistical methods. However, comprehensive assessment of myenteric plexus remains challenging. This study aimed to develop and validate a deep learning system to predict postoperative recurrence through automatic screening and identification of features of the muscular layer and myenteric plexus. We retrospectively reviewed 205 patients who underwent bowel resection surgery from two hospitals. Patients were divided into a training cohort [n = 108], an internal validation cohort [n = 47], and an external validation cohort [n = 50]. A total of 190 960 patches from 278 whole-slide images of surgical specimens were analysed using the ResNet50 encoder, and 6144 features were extracted after transfer learning. We used five robust algorithms to construct classification models. The performances of the models were evaluated based on the area under the receiver operating characteristic curve [AUC] in three cohorts. The stacking model achieved satisfactory accuracy in predicting postoperative recurrence of CD in the training cohort (AUC: 0.980; 95% confidence interval [CI] 0.960-0.999), internal validation cohort [AUC: 0.908; 95% CI 0.823-0.992], and external validation cohort [AUC: 0.868; 95% CI 0.761-0.975]. The accuracy for identifying the severity of myenteric plexitis was 0.833, 0.745, and 0.694 in the training, internal validation and external validation cohorts, respectively. Our work initially established an interpretable stacking model based on features of the muscular layer and myenteric plexus extracted from histological images to identify the severity of myenteric plexitis and predict postoperative recurrence of CD.

Clinical Predictors of Early and Late Endoscopic Recurrence Following Ileocolonic Resection in Crohn's Disease.

Multiple factors are suggested to place Crohn's disease patients at risk of recurrence after ileocolic resection with conflicting associations. We aimed to identify clinical predictors of recurrence at first [early] and further [late] postoperative colonoscopy. Crohn's disease patients undergoing ileocolic resection were prospectively recruited at six North American centres. Clinical data were collected and endoscopic recurrence was defined as Rutgeerts score ≥i2. A multivariable model was fitted to analyse variables independently associated with recurrence. A total of 365 patients undergoing 674 postoperative colonoscopies were included with a median age of 32 years, 189 [51.8%] were male, and 37 [10.1%] were non-Whites. Postoperatively, 133 [36.4%] used anti-tumour necrosis factor [anti-TNF] and 30 [8.2%] were smokers. At first colonoscopy, 109 [29.9%] had recurrence. Male gender (odds ratio [OR] = 1.95, 95% confidence interval [CI] 1.12-3.40), non-White ethnicity [OR = 2.48, 95% CI 1.09-5.63], longer interval between surgery and colonoscopy [OR = 1.09, 95% CI 1.002-1.18], and postoperative smoking [OR = 2.78, 95% CI 1.16-6.67] were associated with recurrence, while prophylactic anti-TNF reduced the risk [OR = 0.28, 95% CI 0.14-0.55]. Postoperative anti-TNF prophylaxis had a protective effect on anti-TNF experienced patients but not on anti-TNF naïve patients. Among patients without recurrence at first colonoscopy, Rutgeerts score i1 was associated with subsequent recurrence [OR = 4.43, 95% CI 1.73-11.35]. We identified independent clinical predictors of early and late Crohn's disease postoperative endoscopic recurrence. Clinical factors traditionally used for risk stratification failed to predict recurrence and need to be revised.

Appearance of the Bowel and Mesentery During Surgery Is Not Predictive of Postoperative Recurrence After Ileocecal Resection for Crohn's Disease: A Prospective Monocentric Study.

Very few risk factors for postoperative recurrence (POR) of Crohn's Disease (CD) after ileocecal resection have been identified. The aim of the present study was to verify the association between an a priori defined list of intraoperative macroscopic findings and POR. This was a prospective observational study including patients undergoing primary ileocecal resection for CD. Four intraoperative factors were independently evaluated by 2 surgeons: length of resected ileum, mesentery thickness, presence of areas of serosal fat infiltration, or abnormal serosal vasodilation on normal bowel proximal to the resected bowel. The primary end point was early endoscopic POR at month 6 and defined as modified Rutgeerts score ≥i2b. Secondary end points were clinical and surgical recurrence. Between September 2020 and November 2022, 83 consecutive patients were included. Early endoscopic recurrence occurred in 45 of 76 patients (59.2%). Clinical and biochemical recurrence occurred in 17.3% (95% confidence interval, [CI], 10.4%-28.0%) and 14.6% of the patients after 12 months. The risk of developing endoscopic and clinical recurrence was 1.127 (95% CI, 0.448;2.834, P = .799) and 0.896 (95% CI, 0.324-2.478, P = .832) when serosal fat infiltration was observed, and 1.388 (95% CI, 0.554-3.476, P = .484), and 1.153 (95% CI, 0.417;3.187, P = .783) when abnormal serosal vasodilation was observed. Similarly, length of the resected bowel and mesentery thickness showed no association with POR. A subgroup analysis on patients who received no postoperative medical prophylaxis did not identify any risk factor for endoscopic POR. The macroscopic appearance of the bowel and associated mesentery during surgery does not seem to be predictive of POR after ileocecal resection for CD.

KONO-S Anastomosis Is Not Superior to Conventional Anastomosis for the Reduction of Postoperative Endoscopic Recurrence in Crohn's Disease.

Surgical resection rates remain high in Crohn's disease (CD). Reducing postoperative recurrence (POR) is challenging. Besides drug therapy, the surgical anastomosis technique may reduce POR. We aimed to compare the endoscopic POR rate after Kono-S vs standard ileocolic anastomosis. The study included all consecutive CD patients operated on for ileocolic resection with a Kono-S anastomosis between February 2020 and March 2022. These patients were prospectively followed, and colonoscopy was performed 6 to 12 months after surgery. Patients were compared with a historical cohort of patients operated on with a conventional anastomosis in the same center. The primary end point was endoscopic POR (Rutgeerts score ≥i2). Factors associated with POR were assessed by univariate and multivariable analyses. A total of 85 patients were included, 30 in the Kono-S group and 55 in the control group. At baseline, there was no significant difference between the 2 groups regarding CD characteristics or known POR risk factors, including previous exposure to biologics. At 6 to 12 months, endoscopic POR rate did not differ significantly between groups (56.7% in the Kono-S group vs 49.1% in the control group; P = .50), nor did endoscopic POR according to the modified Rutgeerts score ≥i2b (46.7% in the Kono-S group vs 40% in the control group; P = .55). Severe endoscopic POR rates were 23.3% and 18.2% in each group, respectively. Clinical recurrence rate was similar in both groups, and no recurrent surgery occurred. By multivariable analysis, the type of anastomosis was not associated with endoscopic POR (OR, 1.229; 95% CI, 0.461-3.274, P = .68); however, postoperative treatment with anti-TNF was (OR, 0.337; 95% CI, 0.131-0.865 P = .02). Kono-S anastomosis was not associated with a reduced rate of endoscopic POR. These results warrant confirmation in prospective, randomized, multicenter studies.

Suboptimal Guideline Adherence and Biomarker Underutilization in Monitoring of Post-operative Crohn's Disease.

Crohn's disease recurrence after ileocecal resection is common. Guidelines suggest colonoscopy within 6-12months of surgery to assess for post-operative recurrence, but use of adjunctive monitoring is not protocolized. We aimed to describe the state of monitoring in post-operative Crohn's. We conducted a retrospective study of patients with Crohn's after ileocolic resection with ≥ 1-year follow-up. Patients were stratified into high and low risk based on guidelines. Post-operative biomarker (C-reactive protein, fecal calprotectin), cross-sectional imaging, and colonoscopy use were assessed. Biomarker, radiographic, and endoscopic post-operative recurrence were defined as elevated CRP/calprotectin, active inflammation on imaging, and Rutgeerts ≥ i2b, respectively. Data were stratified by surgery year to assess changes in practice patterns over time. P-values were calculated using Wilcoxon test and Fisher exact test. Of 901 patients, 53% were female and 78% high risk. Median follow-up time was 60m for LR and 50m for high risk. Postoperatively, 18% low and 38% high risk had CRPs, 5% low and 10% high risk had calprotectins, and half of low and high risk had cross-sectional imaging. 29% low and 38% high risk had colonoscopy by 1year. Compared to pre-2015, time to first radiography (584days vs. 398days) and colonoscopy (421days vs. 296days) were significantly shorter for high-risk post-2015 (P < 0.001). Probability of colonoscopy within 1year increased over time (0.48, 2011 vs. 0.92, 2019). Post-operative colonoscopy completion by 1year is low. The use of CRP and imaging are common, whereas calprotectin is infrequently utilized. Practice patterns are shifting toward earlier monitoring.

Anti-TNF Agents and New Biological Agents (Vedolizumab and Ustekinumab) in the Prevention and Treatment of Postoperative Recurrence After Surgery in Crohn's Disease.

Surgery for Crohn's disease (CD) is not curative, as postoperative recurrence (POR) after ileocolonic resection is the rule in the absence of prophylactic treatment. In the present article, we critically review available data on the role of anti-tumour necrosis factor (TNF) agents and new biologics (including vedolizumab and ustekinumab) in the prevention and treatment of POR after surgery in CD. Several studies (summarised in various meta-analyses) have confirmed the efficacy of anti-TNFs in the prevention of POR. We identified 37 studies, including 1863 CD patients, with mean endoscopic POR at 6-12 months of 29%. Only few randomised controlled trials (RCTs) have directly compared thiopurines and anti-TNFs, with controversial results, although the superiority of the latter is supported by several meta-analyses. Infliximab and adalimumab seem equally effective. The combination of anti-TNFs and immunosuppressives should be considered in patients previously exposed to anti-TNFs. Several studies have shown that anti-TNFs remain an effective option to prevent POR also in patients with anti-TNF failure before surgery. In fact, the use of the same anti-TNF before and after surgery might be effective for the prevention of POR. Prophylactic anti-TNF treatment, once started, should be continued long term. Anti-TNFs are also effective for the treatment of established POR. Retreatment with anti-TNFs for POR is a valid strategy even after their preoperative failure. In six studies (including 156 patients) evaluating vedolizumab, mean endoscopic POR at 6-12 months was 41%. The non-randomised comparison of anti-TNFs and vedolizumab has provided controversial results. One placebo-controlled RCT confirmed that vedolizumab is quite effective in preventing POR in CD patients with increased risk of recurrence. Seven studies (including 162 patients) evaluated ustekinumab, with a mean endoscopic POR at 6-12 months of 41%. The comparative efficacy of ustekinumab and anti-TNFs is still unclear. Ustekinumab and vedolizumab seem to be equally effective, although the experience is very limited. In conclusion, to date, anti-TNFs are the most effective agents in preventing and treating POR in CD. Anti-TNFs remain an effective option to prevent POR also in patients with anti-TNF failure before surgery. Vedolizumab seems to be quite effective in the prevention of POR in patients with increased risk of recurrence. Ustekinumab is probably also effective in the postoperative setting, although the comparative efficacy with anti-TNFs or vedolizumab is still unclear.

Quantitative analysis of adipose tissue for predictingCrohn's disease postoperative endoscopic recurrence and anastomotic ulcer.

Inflammation and ulcers at the anastomotic site are frequently observed after intestinal resection surgery for Crohn's disease (CD), which often signify postoperative recurrence. Crohn's disease causes abnormalities in whole-body fat metabolism, and alterations in subcutaneous and visceral fat are potential indicators of disease development. This study aimed to quantify the areas of subcutaneous (SFA) and visceral fat (VFA) and investigate the relationship between fat tissue and endoscopic recurrence and anastomotic ulceration after Crohn's disease surgery. We conducted a retrospective analysis of clinical data from 279 patients diagnosed with Crohn's disease. Using abdominal CT (Computed Tomography) scans at the level of the umbilicus, we measured the area of subcutaneous and visceral fat, and calculated the Mesenteric Fat Index (MFI), which is defined as the ratio of the area of visceral fat to subcutaneous fat. We compared the changes in fat tissue between surgical Crohn's disease patients and non-surgical patients in remission, as well as changes in fat tissue before and after surgery, and between patients with and without endoscopic recurrence after surgery. The MFI value of the surgical group was higher than that of the non-surgical group(0.88(1.27 ± 1.26) VS 0.39(0.44 ± 0.21), P < 0.001), while the SFA value was lower(70.16(92.97 ± 78.23) VS 157.64(175.96 ± 101.58), P < 0.001). Of the 134 surgical patients who underwent abdominal CT examination after surgery, the SFA value was significantly higher after surgery(143.61 ± 81.86 VS 90.87 ± 71.93, P < 0.001), and the MFI value decreased accordingly(0.57 ± 0.36 VS 1.30 ± 1.35, P < 0.001). Multivariate Cox analysis indicated that high VFA and MFI values, smoking history, and preoperative biologic therapy were all risk factors for postoperative endoscopic recurrence(p < 0.05), while high MFI values and preoperative biologic therapy were also risk factors for anastomotic ulcers(p < 0.05). The Kaplan-Meier analysis showed that these factors increased the risk of reaching the endpoint with time(p < 0.05). The ROC curve results showed that MFI value had high diagnostic value for postoperative endoscopic recurrence [AUC:0.831, 95% CI: 0.75-0.91, p < 0.001] and anastomotic ulcers [AUC:0.801, 95% CI: 0.71-0.89, p < 0.001]. Surgical CD patients have significantly higher MFI values but the values decline after surgery. When the preoperative MFI value is > 0.82, the risk of postoperative endoscopic recurrence increases significantly, and when the MFI value is ≥ 1.10, the risk of anastomotic ulceration after surgery increases significantly. Meanwhile, biologic therapy preoperatively also is a high-risk factor for early postoperative endoscopic recurrence or anastomotic ulcers after intestinal resection surgery.

Granuloma Presence at Initial Surgery Predicts Need for Repeat Surgery Independent of Rutgeerts Score in Crohn's Disease.

Approximately half of Crohn's disease (CD) patients experience recurrence and need for repeat resections, highlighting need for prognostic biomarkers. Presence of epithelioid granuloma on surgical tissue and high Rutgeerts endoscopic score are associated with postoperative CD clinical recurrence. We sought to evaluate presence of epithelioid granuloma at first surgery and Rutgeerts score as a combined risk assessment for CD surgical recurrence. Our study included consented CD patients who underwent initial ileocecal resection and were prospectively followed postoperatively. From 2009 to 2019, 418 CD patients underwent initial ileocecal resection with >4 years of follow-up, including postoperative endoscopic assessment (Rutgeerts score). Postoperative CD patients were grouped based on granuloma presence (30.6%; n = 128) or absence (69.4%; n = 290). Endoscopic recurrence (defined as Rutgeerts score ≥i2) was similar between the granuloma (26%) and no granuloma (25%) groups, respectively (P = .82). Patients with granuloma and CD endoscopic recurrence at first postoperative endoscopy had higher number of bowel surgeries compared with all other groups (no granuloma or CD endoscopic recurrence, P = .007; no granuloma but CD endoscopic recurrence present, P = .04; granuloma present and no CD endoscopic recurrence, P = .04). Epithelioid granuloma presence was associated with 1.65 times higher risk of subsequent surgery independently from first postoperative endoscopic recurrence Rutgeerts score. Granuloma presence on initial surgical histology is immediately available and identifies high-risk CD patients who may benefit from early postoperative treatment, and these precision intervention trials are warranted.

P360 Role of intestinal ultrasound scores in the diagnosis of post-operative recurrence in Crohn's disease

Abstract Background Ileocolonoscopy is the gold standard to evaluate post-operative recurrence (POR) in Crohn's disease (CD) patients. Rutgeerts endoscopic score remains the gold standard in the evaluation of post-operative recurrence in CD. Intestinal ultrasound (IUS) is proposed as a non-invasive alternative to ileocolonoscopy for the diagnosis of POR, with a sensitivity of 94% and specificity of 84%. There are several IUS scores that evaluate CD disease activity such as SUS-CD (validated), IBUS-SAS and Simple US Score, which have not yet been studied in the diagnosis of POR. The aim of this study is to assess whether these ultrasound scores correlate with endoscopy in the diagnosis of PR. Methods A retrospective study was performed. Patients with CD who had undergone ileocecal resection, with both an ileocolonoscopy and intestinal ultrasound performed for the detection of POR were included. The time between tests was less than 6 months and there was no therapeutic change between tests. Endoscopic POR was evaluated with Rutgeers score (RS), considering POR RS ≥i2b. In IUS, were used: Simple US Score, SUS-CD and IBUS-SAS. Results Forty-five patients were included (female 48,89%, male 51,11%). The Montreal classification was: L1 n=22 (48,89%), L2=1 (2,22%), L3 n=22 (48,89%), B1 n=3 (6,67%), B2 24 (54,4%) and B3 n=18 (40%). 24 patients (53%) had no endoscopic POR, 6 (6%) had RS i2b and 15 (33.33%) had severe POR. The mean wall thickness measured by IUS was 4.39 mm (SD +/- 1.92) and 26 patients (57.77%) had hyperemia (Limberg score &amp;gt;1). The mean values for IUS scores were: Simple US Score 5.79 (SD +/- 2.81), SUS-CD 2.35 (SD +/- 1.62) and IBUS-SAS 34.04 (SD +/- 24.21). For the Simple US Score an area under the ROC curve (AUC) of 80.65% (95% CI 67.7 - 93.6) was obtained, with a score ≥5.4. The sensitivity (S) was 95.24% and specificity (E) 66.67%. IBUS-SAS presented an AUC of 87% (95% CI 76.98 - 97.02), a result ≥28 granted a S 90.48% and E 70.83%. The SUS-CD index had an AUC of 79% (95% CI 76.98 - 97.92), a result ≥3 presented S 90.48% and E 62.5%. Conclusion In our experience, IUS scores (IBUS-SAS, SUS-CD and Simple US Score) show a high sensitivity in the diagnosis of POR.

OP01 Sequencing-based gene network analysis reveals a profound role for ferroptosis key gene GPX4 in post-operative endoscopic recurrence in Crohn’s disease

Abstract Background An ileocolonic resection with ileocolonic anastomosis is often required in patients with Crohn’s disease (CD). Postoperative recurrence (POR) is common, with host-luminal interactions being implicated. However, these interactions are poorly understood. We aimed to obtain insights in the early mechanisms of POR CD focusing on sequencing-based gene networks in the mucosa. Methods We included 36 CD patients who underwent ileocolonic resection with ileocolonic anastomosis, and collected mucosal biopsies from the neoterminal ileum 6 months after surgery (Table 1). We defined POR by a Rutgeerts score ≥i2b at month 6, and compared this to complete absence of endoscopic activity (i0). All biopsies underwent single-end RNA sequencing (Illumina TruSeq Stranded mRNA). Gene co-expression network clusters were identified using weighted gene co-expression network analysis (R\WGCNA), were tested for correlation with the primary outcome POR and clinical factors, and multiple testing correction was applied (FDR&amp;lt;0.05). Cellular deconvolution was performed using xCell; and top enriched pathways and upstream regulators were analysed using IPA (p&amp;lt;0.05). Results WGCNA analysis identified 25 co-expression clusters, of which five correlated with the postoperative outcome (clusters V, VI, IX, XV, XXV) (Fig.1). All but cluster XXV were upregulated in POR, with a profound immune-related enrichment in cluster V and VI (eg. (a)granulocyte adhesion and diapedesis, and IL17 signalling); microRNA biogenesis (cluster IX) and wound healing and fibrosis signalling (cluster XV). Interestingly, one cluster (XXV) was inversely correlated with POR, and genes within this cluster were mainly involved in autophagy, ferroptosis and oxidative stress response. The main hub gene (r=0.95, FDR=8.17E-19) within this cluster XXV was GPX4 (Glutathione peroxidase 4), a negative regulator of ferroptosis. Moreover, after cellular deconvolution, we found a positive correlation between the epithelial gene enrichment signature and the expression of GPX4 (r=0.52, p=0.0011). Finally, the main upstream regulator of the genes within this cluster XXV was HNF4A, a transcription factor known to regulate ferroptotic response. Conclusion We identified a mucosal transcriptomic signature associated with postoperative CD recurrence. Both autophagy and ferroptosis were found to be key protective pathways for recurrence with GPX4 as central hub. Our results complement recent findings of impaired epithelial GPX4 activity in ileal CD lesions evoking an inflammatory response to dietary lipids (Mayr et al Nat Comm 2020).

P522 Kono-S anastomosis reduces endoscopic and surgical post-operative recurrence in Crohn’s disease. The SuPREMe-CD Trial Update.

Abstract 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 &amp;gt;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&amp;lt;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.

P569 Can thiopurines prevent crohn’s disease endoscopic postoperative recurrence in at risk patients?

Abstract Background Postoperative relapse (POR) of Crohn’s disease (CD) is frequent in the absence of prophylactic treatment. Screening for known risk factors allows to stratify patients and consider appropriate therapy. In Tunisia, the cost-effectiveness of thiopurines makes it prescribed even when moderate or high risk of POR. The aim was to describe the efficacy of thiopurines in preventing endoscopic POR in patients at risk. Methods We conducted a retrospective study enrolling CD patients who underwent curative ileo-caecal resection and received thiopurines to prevent POR. They all had at least one risk factor for POR knowing: smoking, fistulizing phenotype, extensive ileal resection (≥ 50 cm), previous bowel resection. The risk was moderate in the presence of one risk factor and high if at least two factors. Patients with a follow-up less than 6 months were excluded. All patients had undergone ileocoloscopy to screen for endoscopic POR wich was stratified according to the Rutgeerts score. Endoscopic POR was defined by a score ≥ i2 and was severe if score ≥i3. Results Thirty nine patients were included with a sex ratio M/F =1.8 and a mean age of 31 years. CD was ileal and ileocolic in 92.3% and 7.7% respectively, with perineal involvement in 7.2%. The mean extent of ileal resection was 39.7±4 cm. The ileal and colonic histological margins were pathologic in 17.9% and 7.7% respectively. Risk factors for POR were distributed as follow: Active smoking (28.2%), previous bowel resection (17.9%), fistulizing phenotype (84.6%) extensive resection (35.9%). The risk was high in 51.3% and moderate in 48.7% of cases. The delay of introduction of thiopurines was on average 31.8±53 days from the restoration of digestive continuity at a mean dose of 2.3 mg/kg and ileocoloscopy was performed at a mean delay of 19.3 months. Rutgeerts' score was as follows: i0, i1, i2, i3 and i4 in 34.7%, 8.2%, 16.3%, 6.1% and 10.2% respectively. Endoscopic POR was noted in 43.6% and was severe in 21.6% of cases. The cumulative POR rate was 16% at 6 months, 52% at 12 months and 67.5% at 24 months. In univariate analysis, factors associated with endoscopic POR on thiopurines were male gender (p=0.012), laparotomy (p=0.02), the extent of ileal resection and extensive ileal resection (p=0.003). In multivariate analysis, the factors retained were male gender with an OR=11 (p= 0.024) and the extent of ileal resection with an OR=1.05 (p=0.02). Time to introduction of thiopurines, fistulising phenotype and smoking did not significantly influence the risk of POR. Conclusion Thiopurines would be able to prevent endoscopic POR in more than half of the patients at risk. However, anti-TNF therapy should be indicated immediately in males and in cases of extended ileal resection.

P275 Anastomotic technique drives endoscopic recurrence in Postoperative Crohn's Disease: a systematic review and meta-analysis

Abstract Background Patients with Crohn's disease (CD) after Ileo-colic resection may develop an endoscopic postoperative recurrence (ePOR) that reaches approximately 70% of incidence within six months. ECCO guidelines favour a stapled side-to-side anastomosis. However, the advent of the Kono-S ileocolic anastomosis, a hand-sewn antimesenteric functional end-to-end anastomosis, seems to reduce clinical risk and ePOR. Whilst the majority of the studies have assessed the rate of ePOR individually, currently there is limited data comparing surgical techniques of the anastomosis. Hence, we aimed to assess the impact of different surgical techniques on ePOR in CD Methods We searched PubMed and Embase in October 2022 for eligible studies reporting the surgical types of anastomosis and, based on these, the rate of endoscopic recurrence at a minimum of six months. Studies were grouped by conventional anastomosis vs Kono, and comparisons were made between these groups. Pooled incidence rates of ePOR were computed using random-effect modelling. Meta-regression and subgroup analyses were performed to examine the impact of the type of anastomosis on the incidence of ePOR ≥ 6 months Results Thirteen studies, including 1816 patients who underwent ileocolic resection for CD, were included. Among these patients, 282 (15.5%) received a Kono-S anastomosis, while 1534 (84.4%) had a conventional anastomosis. ePOR at ≥≥ six months showed a pooled incidence of 31.8% (95% CI, 24.8 to 39.2), with significant heterogeneity among the studies (p&amp;lt;0.01). Meta-regression analysis showed that Kono-S anastomosis was associated with a significant reduction in the ePOR at endoscopic follow-up (p=0.001). In detail, patients receiving a Kono-S anastomosis had a pooled incidence of ePOR of 12% (95% CI, 3.1 to 24.9), while patients receiving a conventional anastomosis had an ePOR of 38.2 (95% CI, 30 to 46.9%) [Figure1]. Funnel plot asymmetry [Figure 2] and Egger's regression test (p=0.118) indicated the absence of a publication bias Conclusion Kono-S anastomosis was associated with a significant reduction of ePOR at ≥ six months compared to the conventional anastomosis. Our findings highlight the need to standardize and implement the use of Kono-S anastomosis, particularly for difficult-to-treat patients with high risk for a post-operative recurrence

P694 Long-term monitoring of post-surgical recurrence in Crohn’s disease using a strategy based on the periodic determination of fecal calprotectin in patients without early postoperative recurrence

Abstract Background Current guidelines recommend to perform an ileocolonoscopy 6-12 months after surgery in patients with Crohn’s disease (CD) and ileo-cecal resection with ileocolic anastomosis to assess the occurrence of endoscopic post-operative recurrence (PORe) and escalate therapy if necessary. However, it is not established whether and/or when endoscopic monitoring is advised in patients who do not present early PORe Objective To evaluate the usefulness of a strategy based on the periodic determination of faecal calprotectin (FC) to decide whether to carry out a new endoscopic control in patients without PORe (iR&amp;lt;2) in the last endoscopic assessment performed Methods Pilot, prospective, multicentre and open study. Inclusion criteria: 1) CD with intestinal resection and ileo-colic anastomosis; 2) last ileocolonoscopy after surgery with a Rutgeerts score i0 or i1; 3) No suspicion of clinical POR. Patients with an ostomy or chronic use of NSAIDs or omeprazole were excluded. Centralized FC determinations were performed every 4 months for 2 years and an ileocolonoscopy at the end of follow-up was performed. In the case of FC&amp;gt;250μg/g in 2 consecutive determinations, ileocolonoscopy was advanced and the patient was withdrawn from the study. The main variable of interest was the rate of advanced PORe (as defined by Rutgeerts score &amp;gt;i2) at the final ileocolonoscopy. Results 55 patients were included, 13% perianal disease, 24% smokers and 27% surgery prior to the index surgery. 47% followed prevention with thiopurines and 14% with anti-TNF. During follow-up, 7 patients had FC&amp;gt;250μg/g in two consecutive determinations; advanced PORe was identified in 5 of these patients, PORe i2 in one and intestinal adenocarcinoma in another one. Among the patients who completed the 2-year follow-up, none had advanced PORe at the final ileocolonoscopy although intermediate PORe (i2) was found in 12. The rate of advanced PORe was 71% in those who finished the study before 2 years and 0% in those who were not advanced to endoscopy. The AUC for FC to detect advanced PORe was 0.98 (p=0.002). The cut-off point of FC&amp;gt;250μg/g obtained a sensitivity of 100% and specificity of 60% to detect advanced PORe. Conclusion The serial determination of FC is a suitable long-term monitoring tool to decide whether to perform ileocolonoscopy in patients without early PORe.