Neoterminal Ileum Research Articles

P0373 CLINICAL RECURRENCE AFTER ILEOCOLIC RESECTION FOR CROHN’S DISEASE: Interest of the REMIND group’s endoscopic score

Abstract Background The Rutgeerts score is the most commonly used score for assessing endoscopic recurrence after ileocolic resection in Crohn’s disease. However, a significant drawback of this score is that it combines lesions localized to the anastomosis with those in the neo-terminal ileum in the same category, assigning them equal prognostic significance. The aim of this study was to evaluate the performance of the REMIND score in predicting postoperative recurrence of Crohn’s disease and compare its performance with the Rutgeerts score. Methods We conducted a monocentric, retrospective, evaluative study of patients operated for Crohn’s disease. All patients had a follow-up colonoscopy within one year of surgery. The REMIND score was derived from endoscopic details documented in the colonoscopy reports. Clinical relapse was defined by the Crohn’s disease related symptoms or complications, such as intra-abdominal collection or occlusion, or subsequent surgery Postoperative. Statistical analysis was performed using SPSS.25 for Windows. Results Eighty patients were included, with a mean age of 35.7 years, and a gender ratio H/F=2,2. Median follow-up was 5 years from surgery. Clinical recurrence-free survival was significantly shorter in patients with ileal lesions whatever their severity was I(1,2,3,4)A(x), compared with patients without ileal lesions I(0)A(x): p<0,001 and not significantly different between patients without anastomotic lesions I(x)A(0) and patients with anastomotic lesions whatever their severity was I(x)A(1,2,3): p=0,2. However, patients with at least semicircumferential anastomotic ulcerations A(2,3) had more anastomotic occlusive complications than patients classified A0 or A1: A0 VS A2 p=0,01 A0 VS A3 p<0,001 A0 VS A1 p=0,9. The I(x) score, compared with the Rutgeerts and A(x) scores, had the best values in terms of discriminative capacity (Area under the curve= 0,83 VS 0,73 VS 0,61), monotonicity (linearity test χ2 of 26,77 VS 12,36 VS 3,89), and homogeneity (likelihood ratio χ2 of 33,91 vs 18,45 VS 5,49). Conclusion In contrast to the Rutgeerts and A(x) scores, the I(x) score seems to exhibit superior performance in predicting postoperative recurrence. Therefore, the use of a score describing separately ileal and anastomotic lesions might be more appropriate to define postoperative endoscopic recurrence. References Hammoudi N, Auzolle C, Tran Minh ML, Boschetti G, Bezault M, Buisson A, et al. Postoperative endoscopic recurrence on the neoterminal ileum but not on the anastomosis is mainly driving long-term outcomes in crohn’s disease. Am J Gastroenterol. 2020 Jul;115(7):1084-93.

P0546 Surgical recurrence following repeated ileocolic resection for Crohn’s disease: a retrospective single center cohort study

Abstract Background Surgical recurrence after primary ileocolic resection (ICR) for CD is common. (1) However, data on long-term outcomes following first resection of the neoterminal ileum (re-ICR) are scarce. The present study evaluated the risk on surgical recurrence following first re-ICR in CD patients. In addition we aimed to assess changes in medical treatment strategies and its effect on postoperative outcomes. Methods A retrospective cohort study was conducted in the Amsterdam UMC, including all CD patients undergoing first re-ICR between 2000-2021. The primary outcome was the need for re-ICR due to disease recurrence at the neoterminal ileum. Two time periods were created to assess changes in surgical recurrence and short-term outcomes over time, C1: 2000-2009 and C2: 2010-2021. Results in total, 110 patients were included, comprising 69 females (62.7%) with a median age at time of re-ICR of 39 years (IQR 30.0 – 50.3). Time from primary ICR to re-ICR increased significantly over time. Most patients presented with stricturing disease at time of first re-ICR (64.5%). Rates of surgical recurrence were 13.0% and 24.9% after 5 and 10 years, respectively. Over time an increased use of prophylactic biological use was observed (C1: 16.4% vs C2: 41.7%, p=0.004). Over time, no significant differences in 5-year, and 10 year surgical recurrence rates were observed between C1 and C2, (12.5% vs 11.5%, p=0.636), and (28.6% vs 18.7%, p=0.341), respectively. Conclusion This study demonstrated an overall 10-year surgical recurrence rate of 24.9% in patients undergoing first re-ICR. Over time, postoperative disease management has evolved towards increasing use of biological therapy. However, no significant difference in surgical recurrence rates over time have been observed.

P1153 Intestinal Fibrosis Attenuates the Prophylactic Effect of Antitumour Necrosis Factor Therapy on Postoperative Recurrence of Crohn’s Disease

Abstract Background In biologic era, the postoperative recurrence (POR) of Crohn’s disease (CD) remains a significant concern. The objective is to examine if intestinal fibrosis increases the likelihood of POR when using anti-tumour necrosis factor (anti-TNF) α biologics following ileocecal resection (ICR). Methods We performed a single-centred, retrospective cohort study of CD patients who underwent an ICR. Recurrence was defined by endoscopy (Rutgeerts score, RS ≥ i2), radiography (active inflammation in the neoterminal ileum, neoTI) or surgery (another resection > 3 months from the index ICR) and patients were categorised based on the presence of intestinal fibrosis as determined by histopathological evaluation. Results 102 patients with CD who underwent an ICR and received anti-TNFα prophylaxis within 18 weeks were identified. Of 74 (72.5%) were diagnosed with intestinal fibrosis. A cohort of 60 patients (58.8%) encountered POR in various forms: 52.6%, 41.2%, and 10.8% had endoscopic, radiographic, or surgical recurrence, respectively. Patients with intestinal fibrosis experienced radiographic recurrence at a more accelerated rate compared to those without fibrosis. However, no significant difference was observed when comparing other types of recurrence. After adjusting for factors associated with POR, intestinal fibrosis was found to be more likely to induce early development of radiographic recurrence (adjusted hazard ratio, 4.004; 95% CI, 1.031-15.555). Conclusion Despite the small sample size, our study revealed a strong correlation between the occurrence of radiographic POR and intestinal fibrosis in patients who received postoperative anti-TNFα prophylaxis.

P0310 Intestinal Ultrasound parameters correlate with endoscopic findings in patients with post-operative Crohn’s disease.

Abstract Background In patients with Crohn’s disease (CD) and ileocecal resection, colonoscopy remains the gold-standard for detecting post-operative recurrence (POR). Intestinal ultrasound (IUS) is non-invasive, patient-friendly, with high accuracy for the detection of bowel inflammation. The aim of the present study was to investigate the correlation between post-operative endoscopic findings and those of IUS in patients with CD. Methods We analyzed data from CD patients with ileocecal resection who underwent colonoscopy and IUS for follow up. Post-operative endoscopic recurrence (ER) was defined as Rutgeert’s score (RS)≥i2b. The following IUS parameters were analyzed: bowel wall thickness (BWT), bowel wall stratification (BWS), modified Limberg score for the assessment of bowel wall hyperemia (BWH) and neo-terminal ileum peristalsis. Linear and binary logistic regressions were used to identify associations between RS and IUS parameters. SPSS-23 was used for the statistical analysis with a threshold of P=0.05 for statistical significance. Results In total, 44 patients [29 male, median age (SD): 40 (14.7) years] underwent IUS 42 [2-126] months following ileocecal resection. Thirty-eight (86%) patients were on treatment [infliximab 10 (23%), adalimumab 9 (21%), ustekinumab 11 (25%), vedolizumab 4 (9%), ozanimod 1 (2%) azathioprine 1 (2%), methotrexate 1 (2%)] and 7 (16%) patients were on no treatment. Endoscopic recurrence was detected in 52% of patients. Higher RS was associated with increased BWT, absence of peristalsis in the neo-TI and loss of BWS (P=0.007, P=0.001 and P=0.028 respectively). In multivariate analysis a higher RS was independently associated with the absence of peristalsis in the neo-terminal ileum (P=0.019). A tendency for a positive correlation between RS and ΒWT (P = 0.071) was also observed. RS≥i2b was significantly correlated with loss of BWS (P=0.045), absence of peristalsis (P=0.027) and a tendency was observed with BWT(P=0.081). RS≥i3 was significantly correlated with absence of peristalsis in the neo-TI (P= 0.001), BWT>3mm (P= 0.041), while a tendency was observed with modified Limberg score≥2 (P= 0.082). Conclusion IUS parameters correlate with RS in patients with post-operative CD. IUS may be a valuable monitoring tool for the assessment of POR in CD. Larger prospective studies are needed to determine cut-off values of sonographic parameters that may accurately predict post-operative recurrence of CD.

P1311 Mucosal Microbiome Signatures Associated with Postoperative Endoscopic Recurrence in Paediatric Crohn’s Disease

Abstract Background Following ileocecal resection (ICR) for Crohn’s disease (CD), recurrence is frequent even in the biologic era. Gut microbiota is involved in this setting and a few adult studies have suggested that bacterial recolonization after surgery may predict recurrence. Given the inherent risk of postoperative recurrence associated with age and disease duration, studies investigating the role of the gut microbiota in predicting relapse in children undergoing ICR appears critical. We aimed to identify changes in the mucosal microbiome associated with, and predictive of, endoscopic CD recurrence within the first year post-ICR in a paediatric population. Methods Microbiota composition (16S rDNA sequencing) was assessed from ileal and colonic mucosa at the time of ICR and later during endoscopic evaluation from above and below the surgical anastomosis in 33 patients (26 with paired samples) prospectively recruited at a tertiary care paediatric IBD center. Results The study included 33 children (mean age 16±2.7 years) undergoing ICR. At the time of ileo-colonoscopy, 9 (35%) patients had endoscopic recurrence (Rutgeerts’ score≥ i2). ICR strongly modified the gut mucosal microbiota composition with significant changes in β-diversity (R2= 0.03, PERMANOVA test, p=0.01). Bacterial recolonization post-ICR differed according to recurrence status (Figure 1). Post-operatively, recurrence was associated with an increase in Fusobacterium, Dialister genera and in members of the Lachnospiraceae family, and a decrease in Faecalibacterium, Lactobacillus genera and members of the Streptococcaceae family. Microbiota colonizing the neoterminal ileum and subanastomotic colon differed in children with recurrence and showed, compared to remission, elevated and reduced bacterial abundance of the Enterobacter (q=0.1) and Ruminococcaceae (q=0.05) families in colonic samples respectively while the ileal mucosa exhibited profound depletion in Faecalibacterium (q=0.01). Postoperative colonic mucosal relative abundance of Enterobacteriaceae (q=0.06) and Ruminococcaceae (q=0.06) correlated positively and negatively with length of intestinal resection. At the time of surgery, several bacterial taxa able to predict relapse were identified (Figure 2). Conclusion Predicting postoperative CD relapse remains challenging, although several clinical risk factors of recurrence have been identified. Our study demonstrates that bacterial recolonization following ICR might pave the way towards remission or recurrence. Our results highlight, for the first time in a paediatric population, target species that may help clinicians to better define patients at risk of relapse and allow precise modulations of the overall microbial ecosystem towards remission pattern.

After Surgically Induced Remission, Ileal and Colonic Mucosa-Associated Microbiota Predicts Crohn’s Disease Recurrence

Investigating the tissue-associated microbiota after surgically induced remission may help to understand the mechanisms initiating intestinal inflammation in Crohn's disease. Patients with Crohn's disease undergoing ileocolic resection were prospectively recruited in 6 academic centers. Biopsy samples from the neoterminal ileum, colon, and rectosigmoid were obtained from colonoscopies performed after surgery. Microbial DNA was extracted for 16S rRNA gene sequencing. Microbial diversity and taxonomic differential relative abundance were analyzed. A random forest model was applied to analyze the performance of clinical and microbial features to predict recurrence. A Rutgeerts score ≥i2 was deemed as endoscopic recurrence. A total of 349 postoperative colonoscopies and 944 biopsy samples from 262 patients with Crohn's disease were analyzed. Ileal inflammation accounted for most of the explained variance of the ileal and colonic mucosa-associated microbiota. Samples obtained from 97 patients who were in surgically induced remission at first postoperative colonoscopy who went on to develop endoscopic recurrence at second colonoscopy showed lower diversity and microbial deviations when compared with patients who remained in endoscopic remission. Depletion of genus Anaerostipes and increase of several genera from class Gammaproteobacteria at the 3 biopsy sites increase the risk of further recurrence. Gut microbiome was able to predict future recurrence better than clinical features. Ileal and colonic mucosa-associated microbiome deviations precede development of new-onset ileal inflammation after surgically induced remission and show good predictive performance for future recurrence. These findings suggest that targeted microbial modulation is a plausible modality to prevent postoperative Crohn's disease recurrence.

Interobserver agreement of current and new proposed endoscopic scores for postoperative recurrence in Crohn’s disease

Background and AimsThe modified Rutgeerts’ score (mRS) is widely used for the assessment of endoscopic postoperative recurrence (ePOR) in Crohn’s disease (CD) after ileocolic resection to guide therapeutic decisions. To improve the validity and prognostic value of this endoscopic assessment, two new scores have been proposed. This study assessed the interobserver agreement of the current (mRS) and new endoscopic scores for ePOR in CD. MethodsSixteen Dutch academic and non-academic IBD specialists assessed endoscopic videos (n=71) of postoperative CD patients (n=66) retrieved from nine Dutch centers. Each video was assessed for the degree of inflammation by four gastroenterologists using the mRS and the new proposed endoscopic score: REMIND score (separate score of anastomosis and neoterminal ileum) and updated Rutgeerts score (assessment of lesions at the anastomotic line, ileal inlet, ileal body and neoterminal ileum). In addition, lesions at the ileal body, ileal inlet, neoterminal ileum, colonic and/or ileal blind loop were separately assessed. Interobserver agreement was assessed using Fleiss’ weighted kappa. ResultsFleiss’ weighted kappa for the mRS was 0.67 (95% confidence interval [CI] 0.59–0.74). The weighted kappa for the REMIND score was 0.73 (95% CI 0.65–0.80) for lesions in the neoterminal ileum and 0.46 (95% CI 0.35–0.58) for anastomotic lesions. The weighted kappa for the updated Rutgeerts’ score was 0.69 (95% CI 0.62–0.77). The weighted kappa for lesions in the ileal body, ileal inlet, neoterminal ileum, colonic and ileal blind loop was 0.61 (95% CI 0.49–0.73), 0.63 (95% CI 0.54–0.72), 0.61 (95% CI 0.49–0.74), 0.83 (95% CI 0.62–1.00) and 0.68 (95% CI 0.46–0.89). ConclusionThe interobserver agreement of the mRS is substantial. Similarly, the interobserver agreement is substantial for the updated Rutgeerts’ score. According to the REMIND score, the interobserver agreement was substantial for lesions in the neoterminal ileum, whereas only moderate for anastomotic lesions. Since therapeutic decisions in clinical practice are based on these assessments and these scores are used as outcome measure in clinical studies, further improvement of the interobserver agreement is essential.

P277 Interobserver agreement of current and new proposed endoscopic scores for postoperative recurrence in Crohn’s disease

Abstract Background The modified Rutgeerts’ score (mRS) is widely used for the assessment of endoscopic postoperative recurrence (ePOR) in Crohn’s disease (CD) after ileocolic resection to guide therapeutic decisions. To improve the validity and prognostic value of this endoscopic assessment, two new scores have been proposed. This study assessed the interobserver agreement of the current (mRS) and new endoscopic scores for ePOR in CD. Methods Sixteen academic and non-academic IBD specialists assessed endoscopic videos (n=71) of postoperative CD patients (n=66) retrieved from nine Dutch centers. Each video was assessed for the degree of inflammation by four gastroenterologists using the mRS, REMIND score (separate score of anastomosis and neoterminal ileum) and anatomic score (separate score of lesions at the anastomotic line, ileal body, ileal inlet, neoterminal ileum, colonic and/or ileal blind loop). Interobserver agreement was assessed using Fleiss’ weighted kappa. Results Fleiss’ weighted kappa for the mRS was 0.67 (95% confidence interval [CI] 0.59–0.74). The weighted kappa for the REMIND score was 0.73 (95% CI 0.65–0.80) for lesions in the neoterminal ileum and 0.46 (95% CI 0.35–0.58) for anastomotic lesions. In the anatomic score, the weighted kappa for lesions in the ileal body, ileal inlet, neoterminal ileum, colonic and ileal blind loop was 0.61 (95% CI 0.49–0.73), 0.63 (95% CI 0.54–0.72), 0.61 (95% CI 0.49–0.74), 0.83 (95% CI 0.62–1.00) and 0.68 (95% CI 0.46–0.89), and 0.44 (95% CI 0.32–0.55) for lesions at the anastomotic line. Conclusion The interobserver agreement of the mRS is substantial. Similarly, the interobserver agreement is substantial for lesions in the neoterminal ileum according to both the REMIND and anatomic score, whereas only moderate for anastomotic lesions. Since therapeutic decisions in clinical practice are based on these assessments and these scores are used as outcome measure in clinical studies, further improvement of agreement is essential.

DOP35 Spatial transcriptomics reveals cellular niches associated with histological inflammation in postoperative Crohn’s Disease

Abstract Background Postoperative Crohn’s disease (CD) recurs in ~70% of patients ≤1 year following ileocolonic resection (ICR), as observed endoscopically. Current understanding of molecular determinants underlying histological intestinal inflammation in patients with postoperative CD recurrence is minimal. To address this issue, we used advanced spatial transcriptomic analyses on intestinal biopsy samples with matched histological and endoscopic assessments from neoterminal ileum, anastomosis, and colon of patients with CD who had undergone colonoscopy following ICR. Methods Formalin-fixed paraffin-embedded (FFPE) tissue biopsies from neoterminal ileum, anastomosis, and colon were prospectively collected from a 15-patient cross-sectional cohort with CD who underwent routine endoscopic assessment following ICR. Spatial transcriptomics was performed on samples using 10X Genomics Visium CytAssist Spatial Gene Expression for FFPE V2.0. Annotation of tissue regions of histologically active inflammation and classification of histologically inactive (Robarts Histopathology Index ≤3 with subscores of 0 for neutrophils in the lamina propria and epithelium) or active disease were performed by an expert gastrointestinal pathologist. R programming language was used for data analysis (Figure). Results Fourteen of the 43 (32.6%) FFPE biopsies had histological evidence of inflammation. Spatial transcriptomics clustering revealed a distinct transcriptional signature by the segregation of 4 clusters ("inflamed clusters") composed mostly (≥69%) of cells from samples defined by histologically active disease. Tissue regions identified as inflamed by expert pathologist annotation contributed to >46% of inflamed clusters’ composition and <15% of remaining clusters. Cell type decomposition and cellular niche analysis revealed immune (e.g., myeloid, T cells, and B cells) and epithelial cells in close proximity sharing a similar microenvironment in 3 inflamed clusters while the 4th cluster was composed of >90% epithelial cells. Differentially expressed genes from the inflamed clusters were similarly expressed across intestinal segments including inflamed anastomotic biopsies and were enriched for signalling pathways involving immune cells recruitment/activation, inflammatory signalling, extracellular matrix organisation, and oxidative stress response. Conclusion This is the first study to explore spatial transcriptomic signatures associated with histological inflammation in patients with postoperative CD recurrence. Our analysis revealed a spatial signature of cellular niches and signalling pathways arising upon histological inflammation, providing insight into therapeutic targets and biomarkers across anatomic locations and the anastomosis.

Crohn's disease inflammation severity assessment with iodine density from photon counting CT enterography: comparison with endoscopic histopathology.

To determine optimal iodine density thresholds for active inflammation in CD patients with PCCT enterography and determine if iodine density can be used to stratify CD activity severity. A retrospective PACS search identified patients with CD imaged with PCCT enterography from 4/11/2022 to 10/30/2022 and with clinical notes, endoscopic/surgical pathology and available source PCCT data for iodine density analysis. Two abdominal radiologists with expertise in CD each drew two region of interest measurements within the visibly most affected region of terminal or neoterminal ileum wall on commercially available system (SyngoVia). Radiologists were blinded to clinical information and pathologic findings. Disease activity and severity were recorded from the pathology report. Harvey-Bradshaw Index, medications, and laboratory values were recorded. Receiver operating characteristic (ROC) curves were utilized to determine the optimum iodine density threshold for active inflammation and mild versus moderate-to-severe inflammation. Intra- and inter-reader agreement was assessed by intra-class correlation coefficient (ICC). 23 CD patients (15 females; mean [SD] age: 52 [17] years) imaged with PCCT enterography were included. 15/23 had active inflammation: 9/15 mild, 4/15 moderate, and 2/15 severe active inflammation. The optimal iodine density threshold for active inflammation was 2.7 mg/mL, with 97% sensitivity, 100% specificity, and 98% accuracy (AUC = 1.00). The optimal iodine density threshold for distinguishing mild from moderate-to-severe inflammation was 3.4 mg/mL, with 83% sensitivity, 89% specificity, and 87% accuracy (AUC = 0.85). Intra-reader reliability (R1/R2) ICC was 0.81/0.86. Inter-reader reliability ICC was 0.94. Iodine density from PCCT enterography can distinguish mild from moderate-to-severe active inflammation.

Identification of Potential Genes and Critical Pathways in Postoperative Recurrence of Crohn's Disease by Machine Learning And WGCNA Network Analysis.

Crohn's disease (CD) is a chronic idiopathic inflammatory bowel disease affecting the entire gastrointestinal tract from the mouth to the anus. These patients often experience a period of symptomatic relapse and remission. A 20 - 30% symptomatic recurrence rate is reported in the first year after surgery, with a 10% increase each subsequent year. Thus, surgery is done only to relieve symptoms and not for the complete cure of the disease. The determinants and the genetic factors of this disease recurrence are also not well-defined. Therefore, enhanced diagnostic efficiency and prognostic outcome are critical for confronting CD recurrence. We analysed ileal mucosa samples collected from neo-terminal ileum six months after surgery (M6=121 samples) from Crohn's disease dataset (GSE186582). The primary aim of this study is to identify the potential genes and critical pathways in post-operative recurrence of Crohn's disease. We combined the differential gene expression analysis with Recursive feature elimination (RFE), a machine learning approach to get five critical genes for the postoperative recurrence of Crohn's disease. The features (genes) selected by different methods were validated using five binary classifiers for recurrence and remission samples: Logistic Regression (LR), Decision tree classifier (DT), Support Vector Machine (SVM), Random Forest classifier (RF), and K-nearest neighbor (KNN) with 10-fold cross-validation. We also performed weighted gene co-expression network analysis (WGCNA) to select specific modules and feature genes associated with Crohn's disease postoperative recurrence, smoking, and biological sex. Combined with other biological interpretations, including Gene Ontology (GO) analysis, pathway enrichment, and protein-protein interaction (PPI) network analysis, our current study sheds light on the in-depth research of CD diagnosis and prognosis in postoperative recurrence. PLOD2, ZNF165, BOK, CX3CR1, and ARMCX4, are the important genes identified from the machine learning approach. These genes are reported to be involved in the viral protein interaction with cytokine and cytokine receptors, lysine degradation, and apoptosis. They are also linked with various cellular and molecular functions such as Peptidyl-lysine hydroxylation, Central nervous system maturation, G protein-coupled chemoattractant receptor activity, BCL-2 homology (BH) domain binding, Gliogenesis and negative regulation of mitochondrial depolarization. WGCNA identified a gene co-expression module that was primarily involved in mitochondrial translational elongation, mitochondrial translational termination, mitochondrial translation, mitochondrial respiratory chain complex, mRNA splicing via spliceosome pathways, etc.; Both the analysis result emphasizes that the mitochondrial depolarization pathway is linked with CD recurrence leading to oxidative stress in promoting inflammation in CD patients. These key genes serve as the novel diagnostic biomarker for the postoperative recurrence of Crohn's disease. Thus, among other treatment options present until now, these biomarkers would provide success in both diagnosis and prognosis, aiming for a long-lasting remission to prevent further complications in CD.

OP14 Prevention of postoperative recurrence of Crohn's disease with vedolizumab: First results of the prospective placebo-controlled randomised trial REPREVIO

Abstract Background Crohn’s disease (CD) is a chronic, immune-mediated inflammatory condition of the intestine, for which the majority of patients still needs to undergo surgical resection. Following the most common intervention ileocolonic resection, the vast majority of patients suffers from recurrence of CD in the neoterminal ileum. Endoscopic lesions usually precede symptoms in the first months after resection and predict the severity of the further disease course. No treatments have been approved for recurrence-prevention of CD. REPREVIO is a prospective placebo-controlled randomized trial investigating the preventive effect of vedolizumab, an anti-integrin antibody, on recurrence of CD. Methods Following ileocolonic resection, patients were treated with vedolizumab (300 mg IV at week 0,8,16 and 24) or PLC (1:1) at 12 sites in the Netherlands, France, Italy and Spain. Treatment was initiated within 4 weeks following ileocolonic resection with anastomosis. Six months following surgery, patients underwent ileocolonoscopy for assessment of recurrent lesions. Video recordings were centrally scored using the modified Rutgeerts’ score by 2 readers with adjudication in case of disagreement. The primary endpoint was endoscopic recurrence (ER) of CD (non-parametric); secondary endpoints were the proportion of patients with ER >i2a and clinical recurrence. Adverse events were recorded. Results 95 pts were screened and 80 randomized. All patients have reached month 6 and the videos are being analysed. We will receive the results of all statistical analysis in December, 2022. Conclusion The efficacy of vedolizumab postoperative recurrence-prevention treatment was studied in the REPREVIO study.

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<0.05). Cellular deconvolution was performed using xCell; and top enriched pathways and upstream regulators were analysed using IPA (p<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).

A nomogram incorporating ileal and anastomotic lesions separately to predict the long-term outcome of Crohn's disease after ileocolonic resection.

The Rutgeerts score (RS) is widely used to predict postoperative recurrence after ileocolonic resection for Crohn's disease (CD) based on the severity of lesions at the neoterminal ileum and anastomosis (RS i0-i4). However, the value of anastomotic ulcers remains controversial. Our aim was to establish a nomogram model incorporating ileal and anastomotic lesions separately to predict the long-term outcomes of CD after ileal or ileocolonic resection. A total of 136 patients with CD were included in this retrospective cohort study. Consecutive CD patients who underwent ileal or ileocolonic resections with postoperative ileocolonoscopy evaluation within 1 year after the surgery were included. The primary endpoint was postoperative clinical relapse (CR). An endoscopic classification separating ileal and anastomotic lesions was applied (Ix for neoterminal ileum lesions; Ax for anastomotic lesions). A nomogram was constructed to predict CR. The performance of the model was evaluated by the receiver-operating characteristic (ROC) curve and decision curve analysis (DCA). CR was observed in 47.1% (n = 64) of patients within a median follow-up of 26.9 (interquartile range, 11.4-55.2) months. The risk of CR was significantly higher in patients with an RS ⩾ i2 assessed by the first postoperative endoscopy compared with patients with an RS ⩽ i1 (p < 0.001). Moreover, the cumulative rate of CR was significantly higher in patients with ileal lesions (I1-4) compared with patients without (I0) (p < 0.001). Besides, patients with anastomotic lesions (A1-3) had significantly higher rates of CR than patients without (A0) (p = 0.002). A nomogram, incorporating scores of postoperative ileal or anastomotic lesions, sex, L2-subtype and perianal disease, was established. The DCA analysis indicated that the nomogram had a higher benefit for CR, especially at the timeframe of 24-60 months after index endoscopy, compared to the traditional RS score. A nomogram incorporating postoperative ileal and anastomotic lesions separately was developed to predict CR in CD patients, which may serve as a practical tool to identify high-risk patients who need timely postoperative intervention.

Contemporary Management of Postoperative Crohn's Disease after Ileocolonic Resection.

Surgery remains an important treatment modality in the multidisciplinary management of patients with Crohn's disease (CD). To illustrate the recent advances in the management of postoperative CD we outline the contemporary approach to treatment: diagnosing disease recurrence using endoscopy or noninvasive methods and risk stratification underlying decisions to institute treatment. Endoscopic scoring indices are being refined to guide treatment decisions by accurately estimating the risk of recurrence based on endoscopic appearance. The original Rutgeerts score has been modified to separate anastomotic lesions from lesions in the neoterminal ileum. Two further indices, the REMIND score and the POCER index, were recently developed with the same intention. Noninvasive monitoring for recurrence using a method with high negative predictive value has the potential to simplify management algorithms and only perform ileocolonoscopy in a subset of patients. Fecal calprotectin, intestinal ultrasound, and magnetic resonance enterography are all being evaluated for this purpose. The use of infliximab for the prevention of postoperative recurrence is well supported by data, but management decisions are fraught with uncertainty for patients with previous exposure to biologics. Data on the use of ustekinumab and vedolizumab for postoperative CD are emerging, but controlled studies are lacking.

Comparison of the risk of Crohn's disease postoperative recurrence between modified Rutgeerts score i2a and i2b categories: an individual patient data meta-analysis.

The modified Rutgeerts' score differentiates i2a - lesions confined to the anastomosis - and i2b - more than 5 aphthous ulcers in the neoterminal ileum with normal intervening mucosa, with or without anastomotic lesions - categories. Its relevance for the therapeutic management of Crohn's disease (CD) patients after ileocolic resection is still debated. Our objective was to compare the postoperative recurrence risk in patients with an i2a or i2b score using an individual patient data meta-analysis. We conducted a systematic literature search until July 2020 to identify all relevant studies reporting the i2a/i2b status in the year following ileocolic resection and clinical and/or surgical postoperative CD recurrence in their follow-up. Individual patient level data were obtained from the corresponding authors. The association between the modified RS and time-to-event was evaluated using a mixed Cox model with the center as the random effect. Seven studies published between 2008 and 2019 were included corresponding to 400 patients: 189 (47%) i2a and 211 (53%) i2b. Median (interquartile range, IQR) time from ileocolic resection to ileocolonoscopy was 6.2 (5.5, 7.9) months and median (IQR) follow-up time after ileocolonoscopy was 4.5 (2.9, 7.3) years. The risk of clinical postoperative recurrence at 1 and 3 years was 11% [6%-15%], and 25% [18%-32%] in the i2a group versus 9% [5%-13%] and 33% [26%-41%] in the i2b group (p=0.63 and p=0.12, respectively). No significant difference was observed in terms of time to clinical postoperative recurrence (p=0.16) or surgical postoperative recurrence (p=0.87). Results did not change after excluding patients having initiated an immunosuppressant or a biologic in the three months after endoscopy (remaining cohort, n=361). In this individual patient data meta-analysis, no difference was observed between i2a and i2b subcategories with regards to clinical or surgical postoperative recurrence. As we wait for prospective trials, the same treatment strategy could be applied to all patients classified as i2 on the Rutgeerts score.

Early Initiation of Antitumor Necrosis Factor Therapy Reduces Postoperative Recurrence of Crohn's Disease Following Ileocecal Resection.

Postoperative recurrence (POR) of Crohn's disease (CD) is common after surgical resection. We aimed to compare biologic type and timing for preventing POR in adult CD patients after ileocecal resection (ICR). We performed a retrospective cohort study of CD patients who underwent an ICR at 2 medical centers. Recurrence was defined by endoscopy (≥ i2b Rutgeerts score) or radiography (active inflammation in neoterminal ileum) and stratified by type and timing of postoperative prophylactic biologic within 12 weeks following an ICR (none, tumor necrosis factor antagonists [anti-TNF], vedolizumab, and ustekinumab). We identified 1037 patients with CD who underwent an ICR. Of 278 (26%) who received postoperative prophylaxis, 80% were placed on an anti-TNF agent (n = 223) followed by ustekinumab (n = 28, 10%) and vedolizumab (n = 27, 10%). Prophylaxis was initiated in 35% within 4 weeks following an ICR and in 65% within 4 to 12 weeks. After adjusting for factors associated with POR, compared with no biologic prophylaxis, the initiation of an anti-TNF agent within 4 weeks following an ICR was associated with a reduction in POR (adjusted hazard ratio, 0.61; 95% CI, 0.40-0.93). Prophylaxis after 4 weeks following an ICR or with vedolizumab or ustekinumab was not associated with a reduction in POR compared with those who did not receive prophylaxis. Early initiation of an anti-TNF agent within 4 weeks following an ICR was associated with a reduction in POR. Vedolizumab or ustekinumab, at any time following surgery, was not associated with a reduction in POR, although sample size was limited.

Role of adherent and invasive Escherichia coli in Crohn’s disease: lessons from the postoperative recurrence model

ObjectiveWe used the postoperative recurrence model to better understand the role of adherent and invasive Escherichia coli (AIEC) bacteria in Crohn’s disease (CD), taking advantage of a well-characterised postoperative cohort.DesignFrom...

Identification of Gene Expression Profiles Associated with an Increased Risk of Post-Operative Recurrence in Crohn's Disease.

Ileocolonic resection is frequently needed in the course of Crohn's disease [CD] treatment and post-operative recurrence is extremely common. Our main objective was to analyse gene expression in the mucosa of CD patients at the time of surgery and at post-operative endoscopy, in order to identify predictors and mechanisms of early endoscopic recurrence. We conducted transcriptome analyses on ileal mucosa samples collected from inflamed sections of the surgical specimens [n = 200], from ileal resection margins [n = 149] and in the neo-terminal ileum 6 months after surgery [n = 122]; these were compared with non-inflammatory bowel disease controls [n = 25]. The primary endpoint was post-operative endoscopic recurrence at 6 months. We applied regression models to identify gene signatures predicting endoscopic recurrence. Chronic inflammation was associated with strong expression of inflammatory genes [IL-6, IL-8, IL-1B] and decreased expression of genes involved in metabolic processes, but with a high inter-individual heterogeneity. Gene signatures associated with early endoscopic recurrence were mainly characterized by upregulation of TNFα, IFNγ, IL23A and IL17A. Pathway analyses showed that upregulation of mitochondrial dysfunction within the inflamed sections and JAK/STAT at the ileal margin were predictive of post-operative recurrence. A combined model integrating these top pathway signatures improved the prediction of endoscopic recurrence [area under the curve of 0.79]. STAT3 phosphorylation at the surgical ileal margin was associated with severe recurrence at 6 months. We identified several biological pathways in surgical ileal mucosa specimens associated with an increased risk of disease recurrence. Integration of the JAK/STAT and mitochondrial dysfunction pathways in the clinical model improved the prediction of post-operative recurrence.

POINT-OF-CARE INTESTINAL ULTRASOUND FOR THE DETECTION OF POSTOPERATIVE CROHN’S DISEASE ENDOSCOPIC RECURRENCE

Abstract BACKGROUND In patients with Crohn’s disease (CD), following an ileocolic resection (ICR), colonoscopy is the gold standard for the detection of endoscopic recurrence (ER). Colonoscopy, however, is invasive and not easily accepted by patients for repeated monitoring. In contrast, transabdominal intestinal ultrasound (IUS) is non-irradiating, non-invasive, and easy to repeat. The goal of this study was to assess the accuracy of IUS for ER in CD. METHODS This was a cross-sectional study of CD patients who underwent point-of-care IUS during a postoperative follow-up clinic visit within 30 days of a planned colonoscopy. Parameters on IUS included bowel wall thickness (BWT), bowel wall hyperemia (BWH), layer stratification, inflammatory fat, lymphadenopathy, and complications. C-reactive protein (CRP), fecal calprotectin (FC), endoscopic healing index (EHI) and Harvey Bradshaw Index (HBI) were also measured. ER was defined as a Rutgeerts Score (RS) ≥ i2. Primary outcome was the association between IUS parameters and ER. Secondary outcomes were the association of IUS parameters with other markers of disease activity. Univariable analysis – Fisher’s exact, Wilcoxon Rank Sum and Spearman correlation coefficient tested associations with ER. Area under the receiver operator curve (ROC) was used to determine optimal cut-off values for BWT to accurately identify ER. RESULTS Eighteen CD patients (9 female; 29 [19-40] years old), underwent IUS examination 45 [29-99] months post-ICR. All patients underwent endoscopy within 30 days of IUS examination, four (22%) for the first time post-ICR. Seven (39%) patients were on ustekinumab, four (22%) on adalimumab, two (11%) on infliximab, one (6%) on vedolizumab, and four (22%) on no therapy. ER was found in eight (44%) patients. BWT and BWH in the neo-terminal ileum and BWH at the ileocolic anastomosis were the only IUS parameters associated with ER (Table 1). BWT was 4.0 [3.2-4.8] mm in patients with ER vs. 2.0 [1.5-2.6] mm without (p=0.04). Neo-terminal ileum BWH was abnormal in six (75%) patients with ER vs. 0% without (p=0.007). BWT of 3.2 mm was the optimal cut point for predicting ER with an: AUROC of 0.82, positive predictive value of 100%, negative predictive value of 97.3%, sensitivity of 75%, and specificity of 100% (Figure 1) vs. a CRP of 10.4 mg/L (AUROC = 0.54) or FC of 1146 μg/g (AUROC = 0.56). Significant correlations were observed between neo-terminal ileum BWT and RS (ρ=0.51, p=0.04) and between BWT and CRP (ρ=-0.56, p=0.023), but not BWT and FC (ρ=-0.04, p=0.91), BWT and EHI (ρ=-0.04, p=0.91), or BWT and HBI (ρ=0.09, p=0.75). CONCLUSIONS IUS is a feasible, accurate, non-invasive monitoring tool for detection of postoperative CD recurrence. Larger prospective studies are needed to determine how IUS can be integrated in the monitoring of CD patients after surgery.