Postoperative Recurrence Of Crohn Research Articles

Pre-operative visceral adipose tissue radiodensity is a potentially novel prognostic biomarker for early endoscopic post-operative recurrence in Crohn's disease.

Evidence suggests inflammatory mesenteric fat is involved in post-operative recurrence (POR) of Crohn's disease (CD). However, its prognostic value is uncertain, in part, due to difficulties studying it non-invasively. To evaluate the prognostic value of pre-operative radiographic mesenteric parameters for early endoscopic POR (ePOR). We conducted a retrospective cohort study of CD subjects ≥ 12 years who underwent ileocecal or small bowel resection between 1/1/2007 to 12/31/2021 with computerized tomography abdomen/pelvis ≤ 6 months pre-operatively and underwent ileocolonoscopy ≤ 15 months post-operatively. Visceral adipose tissue (VAT) volume (cm3), ratio of VAT:subcutaneous adipose tissue (SAT) volume, VAT radiodensity, and ratio of VAT:SAT radiodensity were generated semiautomatically. Mesenteric lymphadenopathy (LAD, largest lymph node > 10 mm) and severe vasa recta (VR) engorgement (diameter of the VR supplying diseased bowel ≥ 2 × VR supplying healthy bowel) were derived manually. The primary outcome was early ePOR (Rutgeert's score ≥ i2 on first endoscopy ≤ 15 months post-operatively) and the secondary outcome was ePOR severity (Rutgeert's score i0-4). Regression analyses were performed adjusting for demographic and disease-related characteristics to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). Of the 139 subjects included, 45% of subjects developed early ePOR (n = 63). VAT radiodensity (aOR 0.59, 95%CI: 0.38-0.90) and VAT:SAT radiodensity (aOR 8.54, 95%CI: 1.48-49.28) were associated with early ePOR, whereas, VAT volume (aOR 1.23, 95%CI: 0.78-1.95), VAT:SAT volume (aOR 0.80, 95%CI: 0.53-1.20), severe VR engorgement (aOR 1.53, 95%CI: 0.64-3.66), and mesenteric LAD (aOR 1.59, 95%CI: 0.67-3.79) were not. Similar results were observed for severity of ePOR. VAT radiodensity is potentially a novel non-invasive prognostic imaging marker to help risk stratify CD patients for POR.

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.

Role of ICAM-1 in the Adhesion of T Cells to Enteric Glia: Perspectives in the Formation of Plexitis in Crohn’s Disease

Background & AimsThe presence of myenteric plexitis in the proximal resection margins is a predictive factor of early postoperative recurrence in Crohn’s disease. To decipher the mechanisms leading to their formation, T cell interactions with enteric neural cells were studied in vitro and in vivo. MethodsT cells close to myenteric neural cells were retrospectively quantified in ileocolonic resections from 9 control subjects with cancer and 20 patients with Crohn’s disease. The mechanisms involved in T cell adhesion were then investigated in co-cultures of T lymphocytes with enteric glial cells (glia). Finally, the implication of adhesion molecules in the development of plexitis and colitis was studied in vitro, but also in vivo in Winnie mice. ResultsThe mean number of T cells close to glia, but not neurons, was significantly higher in the myenteric ganglia of relapsing patients with Crohn’s disease (2.42+/-0.5) as compared to controls (0.36+/-0.08, p=0.0007). Co-culture experiments showed that exposure to pro-inflammatory cytokines enhanced T cell adhesion to glia and increased ICAM-1 expression in glia. We next demonstrated that T cell adhesion to glia was inhibited by an anti-ICAM-1 antibody. Finally, using the Winnie mouse model of colitis, we showed that the blockage of ICAM-1/ LFA-1 with lifitegrast reduced colitis severity and decreased T cell infiltration in the myenteric plexus. ConclusionsOur present work argues for a role of Glia-T cell interaction in the development of myenteric plexitis through the adhesion molecules ICAM-1/LFA-1, and suggests that deciphering the functional consequences of Glia-T cell interaction is important to understand the mechanisms implicated in the development and recurrence of Crohn’s disease.

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.

P190 Identification of clinical risk factors for postoperative endoscopic recurrence in Crohn’s disease: a prospective, multicenter cohort study

Abstract Background Further refinement of clinical risk stratification for postoperative endoscopic recurrence in patients with Crohn’s disease is required to identify patients who will benefit from prophylactic therapy. Therefore, we aimed to assess risk factors for endoscopic recurrence in a large prospective, multicenter cohort study. Methods CD patients (≥16 years) scheduled for ileocolic (re-)resection (ICR) and those who underwent an ileocolonoscopy at 6 months following ICR were included. Primary outcome of the study was endoscopic recurrence (modified Rutgeerts’ score ≥ i2b at 6 months). Multivariable logistic regression was performed to identify clinical risk factors. The model included a random effect for the study center to correct for potential correlation between treating center and the outcome. Results In total, 298 patients underwent ICR (79.2% primary ICR, 20.8% re-resection) after a median disease duration of 5.3 years (IQR 1.0 – 12.4). 60.4% of patients were female with a median age at surgery of 34.1 years (IQR 25.7 – 50.5). 67.8% of the patients were exposed to ≥1 biological prior to surgery. Postoperative prophylactic medication (<12 weeks to ICR) was initiated in 85/298 (28.5%) patients; 24.7% immunomodulator, 29.4% anti-TNF, 27.1% combination therapy [immunomodulator with anti-TNF agent], 4.7% vedolizumab, 14.1% ustekinumab. Mean time to postoperative ileocolonoscopy was 6.2 months (SD 1.3). Endoscopic recurrence was diagnosed in 37.9% of the patients. Multivariable logistic regression identified active smoking (adjusted OR [aOR] 3.12; 95% CI 1.63 – 5.98) and penetrating disease behaviour (aOR 1.92; 95% CI 1.04 – 3.57) as risk factors for endoscopic recurrence, whilst ileocolic disease (versus ileal disease; aOR 0.27; 95% CI 0.15 – 0.49) and postoperative prophylactic medication (aOR 0.24; 95% CI 0.12 – 0.47) were identified as protective factors for endoscopic recurrence (Table 1). Conclusion Active smoking and penetrating disease behaviour at time of surgery were identified as risk factors for early postoperative recurrence in Crohn’s disease. Reversely, ileocolic disease at time of surgery and initiation of postoperative prophylactic medication were identified as protective factors for early endoscopic recurrence. Young age at surgery, perianal disease and a prior intestinal resection, included as risk factors in the current international guidelines, were not associated with early endoscopic postoperative recurrence in this large prospective cohort study.

P027 Involvement of PD-L1 in myenteric plexitis associated with postoperative recurrence of Crohn's disease

Abstract Background Despite a growing therapeutic armamentarium, post-operative recurrence (POR) in Crohn’s disease (CD) remains frequent. The presence of myenteric plexitis at the proximal margin of ileocolonic resection has been recognized as a risk factor for early POR. They are defined by the accumulation of immune cells in contact with the ganglia of the myenteric plexus. In preliminary work, we have shown an increase in the number of T lymphocytes (TL) in contact with enteric glial cells (EGC) in patients with CD depending on ICAM-1/LFA-1 pathway. As CD is classically associated with a Th1 immune response, the aim of this work was to study the impact of EGC/CD4+ TL contacts on Th1-type cytokine production (IFNγ and its transcription factor Tbet) and to identify molecules that may be involved in these regulations. Methods In vitro in rats, the impact of EGC/CD4+ TL co-culture on IFNγ production was studied by ELISA and qPCR of the transcription factor Tbet. The expression and regulation of PD-L1, a candidate molecule, was then analyzed in murine and human EGC by qPCR and immunohisto/cytochemistry. Results While EGC alone produced only a small amount of IFNγ, there was a significant reduction in IFNγ production in EGC/CD4+ TL co-cultures compared with CD4+ TL alone. Yet the proportion of CD4+ TL cells capable of producing IFNγ was significantly increased in contact with EGC, as was their survival. In parallel, Tbet was downregulated in CD4+ TL in contact with EGC. These results suggested the involvement of PD-L1, a molecule known to negatively regulate cytokine production (notably IFNγ) and Tbet expression. Expression of PD-L1 mRNA and its protein was demonstrated in murine and human EGC and was upregulated under pro-inflammatory conditions. Analysis of transmural sections at the proximal margin of ileocolonic resection from patients (n=15 controls, n=14 CD without POR, n=15 CD with POR) showed PD-L1 expression in myenteric ganglia that was restricted to EGC (no neuronal expression) (Figure 1A). PD-L1 fluorescence intensity in myenteric ganglia at the proximal resection margin was significantly lower in CD patients with POR than in controls (∆13.5%; p=0.012) (Figure 1B). Conclusion Lower IFNγ production in EGC/CD4+ TL co-cultures associated with reduced Tbet expression by TL in contact with EGC suggest a role of PD-L1 in myenteric plexitis. PD-L1 expression has been demonstrated in murine and human EGC, with significantly lower expression in myenteric ganglia located at the proximal resection margin of CD patients with POR compared with controls. Blocking the ICAM-1/LFA-1 pathway and/or restoring the PD-1/PD-L1 loop could be of interest for developing strategies to prevent and/or treat POR in CD patients.

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.

P081 The integration of transcriptomic and microbiomic data links several intestinal bacterial families with key biological functions in the development of postoperative recurrence in Crohn's disease

Abstract Background Crohn's disease (CD) is characterized by an imbalance between the microbiota and the host. The severity of CD leads to intestinal resection. However, more than half of the patients not receiving prophylaxis experience post-operative recurrence (POR) within one year. The main objective of this study has been to improve the knowledge of the pathophysiological bases of POR through the integration of transcriptome and microbiome data. Methods Samples of inflamed and microscopically non-inflamed ileal mucosa were collected from patients with CD undergoing intestinal resection. The severity of POR was classified according to the Rutgeerts endoscopic index: without recurrence (i0+i1, n=12) and with recurrence (i2+i3+i4, n=8). Samples of healthy ileal tissue were also obtained from patients with colorectal cancer (n=10). Gene expression was evaluated by microarrays and organized into co-expression modules. By sequencing the V3-V4 region of the 16S rRNA gene, intestinal bacteria were identified and classified at the genus and family taxonomic level. The differential expression and correlations between the two sources of omics information were studied. Next, the analysis of pathway enrichment and clustering was carried out according to the severity of the POR and the intestinal area affected or not (graphical abstract A). Results The results of the integrative analysis in the uninflamed area of patients without recurrence showed that Actinomycetales negatively correlated with COX6A1 and MTRF1L, related to mitochondrial respiration (GO:0098803; q=0.004) and protein synthesis (R-HSA-72766; q=0.034) (B). These genes and bacteria also played a key role in modules 3 and 25 related to the respiratory chain. In contrast, the inflamed area of recurrent patients showed a positive correlation of the Xanthomonadaceae family in the regulation of neutrophil granules (GO:0035579; q=0.011), with the key participation of the ITGAM transcript (C). This transcript was also related to integrins (R-HSA-216083; q=0.007) in the transcriptomic analyses. In addition, Porphyromonadaceae correlated with LSR and TFF1, involved in epithelium maintenance (GO:0010669; q=0.012) and A group in the Lachnospiradaceae family correlated with CDC20 and CDT1, linked to the cell cycle (q=0.019). Conclusion Bacterial families, involved in butyrate production, such as Porphyromonadaceae and Lachnospiradaceae, could influence functions that remember to epithelial regeneration in recurrent patients, while Actinomycetales are associated with a normalization in energy production in uninflamed areas of resections of patients without POR. These findings reveal a potential interaction between the microbiota and the pathophysiology of POR in patients with CD.

P168 Specialized pro-resolving lipid mediator Resolvin D1 and omega 6 dihomo-γ-linolenic acid are unable to solve inflammation in the creeping fat of patients with severe postoperative recurrence in Crohn's disease

Abstract Background The ω3 derivate resolvin D1 (RvD1), and the ω6 dihomo-γ-linolenic acid (DGLA) prevent collateral damage by overcoming inflammation and enhancing microbial clearance. In Crohn's disease, the mesenteric adipose tissue becomes inflamed and hyperplasies due to transmural lesions and bacterial translocation, developing the so-called creeping fat. This tissue is unable to clear inflammation and has been linked to severer intestinal inflammation and post-operative recurrence (POR). Recently, we have described the presence of DGLA and the increase in the ω6/ω3 ratio together with pro-inflammatory mediators in the creeping fat at surgery. Our aims were study the mechanisms within the inflammatory resolution related to polyunsaturated fatty acids depending on POR severity. Methods Creeping fat samples were obtained in the intestinal resection of Crohn's disease patients and endoscopic POR was evaluated according to the Rutgeerts score: non recurrence (i0+i1; n=18), mild recurrence (i2; n=14) and severe recurrence (i3+i4; n=10). Mesenteric adipose tissue was also collected from patients with colorectal cancer (n=10) and severe obesity (n=11) as reference groups. RvD1 was evaluated by C18/ELISA, lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) activity by radioassay, and the free fatty acid receptor 1 (FFAR1) expression by qRT-PCR. Results RvD1 was increased in the creeping fat in comparison to the mesenteric adipose tissues of the reference groups (Graphical abstract A) and correlated antagonistically with pro-inflammatory mediators in non-recurrence versus severe recurrence (B). Specifically, factors such as TNF-α, CD14 or IL-18 showed significant positive correlations with RvD1 in severe recurrence while negative in non recurrence. The LPL/HSL ratio indicated greater storage of fatty acids in severe recurrence creeping fats (C), and only in these patients, DGLA negatively correlated with HSL (D) and FFAR1 (E), a receptor that was only detected in Crohn's disease (F). At the same time, this receptor antagonistically correlated with pro-inflammatory mediators such as IL-8 in the creeping fat, positively in non-recurrence and negatively in severe recurrence (G). Conclusion The RvD1 increase suggests a greater production of this factor from ω3, but that would be insufficient to resolve inflammation in severe recurrent creeping fat at surgery time. In this phenotype, HSL activity is linked to a lower presence of DGLA, the only anti-inflammatory ω6. In contrast, the presence of this ligand in severe recurrents seems to reduce the expression of the FFAR1, which acts on the neutrophil function. Thus, immune-inflammation derived from lipid metabolism is antagonistic among the most disparate cases of POR in the creeping fat at surgery.

The Management of Postoperative Recurrence in Crohn's Disease.

Crohn's disease (CD) is a chronic inflammatory bowel disease with different phenotypes of presentation, inflammatory, penetrating, or stricturing disease, that significantly impacts patient well-being and quality of life. Despite advances in medical therapy, surgery sometimes represents the only treatment to address complications, such as strictures, fistulas, or abscesses. Minimizing postoperative recurrence (POR) remains a major challenge for both clinicians and patients; consequently, various therapeutic strategies have been developed to prevent or delay POR. The current review outlines an updated overview of POR management. We focused on diagnostic assessment, which included endoscopic examination, biochemical analyses, and cross-sectional imaging techniques, all crucial tools used to accurately diagnose this condition. Additionally, we delved into the associated risk factors contributing to POR development. Furthermore, we examined recent advances in the prophylaxis and treatment of POR in CD.

Outcomes and endpoints of postoperative recurrence in Crohn's Disease: systematic review and consensus conference.

Outcomes after ileocolonic resection in Crohn's Disease (CD) are heterogeneous and a clear definition of postoperative recurrence remains to be determined. Our Endpoints Working Group of the International Organization for the study of Inflammatory Bowel Disease (IOIBD) aimed to standardize postoperative outcomes, to discuss which endpoints should be used for postoperative clinical trials and to define those which could be used in trials or registries. Based on a systematic review of the literature, recommendations and statements were drafted and sent to all IOIBD members for a first round of voting. Recommendations and statements were revised based on the voters' comments during a consensus hybrid conference open to all IOIBD members. If no agreement was reached after 2 rounds of voting, the statement was excluded. In the systematic review, 3,071 manuscripts were screened, of which 434 were included. Sixteen recommendations were identified, of which 11 were endorsed. Recommendations and statements include that endoscopy remains the gold standard and should be used as a short-term primary endpoint in both observational cohorts and randomized controlled trials. Clinical symptoms classically used in clinical trials for luminal CD are not reliable in this specific situation. For that reason, longer term endpoints should be based on the evidence of macroscopic inflammation assessed by imaging techniques, endoscopy or reflected by the presence of complications. Agencies recommend the use of clinical evaluations, as in the case of luminal CD, and do not recognize primary endpoints based solely on endoscopy. This consensus has led to agreement on the need to define postoperative endoscopy- and/or imaging-based endpoints.

The Management of Postoperative Recurrence in Crohn’s Disease

The Management of Postoperative Recurrence in Crohn’s Disease

Histologic 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 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. In this study, we retrospectively reviewed 205 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. 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 in three cohorts. 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. 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.

Postoperative Recurrence of Crohn’s Disease–Is the Early Use of Postoperative Immunomodulators Able to Modify Prognosis?

Postoperative Recurrence of Crohn’s Disease–Is the Early Use of Postoperative Immunomodulators Able to Modify Prognosis?

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

APMISVolume 131, Issue S147 p. 1-46 Supplement Article Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort Johan Burisch, Corresponding Author Johan Burisch [email protected] University of Copenhagen, Copenhagen, DenmarkSearch for more papers by this author Johan Burisch, Corresponding Author Johan Burisch [email protected] University of Copenhagen, Copenhagen, DenmarkSearch for more papers by this author First published: 19 June 2023 https://doi.org/10.1111/apm.13334Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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Saccharomyces cerevisiae prevents postoperative recurrence of Crohn's disease modeled by ileocecal resection in HLA-B27 transgenic rats

Postoperative recurrence (POR) after ileocecal resection (ICR) affects most Crohn's disease patients within 3-5 years after surgery. Adherent-invasive Escherichia coli (AIEC) typified by the LF82 strain are pathobionts that are frequently detected in POR of Crohn's disease and have a potential role in the early stages of the disease pathogenesis. Saccharomyces cerevisiae CNCM I-3856 is a probiotic yeast reported to inhibit AIEC adhesion to intestinal epithelial cells and to favor their elimination from the gut. To evaluate the efficacy of CNCM I-3856 in preventing POR induced by LF82 in an HLA-B27 transgenic (TgB27) rat model. Sixty-four rats [strain F344, 38 TgB27, 26 control non-Tg (nTg)] underwent an ICR at the 12th wk (W12) of life and were sacrificed at the 18th wk (W18) of life. TgB27 rats were challenged daily with oral administration of LF82 (109 colony forming units (CFUs)/day (d), n = 8), PBS (n = 5), CNCM I-3856 (109 CFUs/d, n = 7) or a combination of LF82 and CNCM I-3856 (n = 18). nTg rats receiving LF82 (n = 5), PBS (n = 5), CNCM I-3856 (n = 7) or CNCM I-3856 and LF82 (n = 9) under the same conditions were used as controls. POR was analyzed using macroscopic (from 0 to 4) and histologic (from 0 to 6) scores. Luminal LF82 quantifications were performed weekly for each animal. Adherent LF82 and inflammatory/regulatory cytokines were quantified in biopsies at W12 and W18. Data are expressed as the median with the interquartile range. nTg animals did not develop POR. A total of 7/8 (87%) of the TgB27 rats receiving LF82 alone had POR (macroscopic score ≥ 2), which was significantly prevented by CNCM I-3856 administration [6/18 (33%) TgB27 rats, P = 0.01]. Macroscopic lesions were located 2 cm above the anastomosis in the TgB27 rats receiving LF82 alone and consisted of ulcerations with a score of 3.5 (2 - 4). Seven out of 18 TgB27 rats (39%) receiving CNCM I-3856 and LF82 had no macroscopic lesions. Compared to untreated TgB27 animals receiving LF82 alone, coadministration of CNCM I-3856 and LF82 significantly reduced the macroscopic [3.5 (2 - 4) vs 1 (0 - 3), P = 0.002] and histological lesions by more than 50% [4.5 (3.3 - 5.8) vs 2 (1.3 - 3), P = 0.003]. The levels of adherent LF82 were correlated with anastomotic macroscopic scores in TgB27 rats (r = 0.49, P = 0.006), with a higher risk of POR in animals having high levels of luminal LF82 (71.4% vs 25%, P = 0.02). Administration of CNCM I-3856 significantly reduced the levels of luminal and adherent LF82, increased the production of interleukin (IL)-10 and decreased the production of IL-23 and IL-17 in TgB27 rats. In a reliable model of POR induced by LF82 in TgB27 rats, CNCM I-3856 prevents macroscopic POR by decreasing LF82 infection and gut inflammation.

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 >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.

P455 Comparison of two strategies for the management of post-operative recurrence in Crohn’s disease patients with one clinical risk factor: a multicentre IG-IBD study

Abstract Background Prevention of postoperative recurrence (POR) in Crohn’s disease (CD) after ileo-colonic (IC) resection is still a highly debated topic. Prophylactic immunosuppression after surgery is currently recommended in presence of at least one clinical risk factor (RF). Due to drug-related adverse events and the relative high cost of biologics, we aimed to determine whether prevention of POR can be postponed and guided by endoscopy in CD patients with only one RF. Methods A multicentre retrospective study was conducted in 12 IG-IBD Italian centres. CD patients with only one RF for POR, including previous intestinal resection, extensive small intestine resection (>50 cm), fistulising phenotype, history of perianal disease, or active smoking were considered. Patients who performed a colonoscopy between 6 to 12 months after curative IC resection were included. Two groups were formed based on whether immunosuppressive therapy was started immediately after surgery (prophylaxis group) or guided by endoscopy (observation group). Primary endpoints were the rates of any endoscopic recurrence (Rutgeerts ≥i2a) and severe endoscopic recurrence (i4) within 12 months after surgery. Secondary outcomes were clinical recurrence (HBI≥5) rates at 6, 12 and 24 months after surgery. Results A total of 195 patients were enrolled. Out of all, 61 (31.3%) received immunoprophylaxis at a median time of 32 days [IQR 26-55] after surgery (n=14 infliximab, n=37 adalimumab, n=7 azathioprine, n=3 ustekinumab). Baseline patient characteristics are detailed in Table 1. Particularly, risk factors for POR were homogeneously distributed between the 2 groups. Colonoscopy was performed after a median time of 8 months [IQR 6-11]. No differences between immunoprophylaxis and endoscopy-driven approach was found regarding any endoscopic recurrence (36.1% in prophylaxis group vs 45.5% in observation group, p=0.10) and severe endoscopic recurrence (9.8% in prophylaxis group vs 15.7% in observation group, p=0.15). In 32 patients with a second colonoscopy at a median time of 30.5 months [IQR 22-43.75] after surgery, any recurrence and severe recurrence rates were also similar (p=0.55 and p=0.43, respectively). Early clinical recurrence at 6 months was reported in 23.4% of patients on immunoprophylaxis vs 31.5% who were not (p=0.43). Clinical recurrence rates between prophylaxis and observation group were also similar at 12 months (17.9% vs 34.8%, respectively, p=0.09) and at 24 months (17.9% vs 24.1%, respectively, p=0.63). Conclusion In CD patients with only one RF for POR, immediate immunoprophylaxis after curative IC resection does not decrease the rate of early clinical and endoscopic recurrence. Prospective and larger studies are needed to confirm our results.

DOP78 Does KONO-S anastomosis reduce recurrence in Crohn's disease compared to conventional ileocolonic anastomosis ? A nationwide propensity score-matched study from GETAID Chirurgie Group (KoCoRICCO study).

Abstract Background The ileocolonic anastomosis is the main site of postoperative recurrence in Crohn's disease. In 2003, Kono et al. described a new operative technique that could reduce the rate of postoperative recurrence (Kono-S anastomosis). Recently, a randomized monocenter study showed a significant decrease in endoscopic recurrence rate at 6 and 18 months (22.2% vs 62.8% and 25% vs 67.4%), as well as a decrease in clinical recurrence (Luglio. AnnSurg 2020). Nevertheless, the level of evidence remains too low to establish practice recommendations. The KoCoRICCO study aimed to compare outcomes between both techniques in two nationwide prospective cohorts. Methods Adult patients with Crohn's disease requiring ileocolonic resection with Kono-S anastomosis (KA Group) were prospectively included in 7 french referral centers between 2020 and 2022. Patients with conventional side-to-side anastomosis (CA Group) were enrolled from a previously publish nationwide cohort (Maggiori et al. Ann Surg 2019). Comparisons between two groups were performed for postoperative morbidity in the overall population. To deal with confounding factors distributed inequally among groups, a propensity score analysis was performed in patients with available endoscopic follow-up to compare recurrence at first endoscopy in a matched 1:2 ratio population. Parameters involved in the propensity score were: sex, active smoking, history of bowel resection, penetrating and anoperineal disease, preop and postop biological therapy. Results A total of 432 patients with ileocolonic anastomosis were enrolled, of whom 155 (35.9%) had a Kono-S anastomosis (Figure 1). Before matching both groups were unbalanced for preoperative, intraoperative and postoperative characteristics. Severe surgical morbidity according to Dindo-Clavien was 4.6% and 7.6% in the KA and CA groups, respectively (p<0.0001). In patients with available endoscopic follow-up, 61 patients in the KA group were matched with 122 in the CA group with the use of the propensity score. In the matched population, mean delay between surgery and endoscopic assessment was 7.4 months (SD ±3.0) and not statistically different between both groups. Endoscopic recurrence ≥ i2 was found in 29 patients (47.5%) and 54 patients (44.3%) in the KA group and CA group, respectively (p=0.6745). In unconditionnal logistic regression, Kono-S anastomosis was not associated with a lower risk of endoscopic recurrence: OR = 1.141 (95% CI 0.616-2.114, p=0.5147). Conclusion Kono-S could be associated with reduced severe morbidity compared to a conventional side-to-side anastomosis in Crohn's disease but does not seem to reduce the risk of endoscopic recurrence. A longer follow-up is mandatory to assess a potential benefit on surgical recurrence.

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 >30% in total endoscopic recurrence (when assuming a 60% to 65% ER expected rate in the control group and a 30% in the case group) was calculated; to allow a 10% drop-out of patients, 36 patients per group were needed (72 patients in the entire population). Results A total of 119 CD patients were included in the study. In all, 51 ileocolic CD patients were randomized in the Kono group and 68 in the conventional side-to-side group. At 6 months, 17 (33.3%) patients in the Kono group and 51 (75%) patients in the conventional group presented an ER (Rutgeerts score≥i2) at colonoscopy (p<0.001). A severe post-operative ER (Rutgeerts score≥i3) was found in 8 (15.7%) patients in the Kono group versus 23 (33.8%) patients in the conventional group (p=0.03). At 24 months, CR rate was 19.6% in the Kono group versus 30.9% in the conventional group (p=0.2), while SR rate was 0% in the Kono group versus 4.4% (3 patients) in the standard group (p=0.2). At 36 months, CR rate was 19.6% in the Kono-s group versus 33.8% in the conventional group (p=0.1). At 36 months, no patients (0%) in the Kono group experienced SR, while 6 patients (8.8%) in the conventional group did (p=0.03). Furthermore, when considering a median follow-up of 54 (42-60) months at interim analysis of SR, the difference between the two groups was confirmed to be significant (0% vs 8.8%; p=0.02). Conclusion This is the first RCT comparing Kono-S anastomosis and conventional side-to-side anastomosis in CD. The results demonstrate a significant reduction in postoperative endoscopic and surgical recurrence rates, no safety issues, and a favourable trend for lower clinical recurrence rate in patients who underwent Kono-S anastomosis compared to the conventional side-to-side anastomosis.