Project description:There are conflicting data assessing the impact of isolated post-operative anastomotic inflammation on future disease progression. The aim of this study was to determine the relative risk of severe disease progression in post-operative Crohn's disease (CD) patients with isolated anastomotic disease.MethodsRetrospective cohort study of adult CD patients undergoing ileocolonic resection between 2009 and 2020. Patients with a post-operative ileocolonoscopy ≤18 months from surgery and ≥1 subsequent ileocolonoscopy were included. Disease activity was assessed using the modified Rutgeerts' score (RS). Primary outcome was severe endoscopic progression, defined as i3 or i4 disease, on immediate subsequent ileocolonoscopy and during entire post-operative follow-up. Secondary outcome was surgical recurrence.ResultsOne hundred and ninety-nine CD patients had an ileocolonoscopy ≤18 months from surgery, index RS of i0-i2b and ≥1 subsequent ileocolonoscopy. At index ileocolonoscopy, 34.7% had i0 disease, 16.1% i1, 24.6% i2a and 24.6% i2b. On multivariable logistic regression, i2b disease was associated with severe endoscopic progression compared to i0 or i1 (aOR 5.53; P < 0.001) and i2a disease patients (aOR 2.63; P = 0.03). However, i2a disease did not confer increased risk compared to i0 or i1 disease (P = 0.09). Furthermore, i2b patients experienced severe endoscopic progression significantly earlier than i0 or i1 disease (aHR 4.68; P < 0.001), whereas i2a disease did not differ from i0 or i1 disease (P = 0.25). Surgical recurrence was not associated with index RS i0-i2b (P = 0.86).ConclusionPost-operative ileal disease recurrence, not isolated anastomotic inflammation, confers increased risk for severe endoscopic disease progression. Location of CD recurrence may impact optimal management strategies.
Project description:BackgroundCrohn's disease (CD) is a chronic inflammatory condition affecting the gastrointestinal tract, characterized by complications such as strictures, fistulas, and neoplasia. Despite medical advancements, a significant number of patients with Crohn's disease require surgery, and many experience post-operative complications and recurrence. Previous studies have analyzed gene expression to study recurrence and post-operative complications independently. This study aims to identify overlapping differentially expressed genes and pathways for recurrence and post-operative complications.MethodsA dataset including 45 patients with Crohn's disease, including gene expression from ileum and colon tissue, endoscopic recurrence, and intra-abdominal septic complications was analyzed. Gene set enrichment analysis was used to identify gene pathways associated with the outcomes. Finally, a multi-variable logistic regression model was created to assess whether gene pathways were independently associated with both outcomes.ResultsIn ileum tissue, several inflammatory pathways, including interferon alpha and gamma response were upregulated in patients with endoscopic recurrence and intra-abdominal septic complications. In addition, there was upregulation of the epithelial mesenchymal transition pathway. In colon tissue, metabolic processes, such as myogenesis and oxidative phosphorylation were downregulated in both outcomes. In a multivariate model, downregulation of myogenesis in colon tissue was significantly associated with both endoscopic recurrence and intra-abdominal septic complications.ConclusionThese findings shed light on the underlying biology of these outcomes and suggest potential biomarkers or therapeutic targets to reduce their occurrence. Further validation and multi-institutional studies are warranted to confirm these results and improve post-operative outcomes for patients with Crohn's disease.
Project description:BackgroundIn Crohn's disease (CD), one of the major inflammatory bowel disease (IBD) in human beings, there is over-expression of Smad7, an intracellular inhibitor of the suppressive cytokine TGF-β1. The aim of this study was to assess whether Smad7 over-expression occurs in the early and/or late phases of CD.MethodsMucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with or without (early CD) post-operative endoscopic recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (late CD). Smad7 was examined by immunohistochemistry and cytokine expression was analysed by flow-cytometry.ResultsBefore the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of Smad7-expressing cells in both the epithelial and lamina propria compartments. Transition from this stage to endoscopic recurrence was marked by persistence of high number of Smad7-positive cells, which reduced significantly in the late stages of the disease, where Smad7 expression remained, however, greater than that seen in normal controls. In samples with early lesions, Smad7 expression positively correlated with the number of interferon-γ-secreting cells.ConclusionsSmad7 induction is an early event in the inflammatory sequence occurring in CD, thus suggesting that knockdown of Smad7 can help prevent post-operative recurrence.
Project description:Background and aimsCrohn's disease [CD] recurrence following ileocolic resection [ICR] is common. We sought to identify blood-based biomarkers associated with CD recurrence.MethodsCD patients undergoing ICR were recruited across six centres. Serum samples were obtained at post-operative colonoscopy. A multiplex immunoassay was used to analyse 92 inflammation-related proteins [Olink Proteomics]. Bayesian analysis was used to identify proteins associated with increasing Rutgeerts score. Identified proteins were used in receiver operating characteristic [ROC] analysis to examine the ability to identify CD recurrence [Rutgeerts score ≥i2]. Existing single cell data were interrogated to further elucidate the role of the identified proteins.ResultsData from 276 colonoscopies in 213 patients were available. Median time from surgery to first and second colonoscopy was 7 (interquartile range [IQR] 6-9) and 19 [IQR 16-23] months, respectively. Disease recurrence was evident at 60 [30%] first and 36 [49%] second colonoscopies. Of 14 proteins significantly associated with Rutgeerts score, the strongest signal was seen for CXCL9 and MMP1. Among patients on anti-tumour necrosis factor drugs, CXCL9 and CXCL11 were most strongly associated with Rutgeerts score. Both are CXCR3 ligands. Incorporation of identified proteins into ROC analysis improved the ability to identify disease recurrence as compared to C-reactive protein alone: area under the curve [AUC] 0.75 (95% confidence interval [CI]: 0.66-0.82] vs 0.64 [95% CI 0.56-0.72], p = 0.012. Single cell transcriptomic data provide evidence that innate immune cells are the primary source of the identified proteins.ConclusionsCXCR3 ligands are associated with CD recurrence following ICR. Incorporation of novel blood-based candidate biomarkers may aid in identification of CD recurrence.
Project description:BackgroundPatients with isolated anastomotic lesions (iAL) are common in postoperative Crohn's disease (CD) and have heterogeneous prognosis.ObjectivesTo investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in CD patients with iAL.DesignA bicenter retrospective cohort study.MethodsCD patients who received ileocolonic resection from 2013 and 2020 and had a modified Rutgeerts score of i2a were recruited. NLR was determined within 1 week around the initial endoscopy after ileocolectomy. The primary outcome was clinical recurrence. Kaplan-Meier method and Cox hazard regression analysis were utilized to assess the association between candidate variables and outcomes of interest.ResultsIn total, 411 postoperative CD patients were preliminarily reviewed and 83 patients were eligible. In total, 36 (48.6%) patients experienced clinical recurrence with a median follow-up time of 16.3 (interquartile range, 9.7-26.3) months. NLR > 2.45 and age at surgery >45 years had higher cumulative incidence of clinical recurrence in the Kaplan-Meier analysis. After adjusted for potential confounders, NLR > 2.45 was the only independent risk factor for clinical recurrence, with an adjusted hazard ratio (HR) of 2.88 [95% confidence interval (CI), 1.39-6.00; p = 0.005]. Furthermore, a risk score based on NLR and age at surgery were built to further stratify patients. Compared to those who scored 0, patients with a score of 1 and 2 had an adjusted HR of 2.48 (95% CI, 1.22-5.02) and 6.97 (95% CI, 2.19-22.16) for developing clinical recurrence, respectively.ConclusionsNLR is a promising prognostic biomarker for CD patients with iAL. The utilization of NLR and the risk score to stratify patients may facilitate the personalized management in patients with iAL.
Project description:Postoperative recurrence after ileocaecal resection for fibrostenotic terminal ileal Crohn's disease is a significant issue for patients as it can result in symptom recurrence and requirement for further surgery. There are very few modifiable factors, aside from smoking cessation, that can reduce the risk of postoperative recurrence. Until relatively recently, the surgical technique used for resection and anastomosis had little or no impact on postoperative recurrence rates. Novel surgical techniques such as the Kono-S anastomosis and extended mesenteric excision have shown promise as ways to reduce postoperative recurrence rates. This manuscript will review and discuss the evidence regarding a range of surgical techniques and their potential role in reducing disease recurrence. Some of the techniques have been shown to be associated with significant benefits for patients and have already been integrated into the routine clinical practice of some surgeons, while other techniques remain under investigation. Current techniques such as resection of the mesentery close to the intestine and stapled side to side anastomosis are being challenged. It is looking more likely that surgeons will have a major role to play when it comes to reducing recurrence rates for patients undergoing ileocaecal resection for Crohn's disease.
Project description:Prediction of endoscopic post-operative recurrence (POR) in Crohn's disease (CD) patients following ileocolonic resection (ICR) using clinical risk factors alone has thus far been inadequate. While peripheral blood leukocyte (PBL) DNA methylation has shown promise as a tool for predicting recurrence in cancer, no data in CD patients exists. Therefore, this study explored the association and predictive value of PBL DNA methylation in CD patients following ICR. From a cohort of 117 CD patients undergoing ICR, epigenome-wide PBL methylation profiles from 25 carefully selected patients presenting either clear endoscopic remission (n = 12) or severe recurrence (n = 13) were assessed using the Illumina MethylationEPIC (850K) array. No statistically significant differentially methylated positions (DMPs) or regions (DMRs) associated with endoscopic POR were identified (FDR p ≤ 0.05), further evidenced by the low accuracy (0.625) following elastic net classification analysis. Nonetheless, interrogating the most significant differences in methylation suggested POR-associated hypermethylation in the MBNL1, RAB29 and LEPR genes, respectively, which are involved in intestinal fibrosis, inflammation and wound healing. Notably, we observed a higher estimated proportion of monocytes in endoscopic POR compared to remission. Altogether, we observed limited differences in the genome-wide DNA methylome among CD patients with and without endoscopic POR. We therefore conclude that PBL DNA methylation is not a feasible predictive tool in post-operative CD.
Project description:Background and aimsAdequate endoscopic scoring in Crohn's disease [CD] is crucial, as it dictates the need for initiating postoperative medical therapy and is utilized as an outcome parameter in clinical trials. Here we aimed to observe anastomotic wound healing in relation to endoscopic scoring of both inverted and everted stapled lines in side-to-side anastomoses.MethodsTwo prospective patient cohorts were included: ileocolic resection [ICR] for CD, and right-sided colon resection for colorectal cancer [CRC]. Videos taken during colonoscopy 6 months postoperatively were evaluated. The Simplified Endoscopic Activity Score for Crohn's Disease and modified Rutgeerts score were determined. The primary outcome was the presence of ulcerations in CD patients on both the inverted and the everted stapled lines. Secondary outcomes were the presence of anastomotic ulcerations in CRC patients and the number of cases having ulcerations exclusively at the inverted stapled line.ResultsOf the 82 patients included in the CD cohort, ulcerations were present in 63/82 [76.8%] at the inverted- vs 1/71 [1.4%] at the everted stapled line. Likewise in the CRC cohort, ulcerations were present in 4/6 [67.7%] at the inverted vs 0/6 [0%] at the everted stapled line. In total, 27% of the 63 patients in the CD cohort had ulcerations exclusively on the inverted stapled line.ConclusionInverted stapled lines heal with ulcerations, whereas everted stapled lines heal without any ulcerations, in both CD and non-CD patients. The abnormalities at the inverted stapled line might interfere with endoscopic scoring of recurrence, with potentially an impact on patients' quality of life and on healthcare costs if postoperative treatment is initiated incorrectly.
Project description:IntroductionSurgical management of Crohn's disease (CD) is common. Postoperative complications include anastomotic stricturing (AS). The natural history and risk factors for AS have not been elucidated.MethodsA retrospective cohort study of patients with CD who underwent ileocolonic resection (ICR) with ≥1 postoperative ileocolonoscopy between 2009 and 2020. Postoperative ileocolonoscopies with corresponding cross-sectional imaging were evaluated for evidence of AS without neoterminal ileal extension. Severity of AS and endoscopic intervention at time of detection were collected. Primary outcome was development of AS. Secondary outcome was time to AS detection.ResultsA total of 602 adult patients with CD underwent ICR with postoperative ileocolonoscopy. Of these, 426 had primary anastomosis, and 136 had temporary diversion at time of ICR. Anastomotic configuration consisted of 308 side-to-side, 148 end-to-side, and 136 end-to-end. One hundred ten (18.3%) patients developed AS with median time of 3.2 years to AS detection. AS severity at time of detection was associated with need for repeat surgical resection for AS. On multivariable Cox proportional hazard regression, anastomotic configuration and temporary diversion were not associated with risk of or time to AS. Preoperative stricturing disease was associated with decreased time to AS (adjusted hazard ratio 1.8; P = 0.049). Endoscopic ileal recurrence before AS was not associated with subsequent AS detection.DiscussionAS is a relatively common postoperative CD complication. Patients with previous stricturing disease behavior are at increased risk of AS. Anastomotic configuration, temporary diversion, and ileal CD recurrence do not increase risk of AS. Early detection and intervention for AS may help prevent progression to repeat ICR.