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Ileal Gene Expression Data from Crohn's Disease Small Bowel Resections Indicate Distinct Clinical Subgroups.

ABSTRACT: BACKGROUND AND AIMS:Heterogeneity in Crohn's disease [CD] provides a challenge for the development of effective therapies. Our goal was to define a unique molecular signature for severe, refractory CD to enable precision therapy approaches to disease treatment and to facilitate earlier intervention in complicated disease. METHODS:We analysed clinical metadata, genetics, and transcriptomics from uninvolved ileal tissue from CD patients who underwent a single small bowel resection. We determined transcriptional risk scores, cellular signatures, and mechanistic pathways that define patient subsets in refractory CD. RESULTS:Within refractory CD, we found three CD patient subgroups [CD1, CD2, and CD3]. Compared with CD1, CD3 was enriched for subjects with increased disease recurrence after first surgery [OR = 6.78, p = 0.04], enhanced occurrence of second surgery [OR = 5.07, p = 0.016], and presence of perianal CD [OR = 3.61, p = 0.036]. The proportion of patients with recurrence-free survival was smaller in CD3 than in CD1 (p = 0.02, median survival time [months] in CD1 = 10 and CD3 = 6). Overlaying differential gene expression between CD1 and CD3 on CD subgroup-associated genetic polymorphisms identified 174 genes representing both genetic and biological differences between the CD subgroups. Pathway analyses using this unique gene signature indicated eukaryotic initiation factor 2 [eIF2] and cyclic adenosine monophosphate [cAMP] signalling to be dominant pathways associated with CD3. Furthermore, the severe, refractory subset, CD3, was associated with a higher transcriptional risk score and enriched with eosinophil and natural killer T [NKT] cell gene signatures. CONCLUSION:We characterized a subset of severe, refractory CD patients who may need more aggressive treatment after first resection and who are likely to benefit from targeted therapy based on their genotype and tissue gene expression signature.

SUBMITTER: Potdar AA

PROVIDER: S-EPMC6939877 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Ileal Gene Expression Data from Crohn's Disease Small Bowel Resections Indicate Distinct Clinical Subgroups.

Potdar Alka A AA Li Dalin D Haritunians Talin T VanDussen Kelli L KL Fiorino Marie F MF Liu Ta-Chiang TC Stappenbeck Thaddeus S TS Fleshner Phillip P Targan Stephan R SR McGovern Dermot P B DPB Bilsborough Janine J

Journal of Crohn's & colitis 20190801 8

<h4>Background and aims</h4>Heterogeneity in Crohn's disease [CD] provides a challenge for the development of effective therapies. Our goal was to define a unique molecular signature for severe, refractory CD to enable precision therapy approaches to disease treatment and to facilitate earlier intervention in complicated disease.<h4>Methods</h4>We analysed clinical metadata, genetics, and transcriptomics from uninvolved ileal tissue from CD patients who underwent a single small bowel resection. ...[more]

PMID: 30877309

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Project description:BackgroundThis study aimed to construct a magnetic resonance imaging (MRI) index for assessing transmural inflammatory activity in the small intestine of patients with Crohn' disease which enables rapid and non-invasive quantitative assessment of Crohn's disease inflammation.MethodsIn this prospective study, magnetic resonance enterography (MRE) was performed to examine 29 consecutive patients with Crohn's disease who had undergone ileocolonoscopy in the Jingling hospital of Nanjing. This diagnostic study was not registered on a clinical trial platform. We grade the T2 signal ratio and T1 enhancement ratio with a score of 0 to 3. The ratios were calculated as follow: terminal ileal inflammation of intestinal T2 signal intensity/adjacent normal intestinal T2 signal intensity (T2 ratio 1), terminal ileal inflammation intestinal T2 signal intensity/vertical muscle T2 signal intensity (T2 ratio 2), the fifth phase of the inflamed intestinal T1 signal intensity/noncontrast intestine T1 signal (T1 ratio 3), and the fifth phase of inflamed intestinal T1 signal intensity/adjacent normal intestinal T1 signal (T1 ratio 4). Wall thickness, lymph nodes, perimural T2 signal, comb sign, and ulceration were graded from 0 to 3. the simple endoscopic score for Crohn's disease (SES-CD) from 0 to 12 was used to assess Crohn's disease activity as a reference. The study calculated the correlations between the MRE activity index and endoscopic activity scores and derived the MRE index model to assess Crohn's disease activity.ResultsThe MRE index model (a T1 ratio 4 score of 1.52 + an ulceration score of 2.03) had a sensitivity of 0.962, a specificity of 0.667, and an area under the curve (AUC) of 0.968 [95% confidence interval (CI): 0.921-1.000]. The intraclass correlation coefficient (ICC) for the interobserver agreement of the MRE index was 0.921 (95% CI: 0.833-0.963).ConclusionsThe study derived an MRE index with good sensitivity to inflammatory changes in the small bowel. The index could be used to assess Crohn's disease activity of the small bowel.

Project description:Background & aimsDeep remission, based on clinical remission and evidence of healing during endoscopic evaluation, are goals of medical treatments for Crohn's disease (CD). We investigated whether histologic healing is associated with outcomes of patients with CD ileitis.MethodsWe performed a retrospective study of 101 patients with CD (52% male) isolated to the terminal ileum who had a colonoscopy between September 2005 and June 2015. Our analysis included patients in clinical remission at colonoscopy who had biopsies collected from colon and ileum. The ileum was evaluated for endoscopic healing (no ulceration) and histologic evidence of healing (no active inflammation, erosions, ulceration, or neutrophil infiltration). We compared times of clinical relapse-free survival, medication escalation, corticosteroid use, or hospitalization secondary to disease activity between patients with and without histological and endoscopic healing, followed for a median 21 months. We identified factors associated with survival using Kaplan Meier analysis and Cox proportional hazard model.ResultsAt ileo-colonoscopy, 63% of patients had endoscopic healing and 55% had histologic evidence of healing. The level of agreement between endoscopic and histologic activity was fair (62%, K = 0.2250, P = .0064). Forty-two patients had clinical relapse, 45 had medication escalation, 30 required corticosteroids, and 17 were hospitalized (3 required surgery). On multivariate analysis, only histologic healing was associated with decreased risk of clinical relapse (hazard ratio [HR], 2.05; 95% CI, 1.07-3.94; P = .031), medication escalation (HR, 2.17; 95% CI, 1.2-3.96; P = .011), and corticosteroid use (HR, 2.44; 95% CI, 1.17-5.09; P = .018). No factors were associated with hospitalization.ConclusionsIn patients with ileal CD in clinical remission, histologic healing but not endoscopic healing is associated with decreased risk of clinical relapse, medication escalation, or corticosteroid use.

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Ileal Gene Expression Data from Crohn's Disease Small Bowel Resections Indicate Distinct Clinical Subgroups.

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Ileal Gene Expression Data from Crohn's Disease Small Bowel Resections Indicate Distinct Clinical Subgroups.

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