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Activity of Inflammatory Bowel Disease After Liver Transplantation for Primary Sclerosing Cholangitis Predicts Poorer Clinical Outcomes.

原发性硬化性胆管炎肝移植后炎症性肠病的活动性预示着较差的临床结局。

  • 影响因子:3.72
  • DOI:10.1093/ibd/izz325
  • 作者列表:"Peverelle M","Paleri S","Hughes J","De Cruz P","Gow PJ
  • 发表时间:2020-01-16
Abstract

BACKGROUND:The impact of inflammatory bowel disease (IBD) activity on long-term outcomes after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is unknown. We examined the impact of post-LT IBD activity on clinically significant outcomes. METHODS:One hundred twelve patients undergoing LT for PSC from 2 centers were studied for a median of 7 years. Patients were divided into 3 groups according to their IBD activity after LT: no IBD, mild IBD, and moderate to severe IBD. Patients were classified as having moderate to severe IBD if they met at least 1 of 3 criteria: (i) Mayo 2 or 3 colitis or Simple Endoscopic Score-Crohn's Disease ≥7 on endoscopy; (ii) acute flare of IBD necessitating steroid rescue therapy; or (iii) post-LT colectomy for medically refractory IBD. RESULTS:Moderate to severe IBD at any time post-transplant was associated with a higher risk of Clostridium difficile infection (27% vs 8% mild IBD vs 8% no IBD; P = 0.02), colorectal cancer/high-grade dysplasia (21% vs 3% both groups; P = 0.004), post-LT colectomy (33% vs 3% vs 0%) and rPSC (64% vs 18% vs 20%; P < 0.001). Multivariate analysis revealed that moderate to severe IBD increased the risk of both rPSC (relative risk [RR], 8.80; 95% confidence interval [CI], 2.81-27.59; P < 0.001) and colorectal cancer/high-grade dysplasia (RR, 10.45; 95% CI, 3.55-22.74; P < 0.001). CONCLUSIONS:Moderate to severe IBD at any time post-LT is associated with a higher risk of rPSC and colorectal neoplasia compared with mild IBD and no IBD. Patients with no IBD and mild IBD have similar post-LT outcomes. Future prospective studies are needed to determine if more intensive treatment of moderate to severe IBD improves long-term outcomes in patients undergoing LT for PSC.

摘要

背景: 炎症性肠病 (IBD) 活动性对肝移植 (LT) 治疗原发性硬化性胆管炎 (PSC) 后长期预后的影响尚不清楚。我们检测了 LT 后 IBD 活性对临床显著结局的影响。 方法: 对来自 2 个中心的 112 例因 PSC 行 LT 的患者进行了中位数为 7 年的研究。根据患者 LT 后 IBD 活动性分为 3 组: 无 IBD 、轻度 IBD 和中重度 IBD。如果符合 3 项标准中的至少 1 项,则将患者归类为中度至重度 IBD :( i) Mayo 2 或 3 结肠炎或单纯内镜评分-内镜下克罗恩病 ≥ 7; (ii) IBD 急性发作需要类固醇抢救治疗; 或 (iii) 内科难治性 IBD 的 LT 结肠切除术后。 结果: 移植后任何时候中重度 IBD 与艰难梭菌感染风险较高相关 (27% vs 8% 轻度 IBD vs 8% 无 IBD; P = 0.02),结直肠癌/高度异型增生 (两组均为 21% vs 3%; P = 0.004) 、 LT 后结肠切除术 (33% vs 3% vs 0%) 和 rPSC(64% vs 18% vs 20%; P <0.001)。多变量分析显示,中重度 IBD 同时增加 rPSC 的风险 (相对危险度 [RR],8.80; 95% 可信区间 [CI],2.81-27.59; P < 0.001) 和结直肠癌/高度异型增生 (RR,10.45; 95% CI,3.55-22.74; P <0.001)。 结论: 与轻度 IBD 和无 IBD 相比,LT 后任何时候中重度 IBD 与 rPSC 和结直肠肿瘤的风险较高相关。无 IBD 和轻度 IBD 的患者 LT 后结局相似。需要未来的前瞻性研究来确定中重度 IBD 的更强化治疗是否能改善 PSC 行 LT 患者的长期预后。

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相关文献
影响因子:6.87
发表时间:2020-01-10
DOI:10.1002/hep.31110
作者列表:["Goeppert B","Folseraas T","Roessler S","Kloor M","Volckmar AL","Endris V","Buchhalter I","Stenzinger A","Grzyb K","Grimsrud MM","Gornicka B","von Seth E","Reynolds GM","Franke A","Gotthardt DN","Mehrabi A","Cheung A","Verheij J","Arola J","Mäkisalo H","Eide TJ","Weidemann S","Cheville JC","Mazza G","Hirschfield GM","Ponsioen CY","Bergquist A","Milkiewicz P","Lazaridis KN","Schramm C","Manns MP","Färkkilä M","Vogel A","International PSC study group.","Boberg KM","Schirmacher P","Karlsen TH"]

METHODS:BACKGROUND & AIMS:Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) exceeds 20% and BTC is currently the leading cause of death in PSC patients. To open new avenues for management, we aimed to delineate novel and clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). APPROACH & RESULTS:We analysed formalin fixed, paraffin embedded tumor tissue from 186 PSC-BTC patients from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations and copy number variations, along with histomorphological and immunohistochemical characterization. Irrespective of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, e.g. TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g. HER2/ERBB2). We found a high frequency of non-typical/non-ductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%) CONCLUSION: Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC show a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.

翻译标题与摘要 下载文献
影响因子:3.72
发表时间:2020-01-16
DOI:10.1093/ibd/izz325
作者列表:["Peverelle M","Paleri S","Hughes J","De Cruz P","Gow PJ"]

METHODS:BACKGROUND:The impact of inflammatory bowel disease (IBD) activity on long-term outcomes after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is unknown. We examined the impact of post-LT IBD activity on clinically significant outcomes. METHODS:One hundred twelve patients undergoing LT for PSC from 2 centers were studied for a median of 7 years. Patients were divided into 3 groups according to their IBD activity after LT: no IBD, mild IBD, and moderate to severe IBD. Patients were classified as having moderate to severe IBD if they met at least 1 of 3 criteria: (i) Mayo 2 or 3 colitis or Simple Endoscopic Score-Crohn's Disease ≥7 on endoscopy; (ii) acute flare of IBD necessitating steroid rescue therapy; or (iii) post-LT colectomy for medically refractory IBD. RESULTS:Moderate to severe IBD at any time post-transplant was associated with a higher risk of Clostridium difficile infection (27% vs 8% mild IBD vs 8% no IBD; P = 0.02), colorectal cancer/high-grade dysplasia (21% vs 3% both groups; P = 0.004), post-LT colectomy (33% vs 3% vs 0%) and rPSC (64% vs 18% vs 20%; P < 0.001). Multivariate analysis revealed that moderate to severe IBD increased the risk of both rPSC (relative risk [RR], 8.80; 95% confidence interval [CI], 2.81-27.59; P < 0.001) and colorectal cancer/high-grade dysplasia (RR, 10.45; 95% CI, 3.55-22.74; P < 0.001). CONCLUSIONS:Moderate to severe IBD at any time post-LT is associated with a higher risk of rPSC and colorectal neoplasia compared with mild IBD and no IBD. Patients with no IBD and mild IBD have similar post-LT outcomes. Future prospective studies are needed to determine if more intensive treatment of moderate to severe IBD improves long-term outcomes in patients undergoing LT for PSC.

翻译标题与摘要 下载文献
影响因子:6.87
发表时间:2020-01-23
DOI:10.1002/hep.31140
作者列表:["Kunzmann LK","Schoknecht T","Poch T","Henze L","Stein S","Kriz M","Grewe I","Preti M","Hartl J","Pannicke N","Peiseler M","Sebode M","Zenouzi R","Horvatits T","Böttcher M","Petersen BS","Weiler-Normann C","Hess LU","Elise Ahrenstorf A","Lunemann S","Martrus G","Fischer L","Li J","Carambia A","Kluwe J","Huber S","Lohse AW","Franke A","Herkel J","Schramm C","Schwinge D"]

METHODS::T cells from patients with primary sclerosing cholangitis (PSC) show a prominent IL-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant TH17 response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T cell response towards Th17. Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using trans-well experiments with cholangiocytes. Cytokine production was measured using flow cytometry, ELISA, RNA in situ hybridization and quantitative real time PCR. Genetic polymorphisms were obtained from Immunochip analysis. Following ex vivo stimulation with PMA/Ionomycin, PSC patients showed significantly increased numbers of IL-17A-producing peripheral blood CD4+ T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo. Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL-1β and IL-6, cytokines known to drive Th17 cell differentiation. Moreover, microbe-activated monocytes induced the secretion of Th17 and monocyte-recruiting chemokines CCL-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14hi CD16int and CD14lo CD16hi monocytes/macrophages were increased compared to alcoholic cirrhosis and monocytes were found to be located around bile ducts. Conclusion: PSC patients show increased Th17 differentiation already in vivo. Microbe-stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC.

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