据估计,长期暴露于甲氨蝶呤(MTX)导致严重肝纤维化的风险约为5%,这促使人们采取强化监测策略。然而,现有证据来源于回顾性研究,这些研究低估了肝病的风险因素。在Atallah等一项纵向队列研究中,使用两种非侵入性标志物评估了长期MTX治疗对肝纤维化的风险。
在2014年—2021年,笔者从6个英国研究中心前瞻性招募了诊断为≥2年类风湿关节炎或银屑病的成年患者。MTX组包括接受MTX治疗≥6个月的患者,而未暴露组包括从未接受MTX的患者。所有的患者都进行了完整的肝脏分析,包括瞬时弹性成像(TE)和增强肝纤维化(ELF)标志物测量。
共纳入999例患者,平均(60.8±12)岁,女性占62.3%。在976例有效TE值中,149例(15.3%)患者肝硬度≥7.9 kPa。在892例有效ELF值中,262例(29.4%)患者ELF≥9.8。年龄和BMI与肝硬度升高和肝纤维化独立相关。MTX累积剂量和持续时间都与肝硬度升高无关。糖尿病是与肝硬度≥7.9 kPa相关性最显著的危险因素(校正比值比=3.19,95%可信区间:1.95~5.20,P<0.001)。定期使用非甾体类抗炎药与ELF≥9.8的相关性最强(优势比=1.76,95%可信区间:1.20~2.56,P=0.003),表明类风湿性关节炎的关节炎症程度可能与作为肝纤维化的非侵入性标志物的ELF相混淆。
笔者认为,先前可能高估了MTX本身导致的肝纤维化风险,有必要考虑修改MTX目前的监测准则。
摘译自ATALLAH E, GROVE JI, CROOKS C, et al. Risk of liver fibrosis associated with long-term methotrexate therapy may be overestimated[J]. J Hepatol, 2023. DOI:
(吉林大学第一医院 肝胆胰内科 纪竹慧 辛桂杰 报道)
[1] |
RAGGI C, TADDEI ML, RAE C, et al. Metabolic reprogramming in cholangiocarcinoma[J]. J Hepatol, 2022, 77( 3): 849- 864. DOI: 10.1016/j.jhep.2022.04.038.
|
[2] |
JANG S, STEVENS T, KOU L, et al. Efficacy of digital single-operator cholangioscopy and factors affecting its accuracy in the evaluation of indeterminate biliary stricture[J]. Gastrointest Endosc, 2020, 91( 2): 385- 393.e1. DOI: 10.1016/j.gie.2019.09.015.
|
[3] |
CHEN S, WANG J. Advances in tumor microenvironment and immunotherapy of cholangiocarcinoma[J]. J Clin Hepatol, 2022, 38( 10): 2428- 2432. DOI: 10.3969/j.issn.1001-5256.2022.10.044.
陈顺, 王俊. 胆管癌肿瘤微环境与免疫治疗[J]. 临床肝胆病杂志, 2022, 38( 10): 2428- 2432. DOI: 10.3969/j.issn.1001-5256.2022.10.044.
|
[4] |
ZUO S, CHEN Q, ZOU WL. Current status and prospect of immunotherapy for cholangiocarcinoma[J]. Chin J Dig Surg, 2022, 21( 7): 873- 879. DOI: 10.3760/cma.j.cn115610-20220506-00254.
左石, 陈乾, 邹卫龙. 胆管癌免疫治疗的现状与展望[J]. 中华消化外科杂志, 2022, 21( 7): 873- 879. DOI: 10.3760/cma.j.cn115610-20220506-00254.
|
[5] |
GIESE MA, HIND LE, HUTTENLOCHER A. Neutrophil plasticity in the tumor microenvironment[J]. Blood, 2019, 133( 20): 2159- 2167. DOI: 10.1182/blood-2018-11-844548.
|
[6] |
JUKIC A, BAKIRI L, WAGNER EF, et al. Calprotectin: From biomarker to biological function[J]. Gut, 2021, 70( 10): 1978- 1988. DOI: 10.1136/gutjnl-2021-324855.
|
[7] |
ARGYRIS PP, SLAMA ZM, ROSS KF, et al. Calprotectin and the initiation and progression of head and neck cancer[J]. J Dent Res, 2018, 97( 6): 674- 682. DOI: 10.1177/0022034518756330.
|
[8] |
SHABANI F, FARASAT A, MAHDAVI M, et al. Calprotectin(S100A8/S100A9): A key protein between inflammation and cancer[J]. Inflamm Res, 2018, 67( 10): 801- 812. DOI: 10.1007/s00011-018-1173-4.
|
[9] |
PAN SG, HU Y, HU MJ, et al. S100A8 facilitates cholangiocarcinoma metastasis via upregulation of VEGF through TLR4/NF-κB pathway activation[J]. Int J Oncol, 2020, 56( 1): 101- 112. DOI: 10.3892/ijo.2019.4907.
|
[10] |
LIANG HJ, QIN SK, SHEN F, et al. Expert consensus on diagnosis and treatment of CSCO biliary systerm tumors(2019 edition)[J]. Chin Clin Oncol, 2019, 24( 9): 828- 838.
梁后杰, 秦叔逵, 沈锋, 等. CSCO胆道系统肿瘤诊断治疗专家共识(2019年版)[J]. 临床肿瘤学杂志, 2019, 24( 9): 828- 838.
|
[11] |
DELONG ER, DELONG DM, CLARKE-PEARSON DL. Comparing the areas under two or more correlated receiver operating characteristic curves: A nonparametric approach[J]. Biometrics, 1988, 44( 3): 837- 845.
|
[12] |
KHAN SA, DAVIDSON BR, GOLDIN RD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: An update[J]. Gut, 2012, 61( 12): 1657- 1669. DOI: 10.1136/gutjnl-2011-301748.
|
[13] |
CAO HS, HUANG T, DAI MR, et al. Tumor microenvironment and its implications for antitumor immunity in cholangiocarcinoma: Future perspectives for novel therapies[J]. Int J Biol Sci, 2022, 18( 14): 5369- 5390. DOI: 10.7150/ijbs.73949.
|
[14] |
MAO ZY, ZHU GQ, XIONG M, et al. Prognostic value of neutrophil distribution in cholangiocarcinoma[J]. World J Gastroenterol, 2015, 21( 16): 4961- 4968. DOI: 10.3748/wjg.v21.i16.4961.
|
[15] |
ZHOU SL, DAI Z, ZHOU ZJ, et al. CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils[J]. Carcinogenesis, 2014, 35( 3): 597- 605. DOI: 10.1093/carcin/bgt397.
|
[16] |
LI YW, QIU SJ, FAN J, et al. Intratumoral neutrophils: A poor prognostic factor for hepatocellular carcinoma following resection[J]. J Hepatol, 2011, 54( 3): 497- 505. DOI: 10.1016/j.jhep.2010.07.044.
|
[17] |
JENSEN HK, DONSKOV F, MARCUSSEN N, et al. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma[J]. J Clin Oncol, 2009, 27( 28): 4709- 4717. DOI: 10.1200/JCO.2008.18.9498.
|
[18] |
JAILLON S, PONZETTA A, DI MITRI D, et al. Neutrophil diversity and plasticity in tumour progression and therapy[J]. Nat Rev Cancer, 2020, 20( 9): 485- 503. DOI: 10.1038/s41568-020-0281-y.
|
[19] |
SHAUL ME, FRIDLENDER ZG. Tumour-associated neutrophils in patients with cancer[J]. Nat Rev Clin Oncol, 2019, 16( 10): 601- 620. DOI: 10.1038/s41571-019-0222-4.
|
[20] |
VOIGTLÄNDER T, WLECKE J, NEGM AA, et al. Calprotectin in bile: A disease severity marker in patients with primary sclerosing cholangitis[J]. J Clin Gastroenterol, 2014, 48( 10): 866- 869. DOI: 10.1097/MCG.0000000000000042.
|
[21] |
GAUSS A, SAUER P, STIEHL A, et al. Evaluation of biliary calprotectin as a biomarker in primary sclerosing cholangitis[J]. Medicine, 2016, 95( 17): e3510. DOI: 10.1097/MD.0000000000003510.
|
[22] |
SRIKRISHNA G. S100A8 and S100A9: New insights into their roles in malignancy[J]. J Innate Immun, 2012, 4( 1): 31- 40. DOI: 10.1159/000330095.
|
[23] |
JAMNONGKAN W, THANAN R, TECHASEN A, et al. Upregulation of transferrin receptor-1 induces cholangiocarcinoma progression via induction of labile iron pool[J]. Tumour Biol, 2017, 39( 7): 1010428317717655. DOI: 10.1177/1010428317717655.
|
[24] |
MANCINELLI R, CUTONE A, ROSA L, et al. Different iron-handling in inflamed small and large cholangiocytes and in small and large-duct type intrahepatic cholangiocarcinoma[J]. Eur J Histochem, 2020, 64( 4): 3156. DOI: 10.4081/ejh.2020.3156.
|