Atallah Edmond, Grove Jane I, Crooks Colin, Burden-Teh Esther, Abhishek Abhishek, Moreea Sulleman, Jordan Kelsey M, Ala Aftab, Hutchinson David, Aspinall Richard J, Murphy Ruth, Aithal Guruprasad P
Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK; National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.
Centre of Evidence Based Dermatology, School of Medicine, University of Nottingham, Nottingham, UK.
J Hepatol. 2023 May;78(5):989-997. doi: 10.1016/j.jhep.2022.12.034. Epub 2023 Jan 23.
BACKGROUND & AIMS: The risk of significant liver fibrosis from prolonged methotrexate (MTX) exposure has been estimated at around 5%, prompting intensive monitoring strategies. However, the evidence is derived from retrospective studies that under-reported risk factors for liver disease. We evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using two non-invasive markers.
Between 2014-2021, adult patients diagnosed with rheumatoid arthritis (RA) or psoriasis for ≥2 years were recruited prospectively from six UK sites. The MTX group included patients who received MTX for ≥6 months, whereas the unexposed group included those who never received MTX. All patients underwent full liver profiling, with transient elastography (TE) and enhanced liver fibrosis (ELF) marker measurements.
A total of 999 patients (mean age 60.8 ± 12 years, 62.3% females) were included. Of 976 with valid TE values, 149 (15.3%) had liver stiffness ≥7.9 kPa. Of 892 with a valid ELF, 262 (29.4%) had ELF ≥9.8. Age and BMI were independently associated with elevated liver stiffness and ELF. Neither MTX cumulative dose nor duration was associated with elevated liver stiffness. Diabetes was the most significant risk factor associated with liver stiffness ≥7.9 kPa (adjusted odds ratio = 3.19; 95% CI 1.95-5.20; p <0.001). Regular use of non-steroidal anti-inflammatory drugs showed the strongest association with ELF ≥9.8 (odds ratio = 1.76; 95% CI 1.20-2.56; p = 0.003), suggesting the degree of joint inflammation in RA may confound ELF as a non-invasive marker of liver fibrosis.
The risk of liver fibrosis attributed to MTX itself might have been previously overestimated; there is a need to consider modifying current monitoring guidelines for MTX.
Current guidelines recommend intensive (2-3 monthly) monitoring strategies for patients on long-term methotrexate therapy due to the potential risk of liver fibrosis. Evaluation of the association using two validated non-invasive markers of liver fibrosis, liver stiffness and enhanced liver fibrosis score, in a large cohort of patients with rheumatoid arthritis or psoriasis shows that the reported risk has previously been overestimated. The clinical focus should be to improve patients' metabolic risk factors, diabetes and BMI, that are independently associated with liver stiffness. There is a need to consider modifying current treatment monitoring guidelines for methotrexate.
长期使用甲氨蝶呤（MTX）导致显著肝纤维化的风险估计约为5%，这促使了强化监测策略的实施。然而，相关证据来自回顾性研究，这些研究对肝病风险因素的报告不足。我们在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年至2021年期间，从英国六个地点前瞻性招募了诊断为类风湿关节炎（RA）或银屑病≥2年的成年患者。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过MTX治疗的患者。所有患者均接受了全面的肝脏检查，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（平均年龄60.8±12岁，62.3%为女性）。在976例有有效TE值的患者中，149例（15.3%）肝脏硬度≥7.9 kPa。在892例有有效ELF值的患者中，262例（29.4%）ELF≥9.8。年龄和体重指数与肝脏硬度升高和ELF独立相关。MTX累积剂量和疗程均与肝脏硬度升高无关。糖尿病是与肝脏硬度≥7.9 kPa相关的最显著风险因素（调整比值比=3.19；95%可信区间1.95-5.20；p<0.001）。经常使用非甾体抗炎药与ELF≥9.8的关联最强（比值比=1.76；95%可信区间1.20-2.56；p=0.003），这表明RA中的关节炎症程度可能会混淆ELF作为肝纤维化的非侵入性标志物。
先前可能高估了MTX本身导致肝纤维化的风险；有必要考虑修改当前的MTX监测指南。
由于存在肝纤维化的潜在风险，当前指南建议对长期接受甲氨蝶呤治疗的患者采取强化（每2-3个月）监测策略。在一大群类风湿关节炎或银屑病患者中，使用两种经过验证的肝纤维化非侵入性标志物（肝脏硬度和增强肝纤维化评分）评估关联表明，先前报告的风险被高估了。临床重点应是改善与肝脏硬度独立相关的患者代谢风险因素，即糖尿病和体重指数。有必要考虑修改当前的甲氨蝶呤治疗监测指南。
