Department of MedicineBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMassachusettsUSA.
Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasTexasUSA.
Hepatology. 2022 Oct;76(4):1058-1068. doi: 10.1002/hep.32478. Epub 2022 Jun 2.
Patients with severe alcohol-associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30 days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180-day survival.
Subjects with a clinical diagnosis of severe AH (Model for End-Stage Liver Disease [MELD] >20, Maddrey discriminant function [MDF] >32) were randomized to receive methylprednisolone (PRED; 28 days) or a combination of anakinra (14 days) plus pentoxifylline (28 days) plus zinc (COMB; 180 days). The primary endpoint was survival at 180 days. The study was designed in 2013, initiated in October 2014, and completed in March 2018. Five hundred patients were screened to randomize 104 subjects with a clinical diagnosis of AH with a MELD score >20. Fifty-three patients were randomized into the COMB and 50 to the PRED treatment; 1 dropped out of the study before randomization. Mean age was 45.3 ± 10.4 years; 60.6% were males, 92.3% White, and mean MELD 25.7 ± 3.9. Kaplan-Meier survival estimate at 180 days was 67.9% in COMB and 56% in PRED (HR = 0.69; p = 0.3001). Survival curves separated by 90 days (COMB, 69.8%; PRED, 58.0%; HR = 0.69; p = 0.28). Survival at 28 days was similar between the COMB (83.4%) and PRED groups (81.2%; HR = 0.91; p = 0.85). There were no unexpected serious adverse events, and incidence of infection was comparable between groups. MELD 20-25 and MELD >26 strata showed nonsignificant treatment effects in favor of COMB.
A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.
患有严重酒精性肝炎（AH）的患者死亡率很高。皮质类固醇仅在 30 天内提高生存率。我们在一项随机临床试验中针对炎症、细胞损伤和肠道通透性进行了靶向治疗，将联合治疗与皮质类固醇治疗进行了比较，以评估其对 180 天生存率的影响。
临床诊断为严重 AH（终末期肝病模型 [MELD] >20，Maddrey 判别函数 [MDF] >32）的患者被随机分为接受甲基泼尼松龙（PRED；28 天）或联合使用阿那白滞素（14 天）、己酮可可碱（28 天）和锌（COMB；180 天）治疗。主要终点为 180 天的生存率。该研究于 2013 年设计，2014 年 10 月启动，2018 年 3 月完成。对 500 名患者进行了筛查，以随机分配 104 名 MELD 评分>20 的 AH 临床诊断患者。53 例患者被随机分为 COMB 组，50 例患者被随机分为 PRED 组；1 例患者在随机分组前退出研究。平均年龄为 45.3 ± 10.4 岁；60.6%为男性，92.3%为白人，平均 MELD 为 25.7 ± 3.9。COMB 组 180 天的 Kaplan-Meier 生存估计为 67.9%，PRED 组为 56%（HR=0.69；p=0.3001）。90 天时的生存曲线分开（COMB，69.8%；PRED，58.0%；HR=0.69；p=0.28）。COMB（83.4%）和 PRED 组（81.2%）的 28 天生存率相似（HR=0.91；p=0.85）。两组均未发生意外严重不良事件，感染发生率相似。MELD 20-25 和 MELD>26 分层显示 COMB 治疗有显著的生存获益趋势。
在严重 AH 中，阿那白滞素、己酮可可碱加锌的联合治疗与皮质类固醇治疗相比，提供了相似的生存获益。
