Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK; Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany.
Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK; School of Transplantation, Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London, London, UK.
J Hepatol. 2021 Aug;75(2):324-332. doi: 10.1016/j.jhep.2021.03.023. Epub 2021 Apr 16.
BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) usually receive maintenance therapy with thiopurines, such as azathioprine (AZA) or mercaptopurine. Genetic polymorphisms in AZA metabolism can lead to variations in thioguanine nucleotide (TGN) and 6-methylmercaptopurine, both of which can cause adverse drug reactions (ADRs). In inflammatory bowel disease, a therapeutic TGN range (225-450 pmol/8x10 erythrocytes) has been identified to optimise effectiveness. We evaluated the benefits of a personalised medicine approach to thiopurine dosing, in comparison to standard weight-based dosing.
A retrospective matched cohort study of 214 patients with AIH who were seen at King's College between 1999-2019 was performed. Metabolite levels were measured in 109 patients. The control group included 105 patients on weight-based thiopurine dosing with no metabolite monitoring.
Biochemical response (BR) occurred more frequently at 6-month follow-up in patients with metabolite monitoring compared to those on a weight-based regimen (77% vs. 60%, p = 0.008). This remained true with data analysis based on clinicians who measure metabolites and those who do not (BR at 6 months: 84% vs. 64%, p = 0.016). Patients with BR had TGN levels within the therapeutic range of 225-450 pmol/8x10 erythrocytes significantly more often than those who failed to achieve or lost BR (40% vs. 13%, p <0.0001). Moreover, TGN levels within the pre-defined therapeutic range predicted more stable disease within 6 months of testing compared to levels outside the range (p <0.0001). A high proportion of patients with sub-therapeutic TGN levels (75-225 pmol/8x10 erythrocytes) remained in BR (75% vs. 81%, p = 0.589) with fewer ADRs (44% vs. 86%, p = 0.0002) when compared to patients with therapeutic TGN levels.
A strategy of personalised medicine using metabolite levels can optimise treatment regimens in AIH, resulting in fewer ADRs whilst maintaining BR.
This study looked to see if measuring the breakdown products of a medication used in autoimmune hepatitis increases the chances of gaining good control of the disease, when compared to a group of patients who were on a dose of this medication based on their weight. A group of 214 patients with autoimmune hepatitis were split into 2 groups: roughly half had their medication dose adjusted according to measurements of breakdown products in the blood, whilst the other half received their weight-based dose as normal. The results confirmed that using a personalised approach and checking drug breakdown products resulted in fewer side effects and potentially improved control of disease.
自身免疫性肝炎（AIH）患者通常接受硫嘌呤类药物（如硫唑嘌呤（AZA）或巯嘌呤）维持治疗。AZA 代谢的遗传多态性可导致硫鸟嘌呤核苷酸（TGN）和 6-巯基嘌呤的变化，两者均可引起药物不良反应（ADR）。在炎症性肠病中，已经确定了优化疗效的治疗性 TGN 范围（225-450 pmol/8x10 红细胞）。我们评估了个体化药物治疗方案与标准体重为基础的治疗方案相比，在硫嘌呤给药方面的优势。
对 1999 年至 2019 年在国王学院就诊的 214 例 AIH 患者进行了回顾性匹配队列研究。对 109 例患者进行了代谢物水平检测。对照组包括 105 例未进行代谢物监测的基于体重的硫嘌呤治疗患者。
与基于体重的治疗方案相比，进行代谢物监测的患者在 6 个月随访时生化缓解（BR）更常见（77%比 60%，p=0.008）。即使根据是否检测代谢物的临床医生进行数据分析，这一结果仍然成立（6 个月时 BR：84%比 64%，p=0.016）。具有 BR 的患者 TGN 水平处于 225-450 pmol/8x10 红细胞的治疗范围内的比例显著高于未达到或失去 BR 的患者（40%比 13%，p<0.0001）。此外，与治疗范围外的水平相比，治疗范围内的 TGN 水平在测试后 6 个月内预测疾病更稳定（p<0.0001）。与治疗性 TGN 水平患者相比，具有亚治疗性 TGN 水平（75-225 pmol/8x10 红细胞）的患者中有很大一部分仍处于 BR（75%比 81%，p=0.589），且 ADR 更少（44%比 86%，p=0.0002）。
使用代谢物水平的个体化医学策略可以优化 AIH 的治疗方案，在维持 BR 的同时减少 ADR。
本研究旨在比较使用药物代谢产物测量值和根据体重给药的方法，观察其对治疗自身免疫性肝炎的影响。214 例自身免疫性肝炎患者被分为两组：一半的患者根据血液中代谢产物的测量值调整药物剂量，而另一半患者则按照正常体重剂量接受治疗。结果证实，采用个体化方法并检查药物代谢产物可减少副作用，并可能改善疾病控制。
