I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany.
European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
Hepatology. 2024 Nov 1;80(5):1026-1040. doi: 10.1097/HEP.0000000000000940. Epub 2024 May 29.
In autoimmune hepatitis, achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response.
The relation between metabolites and treatment response was assessed in 337 individuals from 4 European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanine nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N = 146) revealed higher average 6TGN levels in those with stable CBR (260 pmol/0.2 mL) compared to those failing to maintain CBR (181 pmol/0.2 mL; p = 0.0014) or never achieving CBR (153 pmol/0.2 mL; p < 0.0001), with an optimal 6TGN cutoff of ≥223 pmol/0.2 mL (sensitivity: 76% and specificity: 78%). Only 42% exhibited 6TGN ≥223 pmol/0.2 mL following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%; p < 0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N = 36) raised 6TGN (168→321 pmol/0.2 mL; p < 0.0001) and lowered 6MMP (2125→184 pmol/0.2 mL; p < 0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%.
Maintaining CBR in autoimmune hepatitis was associated with 6TGN ≥223 pmol/0.2 mL. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, comedication of allopurinol alongside low-dose thiopurines represents an efficient alternative.
在自身免疫性肝炎中，当前基于体重的硫嘌呤剂量很难实现完全生化缓解（CBR）。我们研究了根据硫嘌呤代谢物的目标范围，患者是否可以根据 CBR 进行分层。此外，我们还探讨了增加巯嘌呤剂量和小剂量巯嘌呤联合别嘌呤醇治疗对代谢物谱和治疗反应的影响。
在来自 4 个欧洲中心的 337 名个体中评估了代谢物与治疗反应之间的关系。在一项全球性、横断面分析中，活性代谢物 6-硫鸟嘌呤核苷酸（6TGN）在 CBR 患者和无 CBR 患者之间相似。然而，对 4 年内进行连续测量的患者（N=146）进行分析显示，稳定 CBR 患者的平均 6TGN 水平较高（260 pmol/0.2 mL），而未能维持 CBR 的患者（181 pmol/0.2 mL；p=0.0014）或从未达到 CBR 的患者（153 pmol/0.2 mL；p<0.0001），最佳 6TGN 截止值为≥223 pmol/0.2 mL（灵敏度：76%，特异性：78%）。只有 42%的患者在基于体重的剂量下表现出 6TGN≥223 pmol/0.2 mL，因为剂量与 6TGN 弱相关，但与毒性相关的代谢物 6-甲基巯基嘌呤（6MMP）相关。增加巯嘌呤剂量会导致优先形成 6MMP（+127%比 6TGN +34%；p<0.0001）。相反，在难以治疗的患者中（N=36）将别嘌呤醇添加到巯嘌呤中会升高 6TGN（168→321 pmol/0.2 mL；p<0.0001）和降低 6MMP（2125→184 pmol/0.2 mL；p<0.0001），从而使所有患者的转氨酶均得到改善，75%的患者长期 CBR 得到改善。
在自身免疫性肝炎中，维持 CBR 与 6TGN≥223 pmol/0.2 mL 相关。对于因优先形成 6MMP而导致未能达到 CBR 和治疗性 6TGN 水平的患者，在低剂量巯嘌呤的基础上加用别嘌呤醇联合治疗是一种有效的替代方法。
