Thiopurine Methyltransferase Activity Influences Clinical Response to Azathioprine in Inflammatory Bowel Disease
Thiopurine Methyltransferase Activity Influences Clinical Response to Azathioprine in Inflammatory Bowel Disease
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DOI：
10.1016/s1542-3565(04)00127-2
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发表时间：
2004-05-01
影响因子：
12.6
通讯作者：
Bayless, Theodore M.
中科院分区：
文献类型：
--
作者：
Cuffari, Carmen;Dassopoulos, Themistocles;Bayless, Theodore M.
背景和目的：硫嘌呤甲基转移酶（TPMT）活性的遗传多态性可能影响硫唑嘌呤（AZA）治疗的临床反应。我们的目的是确定红细胞 TPMT 酶活性的测量是否可用于优化炎症性肠病 (IBD) 患者对 AZA 治疗的临床反应。方法：总共对 142 名连续患者进行了研究。 41 名患者（32 名克罗恩病 [CD] 和 9 名溃疡性结肠炎 [UC]）参加了一项为期 4 个月的 AZA 前瞻性非随机研究，其中 101 名患者（65 名 CD 患者和 36 名 UC）接受维持 AZA 或 6-巯基嘌呤 (6-MP) 治疗。在不考虑临床反应的情况下测量红细胞 TPMT 活性和 AZA 代谢物水平。结果：连续 AZA 治疗 4 个月后，低于平均水平（12 U/mL 血液（P < 0.001）的患者的缓解率为 69% (9/13)。TPMT 活性为 12 (218 +/- 28) 的患者，尽管 AZA 的平均剂量（1.6 mg/kg/天）相似（P < 0.001）。通过多变量逻辑回归分析，TPMT 活性为 12 的患者（P < 0.001）。血液水平 < 15.3 U/mL 的 6-TGn 水平 > 292 pmol/8 x 10(8) RBC 与 85.7% 的临床反应阳性预测值相关。 结论： TPMT 活性高于平均水平 (> 12) 的患者可能仍对常规剂量的 AZA 耐药，并且可能需要高剂量 (> 292)。 6-TGn 水平需要前瞻性、随机、对照试验来确定是否可以使用先前的 TPMT 表型测试来有效调整 AZA 的剂量，以改善临床反应时间和率。
Background & Aims: Genetic polymorphism in thiopurine methyltransferase (TPMT) activity may influence clinical responsiveness to azathioprine (AZA) therapy. Our aim was to determine if the measurement of erythrocyte TPMT enzyme activity could be used to optimize clinical responsiveness to AZA therapy in patients with inflammatory bowel disease (IBD). Methods: A total of 142 consecutive patients were studied. Forty-one patients (32 with Crohn's disease [CD] and 9 with ulcerative colitis [UC]) were enrolled in a 4-month prospective nonrandomized study with AZA, and 101 (65 with CD and 36 with UC) were on either maintenance AZA or 6-mercaptopurine (6-MP). Erythrocyte TPMT activity and AZA metabolite levels were measured blinded to the clinical response. Results: The response rate after 4 months of continuous AZA therapy was 69% (9/13) in those patients with below-average ( 12 U/mL blood (P < 0.001). Patients with TPMT activity 12 (218 +/- 28), despite similar mean (1.6 mg/kg/day) dosages of AZA (P < 0.001). By multivariate logistic regression analysis, patients with a TPMT level < 15.3 U/mL blood were 6.2 times more likely to respond to AZA therapy. A 6-TGn level of > 292 pmol/8 x 10(8) RBCs was associated with a positive predictive value of clinical response of 85.7%. Conclusions: Patients with higher than average TPMT activity (> 12) may remain refractory to conventional dosages of AZA, and may require high (> 292) 6-TGn levels. Prospective, randomized, controlled trials are needed to determine whether prior TPMT phenotype testing can be used to adjust the dose of AZA effectively to improve clinical response time and rate.