Mazor Yoav, Koifman Eduard, Elkin Hela, Chowers Yehuda, Krivoy Norberto, Karban Amir, Efrati Edna
Gastroenterology Department, Rambam Health Care Campus, Haifa, Israel.
Curr Drug Saf. 2013 Jul;8(3):181-5. doi: 10.2174/15748863113089990033.
Thiopurines are effective in attaining and maintaining remission in patients with inflammatory bowel diseases (IBD). The major drawback of these drugs are their serious adverse effects (SAE), highlighting the importance of preemptive identification of patients at risk. We aimed to examine whether gene polymorphisms in GSTM1, GSTT1 and TPMT, combined with various clinical parameters, can predict thiopurine induced SAE.
A retrospective cohort of 176 Crohn's Disease (CD) patients treated with thiopurines (131 with 6MP and 45 with azathioprine) was genotyped for common polymorphisms in GSTM1, GSTT1 and TPMT. Clinical data including SAE, age, ethnicity, gender and smoking status were extracted from patient charts. SAEs evaluated were myelosuppression, hepatotoxicity and pancreatitis. Associations between demographic, clinical, and genetic variables and thiopurine induced SAE were assessed.
Twenty-four patients (14%) developed SAE, revealing a significant association between thiopurine induced SAE and GSTM1-null genotype (P=0.05), older age (P=0.016) and active smoking status (P=0.043) and SAE. On multi-variant analysis, past or current smokers were at increased risk for developing thiopurine related SAE (OR 2.915, CI 95%: 1.199- 7.084), specifically pancreatitis (p<0.001). No association was found between TPMT or GSTT1 polymorphisms and the development of SAE.
Active smoking and GSTM1-null genotype appear to be risk factors for thiopurine induced SAEs (i.e. myelosuppression, hepatotoxicity and pancreatitis) in patients with CD. Corroboration of these associations in larger cohorts is warranted.
硫嘌呤类药物在诱导和维持炎症性肠病（IBD）患者缓解方面有效。这些药物的主要缺点是其严重不良反应（SAE），这凸显了预先识别高危患者的重要性。我们旨在研究谷胱甘肽S-转移酶M1（GSTM1）、谷胱甘肽S-转移酶T1（GSTT1）和硫代嘌呤甲基转移酶（TPMT）基因多态性与各种临床参数相结合是否能预测硫嘌呤类药物诱导的SAE。
对176例接受硫嘌呤类药物治疗的克罗恩病（CD）患者（131例使用6-巯基嘌呤（6MP），45例使用硫唑嘌呤）进行回顾性队列研究，对GSTM1、GSTT1和TPMT的常见多态性进行基因分型。从患者病历中提取包括SAE、年龄、种族、性别和吸烟状况在内的临床数据。评估的SAE包括骨髓抑制、肝毒性和胰腺炎。评估人口统计学、临床和基因变量与硫嘌呤类药物诱导的SAE之间的关联。
24例患者（14%）发生SAE，显示硫嘌呤类药物诱导的SAE与GSTM1基因缺失型（P = 0.05）、年龄较大（P = 0.016）和当前吸烟状态（P = 0.043）与SAE之间存在显著关联。在多变量分析中，既往或当前吸烟者发生硫嘌呤类药物相关SAE的风险增加（比值比2.915，95%置信区间：1.199 - 7.084），尤其是胰腺炎（p < 0.001）。未发现TPMT或GSTT1基因多态性与SAE的发生之间存在关联。
当前吸烟和GSTM1基因缺失型似乎是CD患者硫嘌呤类药物诱导的SAE（即骨髓抑制、肝毒性和胰腺炎）的危险因素。需要在更大队列中对这些关联进行验证。
