Hlavaty T, Batovsky M, Balakova D, Pav I, Celec P, Gregus M, Zakuciova M, Hlista M, Horakova M, Desatova B, Koller T, Toth J, Kadasi L, Huorka M
Department of Internal Medicine V, Division of Gastroenterology and Hepatology, University Hospital Bratislava Ruzinov, Slovakia.
Bratisl Lek Listy. 2013;114(4):199-205. doi: 10.4149/bll_2013_042.
The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine, are established in the treatment of inflammatory bowel diseases (IBD). Polymorphisms in thiopurine S-methyltransferase (TPMT) gene have been associated with adverse drug reactions (ADRs) to AZA.
The aim of this study was to evaluate TPMT polymorphisms and AZA-related toxicity in a Slovak cohort of 220 IBD patients treated with AZA. In every patient, the dose and duration of AZA therapy, concomitant 5-aminosalicylate (5-ASA) medication, frequency, type, time to onset, dose of ADR and concomitant 5-ASA at the onset of ADR were recorded. Each patient was also genotyped for the presence of variant TPMT alleles (*2,*3A,*3B,*3C). Frequency, type and circumstances of ADRs were compared according to TPMT status.
Of the 220 patients, 205 (93.2 %) were wild-type (TPMT*1/1), one (0.5%) carried a TPMT1/*3C allele, 13 (5.9 %) carried TPMT *1/*3A allele and one was homozygous for TMPT *3A allele. No TPMT 2 mutation was found. The incidence of adverse drug reactions was 62/205 (30.2 %) in the wild-type group as compared to 13/15 (86.7 %) in the TPMT mutation group, p=2.10-5. Leukopenia (WBC< 3.010^9/L) occurred in 21/205 (10.2 %) patients with wild type TPMT versus 11/15 (73.3 %) patients with TPMT mutations, p=0.000001. There was no significant difference between TMPT groups in gastrointestinal or other ADRs. No impact of 5-ASA on the incidence and severity of AZA adverse drug reactions was observed.
The incidence of leukopenia in TPMT mutant patients was significantly higher and more severe as compared to TPMT wild type patients. We observed no impact of concomitant 5-ASA therapy on AZA induced toxicity (Tab. 4, Fig. 2, Ref. 37).
硫唑嘌呤（AZA）和6-巯基嘌呤这两种硫嘌呤类药物已被用于治疗炎症性肠病（IBD）。硫嘌呤甲基转移酶（TPMT）基因多态性与对AZA的药物不良反应（ADR）相关。
本研究的目的是评估220例接受AZA治疗的斯洛伐克IBD患者队列中的TPMT多态性及与AZA相关的毒性。记录每位患者的AZA治疗剂量和持续时间、同时使用的5-氨基水杨酸（5-ASA）药物、ADR的发生频率、类型、发生时间、剂量以及ADR发生时同时使用的5-ASA。还对每位患者进行基因分型，以检测是否存在TPMT变异等位基因（*2、*3A、*3B、*3C）。根据TPMT状态比较ADR的频率、类型和情况。
在220例患者中，205例（93.2%）为野生型（TPMT1/1），1例（0.5%）携带TPMT1/3C等位基因，13例（5.9%）携带TPMT1/3A等位基因，1例为TPMT3A等位基因纯合子。未发现TPMT2突变。野生型组药物不良反应发生率为62/205（30.2%），而TPMT突变组为13/15（86.7%），p = 2.10 - 5。白细胞减少症（白细胞计数<3.0×10^9/L）在205例野生型TPMT患者中有21例（10.2%）发生，而在TPMT突变患者中有11/15（73.3%）发生，p = 0.000001。在胃肠道或其他ADR方面，TPMT组之间无显著差异。未观察到5-ASA对AZA药物不良反应的发生率和严重程度有影响。
与TPMT野生型患者相比，TPMT突变患者白细胞减少症的发生率显著更高且更严重。我们未观察到同时使用5-ASA治疗对AZA诱导的毒性有影响（表4，图2，参考文献37）。
