Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
PLoS One. 2018 Apr 9;13(4):e0195524. doi: 10.1371/journal.pone.0195524. eCollection 2018.
Azathioprine is a widely used immunosuppressive drug. Genetic polymorphisms and activity of the enzyme thiopurine methyltransferase (TPMT) have been associated with azathioprine efficacy and toxicity in several populations. We investigated whether these associations also exist for ANCA associated vasculitis (AAV) patients, who receive azathioprine maintenance therapy after remission induction with cyclophosphamide.
207 AAV patients treated with cyclophosphamide induction and azathioprine maintenance therapy were included and followed for 60 months. TPMT genotype and tertiles of TPMT activity were compared to relapse free survival and occurrence of adverse events, particularly leukopenia. Multivariable regression was performed to account for confounders.
In univariable analysis, relapse free survival was not significantly associated with TPMT genotype (P = 0.41) or TPMT activity (P = 0.07), although it tended to be longer in lower tertiles of TPMT activity. There was no significant association of TPMT genotype and activity with occurrence of any adverse event. In multiple regression, leukocyte counts at the end of cyclophosphamide induction were related to risk of leukopenia during azathioprine therapy [P<0.001; OR 0.54 (95% CI 0.43-0.68)] and risk of relapse during follow-up [P = 0.001; HR 1.17 (95% CI 1.07-1.29)] irrespective of TMPT genotype or activity.
TPMT genotype and activity were not independent predictors of relapse, and could not predict leukopenia or other adverse effects from azathioprine. Leukocyte counts after cyclophosphamide induction were related to both outcomes, implying a greater influence of cyclophosphamide response compared to azathioprine and TPMT in AAV patients.
巯嘌呤甲基转移酶（TPMT）的基因多态性和活性与几种人群中巯嘌呤的疗效和毒性有关。本研究旨在探讨在接受环磷酰胺诱导缓解后接受巯嘌呤维持治疗的抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）患者中，这些关联是否存在。
共纳入 207 例接受环磷酰胺诱导和巯嘌呤维持治疗的 AAV 患者，并进行了 60 个月的随访。比较 TPMT 基因型和 TPMT 活性的三分位与无复发生存和不良事件（特别是白细胞减少症）的发生情况。采用多变量回归来控制混杂因素。
在单变量分析中，无复发生存与 TPMT 基因型（P=0.41）或 TPMT 活性（P=0.07）无显著相关性，尽管 TPMT 活性较低三分位的无复发生存时间较长。TPMT 基因型和活性与任何不良事件的发生均无显著相关性。在多变量回归中，环磷酰胺诱导结束时的白细胞计数与巯嘌呤治疗期间白细胞减少症的风险相关[P<0.001；OR 0.54（95%CI 0.43-0.68）]和随访期间的复发风险[P=0.001；HR 1.17（95%CI 1.07-1.29）]，与 TPMT 基因型或活性无关。
TPMT 基因型和活性不是复发的独立预测因子，不能预测巯嘌呤引起的白细胞减少症或其他不良反应。环磷酰胺诱导结束时的白细胞计数与这两个结局都有关，这意味着环磷酰胺反应对 AAV 患者的影响大于巯嘌呤和 TPMT。
