Wessels Judith A M, van der Kooij Sjoerd M, le Cessie Saskia, Kievit Wietske, Barerra Pilar, Allaart Cornelia F, Huizinga Tom W J, Guchelaar Henk-Jan
Leiden University Medical Center, Leiden, The Netherlands.
Arthritis Rheum. 2007 Jun;56(6):1765-75. doi: 10.1002/art.22640.
To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA).
Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty-four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS < or = 2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients.
The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of < or = 3.5 had a true positive response rate of 95%. Scores of > or = 6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results.
This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better-tailored initial treatment decisions in patients with RA.
建立一种临床药物遗传学模型，以预测甲氨蝶呤（MTX）治疗类风湿关节炎（RA）的疗效。
205例新诊断为RA且疾病活动的患者接受MTX（起始剂量为7.5mg/周，4周后增至15mg/周）和叶酸（1mg/天）治疗。如果3个月时疾病活动评分（DAS）>2.4，则将MTX剂量增至25mg/周。选择了24个可能影响疾病状态和药物反应的基线变量。此外，还测定了与MTX作用机制、嘌呤和嘧啶合成相关的13个基因中的17个多态性。比较了缓解者（定义为6个月时DAS≤2.4的患者）和未缓解者之间的因素。如有差异，采用逐步选择程序确定反应的预测因素。通过简化自变量的回归系数设计了一个临床评分。根据临床评分选择截断水平，并计算阳性和阴性反应率。在第二组患者中对该模型进行了评估。
MTX疗效模型包括性别、类风湿因子和吸烟状况、DAS以及AMPD1、ATIC、ITPA和MTHFD1基因中的4个多态性。该预测模型转化为一个范围从0到11.5的评分系统。评分≤3.5时，真阳性反应率为95%。评分≥6时，真阴性反应率为86%。60%的患者被归类为缓解者或未缓解者，而使用非遗传模型归类的患者为32%。在另外38例RA患者中对该模型的评估支持了这些结果。
本研究建立了一种预测MTX治疗RA患者疗效的模型。这种药物遗传学模型可能会使RA患者的初始治疗决策更加个体化。
