University Medical Center Utrecht, Wilhelmina Children's Hospital, Department of Pediatric Immunology, 3508AB Utrecht, The Netherlands.
Ann Rheum Dis. 2012 Sep;71(9):1484-9. doi: 10.1136/annrheumdis-2011-200942. Epub 2012 Apr 3.
Methotrexate (MTX) is a cheap and efficacious drug in juvenile idiopathic arthritis (JIA) treatment. If JIA patients are unresponsive to MTX, early and effective combination treatment with biologicals is required to prevent joint damage. The authors developed a prediction model to identify JIA patients not responding to MTX.
In a cohort of 183 JIA patients, clinical variables and single nucleotide polymorphisms (SNPs) in genes involved in the mechanism of action of MTX were determined at the start of MTX treatment. These variables were used to construct a prediction model for non-response to MTX treatment during the first year of treatment. Non-response to MTX was defined according the American College of Rheumatology paediatric 70 criteria. The prediction model was validated in a cohort of 104 JIA patients.
The prediction model included: erythrocyte sedimentation rate and SNPs in genes coding for methionine synthase reductase, multidrug resistance 1 (MDR-1/ABCB1), multidrug resistance protein 1 (MRP-1/ABCC1) and proton-coupled folate transporter (PCFT). The area under the receiver operating characteristics curve (AUC) was 0.72 (95% CI: 0.63 to 0.81). In the validation cohort, the AUC was 0.65 (95% CI: 0.54 to 0.77). The prediction model was transformed into a total risk score (range 0-11). At a cut-off of ≥3, sensitivity was 78%, specificity 49%, positive predictive value was 83% and negative predictive value 41%.
The prediction model that we developed and validated combines clinical and genetic variables to identify JIA patients not responding to MTX treatment. This model could assist clinicians in making individualised treatment decisions.
甲氨蝶呤（MTX）是治疗幼年特发性关节炎（JIA）的一种廉价且有效的药物。如果 JIA 患者对 MTX 反应不佳，需要早期且有效的联合生物制剂治疗，以预防关节损伤。作者开发了一种预测模型来识别对 MTX 治疗无反应的 JIA 患者。
在 183 例 JIA 患者的队列中，在开始 MTX 治疗时确定了与 MTX 作用机制相关的基因中的临床变量和单核苷酸多态性（SNP）。这些变量用于构建用于在治疗的第一年中预测 MTX 治疗无反应的模型。根据美国风湿病学会儿科 70 标准定义 MTX 治疗无反应。该预测模型在 104 例 JIA 患者的队列中进行了验证。
预测模型包括：红细胞沉降率和编码甲硫氨酸合成酶还原酶、多药耐药蛋白 1（MRP-1/ABCC1）、多药耐药 1（MDR-1/ABCB1）和质子偶联叶酸转运蛋白（PCFT）的基因中的 SNP。接受者操作特征曲线下的面积（AUC）为 0.72（95%CI：0.63-0.81）。在验证队列中，AUC 为 0.65（95%CI：0.54-0.77）。预测模型转化为总风险评分（范围 0-11）。在≥3 的截断值处，灵敏度为 78%，特异性为 49%，阳性预测值为 83%，阴性预测值为 41%。
我们开发和验证的预测模型结合了临床和遗传变量，以识别对 MTX 治疗无反应的 JIA 患者。该模型可以帮助临床医生做出个体化的治疗决策。
