Association of methotrexate polyglutamates concentration with methotrexate efficacy and safety in patients with rheumatoid arthritis treated with predefined dose: results from the MIRACLE trial.

We aimed to clarify the association of MTX-PGs concentration with efficacy and safety in MTX-naïve patients initiating MTX in a prospective interventional clinical trial.

我们旨在阐明甲氨蝶呤多聚谷氨酸（MTX-PGs）浓度与甲氨蝶呤初治患者疗效和安全性的关联，这在一项前瞻性干预性临床试验中进行。

Methods

The MIRACLE trial enrolled 300 MTX-naïve patients.

MIRACLE试验招募了300名甲氨蝶呤（MTX）初治患者。

Oral MTX was initiated and increased to the maximum tolerated dose by week 12.

口服甲氨蝶呤在第12周前开始并增加至最大耐受剂量。

Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab.

在第24周未根据简化疾病活动指数实现缓解的患者被随机分配到继续剂量组或减少剂量组，并开始接受皮下注射阿达木单抗。

We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety.

我们使用液相色谱-串联质谱法测量了红细胞中MTX-PGs的浓度，并分析了这些浓度与疗效和安全性的关联。

Results

The mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed.

随着甲氨蝶呤（MTX）剂量的增加，总甲氨蝶呤多聚谷氨酸（MTX-PGs）的平均浓度也随之增加，并在剂量固定后的12周内继续上升。

At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week).

在第24周时，总甲氨蝶呤多聚谷氨酸（MTX-PGs）浓度为110.5（标准差43.8）nmol/L，此时甲氨蝶呤（MTX）剂量为每周12.6（3.0）mg（相当于每周每公斤体重0.23（0.07）mg/kg）。

During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose.

在甲氨蝶呤（MTX）单药治疗期间，较高的甲氨蝶呤多聚谷氨酸（MTX-PGs）浓度是疾病活动度较低的独立因素；然而，在继续使用MTX剂量的患者中，这种关联在开始使用阿达木单抗后消失。

Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use.

无论是否使用阿达木单抗，肝毒性都与较高的甲氨蝶呤多聚谷氨酸（MTX-PGs）浓度有关。

The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index.

红细胞中总MTX-PGs浓度显著升高与较低的估算肾小球滤过率、血清白蛋白和体重指数有关。

Conclusions

The MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX.

MIRACLE试验表明，红细胞中较高的总MTX-PGs浓度与甲氨蝶呤较高的疗效和较低的安全性相关。

trial_registration_number

NCT03505008.

NCT03505008。