Griffith S M, Fisher J, Clarke S, Montgomery B, Jones P W, Saklatvala J, Dawes P T, Shadforth M F, Hothersall T E, Hassell A B, Hay E M
Department of Rheumatology, East Surrey Hospital, Surrey, UK.
Rheumatology (Oxford). 2000 Oct;39(10):1102-9. doi: 10.1093/rheumatology/39.10.1102.
It is postulated that some aspects of methotrexate toxicity may be related to its action as an anti-folate. Folic acid (FA) is often given as an adjunct to methotrexate therapy, but there is no conclusive proof that it decreases the toxicity of methotrexate and there is a theoretical risk that it may decrease the efficacy of methotrexate.
To look at the effect of stopping FA supplementation in UK rheumatoid arthritis (RA) patients established on methotrexate <20 mg weekly and FA 5 mg daily, to report all toxicity (including absolute changes in haematological and liver enzyme indices) and to report changes in the efficacy of methotrexate.
In a prospective, randomized, double-blind, placebo-controlled study, 75 patients who were established on methotrexate <20 mg weekly and FA 5 mg daily were asked to stop their FA and were randomized to one of two groups: placebo or FA 5 mg daily. Patients were evaluated for treatment toxicity and efficacy before entry and then at intervals of 3 months for 1 yr.
Overall, 25 (33%) patients concluded the study early, eight (21%) in the group remaining on FA and 17 (46%) in the placebo group (P = 0.02). Two patients in the placebo group discontinued because of neutropenia. At 9 months there was an increased incidence of nausea in the placebo group (45 vs. 7%, P = 0.001). The placebo group had significantly lower disease activity on a few of the variables measured, but these were probably not of clinical significance.
It is important to continue FA supplementation over the long term in patients on methotrexate and FA in order to prevent them discontinuing treatment because of mouth ulcers or nausea and vomiting. Our data suggest that FA supplementation is also helpful in preventing neutropenia, with very little loss of efficacy of methotrexate.
据推测，甲氨蝶呤毒性的某些方面可能与其作为抗叶酸剂的作用有关。叶酸（FA）常作为甲氨蝶呤治疗的辅助用药，但尚无确凿证据表明其能降低甲氨蝶呤的毒性，且理论上存在降低甲氨蝶呤疗效的风险。
观察在英国类风湿关节炎（RA）患者中，停止补充FA对已确定每周服用甲氨蝶呤剂量<20 mg且每日服用FA 5 mg患者的影响，报告所有毒性反应（包括血液学指标和肝酶指标的绝对变化）以及甲氨蝶呤疗效的变化。
在一项前瞻性、随机、双盲、安慰剂对照研究中，75例已确定每周服用甲氨蝶呤剂量<20 mg且每日服用FA 5 mg的患者被要求停止服用FA，并随机分为两组：安慰剂组或每日服用FA 5 mg组。在入组前以及之后1年中每3个月对患者进行治疗毒性和疗效评估。
总体而言，25例（33%）患者提前结束研究，继续服用FA组有8例（21%），安慰剂组有17例（46%）（P = 0.02）。安慰剂组有2例患者因中性粒细胞减少而停药。在9个月时，安慰剂组恶心发生率增加（45%对7%，P = 0.001）。在一些测量变量上，安慰剂组疾病活动度显著较低，但这些可能无临床意义。
对于服用甲氨蝶呤和FA的患者，长期持续补充FA很重要，以防止他们因口腔溃疡或恶心呕吐而停止治疗。我们的数据表明，补充FA也有助于预防中性粒细胞减少，且甲氨蝶呤的疗效几乎没有损失。
