van Ede A E, Laan R F, Rood M J, Huizinga T W, van de Laar M A, van Denderen C J, Westgeest T A, Romme T C, de Rooij D J, Jacobs M J, de Boo T M, van der Wilt G J, Severens J L, Hartman M, Krabbe P F, Dijkmans B A, Breedveld F C, van de Putte L B
University Medical Center St Radboud, Nijmegen, The Netherlands.
Arthritis Rheum. 2001 Jul;44(7):1515-24. doi: 10.1002/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7.
To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial.
Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX.
Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively).
Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.
在一项为期48周的随机、双盲、安慰剂对照试验中，研究叶酸对因毒性而停用甲氨蝶呤（MTX）作为单药抗风湿治疗的影响，确定哪种不良事件减少，研究对MTX疗效的影响，并比较叶酸与亚叶酸补充剂的效果。
活动性类风湿关节炎患者（n = 434）被随机分配接受MTX加安慰剂、叶酸（1毫克/天）或亚叶酸（2.5毫克/周）。初始MTX剂量为7.5毫克/周；对于反应不足的情况，允许剂量增加至最大25毫克/周。一旦MTX剂量达到15毫克/周，叶酸剂量加倍。主要终点是因不良事件而停用MTX。次要终点是MTX剂量以及MTX疗效和毒性参数。
安慰剂组中38%的患者因毒性停用MTX，叶酸组为17%，亚叶酸组为12%。叶酸补充剂组肝酶水平升高的发生率降低解释了这些组间差异。在其他不良事件的频率或不良事件的持续时间方面未发现组间差异。所有组的疾病活动参数均有同等改善。研究结束时，安慰剂组MTX的平均剂量（14.5毫克/周）低于叶酸组和亚叶酸组（分别为18.0毫克/周和16.4毫克/周）。
两种叶酸补充方案均降低了MTX治疗期间肝酶水平升高的发生率，因此，这些患者中MTX停药的频率较低。叶酸似乎对包括胃肠道和黏膜副作用在内的其他不良事件的发生率、严重程度和持续时间没有影响。在叶酸补充剂组中，为获得相似的疾病活动改善，MTX的处方剂量略高。
