Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Pharmacoepidemiol Drug Saf. 2018 Aug;27(8):885-893. doi: 10.1002/pds.4555. Epub 2018 May 24.
Case reports and pharmacokinetic studies have suggested that concomitant use of low-dose methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with increased risk of methotrexate toxicity. This study aimed to investigate the risk of serious adverse events associated with concomitant use of low-dose methotrexate and NSAIDs, compared with use of methotrexate alone, among patients with rheumatoid arthritis.
The study was conducted as a register-based cohort study in Denmark, 2004 to 2015, including episodes of concomitant use of methotrexate and NSAIDs (n = 21 536) and control episodes of use of methotrexate alone (n = 21 725). The primary outcome was the composite end point any serious adverse event, including liver toxicity, acute renal failure, and cytopenia. Secondary outcomes were the individual outcome components. Analyses were conducted using proportional-hazards regression, with adjustment using inverse-probability-of-treatment weighting based on propensity scores.
During follow-up, 110 cases of the primary outcome occurred during concomitant use of methotrexate and NSAIDs (unadjusted incidence rate 12.1 per 1000 person-years) and 129 during control episodes (11.0 per 1000 person-years). Concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of any serious adverse event (weighted hazard ratio 1.40; 95% CI, 1.07-1.82). In secondary analyses, concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of acute renal failure and cytopenia.
Concomitant use of low-dose methotrexate and NSAIDs was associated with a significantly increased risk of serious adverse events, expanding on the evidence base for current regulatory recommendations that advocate caution when low-dose methotrexate and NSAID are coprescribed.
病例报告和药代动力学研究表明，低剂量甲氨蝶呤与非甾体抗炎药（NSAIDs）同时使用可能与甲氨蝶呤毒性增加有关。本研究旨在调查与类风湿关节炎患者单独使用甲氨蝶呤相比，同时使用低剂量甲氨蝶呤和 NSAIDs 相关的严重不良事件风险。
这是一项在丹麦进行的基于登记的队列研究，时间为 2004 年至 2015 年，包括同时使用甲氨蝶呤和 NSAIDs 的发作（n=21536）和单独使用甲氨蝶呤的对照发作（n=21725）。主要结局是任何严重不良事件的复合终点，包括肝毒性、急性肾衰竭和细胞减少症。次要结局为各别结局组成部分。使用比例风险回归进行分析，并基于倾向评分使用逆概率治疗加权进行调整。
在随访期间，同时使用甲氨蝶呤和 NSAIDs 时发生 110 例主要结局（未经调整的发生率为每 1000 人年 12.1 例），对照发作时发生 129 例（每 1000 人年 11.0 例）。同时使用甲氨蝶呤和 NSAIDs 与任何严重不良事件的风险显著增加相关（加权风险比 1.40；95%CI，1.07-1.82）。在次要分析中，同时使用甲氨蝶呤和 NSAIDs 与急性肾衰竭和细胞减少症的风险显著增加相关。
低剂量甲氨蝶呤与 NSAIDs 同时使用与严重不良事件风险显著增加相关，这扩展了当前监管建议的证据基础，即当低剂量甲氨蝶呤与 NSAID 同时处方时应谨慎。
