The Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, UK.
Drug Saf. 2009;32(12):1123-34. doi: 10.2165/11316650-000000000-00000.
Evidence is accumulating for the early sustained usage of disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis. Leflunomide was licensed for the treatment of rheumatoid arthritis in 1998. Postmarketing surveillance, case reports and observational studies have highlighted less common or unexpected adverse events. Therefore, it is appropriate that we review the benefit-risk profile of leflunomide after 10 years of widespread usage. A wide-based search of relevant literature was performed to formulate this assessment. The improvements in rheumatoid arthritis shown by double-blind, randomized controlled trials (RCTs) of leflunomide have now been shown to be maintained beyond 4 years in open-label extension studies. Leflunomide is comparable to methotrexate, but better than sulfasalazine at 24 months in only one study. However, tolerance in clinical practice research shows higher than expected withdrawal rates due to both toxicity and lack of efficacy when compared with methotrexate and placebo. Adverse events reported include gastrointestinal upset, hypertension, headache, hepatotoxicity and hair loss, as well as predisposition to infection and peripheral neuropathy. The incidence of gastrointestinal adverse effects for leflunomide is similar to sulfasalazine but higher than those seen with methotrexate. Serious drug-induced hepatotoxicity leading to hospitalization is rare (0.02%), but isolated fatalities from liver failure have been documented. It is considered likely, but not yet proven, that there may be an increased incidence of weight loss and interstitial lung disease with leflunomide. Leflunomide in combination with methotrexate or sulfasalazine is an effective regimen in RCTs utilizing placebo controls, but more research is needed to confirm its effectiveness in combination with other DMARDs, particularly biologicals. The active metabolite of leflunomide is teratogenic in animal studies and is also found in breast milk. Therefore, contraception is advised in both males and females of child-bearing potential. There are genetic, pharmacokinetic and biochemical reasons to explain variation in both patient response and adverse event profile. Hence, blood and blood pressure monitoring are recommended and therapeutic drug monitoring should be considered in clinical nonresponders. Leflunomide is an effective DMARD that sustains a clinical and radiological response comparable to sulfasalazine and methotrexate. However, adverse effects necessitate frequent monitoring. It should be used with caution in those of child-bearing potential and with pre-existing lung and liver disease.
越来越多的证据表明，在类风湿关节炎中应尽早持续使用疾病修饰抗风湿药物（DMARDs）。来氟米特于 1998 年被批准用于治疗类风湿关节炎。上市后监测、病例报告和观察性研究突出了不太常见或意外的不良事件。因此，在广泛使用 10 年后，我们有必要重新评估来氟米特的获益-风险比。广泛搜索了相关文献，以制定此评估。来氟米特的双盲、随机对照试验（RCT）显示的类风湿关节炎改善，现已在开放标签扩展研究中得到证实，可维持 4 年以上。在一项研究中，来氟米特在 24 个月时与甲氨蝶呤相当，优于柳氮磺胺吡啶，但在另外两项研究中，与甲氨蝶呤和安慰剂相比，耐受性较差，导致预期之外的停药率较高。报告的不良反应包括胃肠道不适、高血压、头痛、肝毒性和脱发，以及感染和周围神经病的易感性。来氟米特的胃肠道不良反应发生率与柳氮磺胺吡啶相似，但高于甲氨蝶呤。导致住院的严重药物性肝毒性罕见（0.02%），但有孤立的肝衰竭死亡病例。虽然尚未得到证实，但来氟米特可能会导致体重减轻和间质性肺病的发生率增加，这被认为是合理的。来氟米特联合甲氨蝶呤或柳氮磺胺吡啶在利用安慰剂对照的 RCT 中是一种有效的方案，但需要更多的研究来证实其与其他 DMARDs（特别是生物制剂）联合使用的有效性。来氟米特的活性代谢物在动物研究中具有致畸性，并且在母乳中也有发现。因此，建议有生育能力的男性和女性都采取避孕措施。由于遗传、药代动力学和生化原因，患者的反应和不良反应谱都存在差异。因此，建议进行血液和血压监测，对于临床无应答者应考虑进行治疗药物监测。来氟米特是一种有效的 DMARD，可维持与柳氮磺胺吡啶和甲氨蝶呤相当的临床和影像学应答。然而，不良反应需要频繁监测。对于有生育能力的患者和有潜在肺和肝疾病的患者，应谨慎使用。
