Efficacy and safety of leflunomide or methotrexate plus subcutaneous tumour necrosis factor-alpha blocking agents in rheumatoid arthritis.

Benucci M, Saviola G, Baiardi P, Manfredi M, Sarzi-Puttini P, Atzeni F.

Abstract

Several smaller retrospective case series have concluded that leflunomide (LEF) in combination with anti-TNF-alpha blocking agents appears to be effective and safe. Prospective case series and cohort studies have generally confirmed the efficacy of this combination. Overall, there is currently no evidence from controlled trials that an anti-TNF-alpha combination with LEF is as effective as an anti-TNF-alpha combination with methotrexate (MTX). We compared the effectiveness and safety of a therapeutic regimen associating subcutaneous anti-TNF-alpha agents, etanercept (ETN) and adalimumab ( ADA), with leflunomide (LEF) or methotrexate (MTX), in a two year open-label study performed in clinical practice.

We evaluated 96 patients with active rheumatoid arthritis undergoing therapy with ADA at the dose of 40 mg every other week, or with ETN at the dose of 50 mg/week for two years added to prednisolone (PDN) at the mean dose of 5.2±2.6 mg/day. Fifty-four of these patients were also undergoing therapy with MTX at the mean dose of 11.7±2.6 mg/week, while 42 patients were undergoing therapy with LEF at the daily dose of 20 mg. At 12 months, the analysis of variance showed an improvement of DAS28 in both groups (p<0.001), with a reduction in 33.3% of the patients in treatment with LEF and in 51.8% of the patients in treatment with MTX (p = 0.20). At 18 months, improvement was present in 33.3% of the patients in the LEF group and in 81.5% of the patients in the MTX group (p=0.001). This improvement seems to be independent of the anti-TNF-alpha agent, even if MTX produces the highest DAS28 reduction when used in association with ETN (p<0.078). We found no difference in drug discontinuation rates or in effectiveness measures between anti-TNFalpha+MTX and anti-TNFalpha+LEF. Our data showed a greater reduction of DAS28 in the MTX group and, in combination with ETN, better results after two years of therapy.

TNF拮抗剂联合甲氨蝶呤或来氟米特治疗RA的疗效差异

Benucci M, et al. Int J Immunopathol Pharmacol. 2011; 24(1): 269-76.

由几个小样本的回顾性案例研究所得结论是，来氟米特(LEF)联合TNF拮抗剂似乎是有效而安全的。前瞻性案例系列和队列研究总体上都证实了这种组合的疗效。总体而言，目前尚无对照研究比较LEF联合TNF拮抗剂的疗效是否优于甲氨蝶呤(MTX)联合TNF拮抗剂。

在一项为期2年、单中心、开放性研究中，我们比较了皮下注射用TNF拮抗剂依那西普（ETN）和阿达木单抗（ADA）联合LEF或MTX的疗效和安全性。

我们评估了96例接受TNF拮抗剂治疗的RA患者。ADA剂量为40mg、每2周1次， ETN剂量为每周50mg。同时可以联用强的松（PDN），平均剂量为5.2±2.6 mg/日。有54例病人同时联用MTX，平均剂量为11.7± 2.6 mg /周。42例病人联用LEF，剂量为每日20毫克。

方差分析显示，两种治疗在12月时均显著改善了DAS28评分（P 值均小于0.001）。LEF组DAS28评分平均下降33.3％，MTX组平均下降51.8%（p=0.20）。第18月时，DAS28改善维持率为33.3％，MTX组为81.5％（P=0.001）。这种改善与TNF拮抗剂种类无关，尽管MTX联合ETN组DAS28改善幅度是最大的（P<0.078）。

我们没有发现两种TNF拮抗剂联合LEF或MTX在停药率、药物安全性方面存在差异。

本研究显示，经过2年治疗后，MTX联合依那西普获得更好的DAS28改善以及更好的结局。