針對具DMARDs抗藥性類風濕性關節炎病人使用Leflunomide治療之本土經驗

Treatment of DMARD-resistant active rheumatoid arthritis patients with leflunomide: central Taiwan experience

目的：調查Leflunomide（LEF）在有活動性類風濕性關節炎（RA）病人已經對傳統的病程修改抗風濕藥物（disease-modifying anti-rheumatic drugs, DMARD），包括methotrexate（MTX），有抵抗力時的效力和安全性。方法：在這個open-label，48週的研究，61位儘管用傳統DMARDs治療至少四個月仍是活動性（DAS28≧5.1）的RA病人給予LEF 10mg/day。其中病人要求已經接受一個穩定劑量的MTX 12.5mg/week至少八週。研究變量包括晨問僵硬（分鐘），病人的總體評估，醫師的總體評估，腫脹的關節數，壓痛的關節數，IgM類風濕因子，IgA類風濕因子，紅血球沉降速率，C-反應蛋白，和血小板數。安全性的衡量標準包括藥物副作用和實驗室數值。結果：60位活動性RA病人完成一年的治療。病人平均DAS28在LEF之前為6.3 ± 0.9，在4, 12, 24和48週的LEF治療之後，包括晨間僵硬（分鐘），病人的總體評估，醫師的總體評估，腫脹的關節數，壓痛的關節數，IgM類風濕因子，IgA類風濕因子，紅血球沉降速率，C-反應蛋白，和血小板數，都與基準線有顯著差異。這些研究變量在第4週和第12週，第4週和第24週，第4週和第48週之間的變化也有顯著差異；但在第12週與第24週和第48週之間則無顯著差異。顯示LEF作用的高原在LEF治療的第12週，並持續維持至研究終點。前接受的肝臟酵素上升為主要的副作用，而即使沒有停止LEF治療，大多數病人的肝功能可回到正常範圍，只有一位病人因持續肝臟酵素上升而退出本研究。其他的副作用如腹瀉，口腔炎，皮疹等大多輕微。合併MTX治療無附加的副作用。結論：在對包括MTX等傳統的DMARDs有抗力的活動性RA病人，合併LEF為安全和有效的治療。

Objective: To examine the efficacy and safety of leflunomide (LEF) for patients with active rheumatoid arthritis (RA) who have been resistant to conventional disease-modifying antirheumatic drugs (DMARDs) including methotrexate (MTX). Methods: In this open-label, 48-week study, 61 patients with RA who remained active (DAS28 > 5.1) despite therapy with conventional DMARDs for at least 4 months were given LEF, 10mg/day. Patients were required to have been receiving a stable dosage of MTX 12.5mg/week for at least 8 weeks prior to study enrollment. Efficacy variables were morning stiffness, patient global assessment, physician assessment, number of swollen joints, number of tender joints, IgM rheumatoid factor (RF), IgA RF, Wintrobe erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelet count. Safety measures included monitoring of adverse events and laboratory values. Results: Sixty active RA patients completed one year of treatment. The mean DAS28 of patients before LEF were 6.3 ± 0.9. Measurements after 4, 12, 24, and 48 weeks of LEF treatment all differed significantly from baseline, including tender joint count, swollen joint count, patient global assessment, physician global assessment, DAS28, and serology index of ESR, CRP, and RF. Changes between weeks 4 and 12, week 4 and 24, weeks 4 and 48 were also significant in variables described. The changes among week 12, 24 and 48 were of no significance. LEF efficacy showed a plateau of response after 12 months with treatment of LEF. However, improvement was sustained to the end point of the study. In these 61 patients, LEF treatment was generally well tolerated with the exception of elevation of liver enzyme. Most patients with abnormal liver function returned to normal range without discontinuation of LEF. Only one patient withdrew from the study for persistent elevation of liver enzymes. The most commonly mentioned adverse events of diarrhea, nausea, stomatitis, upper respiratory tract infection, and rash were found and most adverse events were rated as mild in severity. No additional side effect was observed in combination therapy of MTX with LEF. Conclusion: LEF has therapeutic potential in DMARD-resistant active RA patients. It is a logical alternative for patients who have an incomplete response to optimal effective DMARDs. Results indicate that combination therapy with LEF is a safe and effective treatment for DMARD-resistant RA, with clinical benefit sustained over one year of treatment without evidence of new or increased toxicity.