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Methotrexate for treating rheumatoid arthritis

  • Review
  • Intervention

Authors


Abstract

Background

Methotrexate (MTX) is a folic acid antagonist widely used for the treatment of neoplastic disorders. MTX inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and proteins by binding to dihydrofolate reductase. Currently, MTX is among the most commonly used drugs for the treatment of rheumatoid arthritis (RA).

Objectives

To evaluate the short term efficacy and toxicity of methotrexate (MTX) for the treatment of rheumatoid arthritis (RA).

Search methods

We searched the Cochrane Musculoskeletal Group register, Cochrane Controlled Trials Register (CCTR), MEDLINE (1966 to July 1997) and EMBASE (1988 to July 1997) using the strategy developed by Dickersin 1994. The search was complemented with a bibliography search of the reference lists of the trials retrieved from the electronic search. Key experts in the area were contacted for further published and unpublished articles.

Selection criteria

Randomized controlled trials and controlled clinical trials comparing MTX against placebo in people with RA.

Data collection and analysis

Two reviewers determined the studies to be included based on inclusion and exclusion criteria. Data were independently extracted by two reviewers, and checked by a third reviewer, using a pre-developed form for the rheumatoid arthritis sub-group of the Cochrane Musculoskeletal Group.

The same two reviewers independently assessed the methodological quality of the trials using a validated scale (Jadad 1996). Rheumatoid arthritis outcome measures were extracted from the publications. The pooled analysis was performed using standardized mean differences (SMDs) for joint counts, pain, and global and functional assessments. Weighted mean differences (WMDs) were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios (OR) for withdrawals. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout, although random effects models were used for outcomes showing heterogeneity.

Main results

Five trials and 300 participants were included. A statistically significant benefit was observed for MTX when compared to placebo. Statistically significant differences were observed for all measures except ESR. The standardized weighted difference (effect size) between MTX and placebo for the various outcome measures varied between -0.43 and -1.5. No differences were observed in the total number of withdrawals and dropouts (OR 0.95) although participants on MTX were three times more likely to discontinue treatment because of adverse reactions (OR 3.47) and four times less likely to withdraw due to lack of response (OR 0.22). Twenty-two percent of people on MTX withdrew due to adverse effects compared to seven percent of the placebo group.

Authors' conclusions

MTX has a substantial clinical and statistically significant benefit compared to placebo in the short term treatment of people with RA although its use is associated with a high withdrawal rate due to adverse events.

摘要

背景

以Methotrexate治療類風溼性關節炎

Methotrexate (MTX)是廣泛用於治療腫瘤疾病的葉酸拮抗劑(folic acid antagoinist)。MTX透過與二氫葉酸還原?(dihydrofolate reductase)的結合來抑制去氧核糖核酸(DNA),核糖核酸(RNA)和蛋白質的合成。目前,MTX是最常用於治療類風濕關節炎的藥物。

目標

評估治療類風濕關節炎的Methotrexate之短期療效和毒性。

搜尋策略

我們用1994年Dickersin發明的方法搜尋了下列資料庫:Cochrane Musculoskeletal Group register, Cochrane Controlled Trials Register (CCTR), MEDLINE (自1966年至1997年7月) and EMBASE (自1988年至1997年7月)。從電子搜索中擷取試驗的參考文獻作為補充。並連絡相關領域的專家以取得更進一步已發表和未發表的文章。

選擇標準

在類風濕關節炎的病患中,用隨機對照試驗(Randomized controlled trials)和受控臨床試驗(Controlled clinical trials)來進行MTX與安慰劑(placebo)的比較。

資料收集與分析

兩位檢閱者根據選擇標準來決定研究是否被採納。由兩位檢閱者各自蒐集數據,再由第三位檢閱者使用Cochrane Musuloskeletal Group的類風濕關節炎小組所預先制訂的表格來核對。接著由相同的兩位檢閱者各自用合格標準(1996年Jadad)去評估試驗方法的品質。從出版物中蒐集類風濕關節炎的結果測量。利用類風濕關節炎所侵犯的關節數量,疼痛,以及整體性和功能性評估的Standard Mean Differences (SMDs)來做匯合分析。用Weighted Mean Differences (WMDs)來檢驗Erythrocyte Sedimentation Rate (ESR)。毒性的評估是將所有的報告中停藥的案例數加總,以計算出pooled odds ratios (OR),再決定要不要斷藥。Chisquare test是用來評估試驗之間的異質性。整體的結果是用固定效果模型,但是異質性是用隨機效果模型。

主要結論

共包括五個試驗和300名參加者。除了ESR指數以外的所有的指數顯示,MTX比安慰劑要有統計學上顯著的助益。各種結果測量中,MTX和安慰劑的Standardized Weighted Difference變數介於 −0.43和1.5之間。儘管3倍左右的病患使用MTX會因為不良反應(OR 3.47)而停止治療(OR 0.95),以及小於4倍的病患會因為缺乏反應的關係而斷藥(OR 0.22),可是在斷藥和退出的總數上並無顯著的差異。由於不良作用的關係,相較於7%使用安慰劑的病患,22%使用MTX的病患由於不良作用的關係,而停止用藥。

作者結論

對短期內治療類風濕關節炎的人而言,相較於安慰劑,MTX在臨床及統計學上有顯著的助益,然而因為藥物的副作用,經常會導致治療中斷與退出。

翻譯人

本摘要由林口長庚醫院蔡宗廷翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

對短期內治療類風濕關節炎的人而言,Methotrexate (MTX)在臨床上有顯著的助益。MTX是用來治療類風濕關節炎的一種二氫葉酸還原?抑制劑。本研究共包含五個試驗和300名參加者。參加者都有長期嚴重的類風濕關節炎和先前接受過其他治療都無效。他們接受為期12至18週的MTX或安慰劑的治療。使用MTX治療的病人,有症狀的關節數量,疼痛,以及整體性和功能性的評估在統計學上有顯著的助益。3倍左右的病患使用MTX會因為不良反應的關係而停止治療。

Plain language summary

Methotrexate has substantial clinical benefit in the short term treatment of people with rheumatoid arthritis

Methotrexate (MTX) is a dihydrofolate reductase inhibitor used in the treatment of rheumatoid arthritis (RA). Five trials and 300 participants were included in this review. Participants had severe RA of long duration and had previously failed other therapy. They received MTX treatment, or placebo, over 12 to 18 weeks. Statistically significant benefits were observed with MTX on joint counts, pain, and global and functional assessments. People on MTX were three times more likely to discontinue treatment because of adverse reactions.

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