Leflunomide for the treatment of rheumatoid arthritis

  • Review
  • Intervention




Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. Leflunomide is one of the more recent oral agents, classified as a disease-modifying antirheumatic drug (DMARD). It has a different mechanism of action than other existing DMARDs.


To determine the efficacy and toxicity of leflunomide (monotherapy or combined with another DMARD) compared to placebo or other DMARDs in the treatment of RA.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, and Current Contents for trials (to June 2008). We also handsearched reference lists and consulted content experts.

Selection criteria

Two independent authors selected the trials that met predetermined inclusion criteria.

Data collection and analysis

Two authors independently extracted data and assessed methodologic quality using standardized forms.

Main results

Thirty-three trials were included, compared with six trials in the first review. The trials compared the efficacy and safety of leflunomide monotherapy with placebo or another DMARD; leflunomide combined with another DMARD (biologic or non-biologic) with DMARD monotherapy; and for different dosages of leflunomide. The ACR20 improvement criteria, demonstrated a 28% absolute difference in improvement in favour of leflunomide compared to placebo. There was no difference in ACR20 response rate between patients treated with leflunomide and sulfasalazine (SSZ) or methotrexate (MTX), at six and 12 months. Other clinical and radiological outcomes were improved significantly in the leflunomide group compared to placebo but were not different from SSZ or MTX. The efficacy of leflunomide combined with MTX was superior to MTX alone. On the other hand, leflunomide plus SSZ was not better than SSZ alone. Half-dose or weekly administration of leflunomide was shown to be as efficacious as regular doses (20 mg/day).

Withdrawals due to adverse events were 10% greater with leflunomide than placebo. Important adverse events included gastrointestinal symptoms, elevated liver function tests, alopecia, allergic reactions and rashes, and infections. Overall, adverse events and withdrawals with leflunomide monotherapy were not significantly different from SSZ or MTX. However, adverse events were reported more frequently in leflunomide plus MTX than with MTX but withdrawal rates were not significantly different.

Authors' conclusions

Leflunomide appears to improve all clinical outcomes and delay radiologic progression at both six and 12 months of treatment compared to placebo. Its efficacy and adverse events are comparable to MTX, SSZ, and cyclosporin A up to two years of treatment. Combined leflunomide and MTX was more efficacious than MTX alone up to three years of treatment and the adverse events did not increase. Different dosages of leflunomide were similar regarding their effectiveness and toxicity.








搜尋包括MEDLINE, EMBASE, Current Contents and the Cochrane Controlled Trial Register (直到2001年12月)。同時手動搜尋所選文章之參考文獻及徵詢專家。






6個研究包含於分析中。使用ACR20進步條件時,進步之絕對差異為28% (95% CI: 21 – 35%) (413位 leflunomide使用者中232位達到ACR20進步vs 11位安慰劑使用者中89位達到ACR20進步)。在6及12月時leflunomide使用者與sulfasalazine或methtrexate使用者之ACR20進步上並無顯著差異。Leflunomide在其它指標比安慰劑進步,但與sulfasalazine或methtrexate使用者並無顯著差異。因副作用而退出在leflunomide組較多10% 413位 leflunomide使用者中70位退出 s. 311位安慰劑使用者中18位退出)。重要副作用及退出上,在leflunomide與sulfasalazine或methtrexate使用者並無顯著差異。





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



Plain language summary

Leflunomide for the treatment of rheumatoid arthritis

This summary of a Cochrane review presents what we know from research about the effect of Leflunomide on rheumatoid arthritis. The review shows that in people with rheumatoid arthritis:

- Leflunomide probably improves pain.

-Leflunomide improves number of tender or swollen joints and other outcomes such as pain and disability. 
- Leflunomide causes side effects such as diarrhea, upset stomach, elevated liver function tests, and allergic reactions.  We often do not have precise information about side effects and complications. This is particularly true for rare but serious side effects.

What is rheumatoid arthritis and what is Leflunomide?
When you have rheumatoid arthritis, your immune system, which normally fights infection, becomes over-active and attacks the lining of your joints. This makes your joints swollen, stiff and painful. The small joints of your hands and feet are usually affected first. There is no cure for rheumatoid arthritis at present, so the treatments aim to relieve pain and stiffness and improve your ability to move. 

Leflunomide is a disease-modifying antirheumatic drug (DMARD). It works by stabilizing the over-active cells in the immune system that cause inflammation in the joints.  Reducing the inflammation can prevent damage to the joints.  Leflunomide is taken in pill form.  It costs more than other DMARDs, so doctors usually prescribe it if other DMARDs haven’t worked well.


Best estimate of what happens to people with rheumatoid arthritis who take Leflunomide after 6 months:

Pain (higher scores mean worse or more severe pain)

- People who took Leflunomide rated their pain to be10 points lower on a scale of 0 to 100 with Leflunomide (10% absolute improvement).  This may be due to chance.
- People who took Leflunomide rated their pain to be about 14 points lower on a scale of 0 to 100.
- People who took a placebo rated their pain to be about 4 points lower on a scale of 0 to 100. 


ACR 50 (number of tender or swollen joints and other outcomes such as pain and disability).

- 19 people out of 100 who took a placebo experienced improvement. (19% absolute improvement)

- 33 more people out of 100 experienced improvement in the symptoms of their rheumatoid arthritis with Leflunomide
- 14 people out of 100 experienced improvement in the symptoms of their rheumatoid arthritis with a placebo.

Side effects
- 10 more people who took Leflunomide dropped out from the trial because of side effects.  (10% absolute difference)

- 16 people out of 100 who took Leflunomide dropped out from the trial because of side effects

- 6 people out of 100 who used a placebo dropped out from the trial because of side effects.