What is the comparison between Methotrexate (MTX) and Leflunomide?

From the Guidelines

Methotrexate is strongly recommended over leflunomide as the initial treatment for rheumatoid arthritis due to its established efficacy and safety profile, as stated in the 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis 1.

Key Considerations

• Methotrexate monotherapy is conditionally recommended over leflunomide, with a low certainty of evidence, as per the guideline 1.
• The guideline suggests that methotrexate is preferred due to its extensive safety data and lower cost compared to leflunomide 1.
• Methotrexate and leflunomide have different mechanisms of action, with methotrexate inhibiting dihydrofolate reductase and leflunomide blocking pyrimidine synthesis.

Treatment Regimens

• Methotrexate is typically started at 7.5-10mg weekly, potentially increasing to 20-25mg weekly, with folic acid supplementation to reduce side effects.
• Leflunomide is often used when methotrexate is not tolerated or ineffective, administered as a loading dose of 100mg daily for 3 days followed by 20mg daily maintenance (or sometimes 10mg daily if side effects occur).

Monitoring and Side Effects

• Both medications require regular blood monitoring for liver function and blood counts.
• Methotrexate more commonly causes nausea, mouth sores, and potential liver toxicity, while leflunomide more frequently causes diarrhea, hair thinning, and has a longer half-life requiring washout procedures if rapid elimination is needed.

Combination Therapy

• Some patients may benefit from combination therapy when either medication alone provides insufficient disease control, although the guideline conditionally recommends methotrexate monotherapy over combination therapy with a biologic or targeted synthetic DMARD 1.

From the FDA Drug Label

Leflunomide was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study US301 (at the primary 12 months endpoint) and MN301 (at 6 month endpoint) ACR20 Responder at Endpoint rates with leflunomide treatment were consistent across the 6 and 12 month studies (41 to 49%). No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. MN302Leflunomide vs. Methotrexate(-19, -7)<0. 0001

Methotrexate vs Leflunomide:

• Methotrexate was statistically significantly superior to leflunomide in the MN302 study, with an ACR20 Responder at Endpoint rate of 65.2% compared to 51.1% for leflunomide 2.
• The 95% Confidence Interval for the comparison between leflunomide and methotrexate was (-19, -7) with a p-value of <0.0001, indicating a statistically significant difference in favor of methotrexate 2.
• No consistent differences were demonstrated between leflunomide and methotrexate in other studies, such as US301 and MN301 2.

From the Research

Comparison of Methotrexate and Leflunomide

• Methotrexate and leflunomide are both used to treat rheumatoid arthritis (RA), but their efficacy and safety have been compared in several studies 3, 4, 5, 6, 7
• A meta-analysis found that methotrexate and leflunomide have similar clinical efficacy and safety in the treatment of RA 3
• Another study found that leflunomide and methotrexate have different mechanisms of action, but may be used in combination therapy for patients with RA 4
• A clinical trial found that leflunomide and methotrexate have similar efficacy and safety in the treatment of active RA, and that combination therapy with both drugs may be effective for patients with active RA 5, 6
• A more recent study found that leflunomide-based combination therapy is non-inferior to sulfasalazine-based combination therapy in methotrexate-failed RA patients, with a comparable safety profile 7

Efficacy of Methotrexate and Leflunomide

• The American College of Rheumatology (ACR) response rates for leflunomide and methotrexate were similar in several studies 5, 6
• Leflunomide and methotrexate have been shown to improve signs and symptoms of RA, delay disease progression, and improve function and health-related quality of life 5, 6
• The combination of leflunomide and methotrexate has been shown to be effective in the treatment of active RA, with a response rate of 71.6% based on the ACR20 criteria 6

Safety of Methotrexate and Leflunomide

• Common adverse events associated with leflunomide include gastrointestinal complaints, skin rash, and reversible alopecia 5
• Asymptomatic transaminase elevations were more common in patients receiving leflunomide than in those receiving methotrexate or placebo 5
• The combination of leflunomide and methotrexate was generally well-tolerated, with adverse events occurring in 40.5% of patients 6