What is safer, Arava (Leflunomide) versus Methotrexate (MTX)?

From the Guidelines

Methotrexate is generally considered safer than Arava (leflunomide) for the treatment of rheumatoid arthritis, due to its longer track record of use and more comprehensive safety data, as well as the availability of folate supplementation to mitigate its side effects 1. When comparing the safety profiles of these two medications, it's essential to consider the potential risks and benefits associated with each. Methotrexate is commonly associated with folate deficiency and related side effects, which can be mitigated with folate supplementation, as demonstrated by a Cochrane systematic review that found folic acid supplementation significantly reduced the incidence of gastrointestinal side effects and protected against elevated liver function tests 1.

Key Considerations

• Methotrexate has a longer track record of use, providing more comprehensive safety data, and is generally considered the first-line treatment for rheumatoid arthritis 1.
• Leflunomide may have a slightly higher risk of liver enzyme elevations and has a very long half-life in the body, requiring a cholestyramine washout procedure if rapid elimination is needed.
• Both medications are contraindicated in pregnancy, with leflunomide carrying a Category X pregnancy warning due to its teratogenic potential.
• Regular monitoring of blood counts and liver function is essential with either medication to ensure safety during treatment.

Recommendations

• The choice between methotrexate and leflunomide should be individualized based on the patient's medical history, particularly regarding liver function, pregnancy plans, and other comorbidities.
• Methotrexate is conditionally recommended over leflunomide for DMARD-naive patients with moderate-to-high disease activity, due to its greater dosing flexibility and lower cost, as well as its value as an anchor DMARD in combination regimens 1.

From the FDA Drug Label

Table 6 Summary of ACR Response Rates * N is the number of ITT patients for whom adequate data were available to calculate the indicated rates. † p<0.001 leflunomide vs placebo Study and Treatment Group ACR20 ACR50 ACR70 Placebo-Controlled Studies US301 (12 months) Leflunomide (n=178)* 52.2† 34.3† 20.2† Placebo (n=118)*26.3 7.6 4.2 Methotrexate (n=180)45.622.8 9.4 MN301 (6 months) Leflunomide (n=130) 54. 6† 33.1† 10.0 Placebo (n=91)*28.614.3 2.2 Sulfasalazine (n=132)*56.830.3 7.6 Non-Placebo Active-Controlled Studies MN302 (12 months) Leflunomide (n=495)*51.131.1 9.9 Methotrexate (n=489)*65.243.816. 4 The safety of Arava (leflunomide) versus methotrexate cannot be directly compared based on the provided drug label, as it does not contain direct safety comparisons between the two drugs. However, the label does provide information on the efficacy of leflunomide compared to methotrexate in terms of ACR response rates.

• Key points:
  • Efficacy: Leflunomide was significantly superior to placebo in all components of the ACR Response criteria in study US301 and MN301.
  • Comparison to methotrexate: No consistent differences were demonstrated between leflunomide and methotrexate in terms of ACR response rates.
  • Safety: The label does not provide a direct comparison of the safety of leflunomide and methotrexate. Based on the provided information, no conclusion can be drawn regarding the safety of Arava (leflunomide) compared to methotrexate 2.

From the Research

Safety Comparison of Arava and Methotrexate

• The safety of Arava (leflunomide) and methotrexate can be compared based on their potential side effects and interactions.
• Methotrexate has been shown to have a well-established safety profile, with studies indicating that it can be used safely in patients with rheumatoid arthritis 3.
• However, the combination of leflunomide and methotrexate has been associated with increased risk of liver toxicity and thrombotic microangiopathy 4, 5.
• Leflunomide has been shown to increase the risk of silent liver fibrosis in patients with rheumatoid arthritis receiving methotrexate 5.
• Methotrexate has been found to have multiple mechanisms of action, including the inhibition of purine and pyrimidine synthesis, and the promotion of adenosine release 6.
• The safety of methotrexate has been evaluated in various studies, including a study that found no significant difference in liver function tests, renal function tests, and complete blood count between baseline and day 7 after single- or double-dose methotrexate treatment 7.

Potential Side Effects

• Methotrexate: liver toxicity, renal toxicity, hematologic toxicity 7, 6
• Leflunomide: liver toxicity, thrombotic microangiopathy, silent liver fibrosis 4, 5
• Combination of leflunomide and methotrexate: increased risk of liver toxicity and thrombotic microangiopathy 4, 5

Dosage and Administration

• Methotrexate: oral or subcutaneous administration, with a high initial dose and rapid titration 3
• Leflunomide: oral administration, with a cumulative dose that correlates with abnormal liver stiffness measurement values 5