What is the use of Leflunomide (Disease Modifying Antirheumatic Drug - DMARD)?

From the Guidelines

Leflunomide is recommended as a first-line treatment option for rheumatoid arthritis, particularly in patients with a contraindication to methotrexate or early intolerance, due to its efficacy in reducing inflammation and slowing disease progression 1.

Key Points

• Leflunomide is a disease-modifying antirheumatic drug (DMARD) that inhibits pyrimidine synthesis, reducing inflammation and slowing disease progression by suppressing T-cell proliferation and autoimmune responses.
• The standard dosing is typically a loading dose of 100mg daily for 3 days, followed by a maintenance dose of 10-20mg once daily.
• Common side effects include diarrhea, hair loss, elevated liver enzymes, and increased risk of infections.
• Regular blood monitoring is essential, particularly liver function tests and complete blood counts.
• Patients should avoid pregnancy while taking leflunomide due to its teratogenic potential, and a drug elimination procedure using cholestyramine may be necessary if pregnancy is planned.
• Leflunomide has a very long half-life (approximately 2 weeks), so its effects persist even after stopping the medication.

Treatment Guidelines

• According to the 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis, leflunomide is considered a conventional synthetic DMARD (csDMARD) and can be used as part of the first treatment strategy in patients with a contraindication to methotrexate or early intolerance 1.
• The European League Against Rheumatism (EULAR) also recommends leflunomide as a treatment option for rheumatoid arthritis, particularly in patients who cannot use methotrexate as comedication 1.

Important Considerations

• Leflunomide can be used in combination with other DMARDs, such as methotrexate, for enhanced efficacy in controlling joint inflammation and preventing joint damage.
• Patients should be closely monitored for potential toxicities, including gastrointestinal irritation, elevated liver enzymes, leukopenia, and increased risk of infections.
• Leflunomide has been shown to be effective in treating psoriatic arthritis and psoriasis, with a significant reduction in disease activity and improvement in quality of life 1.

From the FDA Drug Label

Leflunomide is indicated in adults for the treatment of active rheumatoid arthritis (RA): to reduce signs and symptoms to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing to improve physical function The primary use of leflunomide is for the treatment of active rheumatoid arthritis (RA) in adults, with the goals of:

• Reducing signs and symptoms
• Inhibiting structural damage
• Improving physical function 2, 2

From the Research

Leflunomide Overview

• Leflunomide is a reversible inhibitor of "de novo" synthesis of pyrimidine, resulting in a restriction of lymphocyte proliferation 3.
• It is used for the treatment of active rheumatoid arthritis, with efficacy and side effects similar to methotrexate and sulphasalazine 3.

Mechanism of Action

• Leflunomide arrests the growth of activated lymphocytes by inhibiting the enzyme dihydroorotate dehydrogenase, a critical link in the production of uridine monophosphate 4.
• It is rapidly metabolized to the active major metabolite A77 1726, which is responsible for the drug's pharmacologic activity 4.

Clinical Efficacy

• Leflunomide has demonstrated clinical efficacy in a number of controlled trials, with significant improvements in signs and symptoms of rheumatoid arthritis 4, 5.
• It has been shown to be effective in retarding the progression of disease, with no consistent difference from methotrexate or sulfasalazine 4.
• Combination treatment with leflunomide and methotrexate has been found to be effective and well-tolerated in the treatment of active rheumatoid arthritis 6.

Dosage and Administration

• Treatment with leflunomide is typically started with a loading dose of 100 mg orally for three days, followed by 20 mg daily 3, 7.
• A weekly dose of 100 mg has also been found to be effective, with better treatment compliance and reduced monthly cost of medication 7.

Safety and Adverse Events

• Common adverse events associated with leflunomide include gastrointestinal complaints, skin rash, and reversible alopecia 4, 5.
• Asymptomatic transaminase elevations have been reported, resulting in treatment discontinuations in some cases 5.
• Regular haematological measurements, determination of serum chemistry, and blood pressure monitoring are recommended during treatment with leflunomide 3.