Role of Leflunomide in the Treatment of Rheumatoid Arthritis
Leflunomide is a conventional synthetic disease-modifying antirheumatic drug (csDMARD) that serves as an effective alternative first-line therapy when methotrexate is contraindicated or not tolerated, and can be used as part of combination therapy in patients with inadequate response to initial treatment. 1, 2
Mechanism of Action and Efficacy
Leflunomide works by inhibiting dihydroorotate dehydrogenase (DHODH), the enzyme critical for pyrimidine production necessary for DNA synthesis, thereby inhibiting lymphocyte proliferation associated with T-cell expansion in RA 3. Clinical trials have demonstrated that leflunomide:
- Reduces signs and symptoms of RA
- Inhibits structural damage as evidenced by X-ray erosions and joint space narrowing
- Improves physical function 4
- Has efficacy comparable to methotrexate and sulfasalazine 3
- Shows rapid onset of action, typically within 1 month, with effects stabilizing by 3-6 months 4
Position in Treatment Algorithm
First-Line Therapy
- Methotrexate remains the preferred first-line csDMARD for RA 1
- Leflunomide is conditionally recommended as an alternative when methotrexate is contraindicated or not tolerated 1, 2
- The 2021 ACR guidelines conditionally recommend methotrexate monotherapy over leflunomide based on low-quality evidence 1
Second-Line Therapy
- In patients with inadequate response to initial csDMARD therapy and without poor prognostic factors, leflunomide can be considered as part of the second csDMARD strategy 1
- Can be used alone or in combination with other csDMARDs 1
Combination Therapy
- Leflunomide may be combined with methotrexate in patients with inadequate response to methotrexate monotherapy 5, 6
- The combination of leflunomide with methotrexate appears safe and does not significantly increase the frequency of adverse reactions 5
Dosing and Administration
- Standard regimen: Initial loading dose of 100 mg daily for 3 days, followed by 20 mg daily maintenance dose 4
- Alternative approach: Start with 20 mg daily without loading dose to improve tolerability 7
- Experts recommend observing patients for at least 3-4 months before assessing efficacy 7
- Dose reduction to 10 mg daily may be considered if side effects occur 6
Monitoring and Safety
Common adverse events include:
- Gastrointestinal symptoms (diarrhea, nausea)
- Allergic reactions
- Reversible alopecia
- Elevated liver enzymes 3
Most adverse events are mild to moderate and can be managed by:
- Dose reduction
- Symptomatic therapy
- Close monitoring 6
Monthly monitoring is recommended during active disease, with assessment of:
- Blood count
- Liver enzymes
- ESR/CRP 5
Clinical Pearls
- Consider avoiding the loading dose to reduce initial "nuisance" side effects, though this may delay onset of action 6
- Combination with low-dose glucocorticoids (≤10 mg/day prednisone) may be beneficial as bridge therapy during the first few months 2, 7
- Leflunomide has a long half-life; if serious toxicity occurs, cholestyramine washout may be necessary
- Therapy should be initiated by a rheumatologist, but repeat prescribing can be managed through shared care protocols 6
Special Considerations
- Leflunomide is contraindicated in pregnancy due to teratogenic potential
- Women of childbearing potential should use effective contraception during treatment
- Due to its long half-life, drug elimination procedures may be necessary before conception
Leflunomide represents an important option in the RA treatment armamentarium, particularly for patients who cannot tolerate or have contraindications to methotrexate, offering comparable efficacy with a different side effect profile.