What is Arava (Leflunomide)?
Arava (leflunomide) is a disease-modifying antirheumatic drug (DMARD) that inhibits dihydroorotate dehydrogenase, an enzyme involved in pyrimidine synthesis, and is FDA-approved for treating active rheumatoid arthritis to reduce symptoms, inhibit structural damage, and improve physical function. 1
Mechanism of Action
Leflunomide works through a unique mechanism compared to other DMARDs:
- Inhibits dihydroorotate dehydrogenase (DHODH), a critical enzyme in de novo pyrimidine synthesis
- After oral administration, it's rapidly metabolized to its active form M1, which is responsible for its therapeutic effects
- Blocks proliferation of activated lymphocytes (particularly T-cells) by limiting DNA and RNA synthesis
- Has anti-inflammatory and immunomodulatory properties
- Also inhibits tyrosine kinases, reducing pro-inflammatory cytokines like TNF and IL-1 1, 2
Clinical Use in Rheumatoid Arthritis
Leflunomide is positioned in treatment algorithms as:
- An alternative to methotrexate when there are contraindications or early intolerance to MTX 3
- A monotherapy option for active rheumatoid arthritis
- A potential combination therapy with other DMARDs, most commonly with methotrexate 3
The usual dosing regimen includes:
- Loading dose: 100 mg daily for 3 days
- Maintenance dose: 20 mg daily
- This regimen facilitates rapid attainment of steady-state levels of the active metabolite, which has a very long half-life (~2 weeks) 1
Efficacy
Clinical trials have demonstrated that leflunomide:
- Is significantly more effective than placebo
- Has efficacy comparable to sulfasalazine and methotrexate in short-term studies
- Shows significant improvements in functional disability and health-related quality of life
- Consistently slows radiographic progression of rheumatoid arthritis
- Has a relatively rapid onset of action (within 4 weeks) 2, 4
Safety Profile and Monitoring
Common adverse effects include:
- Gastrointestinal disturbances (diarrhea, nausea, abdominal pain)
- Reversible alopecia
- Rash
- Hypertension
- Elevated liver enzymes 1, 5
Important safety considerations:
- Monthly liver enzyme monitoring is required until stable concentrations are reached
- Contraindicated in pregnancy due to teratogenic potential - contraception is advised for both males and females of childbearing potential
- Caution in patients with pre-existing liver or lung disease
- Increased risk of infections due to immunosuppressive effects 1, 5
Clinical Pearls
- The active metabolite has an extremely long half-life (~2 weeks), which necessitates the loading dose strategy but also means that drug elimination can take months after discontinuation
- In cases of toxicity or planned pregnancy, a drug elimination procedure using cholestyramine may be necessary
- Blood pressure monitoring is recommended due to potential hypertensive effects
- Therapeutic drug monitoring should be considered in clinical non-responders 5
Leflunomide represents an important option in the DMARD armamentarium, particularly for patients who cannot tolerate or have contraindications to methotrexate, which remains the anchor drug for rheumatoid arthritis treatment 3.