Can I combine methotrexate and leflunomide for the treatment of rheumatoid arthritis?

Combining Methotrexate and Leflunomide for Rheumatoid Arthritis Treatment

The combination of methotrexate and leflunomide can be used for patients with moderate to high rheumatoid arthritis disease activity who have not achieved adequate response with methotrexate monotherapy, but requires careful monitoring of liver function. 1, 2

Efficacy of Combination Therapy

• The American College of Rheumatology guidelines suggest that methotrexate-leflunomide combination is appropriate for patients with inadequate response to methotrexate alone, and should be considered before moving to biological agents 1
• This combination has complementary mechanisms of action - methotrexate inhibits cytokine production and purine biosynthesis, while leflunomide regulates lymphocyte proliferation through inhibition of pyrimidine biosynthesis 3
• Clinical studies have shown that 71.6% of patients achieve ACR20 response after 20 weeks of combination therapy 4

Safety Considerations and Monitoring Requirements

• The FDA label specifically requires more intensive monitoring when combining these medications: "If leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly" 2
• Liver enzyme elevations occur in approximately 21.6% of patients on combination therapy, though most are mild and reversible 4
• Monthly liver function monitoring is mandatory during the first six months of combination therapy, then every 6-8 weeks thereafter if stable 2

Dosing Recommendations

• When initiating combination therapy, consider:
  • Starting leflunomide without a loading dose (10 mg/day) to reduce initial side effects 4
  • Using established methotrexate dosing (7.5-15 mg/week) 4
• Dose adjustments for liver enzyme elevations:
  • For ALT elevations 2-3 times upper limit of normal (ULN): reduce leflunomide to 10 mg/day 2
  • For persistent elevations 2-3 times ULN or elevations >3 times ULN: discontinue leflunomide and administer cholestyramine or charcoal for drug elimination 2

Contraindications and Special Populations

• The combination is contraindicated in patients with:
  • Significant hepatic impairment 2
  • Evidence of hepatitis B or C infection 2
  • Pregnancy or women planning pregnancy (leflunomide is teratogenic) 2
• Women of childbearing potential must use reliable contraception and undergo drug elimination procedure if pregnancy is desired 2

Clinical Decision Algorithm

1. Assess current disease activity in patient on methotrexate monotherapy
2. If moderate to high disease activity persists despite optimal methotrexate dosing:
   • Check baseline liver function tests and complete blood count 2
   • Start leflunomide 10 mg daily (without loading dose) 4
3. Monitor:
   • Monthly liver function tests for first 6 months 2
   • Disease activity assessment every 1-3 months 5
4. If no improvement within 3 months or target not reached by 6 months, consider alternative therapy 5

Common Pitfalls and Management

• Gastrointestinal side effects (particularly diarrhea) are common but can often be managed without discontinuation 6
• The route of administration (oral vs. intramuscular) and dose of methotrexate do not significantly affect the toxicity profile of the combination 6
• If severe adverse events occur, leflunomide has a long half-life and may require accelerated elimination with cholestyramine or charcoal 2

This combination therapy offers a valuable option for patients with inadequate response to methotrexate before progressing to more expensive biological agents, provided that appropriate monitoring protocols are followed 1, 4.