What is an alternate agent for methotrexate (MTX) and hydroxychloroquine (HCQ) for Rheumatoid Arthritis (RA)?

Alternative Agents for Methotrexate and Hydroxychloroquine in Rheumatoid Arthritis

For patients who cannot use methotrexate (MTX) and hydroxychloroquine (HCQ) for rheumatoid arthritis, leflunomide is the preferred alternative conventional DMARD, followed by sulfasalazine, or a biologic DMARD if disease activity is moderate to high.

First-Line Alternatives to MTX and HCQ

Conventional Synthetic DMARDs (csDMARDs)

• Leflunomide: First choice alternative conventional DMARD

  • Despite low-certainty evidence of comparable efficacy to MTX, leflunomide has proven effectiveness as monotherapy 1
  • Typical dose: 20 mg daily (after loading dose)
  • Monitor for hepatotoxicity and gastrointestinal side effects

• Sulfasalazine: Second choice conventional DMARD

  • Less effective than MTX but still viable option 1
  • Typical dose: 2-3 g/day in divided doses
  • Monitor for gastrointestinal intolerance and potential hematologic effects
  • Long-term tolerability concerns may limit use 1

For Moderate-to-High Disease Activity

Biologic DMARDs (bDMARDs)

If csDMARDs are contraindicated or ineffective, consider:

• TNF Inhibitors:

  • Etanercept (50 mg weekly) 2
  • Adalimumab (40 mg every other week) 3
  • Can be used as monotherapy when MTX is contraindicated

• Non-TNF Biologics:

  • IL-6 inhibitors (tocilizumab)
  • T-cell co-stimulation modulator (abatacept)
  • B-cell depleting therapy (rituximab)

Targeted Synthetic DMARDs (tsDMARDs)

• JAK Inhibitors (baricitinib, tofacitinib, upadacitinib)
  • Effective as monotherapy when MTX cannot be used 1

Treatment Algorithm

1. First attempt: Leflunomide monotherapy

   • Assess response at 3 months
   • If inadequate response, proceed to step 2

2. Second attempt: Sulfasalazine monotherapy

   • Assess response at 3 months
   • If inadequate response, proceed to step 3

3. Third attempt: bDMARD or tsDMARD monotherapy

   • TNF inhibitor (preferred first biologic option)
   • Non-TNF biologic or JAK inhibitor if TNF inhibitor contraindicated

Special Considerations

• Disease severity: For high disease activity or poor prognostic factors (RF/ACPA positivity, early erosions), consider earlier escalation to biologics 4

• Elderly patients: Hydroxychloroquine or sulfasalazine may be preferred for mild-to-moderate disease due to better safety profiles 5

• Combination therapy: If single agent is insufficient, consider combination of leflunomide with sulfasalazine before moving to biologics 1

Monitoring Requirements

• Leflunomide: Liver function tests, CBC, blood pressure monitoring
• Sulfasalazine: CBC, liver function tests
• Biologics: TB screening before initiation, monitoring for infections

Common Pitfalls

• Inadequate trial duration: Allow sufficient time (3 months) to evaluate full response to therapy before switching
• Underdosing: Ensure optimal dosing of alternative DMARDs before declaring treatment failure
• Overlooking comorbidities: Consider patient-specific factors that might influence treatment choice
• Infection risk: All immunomodulatory therapies carry infection risks; screen appropriately before initiation

Remember that while MTX remains the anchor drug for RA treatment, these alternatives can effectively manage disease activity when MTX and HCQ cannot be used.