Is methotrexate (MTX) plus leflunomide (Lefra) or methotrexate (MTX) plus sulfasalazine (SAAZ) plus hydroxychloroquine (HCQ) a better combination for treating rheumatoid arthritis?

Methotrexate Plus Triple Therapy (MTX+SAAZ+HCQ) Is Superior to Methotrexate Plus Leflunomide for Rheumatoid Arthritis

For patients with rheumatoid arthritis requiring combination therapy, methotrexate plus sulfasalazine plus hydroxychloroquine (triple therapy) is superior to methotrexate plus leflunomide based on evidence of better efficacy and safety profiles. 1

Evidence-Based Comparison of Combination Therapies

• Triple therapy (MTX+SAAZ+HCQ) has demonstrated superior efficacy with 77% of patients achieving and maintaining 50% improvement over two years compared to only 33% with methotrexate monotherapy 1
• Methotrexate is conditionally recommended over leflunomide for patients with rheumatoid arthritis due to its greater dosing flexibility, lower cost, and established efficacy as an anchor drug in combination regimens 2
• The American College of Rheumatology (ACR) 2021 guidelines specifically note that methotrexate is preferred over leflunomide because of these advantages 2
• Triple therapy has shown better long-term outcomes with significant improvements in clinical and laboratory parameters compared to two-drug combinations or monotherapy 3

Safety Considerations

• Leflunomide has a less favorable safety profile compared to hydroxychloroquine, which is conditionally recommended over other csDMARDs because it is better tolerated 2
• Hydroxychloroquine has a more favorable risk profile in patients with RA, making it a valuable component of triple therapy 2
• Sulfasalazine is conditionally recommended over methotrexate for patients with low disease activity because it is less immunosuppressive 2
• The combination of MTX+SAAZ+HCQ has not shown significant increase in adverse events compared to monotherapy, while maintaining better efficacy 4

Treatment Algorithm for Combination Therapy Selection

1. First-line approach: Start with methotrexate monotherapy with rapid dose escalation to 15-25mg weekly within 4-6 weeks 2, 5
2. If inadequate response after 3 months:
   • For patients with moderate-to-high disease activity: Add SAAZ and HCQ to form triple therapy 1, 3
   • For patients with contraindications to either SAAZ or HCQ: Consider MTX+LEF combination 6
3. Monitoring: Assess response every 3 months using validated disease activity measures 2
4. Dose optimization:
   • Methotrexate: 15-25mg weekly (oral or subcutaneous) 2
   • Sulfasalazine: 1-2g daily 3
   • Hydroxychloroquine: 200mg twice daily 1
   • Leflunomide (if used): 20mg daily 7

Important Clinical Considerations

• Triple therapy is particularly beneficial for patients who cannot use or afford biologic DMARDs, as it provides comparable efficacy at a lower cost 1, 3
• The synergistic anti-inflammatory properties of methotrexate and hydroxychloroquine contribute to the effectiveness of triple therapy 5, 4
• Low-dose leflunomide monotherapy has not shown superiority to combination therapy, making it a less preferred option 6
• Always supplement methotrexate with folic acid to reduce side effects regardless of which combination is chosen 5

Common Pitfalls to Avoid

• Failing to optimize methotrexate dosing before adding other DMARDs - ensure adequate dose and duration of methotrexate trial 2, 5
• Neglecting regular monitoring of disease activity and drug toxicity - check liver function, complete blood count, and renal function regularly 5
• Using leflunomide without considering its longer half-life and potential for prolonged adverse effects if discontinuation is needed 7
• Overlooking the importance of patient education regarding the different side effect profiles of each medication combination 2

In conclusion, based on the available evidence, triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine provides better outcomes in terms of efficacy and safety compared to methotrexate plus leflunomide for most patients with rheumatoid arthritis requiring combination therapy.