What is the typical triple therapy regimen for Rheumatoid Arthritis (RA)?

Triple Therapy for Rheumatoid Arthritis

Triple therapy for RA consists of methotrexate (MTX) plus sulfasalazine (SSZ) plus hydroxychloroquine (HCQ), and is a well-established treatment option for patients who have not achieved adequate disease control with methotrexate monotherapy. 1, 2

Standard Triple Therapy Regimen

The typical dosing regimen includes:

• Methotrexate: 15-25 mg weekly (oral or subcutaneous), with rapid escalation to target dose within 4-6 weeks 2, 3
• Sulfasalazine: 2.0 g daily (typically 500 mg twice daily, though can be given as 1000 mg twice daily) 4, 5
• Hydroxychloroquine: 200 mg daily 4, 5
• Folic acid supplementation: Always required with methotrexate to reduce adverse effects 2, 3

When to Use Triple Therapy

Triple therapy is conditionally recommended for patients without poor prognostic factors who have not achieved target disease activity (remission or low disease activity) after 3-6 months of optimized methotrexate monotherapy. 2

However, the 2021 ACR guidelines note an important caveat: addition of a biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD) is conditionally recommended over triple therapy for patients taking maximally tolerated doses of methotrexate who are not at target. 1 This represents a shift from earlier guidelines, reflecting the increasing availability and evidence for biologic agents.

Clinical Efficacy Evidence

Triple therapy demonstrates superior efficacy compared to methotrexate monotherapy:

• 72.2% of patients on triple therapy achieved ACR 50% response versus 30% on methotrexate alone (p=0.013) at 18 months 5
• 61.1% maintained ACR 50% response from month 9-18 on triple therapy versus 25% on methotrexate monotherapy (p=0.024) 5
• Both patients previously failing methotrexate alone and those failing sulfasalazine-hydroxychloroquine combination showed statistically significant improvements when switched to triple therapy 4
• Disease activity scores (DAS28-ESR) at 6 and 12 months were significantly lower with triple therapy compared to methotrexate-leflunomide combination (mean DAS28 at 6 months: 3.4 vs 3.9, p<0.0001) 6

Treatment Algorithm

For patients with moderate-to-high disease activity on methotrexate monotherapy:

1. First, ensure methotrexate is optimized to 15-25 mg weekly (consider switching to subcutaneous route if oral is inadequate) 2, 3
2. Assess for poor prognostic factors (high disease activity, positive RF/anti-CCP, erosions, functional limitation) 2
3. If poor prognostic factors present: Add biologic DMARD or JAK inhibitor rather than triple therapy 1, 2
4. If poor prognostic factors absent: Consider adding sulfasalazine plus hydroxychloroquine (triple therapy) 2
5. Reassess disease activity at 3 months: If no improvement, or at 6 months if target not reached, escalate to biologic therapy 2

Safety and Tolerability

Triple therapy is generally well tolerated with no significant increase in adverse events compared to monotherapy. 7

• Discontinuation rates due to toxicity are comparable: 11.1% for triple therapy versus 20% for methotrexate monotherapy 5
• The combination does not appear to have additive toxicity despite using three agents simultaneously 4, 7
• Regular monitoring of liver function, complete blood count, and renal function remains essential 3

Critical Pitfalls to Avoid

• Do not add sulfasalazine and hydroxychloroquine before optimizing methotrexate dose to 15-25 mg weekly—underdosing methotrexate is a common error 2, 3
• Do not forget folic acid supplementation with methotrexate regardless of which combination is used 2, 3
• Do not continue triple therapy beyond 6 months if inadequate response—escalate to biologic therapy rather than persisting with ineffective treatment 2
• Do not use triple therapy as first-line in patients with poor prognostic factors—these patients should receive methotrexate plus biologic/JAK inhibitor from the outset 1, 2
• Do not combine leflunomide with sulfasalazine and hydroxychloroquine—this triple combination was terminated early in trials due to gastrointestinal complications and showed no benefit over standard triple therapy 1

Tapering Considerations

If a patient on triple therapy wishes to discontinue one DMARD after achieving sustained remission, gradual discontinuation of sulfasalazine is conditionally recommended over gradual discontinuation of hydroxychloroquine. 1 This reflects hydroxychloroquine's favorable safety profile and potential synergistic anti-inflammatory properties with methotrexate. 3, 7