Triple DMARD Therapy Dosing for Rheumatoid Arthritis
The recommended triple DMARD therapy consists of methotrexate 15-25 mg weekly (optimized to 20-25 mg/week or maximum tolerated dose), sulfasalazine 2 g daily, and hydroxychloroquine 200 mg daily. 1
Methotrexate Component
- Start methotrexate at 15 mg weekly and titrate to at least 15 mg within 4-6 weeks, with further escalation to 20-25 mg weekly as tolerated to optimize efficacy 1
- Oral administration is preferred initially, but switch to subcutaneous route if inadequate response at maximum tolerated oral dose or if gastrointestinal intolerance occurs 1
- Prescribe at least 5 mg folic acid weekly to reduce gastrointestinal and hepatic toxicity without compromising efficacy 1
Sulfasalazine Component
- Administer sulfasalazine at 2 g daily (typically 1 g twice daily) 2, 3
- This dose has been consistently validated in clinical trials demonstrating efficacy in triple therapy regimens 4, 3
Hydroxychloroquine Component
- Give hydroxychloroquine 200 mg daily 1, 2, 3
- This standard dose is used across all major studies of triple therapy 4, 3
Clinical Context for Triple Therapy Initiation
Triple DMARD therapy should be initiated when patients have inadequate response to methotrexate monotherapy at optimized doses (SDAI >11 or CDAI >10 after 6-12 months), particularly in those with moderate disease activity (SDAI 11-26) 1
Key Evidence Supporting This Approach:
- The RACAT trial demonstrated that triple therapy was noninferior to etanercept plus methotrexate in patients with active RA despite methotrexate, with similar improvements in DAS28 (-2.1 vs -2.3), radiographic progression, and safety profiles 4
- Multiple studies show 61-72% of patients achieve ACR 50% response with triple therapy versus 25-30% with methotrexate monotherapy 3
- The 2021 ACR guidelines conditionally recommend adding biologics or targeted synthetics over triple therapy, but triple therapy remains a highly effective and cost-efficient option, particularly for patients with moderate disease activity 1
Important Caveats
- Allow 3-6 months to fully assess efficacy of triple therapy before considering it a failure 1
- Monitor liver enzymes (ALT/AST), creatinine, and complete blood count every 1-1.5 months during dose escalation, then every 1-3 months once stable 1
- If sulfasalazine needs to be discontinued from triple therapy (due to adverse events), it should be the first drug removed rather than hydroxychloroquine, as sulfasalazine has poorer treatment persistence 1
- Triple therapy can be safely continued long-term in patients who achieve and maintain disease control 1