Should Folitrax (Methotrexate) Be Given Together with Hydroxychloroquine in Rheumatoid Arthritis?
Yes, methotrexate should be combined with hydroxychloroquine in patients with rheumatoid arthritis who have an inadequate response to methotrexate monotherapy, particularly when used as part of triple therapy with sulfasalazine, which demonstrates superior efficacy compared to methotrexate alone. 1, 2
Evidence Supporting Combination Therapy
Superior Efficacy of Combination Regimens
The 2012 American College of Rheumatology guidelines explicitly recommend combination DMARD therapy including methotrexate plus hydroxychloroquine as a standard treatment option for established rheumatoid arthritis. 1 This recommendation is supported by high-quality evidence showing that methotrexate combined with sulfasalazine and hydroxychloroquine did not increase the risk of withdrawal due to toxicity, unlike other DMARD combinations. 1
Triple therapy (methotrexate + sulfasalazine + hydroxychloroquine) achieved 77% sustained improvement at two years compared to only 33% with methotrexate alone (P < 0.001), demonstrating clear superiority in patients with inadequate response to prior DMARDs. 2 A separate trial confirmed that 78% of patients on triple therapy achieved ACR 20% response at 2 years versus 60% with methotrexate plus hydroxychloroquine alone (P = 0.05). 3
When to Use This Combination
Start with methotrexate monotherapy in DMARD-naive patients, rapidly escalating to 25-30 mg weekly with folic acid supplementation. 4, 5 The 2009 multinational evidence-based recommendations state that in DMARD-naive patients, the balance of efficacy/toxicity favors methotrexate monotherapy over combination therapy initially. 1
Add hydroxychloroquine (and sulfasalazine for complete triple therapy) when:
- Inadequate response after 3 months of optimized methotrexate monotherapy 1, 4
- Moderate or high disease activity persists despite methotrexate 20-25 mg weekly 4, 5
- Poor prognostic factors are present (high RF/anti-CCP, erosions, high disease activity) 1, 5
Pharmacokinetic Advantage
Hydroxychloroquine increases methotrexate exposure (AUC increased, P = 0.005) while decreasing peak concentration (Cmax decreased, P = 0.025), which may explain both the enhanced efficacy and potentially reduced acute liver adverse effects of the combination. 6 This sustained methotrexate exposure provides a pharmacokinetic rationale for the clinical superiority observed in trials. 6
Treatment Algorithm
Initial Therapy (DMARD-Naive Patients)
- Start methotrexate 15-25 mg weekly with folic acid supplementation 4, 5
- Add low-dose glucocorticoids (≤10 mg/day prednisone) as bridge therapy for <3 months 4, 5
- Assess at 3 months: expect ≥50% improvement in disease activity 4, 5
Escalation Strategy (Inadequate Response)
- At 3 months without adequate response: Add hydroxychloroquine 400 mg daily and sulfasalazine (titrate from 500 mg twice daily to 1000 mg twice daily) 1, 4, 3
- At 6 months if target not reached: Consider adding biologic DMARD if poor prognostic factors present 1, 4
Maintenance After Response
Hydroxychloroquine can maintain the response achieved with combination therapy after methotrexate withdrawal, delaying disease flare (P = 0.023) for up to 36 weeks. 7 However, current guidelines favor maintaining combination therapy rather than withdrawing methotrexate in responders. 4, 5
Critical Pitfalls to Avoid
Do not use hydroxychloroquine as first-line monotherapy when methotrexate is appropriate—hydroxychloroquine has only weak clinical efficacy and no structural efficacy in preventing joint damage. 4, 8 The 2019 EULAR recommendations reserve hydroxychloroquine primarily for patients with very mild disease or as part of combination therapy. 4, 8
Do not delay escalation to combination therapy if <50% improvement at 3 months or target not reached at 6 months—even modest ongoing joint damage accumulates and leads to irreversible disability. 4, 5
Monitor for increased methotrexate toxicity during combination therapy with hydroxychloroquine, especially in patients with decreased renal function, due to increased methotrexate exposure. 6 However, clinical trials showed no increased withdrawal rates due to toxicity with this specific combination. 1
FDA-Approved Indication
The FDA label for methotrexate explicitly states: "Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects." 9 Despite this cautionary language, extensive post-approval clinical trial evidence and guideline recommendations support the methotrexate-hydroxychloroquine combination as safe and effective. 1, 2, 3