In a newly diagnosed adult with rheumatoid arthritis already receiving methotrexate (15–25 mg weekly with folic acid) and iguratimod (25 mg twice daily), which add‑on therapy—leflunomide or hydroxychloroquine—is more appropriate?

Hydroxychloroquine is the Preferred Add-On in This Clinical Scenario

In a patient already receiving methotrexate (15–25 mg weekly) plus iguratimod (25 mg twice daily), adding hydroxychloroquine is more appropriate than leflunomide due to its superior safety profile, lower toxicity burden, and the fact that leflunomide would create excessive immunosuppression when combined with this existing dual-DMARD regimen.

Rationale Based on Current Guidelines

Hydroxychloroquine's Favorable Position

• The 2021 ACR guidelines conditionally recommend hydroxychloroquine over other csDMARDs, including leflunomide, specifically citing its better tolerability and more favorable risk profile in RA patients 1.

• Hydroxychloroquine is explicitly preferred over leflunomide in the treatment hierarchy for RA, with the ACR stating that "methotrexate is conditionally recommended over leflunomide" due to leflunomide's greater dosing inflexibility and higher cost—and hydroxychloroquine ranks even higher than methotrexate in the safety hierarchy 1.

• The 2014 EULAR recommendations support using antimalarials (hydroxychloroquine) in combination strategies, particularly when building triple-DMARD therapy 1.

Why Leflunomide is Less Appropriate Here

• Leflunomide has similar efficacy to methotrexate but significantly overlapping toxicity profiles, including hepatotoxicity, gastrointestinal effects, and immunosuppression 1, 2.

• Adding leflunomide to a patient already on methotrexate plus iguratimod would create a triple-DMARD regimen with three potent immunosuppressive agents, substantially increasing the risk of hepatotoxicity, bone marrow suppression, and infection without clear evidence supporting this specific combination 3, 2.

• A head-to-head trial demonstrated that while leflunomide and methotrexate have comparable efficacy, methotrexate showed superior clinical outcomes in tender joint count and patient global assessment, and leflunomide caused more treatment-related adverse events including diarrhea, alopecia, and rash 3.

• The standard leflunomide dose is 20 mg daily, and there is no established evidence for combining leflunomide with both methotrexate and iguratimod simultaneously 4.

Clinical Algorithm for This Decision

Step 1: Assess Current Disease Control

• If the patient has inadequate response to methotrexate (15–25 mg weekly) plus iguratimod after 3–6 months, escalation is warranted 5, 6.

Step 2: Choose the Safest Add-On

• Add hydroxychloroquine 200–400 mg daily as the third agent in a triple-DMARD strategy, which has established safety data and guideline support 1.
• This creates the classic "triple therapy" regimen (methotrexate + sulfasalazine/iguratimod + hydroxychloroquine) that has proven efficacy in early RA 1.

Step 3: Avoid Leflunomide in This Context

• Do not add leflunomide when the patient is already on two DMARDs with overlapping hepatic metabolism and immunosuppressive effects 7, 2.
• Reserve leflunomide for patients who cannot tolerate methotrexate (as a replacement, not an addition) or as monotherapy in methotrexate-intolerant patients 1, 7.

Key Safety Considerations

Hepatotoxicity Risk

• Both methotrexate and leflunomide carry significant hepatotoxicity risk, with the combination requiring intensive monitoring 3, 2.
• Hydroxychloroquine has minimal hepatotoxic potential, making it safer in combination with methotrexate 1.

Immunosuppression Burden

• Leflunomide is highly immunosuppressive and would compound the effects of methotrexate and iguratimod, increasing infection risk 7, 2.
• Hydroxychloroquine is less immunosuppressive and actually has antimicrobial properties, making it safer in triple-DMARD regimens 1, 7.

Monitoring Requirements

• Adding leflunomide would necessitate more frequent liver function tests, complete blood counts, and blood pressure monitoring 3.
• Hydroxychloroquine requires only annual ophthalmologic screening after the first 5 years of use, with minimal laboratory monitoring 1.

Common Pitfalls to Avoid

• Do not assume "more potent equals better": Leflunomide's similar efficacy to methotrexate does not justify adding it when methotrexate is already optimized 3, 2.

• Do not ignore the existing iguratimod: This patient is already on dual-DMARD therapy; adding a third highly immunosuppressive agent (leflunomide) lacks evidence and increases risk 8.

• Do not delay biologic therapy if triple-DMARD therapy fails: If hydroxychloroquine addition does not achieve low disease activity or remission within 3–6 months, escalate to a TNF inhibitor or other biologic rather than substituting leflunomide 1, 5, 6.