What is the comparison between Hydroxychloroquine (Plaquenil) and Leflunomide?

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From the Guidelines

Hydroxychloroquine (Plaquenil) is conditionally recommended over leflunomide for patients with low disease activity, according to the 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis 1. When considering the treatment of rheumatoid arthritis, the choice between hydroxychloroquine and leflunomide depends on various factors, including disease activity, patient comorbidities, and potential side effects.

  • Key differences between the two medications include their mechanisms of action, with hydroxychloroquine reducing inflammation through interference with toll-like receptor signaling, and leflunomide inhibiting pyrimidine synthesis to reduce T-cell proliferation.
  • The safety profiles of the two medications also differ, with hydroxychloroquine having a relatively favorable profile with common side effects including gastrointestinal upset, skin rashes, and rarely retinal toxicity, while leflunomide carries more significant side effects including liver toxicity, bone marrow suppression, and teratogenicity.
  • According to the guideline, methotrexate is conditionally recommended over leflunomide for patients with low disease activity, and hydroxychloroquine is conditionally recommended over other csDMARDs, including leflunomide, in this patient population 1.
  • Regular monitoring is essential with both medications, including eye exams for hydroxychloroquine and liver function tests for leflunomide, to minimize the risk of adverse effects.
  • In terms of specific recommendations, the guideline suggests that hydroxychloroquine may be preferred as first-line therapy for milder disease or in combination therapy, while leflunomide may be chosen for more aggressive disease or when other DMARDs have failed 1.

From the Research

Comparison of Plaquenil and Leflunomide

  • Plaquenil, also known as Hydroxychloroquine, is a medication used to treat rheumatoid arthritis, while Leflunomide is another disease-modifying antirheumatic drug (DMARD) used for the same purpose.
  • A study published in 2022 2 compared the efficacy and safety of Leflunomide and Sulfasalazine in combination with Methotrexate and Hydroxychloroquine in patients with rheumatoid arthritis, but did not directly compare Plaquenil and Leflunomide.
  • Another study published in 2021 3 reviewed the safety of long-term use of four common conventional DMARDs, including Leflunomide, Hydroxychloroquine, and Sulfasalazine, but did not provide a direct comparison between Plaquenil and Leflunomide.

Safety and Efficacy

  • A study published in 1998 4 discussed the use of triple therapy with Methotrexate, Sulfasalazine, and Hydroxychloroquine in patients with rheumatoid arthritis, highlighting the potential benefits and risks of this combination.
  • A more recent study published in 2021 5 examined the risk versus benefit of using Hydroxychloroquine to treat patients with COVID-19, but did not provide information on its use in rheumatoid arthritis or a comparison with Leflunomide.
  • Another study published in 2022 6 compared the cardiovascular risks of Hydroxychloroquine and Methotrexate in patients with rheumatoid arthritis, finding that Hydroxychloroquine was not associated with an increased risk of sudden cardiac arrest or ventricular arrhythmia, but may be associated with an increased risk of major adverse cardiovascular events in patients with a history of heart failure.

Key Findings

  • The available evidence does not provide a direct comparison between Plaquenil and Leflunomide in terms of efficacy and safety in patients with rheumatoid arthritis.
  • However, studies suggest that both medications can be effective in treating rheumatoid arthritis, but may have different safety profiles, particularly with regards to cardiovascular risk 6.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Risk versus Benefit of Using Hydroxychloroquine to Treat Patients with COVID-19.

The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale, 2021

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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