What is the role of leflunomide in treating psoriatic arthritis?

Leflunomide in Psoriatic Arthritis

Leflunomide is an effective conventional synthetic DMARD (csDMARD) for treating peripheral arthritis in psoriatic arthritis, recommended as a first-line option alongside methotrexate and sulfasalazine, with the added benefit of improving both joint and skin manifestations. 1

Role as First-Line Therapy for Peripheral Arthritis

Leflunomide should be initiated rapidly in patients with polyarthritis or oligoarthritis with poor prognostic factors (structural damage, elevated ESR/CRP, dactylitis, or nail involvement). 1 The 2020 EULAR guidelines explicitly list leflunomide among the three preferred csDMARDs (methotrexate, sulfasalazine, or leflunomide) for peripheral arthritis. 1

• For polyarticular disease, leflunomide carries Level A evidence supporting its use for moderate to severe peripheral arthritis. 1
• The 2009 GRAPPA recommendations assigned leflunomide Grade A evidence for peripheral arthritis treatment. 1

Efficacy Profile

Joint Outcomes

In the pivotal TOPAS trial, 58.9% of leflunomide-treated patients achieved PsARC response versus 29.7% with placebo (p < 0.0001) at 24 weeks. 2 This represents a clinically meaningful difference with a number needed to treat of approximately 3-4 patients. 2

• Modified ACR20 response was achieved in 59% of leflunomide-treated patients. 2
• Leflunomide demonstrated efficacy in reducing painful and inflamed joint counts, with significant improvements observed as early as 4 weeks. 3
• Quality of life improved significantly, with HAQ index decreasing by 36% at 6 months. 3

Skin Outcomes

Leflunomide provides dual benefit by treating both arthritis and psoriasis, making it particularly valuable when relevant skin involvement is present. 1

• PASI 50 was achieved in 30.4% of patients versus 18.9% with placebo (p = 0.05). 4
• Target lesion response occurred in 46.4% versus 25.3% with placebo (p = 0.0048). 4
• Combined skin and joint response was achieved in 27.2% versus 8.9% with placebo (p < 0.0001). 4
• Dermatology Life Quality Index improved by 1.9 points versus 0.2 with placebo (p = 0.0173). 4
• Leflunomide carries Level A evidence for treating moderate to severe skin disease in psoriasis. 1

Dosing and Administration

Standard dosing is 100 mg/day loading dose for 3 days, followed by 20 mg/day orally for maintenance. 2, 5 This loading dose strategy achieves therapeutic levels more rapidly than starting at maintenance dose. 2

Limitations and When NOT to Use Leflunomide

Leflunomide has NOT been shown effective for axial disease in psoriatic arthritis. 1 Traditional oral DMARDs including leflunomide, methotrexate, and sulfasalazine lack efficacy for axial manifestations based on extrapolation from ankylosing spondylitis data. 1

For predominantly axial disease with inadequate response to NSAIDs, TNF inhibitors should be considered instead, with IL-17 inhibitors preferred when relevant skin involvement exists. 1

Leflunomide is not appropriate as monotherapy for isolated enthesitis or dactylitis without peripheral arthritis. 1

Safety Monitoring

Transaminase enzymes require careful monitoring due to potential hepatotoxicity, particularly in patients with alcohol consumption, obesity, type II diabetes, non-alcoholic steatohepatitis, or concurrent hepatotoxic medications. 1

Common adverse effects include:

• Diarrhea and nausea (most common, usually diminishing with continued use) 2, 6
• Alanine aminotransferase elevations (occurred at higher rates than placebo but serious liver toxicity was not observed in clinical trials) 2
• Hair loss, hypertension, peripheral neuropathy, pneumonitis, and cytopenia occur more rarely 6

Leflunomide is contraindicated in pregnancy and requires caution in women of childbearing age. 6

Position in Treatment Algorithm

When csDMARD therapy fails after at least one adequate trial, escalation to biologic DMARDs (bDMARDs) is indicated, with IL-17 or IL-12/23 inhibitors preferred when relevant skin involvement exists. 1

If both csDMARD and bDMARD therapy fail, or when bDMARDs are inappropriate, JAK inhibitors may be considered. 1

Leflunomide can be combined with biologic DMARDs including TNF inhibitors and rituximab as part of the treatment algorithm, similar to methotrexate. 6

Clinical Advantages

Retention on leflunomide treatment equals methotrexate and is superior to other DMARDs in postmarketing studies. 6 This suggests good real-world tolerability and patient acceptance. 6

Leflunomide offers a relatively inexpensive therapeutic option compared to biologic agents while providing efficacy for both joint and skin manifestations. 5

The once-daily oral formulation provides convenience compared to weekly injectable or oral methotrexate. 4

Common Pitfalls

Do not use leflunomide as monotherapy for axial disease—this is ineffective and delays appropriate treatment with TNF or IL-17 inhibitors. 1

Do not combine leflunomide with antimalarials, intramuscular or oral gold, D-penicillamine, azathioprine, or methotrexate without adequate study data supporting safety. 7 The FDA label specifically notes these combinations have not been adequately studied. 7

Monitor liver function closely, especially in patients with risk factors for hepatotoxicity—this is the most significant safety concern in clinical use. 1, 6