Reappraisal of the clinical use of leflunomide in rheumatoid arthritis and psoriatic arthritis

Abstract

Leflunomide is a disease-modifying antirheumatic drug (DMARD) that has been in routine clinical use for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis for a decade. In RA, clinical trials of up to two years' duration showed that leflunomide monotherapy was equivalent to methotrexate in clinical and radiographic disease outcomes (tender and swollen joint counts, physician and patient global assessments, American College of Rheumatology and Disease Activity Score responses, slowing or halting of radiographic progression). In a number of studies, quality of life measurements indicated that leflunomide is superior to methotrexate. Leflunomide has been studied in combination with methotrexate and shows efficacy in patients only partly responsive to this agent. Recent trials have shown that leflunomide can be used safely with biologic DMARDs, including antitumor necrosis factor agents and rituximab as part of the treatment algorithm in place of methotrexate as a cotherapy. Leflunomide has demonstrated efficacy as a monotherapy in psoriatic arthritis, and it also has a beneficial effect in psoriasis. Postmarketing studies have shown that retention on treatment with leflunomide is equal to methotrexate and superior to other DMARDs. In general, its side effect profile is acceptable compared with other DMARDS, with nausea, diarrhea, and hair fall occurring commonly, but only rarely leading to discontinuation. Liver toxicity is the most significant problem in clinical use although it is uncommon. Peripheral neuropathy, hypertension, pneumonitis, and cytopenia occur more rarely. Leflunomide is contraindicated in pregnancy and should be used with caution in women during child-bearing years. In this review, the place of leflunomide in therapy is discussed and practical advice informed by evidence is given regarding dosing regimens, safety monitoring, and managing side effects. Leflunomide remains one of the most useful of the nonbiologic DMARDs.

Keywords: disease-modifying antirheumatic drugs; efficacy; evidence-based practice; leflunomide; psoriatic arthritis; review; rheumatoid arthritis; safety.

Figure 1

Range of American College of Rheumatology responder rates from different clinical studies of leflunomide. Data at six months and one year are taken from double-blind randomized placebo and active comparator-controlled clinical trials.,, Patients completing 12 months were re-enrolled to a year 2 cohort and remained blinded to treatment allocation.– Those completing two years were eligible to enroll in an open-label, non-controlled extension study to complete five years of treatment.

Figure 2

Sustained DAS28 response over time for leflunomide 20 mg daily following a loading dose of 100 mg daily for three days (percentage of patients with a response maintained to 24 weeks). Data from the RELIEF study. Abbreviation: DAS 28, Disease Activity Score 28 joint count.

Figure 3

Quality of life changes in randomized controlled trials of LEF versus MTX over two years assessed by Medical Outcomes Survey Short Form 36 (SF-36). Vertical bars show baseline and 24-month data for each domain of the SF-36, dashed horizontal lines show US population norms. Abbreviations: LEF, leflunomide, MTX, methotrexate.

Figure 4

American College of Rheumatology response rates for combination therapy of leflunomide plus methotrexate versus methotrexate plus placebo. Abbreviations: MTX, methotrexate; PBO, placebo; LEF, leflunomide.

Figure 5

Change in quality of life occurring over time by treatment allocation with biologic DMARDs in combination with methotrexate or leflunomide. Abbreviations: ADA, adalimumab; ETN, etanercept; INF, infliximab; LEF, leflunomide; MTX, methotrexate; MCID, minimum clinically important difference; mHAQ, modified Health Assessment Questionnaire; DMARDs, disease-modifying antirheumatic drugs.