Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: Results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis

Abstract

on behalf of the LEFLUNOMIDE RHEUMATOID ARTHRITIS INVESTIGATORS GROUP Objective. To determine whether treatment with leflunomide (LEF), methotrexate (MTX), or sulfasala-zine (SSZ) for 6-12 months retards progression of radiographic damage and to identify clinical variables that correlate with radiographic progression. Methods. Radiographs of the hands and feet were performed at baseline and at the end of study or early exit in 3 randomized controlled trials. Protocol US301 was a 12-month controlled trial of LEF or MTX treatment compared with placebo in 482 patients random-ized in a 3:3:2 ratio. Protocol MN301 compared 6 months of LEF or SSZ treatment with placebo in 358 patients, randomized in a 3:3:2 ratio, with continued blinded treatment in the active control arms for 12 months. Protocol MN302 compared 12 months of LEF treatment with MTX in 999 patients. Radiographs were blinded for sequence and treatment and were scored for erosions and joint space narrowing. All analyses were by intent-to-treat. Sensitivity analyses were performed to account for missing data. Results. LEF, MTX, and SSZ treatment resulted in statistically significantly less radiographic progression compared with placebo at 6 and 12 months: for protocol US301, LEF versus placebo P 0.0007 and MTX versus placebo P 0.0196; for protocol MN301, LEF versus placebo P 0.0004 and SSZ versus placebo P 0.0484. The effect of LEF treatment was similar to that of MTX and SSZ. Conclusion. These are the first 6-and 12-month randomized placebo-and active drug-controlled trials to demonstrate retardation of radiographic progression by a new disease-modifying antirheumatic drug (DMARD), LEF, as well as 2 commonly used DMARDs, MTX and SSZ.

Guidelines for the management of rheumatoid arthritis: 2002 Update

“…In the last decade, a number of studies have documented the symptomatic benefit of HCQ and SSZ, particularly for patients with early, milder disease (27)(28)(29)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). Although HCQ alone does not slow radiologic damage, early treatment with HCQ has a significant impact on long-term patient outcome.…”

“…More importantly, SSZ has been shown to 336 ACR SUBCOMMITTEE ON RA GUIDELINES retard radiographic progression of RA (63). SSZ is usually well tolerated, with most side effects, which include nausea and abdominal discomfort, occurring in the first few months of therapy.…”

“…Randomized clinical trials have established the efficacy of MTX in RA, particularly in patients with more severe disease (64)(65)(66)(67)(68)(69)(70). Longitudinal observational studies and randomized controlled trials show that MTX retards the progression of radiographic erosions (63,(71)(72)(73)(74)(75).…”

Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis

“…Disease activity is an important predictor of the progression of joint damage (7,8) and the long-term requirement for joint-replacement surgery (9). Effective control of RA disease activity reduces radiographic progression of joint damage and improves physical function and quality of life (10)(11)(12). Thus, the primary goal of therapy is to achieve rapid, effective disease control to prevent the long-term damaging effects on joint structure and function.…”

Comparative assessment of leflunomide and methotrexate for the treatment of rheumatoid arthritis, by dynamic enhanced magnetic resonance imaging

“…A number of traditional disease-modifying antirheumatic drugs (DMARDs), including sulfasalazine (13,14), methotrexate (15), and ciclosporin A (16), all of which suppress the acute-phase response, have also been shown to delay the progression of cartilage and bone damage. Leflunomide, a new DMARD, has demonstrated efficacy in the treatment of RA, both clinically and in slowing radiographic progression (14,17,18).…”