Treatment of Active Rheumatoid Arthritis With Leflunomide Compared With Placebo and Methotrexate

Strand, Vibeke; Cohen, Stanley; Schiff, Michael; Weaver, Arthur L.; Fleischmann, Roy; Cannon, Grant W.; Fox, Robert I.; Moreland, Larry W.; Olsen, Nancy J.; Furst, D E; Caldwell, Jacques R.; Kaine, Jeffrey; Sharp, John T.; Hurley, Frank L.; Loew-Friedrich, Iris

doi:10.1001/archinte.159.21.2542

Cited by 652 publications

(453 citation statements)

References 19 publications

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“…In fact, when reviewing results from the various leflunomide clinical trials, ACR response rates of patients receiving leflunomide monotherapy were similar, if not superior, compared with the addition of leflunomide to MTX therapy (33)(34)(35) (Table 1). Again, comparing clinical trials has its limitations, but the results are clearly consistent with this interpretation.…”

Section: Study Design Issuesmentioning

confidence: 99%

Superior efficacy of combination therapy for rheumatoid arthritis: Fact or fiction?

Smolen

Aletaha

Keystone

2005

Arthritis & Rheumatism

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Section: Study Design Issuesmentioning

confidence: 99%

Superior efficacy of combination therapy for rheumatoid arthritis: Fact or fiction?

Smolen

Aletaha

Keystone

2005

Arthritis & Rheumatism

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“…Newer data suggest that radiographic evidence of joint damage is apparent even in patients with very early disease (11)(12)(13)(14)(15). Therefore, it is important to consider implementation of diseasemodifying drugs at earlier stages of disease.…”

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confidence: 99%

“…Therefore, it is important to consider implementation of diseasemodifying drugs at earlier stages of disease. In addition, it has been shown that despite treatment with traditional DMARDs, patients with persistent disease continue to deteriorate radiographically and lose functional capacity (13)(14)(15). This finding is especially important considering that studies have demonstrated a direct correlation between declining functional status and increased rates of morbidity and mortality (16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Etanercept added to background methotrexate therapy in patients with rheumatoid arthritis: Continued observations

Kremer¹,

Weinblatt²,

Bankhurst³

et al. 2003

Arthritis & Rheumatism

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Objective. To observe the long-term safety and efficacy of combination therapy with etanercept and methotrexate in patients with rheumatoid arthritis (RA), and to determine whether the addition of etanercept allowed reductions in methotrexate or corticosteroid dosages while maintaining a clinical response.Methods. Patients with RA who received methotrexate plus etanercept in a previous randomized, placebo-controlled trial were offered the opportunity to enroll in an open-label extension study for further evaluation of treatment with etanercept and methotrexate.Results. Seventy-nine of the 89 patients in the original blinded study enrolled in the extension study, and 65 of these patients continue in the study. Patients have received etanercept therapy for up to 47 months (median 44 months). The types and rate of adverse events noted during the extension trial were similar to those observed in the controlled trial. At the 3-year assessment, 77% of the 57 patients available for evaluation met American College of Rheumatology 20% (ACR20) criteria for improvement in RA, 47% met the ACR50 criteria, and 23% met the ACR70 criteria. Of the 36 patients assessed at 3 years in the extension study, 30 (83%) were able to decrease their dosages of corticosteroids, and 20 (56%) were able to discontinue corticosteroid therapy. At 3 years, the dosage of methotrexate was decreased in 41 of 66 patients (62%), and methotrexate therapy was discontinued in 19 patients (29%).Conclusion. In this observational continuation study, the addition of etanercept to background methotrexate provided sustained clinical benefit over a median period of 44 months. With etanercept therapy, there were trends toward dosage reduction or discontinuation of methotrexate and corticosteroids, without apparent worsening of ACR response rates. Compared with the controlled trial, no increases in the rate of adverse events were observed.Over the past several decades, methotrexate has become increasingly recognized among rheumatologists as the gold standard in treating patients with rheumatoid arthritis (RA) (1,2). Compared with other, more traditional disease-modifying antirheumatic drugs (DMARDs), methotrexate has a more rapid onset of action, superior long-term effectiveness, and fewer cumulative toxicities (3-6). Studies show that 80% of patients discontinue other DMARDs after 2 years, while at least 50% continue to take methotrexate for Ͼ5 years (7-9). However, despite its advantages over traditional agents, methotrexate is associated with toxicity, and Supported by Immunex Corporation, Seattle, Washington (study drug and grants to the investigational sites).

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“…Leflunomide, a new DMARD, has demonstrated efficacy in the treatment of RA, both clinically and in slowing radiographic progression (14,17,18). Leflunomide is a prodrug rapidly converted into the active metabolite A77 1726, which acts predominantly by inhibiting dihydroorotate dehydrogenase, an enzyme critical for the de novo biosynthesis of pyrimidine, thus prohibiting the clonal expansion of activated T cells (19).…”

mentioning

confidence: 99%

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

Reece¹,

Kraan²,

Radjenovic³

et al. 2002

Arthritis & Rheumatism

103

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Objective. Ethical constraints on the conduct of placebo-controlled trials evaluating new therapies for serious chronic diseases, such as rheumatoid arthritis (RA), indicate the need for discerning methods to assess treatment effect in active-controlled clinical trials. Dynamic gadolinium-enhanced magnetic resonance imaging (DEMRI) is a sensitive technique for the detection of synovial inflammation in RA. Therefore, this investigation was undertaken to evaluate DEMRI as an efficacy assessment tool for differentiating treatment effect in a randomized, active-controlled trial comparing leflunomide and methotrexate.Methods. Patients with active RA (n ‫؍‬ 39) were randomized in a 2-center, prospective, double-blind clinical trial to receive either leflunomide (n ‫؍‬ 18) or methotrexate (n ‫؍‬ 21) therapy for 4 months. DEMRI scans were obtained at baseline and at 4 months, and the initial rate of enhancement (IRE) and the maximal signal intensity (SI) enhancement (ME) were calculated from the SI curves. Clinical improvement was assessed by conventional outcome measures.Results. Thirty-four patients (17 treated with leflunomide and 17 with methotrexate) had usable baseline and end point DEMRI scans. Leflunomide treatment was associated with a significantly greater improvement in IRE compared with methotrexate treatment (P < 0.05). Average values of ME indicated reduction of inflammation with both leflunomide and methotrexate. The improvement in clinical signs and symptoms, as measured by traditional assessments, was comparable for both active treatments.Conclusion. Results of this study validate the sensitivity of DEMRI in detecting inflammatory changes in active RA in response to treatment. Improvement in synovial inflammation as measured by IRE was significantly better with leflunomide than with methotrexate over 4 months of therapy.

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Treatment of Active Rheumatoid Arthritis With Leflunomide Compared With Placebo and Methotrexate

Cited by 652 publications

References 19 publications

Superior efficacy of combination therapy for rheumatoid arthritis: Fact or fiction?

Superior efficacy of combination therapy for rheumatoid arthritis: Fact or fiction?

Etanercept added to background methotrexate therapy in patients with rheumatoid arthritis: Continued observations

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

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