COCHRANE FOR CLINICIANS: PUTTING EVIDENCE INTO PRACTICE

Is Leflunomide as Safe and Effective in the Treatment of Rheumatoid Arthritis as Other DMARDs?

MICHAEL SCHOOFF, M.D., and JASON WICKERSHAM, M.D., Clarkson Family Medicine Residency Program, Omaha, Nebraska

See page 785 for definitions of strength-of-evidence levels.

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Michael Schooff, M.D., and Jason Wickersham, M.D., present a clinical scenario and question based on the Cochrane Abstract, along with the evidence-based answer and a full critique of the abstract.

Clinical Scenario

A 43-year-old woman is newly diagnosed with rheumatoid arthritis. You want to choose a disease-modifying anti-rheumatic drug (DMARD) to help prevent disease progression.

Clinical Question

Is leflunomide as safe and effective in the treatment of rheumatoid arthritis as other DMARDs?

Evidence-Based Answer

Compared with placebo, leflunomide improves clinical outcomes and delays radiologic progression of rheumatoid arthritis. After two years of treatment, leflunomide is as safe as sulfasalazine and more effective. Leflunomide's efficacy and adverse events are similar to those of methotrexate. Leflunomide costs significantly more than sulfasalazine and methotrexate. [Evidence level A, systematic review of randomized controlled trials]

Cochrane Abstract Background. Rheumatoid arthritis is a chronic, inflammatory joint disease. Leflunomide, as an inhibitor of pyrimidine synthesis, has a different mechanism of action than other DMARDs. Objectives. To determine the efficacy and toxicity of leflunomide compared with placebo or other DMARDs in the treatment of rheumatoid arthritis. Search Strategy. The authors1 conducted a search in MEDLINE, EMBASE, Current Contents, and the Cochrane Controlled Trial Register for trials up to December 2001. The authors also hand- searched reference lists and consulted content experts. Selection Criteria. Two independent reviewers selected the trials that met predetermined inclusion criteria. Data Collection and Analysis. Two independent reviewers extracted data and assessed methodologic quality using standardized test forms. Primary Results. Six trials were included in this review. Using the American College of Rheumatology 20 (ACR20) improvement criteria, there was an absolute difference in improvement of 28 percent (95 percent confidence interval, 21 to 35 percent) favoring leflunomide (232 of 413 leflunomide-treated patients compared with 89 of 311 placebo patients met the criteria). At six and 12 months, there was no difference in ACR20 response rate between patients treated with leflunomide and patients treated with sulfasalazine or methotrexate. Other clinical outcomes were improved significantly in the leflunomide group compared with the placebo group, but they were not different from sulfasalazine or methotrexate. Withdrawals related to adverse events were 10 percent greater in the leflunomide group than in the placebo group (70 of 416 compared with 18 of 311, respectively). Important adverse events include gastrointestinal symptoms, elevated liver function values, alopecia, and infections. Overall adverse events and withdrawals in the leflunomide group were not significantly different from those in the sulfasalazine or methotrexate groups. Reviewers' Conclusions. Leflunomide appears to improve all clinical outcomes and delay radiologic progression at both six and 12 months of treatment compared with placebo. Its efficacy and adverse events at two years of treatment are comparable to those of sulfasalazine or methotrexate. Long-term efficacy and toxicity remains to be established. These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in The Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (www.cochrane.org).

Cochrane Critique

Did the authors address a focused clinical question? Yes.

Were the criteria used to select articles for inclusion appropriate? Yes.

Is it likely that important and relevant articles were missed? No.

Was the validity of the individual articles appraised? Yes.

Were the assessments of studies reproducible? Yes.

Were the results similar from study to study? No. Five of the six trials had similar results (treatment with leflunomide and methotrexate were equally effective). In one study that compared leflunomide with methotrexate at 12 months and two years, improvements with methotrexate were significantly greater than those with leflunomide. Therefore, the comparison of outcomes between leflunomide and methotrexate was based on random effects models.

Can the results be applied to patient care? Yes.

Do the conclusions make biologic and clinical sense? Yes.

Are the benefits worth the harms and cost? No.

Practice Pointers

Leflunomide is a new drug with a different mechanism of action than other DMARDs such as methotrexate, antimalarial drugs (chloroquine and hydroxychloroquine), sulfasalazine, gold, azathioprine, d-penicillamine, and cyclosporin A. Leflunomide is given in a dosage of 100 mg per day for the first one to three days and 20 to 25 mg per day thereafter.

Studies were found that compared leflunomide with sulfasalazine and methotrexate. Adverse events were 10 percent greater in the leflunomide-treated group compared with placebo. However, the total withdrawal rate was higher in the placebo group because of lack of treatment efficacy.

The efficacy of leflunomide was not significantly different from that of sulfasalazine at six and 12 months. At 24 months, however, leflunomide was significantly better than sulfasalazine in most of the clinical outcomes measured. There were no differences in adverse events or discontinuation rates between leflunomide and sulfasalazine.

Compared with methotrexate, leflunomide was not significantly more effective on most outcome measures. There was no difference in the number of tender or swollen joints, pain scores, or work productivity. Patients who took leflunomide were more likely than those who took methotrexate to discontinue treatment but not because of adverse events. There was no significant difference between the leflunomide and methotrexate groups in the likelihood of elevated hepatic transaminase levels or weight loss. Patients in the leflunomide group were more likely to experience gastrointestinal symptoms, allergic reactions, infections, alopecia, and hypertension.

Safety profiles were similar for the three medications studied. However, leflunomide has not been studied for longer than two years. Leflunomide is much more expensive than sulfasalazine or methotrexate. One month of therapy with leflunomide costs $375 compared with $15 to $31 for sulfasalazine and $36 to $47 for methotrexate (figures based on average wholesale prices in Red Book. Montvale, N.J.: Medical Economics Data, 2003). Based on the evidence in this review, leflunomide was much more effective than placebo after two years of therapy, somewhat more effective than sulfasalazine, and equally as effective as methotrexate, although at a much higher cost.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available at www.update-software.com/abstracts/ab002047.htm.

REFERENCE

1. Osiri M, Shea B, Robinson B, Suarez-Almazor M, Strand V, Tugwell P, et al. Leflunomide for treating rheumatoid arthritis. Cochrane Database Syst Rev 2003:CD002047.

Michael Schooff, M.D., is associate director of the Clarkson Family Medicine Residency Program in Omaha. He received his medical degree from the Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, Md., and completed a family practice residency at Womack Army Medical Center, Fort Bragg, N.C.

Jason Wickersham, M.D., is a third-year family practice resident at the Clarkson Family Medicine Residency Program. He received his medical degree from the University of South Dakota School of Medicine, Vermillion.

Address correspondence to Michael Schooff, M.D., Clarkson Family Medicine, 4200 Douglas St., Omaha, NE 68131 (e-mail: mschooff@ nhsnet.org). Reprints are not available from the author.