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Review: Adding newer disease-modifying drugs or biological agents to methotrexate improved rheumatoid arthritis symptoms

Deborah P.M. Symmons, MD
[+] Article, Author, and Disclosure Information

Source of funding: No external funding.

For correspondence: Dr. M.C. Hochberg, University of Maryland School of Medicine, Baltimore, MD, USA. E-mail mhochber@umaryland.edu.

Ann Intern Med. 2002;136(3):97. doi:10.7326/ACPJC-2002-136-3-097
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Question: In patients with rheumatoid arthritis (RA) and an incomplete response to methotrexate, does the addition of biological agents or newer, disease-modifying antirheumatic drugs (DMARDs) to methotrexate prompt a more complete response than does the addition of placebo?

Data sources: An existing systematic review was updated. Additional studies were identified by searching MEDLINE (July 1997 to December 2000) with the terms rheumatoid arthritis and combination drug therapy, bibliographies of relevant studies, and abstracts of scientific presentations of the American College of Rheumatology (ACR) from 1998 to 2000 and by contacting authors of studies that used a step-up strategy in patients with RA.

Study selection: Studies were selected if they were randomized, double-blind, placebo-controlled trials that added therapeutic agents to methotrexate in patients with active RA.

Data extraction: Data were extracted on patient characteristics (age, sex, race, duration of RA, proportion who were rheumatoid-factor positive), concomitant treatment, study drug and methotrexate dose and duration, eligibility criteria, baseline disease activity, and outcome measures. The primary outcome was ACR 20 response (i.e., improvement of ≥ 20% in swollen and tender joint counts in 3 of 5 ACR end points [pain, patient global assessment, physician global assessment, disability score, and erythrocyte sedimentation rate]).

Main results: 4 trials were included (928 patients). The active treatments (in addition to methotrexate) were cyclosporin, 2.5 mg/kg of body weight per day; etanercept, 25 mg twice weekly; infliximab, 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks; and leflunomide, 100 mg/d for 2 days, then 10 mg/d. Treatment duration ranged from 24 to 30 weeks. Each of the 4 active treatments was more effective than placebo. No evidence of heterogeneity existed among the trials, and the 95% CIs for the relative risks of the individual trials overlapped (Table).

Conclusion: In patients with rheumatoid arthritis and an incomplete response to methotrexate, the addition of cyclosporin, etanercept, infliximab, or leflunomide led to an American College of Rheumatology 20 response in 2 to 3 times as many patients as did the addition of placebo.

Active treatment (cyclosporin, etanercept, infliximab, or leflunomide) vs placebo for rheumatoid arthritis with incomplete response to methotrexate (4 trials)*

Outcome at 24 to 30 wkTherapeutic agentActive treatmentPlaceboRBI (95% CI)NNT (CI)
ACR 20Cyclosporin48%16%192% (65 to 415)3 (2 to 6)
Etanercept71%27%167% (44 to 394)2 (1 to 4)
Infliximab53%20%160% (70 to 298)3 (2 to 4)
Leflunomide46%20%136% (60 to 249)4 (3 to 6)

*ACR 20 = American College of Rheumatology ≥ 20% improvement in tender and swollen joints. Other abbreviations defined in Glossary.





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