The efficacy and toxicity of combination therapy in rheumatoid arthritis. A meta-analysis

Arthritis Rheum. 1994 Oct;37(10):1487-91. doi: 10.1002/art.1780371012.


Objective: To evaluate the efficacy and toxicity of combination therapy, compared with single second-line drug therapy, in rheumatoid arthritis.

Methods: This study was a meta-analysis of published trials that evaluated combinations of full-dose second-line drugs and compared them with single second-line drugs at full dose. Using a random effects model, we summarized the difference between improvement with combination therapy and improvement with single-drug therapy.

Results: Five trials that met inclusion criteria, which contained 749 entering patients and 516 completing patients, were identified. The mean +/- SEM difference in improvement in tender joint count between combination and single-drug therapy at end of trial (24-52 weeks) was 2.4 +/- 0.7 joints (out of 60) (P < 0.001). At end of trial the difference between therapies in swollen joint counts was 1.0 +/- 1.2 joints (P = 0.42). The difference in grip strength improvement was 3.7 +/- 4.3 mm Hg (P = 0.40), and for erythrocyte sedimentation rate it was 3.4 +/- 3.1 mm/hour (P = 0.27). In general, the differences in efficacy between combination and single-drug therapy were clinically marginal. Nine percent more combination therapy-treated patients experienced side effect-related discontinuation of therapy than patients receiving single-drug therapy (P = 0.008).

Conclusion: Combination therapy, as it has been used in recent clinical trials, does not offer a substantial improvement in efficacy, but does have higher toxicity than single drug therapy. These combination therapy regimens are not recommended for widespread use. Other more aggressive regimens with additional drugs or higher drug doses than have been studied might be more efficacious, but with an even higher rate of toxicity.

Publication types

  • Meta-Analysis
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antirheumatic Agents / adverse effects
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / complications
  • Arthritis, Rheumatoid / drug therapy*
  • Clinical Trials as Topic
  • Drug Therapy, Combination*
  • Humans
  • Severity of Illness Index
  • Treatment Outcome


  • Antirheumatic Agents