Early developments in combination therapy

The concept of combination therapy implies the concurrent use of two or more slow-acting antirheumatic drugs to treat rheumatoid arthritis. This review places such combination therapy into an historical context and evaluates studies carried out before 1990. There were no published studies before 1980 of combination therapy, and between 1980 and 1990 there were 11 published studies. Three were conventional randomised controlled trials, three were non-randomised studies of parallel group design, four were observational open studies, and one was a retrospective review. Altogether 486 patients were studied with the numbers of cases in each study varying between 12 and 101. The main combinations used were penicillamine + hydroxychloroquine or chloroquine, gold + hydroxychloroquine, and sulphasalzine + penicillamine. Six studies concluded that combination therapy helped patients, three suggested possible benefits, and two gave essentially negative findings. These two negative studies were randomised controlled trials. Most studies indicated an increase in adverse events with combination therapy. The average erythrocyte sedimentation rate on combination therapy fell by 21.4%. A majority of patients remained on the therapy for 6-12 months. The balance of evidence in 1990 suggested that combination therapy had a modest advantage. However, the trials were too small to detect its true value, and the combinations used were not ideal. In particular, combining gold or penicillamine with other drugs appeared to give too much toxicity. The future development of the field would depend on identifying more effective combinations of drugs and undertaking larger and better-designed trials.