Mechanisms of action of second-line agents and choice of drugs in combination therapy.

Second-line agents are used commonly for the treatment of rheumatoid arthritis (RA). They suppress inflammation and ameliorate symptoms but often fail to substantially improve long-term disease outcome. Their use in RA was discovered serendipitously and their modes of action were largely unknown. Recent researches have identified some of their mechanisms of action. Most of them have antiinflammatory properties and some are immunomodulators. Traditionally, second-line agents are used as monotherapy, but recent evidence suggests that combination treatment with two or more drugs may be more efficacious. However, the choice of agents in combination therapy is not based on their mechanisms of action. We review current knowledge on the modes of action of second-line agents and assess whether such understanding may offer a rational basis for combination therapy.