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 arthri tis (RA). They suppress inflammation and ameliorate symptoms but often fail to substantially improve long-term disease outcome. Their use in RA was di scovered serendipitously and their modes of action were largely unknown. Re cent researches have identified some of their mechanisms of action. Most of them have antiinflammatory properties and some ape immunomodulators. Tradi tionally, second-line agents are used as monotherapy, but recent evidence s uggests that combination treatment with two or more drugs may be more effic acious. However, the choice of agents in combination therapy is not based o n their mechanisms of action. We review current knowledge on the modes of a ction of second-line agents and assess whether such understanding may offer a rational basis for combination therapy.