Modes of action of second-line agents.

The slow acting anti-rheumatic drugs (SARDS) are a chemically heterogeneous group. They produce a more profound effect on clinical and biochemical aspects of rheumatoid arthritis than do the aspirin-like non steroidals. The similarities in their clinical effects suggest that they have a common mode of action. Review of the known activity of SARDs on different cell types at various anatomical sites suggest that in fact different SARD drugs act in differing and sometimes conflicting ways. The site of action of SARDs within the body--whether at the level of synovial inflammation or of the systemic immune response--is largely undetermined. The effects produced by a single agent in vivo and in vitro are not always the same so a single mode of action, for example through possession of a thiol group, cannot explain the effects of all SARDs. Indeed a single agent such as aurothiomalate may show multiple effects and the same is now shown to be true for the newer agent sulphasalazine. A unifying hypothesis is put forward to explain the clinical similarities but different cellular effects. It is proposed that all SARDs act on some aspect of the central reaction in the ongoing immune response where antigen presentation to T helper cells results in interleukin 2 production and the generation of activated T cells. The precise site affected in this cell to cell/monokine reaction will vary between drugs, but the overall effect of blocking this will be similar for all drugs, both in short term clinical benefit and in the problem of disease flares after withdrawal of therapy.