Small-molecule therapeutics in rheumatoid arthritis: scientific rationale, efficacy and safety

Rheumatoid arthritis (RA) remains a formidable clinical challenge. This is despite remarkable recent advances in our understanding of pathogenesis and the introduction of a variety of novel agents, particularly biologic therapeutics that are potent inhibitors of extracellular immune pathways. Whereas the latter have brought substantial improvements in efficacy and thus outcomes, there remain significant numbers of non- or partial responders to current standard of care. The discovery of key intracellular pathways, particularly kinases that subserve the function of these pivotal cytokine and immune cell receptors implicated in RA pathogenesis, has facilitated the advent of a new phase of RA drug development. Thus, a range of kinase inhibitors has entered clinical trials and one agent has been licenced for use in some regions. Herein we summarise the chequered history of kinase inhibitor development in RA, describing successes and failures alike, and thereafter examine future trends in this exciting field.