Molecular differences in anticytokine therapies.

Biologic agents that inhibit proinflammatory cytokines have made a profound impact on the treatment of rheumatoid arthritis (RA). Of the agents that are currently approved by the US Food and Drug Administration (FDA) for this indication, etanercept and infliximab neutralize tumor necrosis factor (TNF), and anakinra inhibits interleukin-1 (IL-1). Adalimumab, which was just recently approved by the FDA, is also a TNF inhibitor. Despite their common ability to inhibit cytokine bioactivity, the molecular structures and mechanisms of action of these biologic agents are significantly different. The TNF-binding moiety of etanercept is derived from soluble TNF receptor subunits. Infliximab is a chimeric (mouse-human) monoclonal antibody to TNF, while adalimumab is a fully human anti-TNF monoclonal antibody. Anakinra has yet another mechanism of action: it is an IL-1 receptor antagonist. The molecular characteristics of these agents may be relevant to clinical efficacy and safety. These agents are still relatively new: to date, the longest reporting time is 5 years, for etanercept. Additional long-term data will be required to determine the relative benefits and drawbacks of different molecular characteristics in these anticytokine agents.