BACKGROUND: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory arthritis that clinically manifests as joint pain, stiffness, and swelling. If left untreated, persistent synovial inflammation can progress to cartilage and bone destruction and ultimately to major long-term disability and mortality. Synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, leflunomide, and sulfasalazine, have markedly improved clinical symptoms and slowed joint damage in RA patients. However, despite the effectiveness of synthetic DMARDs, many patients who use them continue to have clinical symptoms of inflammation and progressive joint destruction. Recent advances in our understanding of the pathogenesis of RA have led to the identification of novel cellular and molecular therapeutic targets. Biologic agents aimed at these targets have provided some evidence of effectiveness that is transforming the management of RA.

OBJECTIVE: To inform health care providers about some of the recent advances in RA pathogenesis and innovative biologic therapies that have shown effectiveness in improving clinical outcomes and inhibiting radiographic progression.

SUMMARY: Although the specific trigger of the autoimmune response in RA is not known, pathogenesis is generally believed to be associated with the generation of autoantibodies through interactions of antigen-presenting cells with the adaptive immune system (CD4" + T cells and B cells). The main inflammatory mediators of joint inflammation and destruction in RA are tumor necrosis factor (TNF)-alpha, interleukin-1 (IL-1), IL-6, chemokines, and proteases. Advances in our understanding of the key cells and inflammatory cytokines have led to the development of targeted biologic agents. As of 2011, 5 TNF-alpha inhibitors are approved for use by the FDA: infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol. In randomized clinical trials, all of these agents have been shown to be effective in reducing clinical signs of inflammation in RA patients who have failed synthetic DMARDs. Multiple studies have demonstrated significant benefits of early treatment with TNF-alpha inhibitors combined with methotrexate. Other FDA-approved biologic agents for treating moderate-to-severe RA include abatacept, rituximab, and tocilizumab. All biologic agents carry an increased risk of infections. Additional potential side effects include infusion and injection site reactions for intravenous and subcutaneously administered agents, respectively. All patients being considered for biologic agents should be screened annually for tuberculosis and should receive pneumococcal, influenza, and hepatitis B vaccinations.