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The currently available biological DMARDs work by targeting downstream inflammatory cytokines, which are produced by a number of immune cells in response to stimulation by CD4+ T cells. Several large, randomized, controlled trials demonstrate that these agents have resulted in significant progress toward the alleviation of symptoms, the slowing of disease progression, and the restoration of function in many patients with RA. Evidence continues to suggest the long-term utility of these agents in both early and longstanding disease, particularly when used in combination with background DMARDs, such as MTX. They are not effective or well tolerated in all patients. Treatment strategies that target earlier steps in the inflammatory cascade may provide valuable alternatives to these therapies.