Emerging Biologic Therapies in Rheumatoid Arthritis
Purpose of Review: Biologic therapy for rheumatoid arthritis targets specific molecules, both cell-bound and soluble, that mediate and sustain the clinical manifestations of this complex disease. The aim of all the therapeutic strategies is to achieve complete and sustained suppression of inflammation, in the absence of unacceptable short-term and long-term toxicity. Despite the success of the currently available biologic inhibitors of tumor necrosis factor-a and interleukin-1, a substantial number of rheumatoid arthritis patients are refractory to these treatments. The purpose of this review is to highlight recent clinical trials of emerging biologic treatments for rheumatoid arthritis.
Recent Findings: T cell co-stimulation has been targeted by the use of cytotoxic T lymphocyte-associated antigen 4-Ig, a genetically engineered fusion protein. In a large controlled clinical trial, this nondepleting approach was shown to achieve impressive clinical responses, without evidence of short-term toxicity. Likewise, rituximab, a B cell-deleting monoclonal antibody, was shown in a controlled clinical trial to have sustained benefit in patients with refractory rheumatoid arthritis. Despite profound B cell depletion with rituximab, there was an acceptable safety profile with this treatment. MRA, a monoclonal antibody that inhibits interleukin-6 by binding to its receptor interleukin-6R, demonstrated clinically significant improvement in rheumatoid arthritis and a particularly impressive reduction in the acute phase response.
Summary: The response of rheumatoid arthritis to a wide spectrum of therapeutic strategies attests to the complexity and heterogeneity of the disease and provides further impetus for studies that use these therapies to enhance our understanding of disease pathogenesis.

The pathogenesis of rheumatoid arthritis (RA) remains incompletely understood. It involves complex interactions between T and B lymphocytes, macrophages, and fibroblast-like synoviocytes, involving a network of cytokines acting in an autocrine and paracrine manner. In recent years, the development of biologic agents that target specific soluble or membrane-bound molecules has revolutionized the treatment of RA. The success of tumor necrosis factor-α (TNF-α) inhibition, and to a lesser extent interleukin (IL)-1 inhibition, has firmly established these therapies in the clinical management of RA. Moreover, this approach has allowed unprecedented opportunities for developing a better understanding of the pathogenesis of this complex and heterogeneous disease. Despite the success particularly of the TNF-α inhibitors, data from both clinical trials and real-life clinical experience have clearly suggested that a substantial proportion of RA patients either do not respond, or lose their initial responses, to these agents. Thus, there continues to be a compelling need for the development of new therapeutic strategies. This review highlights recent research activity in the clinical development of novel biologic therapies for RA, focusing on therapies that target specific immune cells, and therapies that target cytokines.