The rationale for combination therapy of rheumatoid arthritis based on pathophysiology

Rheumatoid arthritis begins with activation of a few cells within joints. The initial process is most likely caused by presentation of an antigen or superantigen by specific HLA-DR glycoproteins to receptive lymphocytes, perhaps accompanied by retroviral activation of synoviocytes and macrophages. After this initial activation process, many different components of host immune, inflammatory, and proliferative responses are activated as well. These include: B cell proliferation, proteolytic enzyme biosynthesis, cytokine expression, activation of kinin, complement, clotting and fibrinolytic pathways, prostaglandin and leukotriene production generation of oxygen free radicals and nitric oxide, and proliferation of synoviocytes (pannocytes)/chondrocytes and their gene products. At some point after the initial stimulus, the rheumatoid synovitis may become self-sustaining, without a need for the initial inciting protein or virus. In consideration of the multiple activated pathways that become operational, it is appropriate to consider therapies that attack more than one pathway. This is the rationale for combination therapy. In practice it does not imply using 2 agents directed against the same pathway (e.g., 2 different nonsteroidal antiinflammatory drugs) but rather agents (e.g., methotrexate and cyclosporine) that have proven in vitro/in vivo to suppress different components of the immune/inflammatory/proliferative lesion. Thus, since many data suggest that irrevocable destruction of joints begins relatively early in the disease process, it is appropriate to begin substantial combination therapy early as well.