This figure summarizes the cellular interactions believed to be of importance in the pathogenesis of RA and describes the interaction among macrophages, T cells, B cells, and nonhematopoietic cells (fibroblasts, connective tissue cells, and bone). These interactions are facilitated by the actions of cytokines released from the activated cells that then, through both autocrine (feedback on same cell) and paracrine (via other cell types) mechanisms, induce the production of other proinflammatory cytokines, which together contribute to the pathogenesis of this disease. Based on ex vivo studies from diseased tissue and in vivo studies on animal models, those cytokines with pathogenic potential have been identified and biological therapies developed to block their action. This figure identifies those therapeutic modalities and the stage in clinical development that these interventions have reached. sIL-6R, soluble IL-6 receptor.

This figure illustrates the biological actions of TNF-α, which is produced mainly by activated macrophages in the inflamed synovial membrane tissue in patients with RA. The actions of TNF-α perceived to be important in the pathogenesis of RA include its ability to induce the production of other (equally) proinflammatory cytokines, including IL-1 and IL-6, together with its ability to induce the production and release of chemokines that attract leukocytes from the blood into the inflamed tissue. This process is facilitated by upregulation of key integrins and adhesion molecules, including E-selectin and VCAM-1, on endothelium. Finally, the destruction of the underlying articular cartilage and subchondral bone is initiated by the induction of proteolytic and metalloproteinase enzymes, which bring about the destruction of the underlying cartilage, and the initiation of osteoclast resorptive activity, which brings about the destruction of the subchondral bone. SDF-1, stromal cell–derived factor–1.