Treatment of rheumatoid arthritis in the 21st century: targeting B-lymphocytes

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent inflammation of synovial tissue. Although the initiating event of RA is still unknown, recent research has demonstrated the importance of the increased production of tumor necrosis factor (TNF) alpha in the perpetuation of the inflammatory process of this disease. Targeting this molecule with soluble receptors, i.e., etanercept, or antibodies, like infliximab or adalimumab, a new class of highly effective anti rheumatic drugs has been developed. Unfortunately, not all patients respond sufficiently to TNF blockade and some of the patients become unresponsive to TNF-blocking agents. Targeting B-lymphocytes in these patients has opened a new therapeutic window. It has been demonstrated that B-lymphocytes have an important impact in the pathophysiology of RA. These cells produce not only a variety of autoantibodies, but directly stimulate autoaggressive T lymphocytes in the synovium. Furthermore, B-lymphocytes produce a variety of proinflammatory cytokines that also activate monocytes and synoviocytes. Several placebo-controlled clinical trials have demonstrated the efficacy of B-lymphocyte-directed therapy in patients that have responded poorly to conventional disease-modifying drugs or TNF blockade. In addition, several other B-cell specific antigens are potential targets in different autoimmune diseases.