Targeting Complement in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarticular synovitis leading to cartilage, tendon and bone destruction, and pain and dysfunction of the joints. It is considered to be an immune-mediated inflammatory disorder, in which the complement system also plays a fundamental role. In the circulation of RA patients, increased levels of complement activation products have been found, often correlating with disease activity. In synovial fluid of the patients, decreased levels of native complement components and increased levels of activation products have been detected. Furthermore, in synovial tissue and cartilage, deposition of activated complement components has been demonstrated. As activators of the complement system in RA, immune complexes, C-reactive protein, and certain immunoglobulin G glycoforms have been identified. A role for complement activation in the pathogenesis of this disease is supported by studies showing an association between complement activation and inflammatory responses in the diseased joints or in individual cell types found in RA joints, and by extensive studies on animal models of the disease, utilizing for example animals deficient for certain complement components. Finally, several agents are under development to therapeutically influence the complement system, and some have already been tested in clinical trials of RA.