Pathophysiology of RA

Rheumatoid factors (RFs) usually consist of two classes of immunoglobulin antibodies -- antibodies for IgM and IgG (occasionally IgA). Their main targets are portions of the immunoglobulin molecule. RFs bind with their target self-antigens in the blood and synovial membrane, forming immune complexes (antigen-antibody). Synovial inflammation (synovitis) occurs when the immune complexes in blood and synovial tissue trigger the inflammatory response by activating the plasma protein complement. This stimulation activates kinin and prostaglandin release that increases the permeability of blood vessels in the synovial membranes. This attracts several types of leukocytes and lymphocytes to the synovial membrane out of the circulation.

The phagocytes of inflammation (neutrophils and macrophages) ingest the immune complexes which releases powerful enzymes that degrade synovial tissue and articular cartilage. The immune system's B and T lymphocytes are also activated. The B lymphocytes are stimulated into producing more RFs, and the T lymphocytes produce enzymes that increase the inflammatory response. A microorganism, which may originally be responsible, can be killed off and removed from the body. However, in an autoimmune response, the newly targeted self-antigens (immunoglobulins) are in constant supply and unable to stop. They keep on perpetuating the formation of immune complexes indefinitely.

Inflammatory and immune processes have several damaging effects on the synovial membrane. Inflammation causes hemorrhage, coagulation, and fibrin deposits on the synovial membrane, in the intracellular matrix, and in the synovial fluid. Over denuded areas of the synovial membrane, fibrin develops into granualtion tissue called pannus, which is the earliest tissue produced in the healing process. Researchers disagree about whether pannus is a cause or an effect of articular cartilage involvement in RA. Some believe that, as the disease progresses, pannus extends from the synovial membrane into adjacent articular cartilage and destroys the cartilage. Others think that pannus forms on articular cartilage after the cartilage has been destroyed by inflammation. In any case, pannus formation does not lead to synovial or articular regeneration, but rather to formation of scar tissue that immobilizes the joint.

Along with the swelling caused by leukocyte infiltration, the synovial membrane undergoes hyperplastic thickening as its cells abnormally proliferate and enlarge. As synovial inflammation progresses to involve its blood vessels, small venules (a tiny vessel that collects blood from the capillaries and joins to form veins) become occluded by hypertrophied endothelial cells, fibrin, platelets, and inflammatory cells. These vascular derangements decrease blood flow to the synovial tissue and compromised circulation. This, coupled with increased metabolic needs due to hypertrophy and hyperplasia, causes hypoxia (oxygen depletion) and metabolic acidosis. Acidosis stimulates the release of hydrolytic enzymes from synovial cells into the surrounding tissue, initiating erosion of the articular cartilage and inflammation spreads into the supporting ligaments and tendons.