Rheumatoid arthritis is a chronic systemic inflammatory disorder that may affect many tissues and organs-skin,blood vessels, heart, lungs and muscles- but principally attacks the joints, producing a nonsuppurative proliferative synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints. Although the cause of RA remains unknown, autoimmunity plays a pivotal role in its chronicity and progression.



About 1% of the world's population is affected by RA, women three to five times more often than men. The peak incidence is in the twenties and forties, but no age is immune. We first consider the morphology as a back ground to discuss pathogenesis.

Although much remains uncertain, it is currently believed that RA is triggered by exposure of an immunogenetically susceptible host to an arthritogenic microbial antigen. In this manner, an acute is intiated but it is the continuing autoimmune reaction, the activation of CD4+ helper T cells and the local release of inflammatory mediators and cytokines that ultimately destroys the joint.

Genetic susceptibility is clearly a major determinant of susceptibility to RA. There is a high rate of concordance between monozgotic twins and a well defined familial predisposition. More importantly the majority of individuals who develop RA are HLA-DRA4 or DR1 or both, and 75% of patients with RA in the United States and Europe have the motif O(K/R)RA in the antigen binding BRB1-HV3 region of the T-cell antigen receptor. All the DR alleles associated with susceptibility to RA share a common region of four amino acids located in the antigen-binding cleft of the DR molecular adjacent to the T-cell receptor. This location is presumably the specific binding site of the arthritogen that initiates the inflammatory synovitis.

Microbial agents

It is thought that the initiator of the disease is a microbial agent. But its identity continues to be elusive. Epstein-Barr virus is a current suspect, but closely following are retrovirus, parvoviruses myco bacteria, Borrelia, and mycoplasma as well as numerous others. For each tentative support is offered but the evidence implicating Epstein-Barr virus is particularly intriguing. Autoimmunity to type 2 collagen can bedemonstrated in most patients with RA. The epistein barr virus and type collagen have some homologous HLA-dr? chain epitopes and conceivably an immunologic reaction against the Epstein-Barr virus might cross over to affect joint cartilage rich in type collagen.

Autoimmunity

Once an inflammatory synovitis has been initiated by an exogenous agent an autoimmune reaction in which T cells play the piotal role is resposible for the chronic destructive nature of RA. The antigen inducing this reaction has not been identified with certainity. The possible role of type 2 collogen was mentioned earlier, but there is additional evidence suggesting that human cartilage glycoprotein-39 is an autoantigen. This protein is a product of hyaline cartilage chondrocytes and has been shown to bind to DR4 peptides thereby making it a potential target of the T cell regulated immune reaction. Regardless, T cells mainly CD4+ memory cells appear within the affected joints early in the development of RA. Soon the endothelial cells of synovial capillaries are activated with the expression of intercellular adhesion molecule-1 leaqding to further attachment and transmigration of other inflammatory cells including CD4 and T cells. This sequence is further enhanced by release of cytokines by inflammatory cells and the sequence is cell/cytokine loops. Leading to chronic immunologic injury. In RA, a role for IL-15 secreted by activated T cells and macrophages seems prominent.

ActivatedCD4 cells simultaneously activate B cells resulting in antibody production in affected joints. About 80% of individuals with RA have autoantibodies to the Fc protion of autologous IgG. These are mostly IgM antibodies, perhaps generated within joints, but may be of other classes. These self associate to form immune complexes in the sera, synovial fluid and synovial membranes. ?The circulating immune complexes underlie manyu of the extra articular manifestations of RA. They are localized within the inflamed cartilage, activating complement, augmenting the synovial inflammatory reaction and contributing to the degradation of cartilage. Rhemautoid factor, however, is not present in some patients with the disease, is sometimes found in other disease states and even in otherwise healthy people and is probably not critical to the causation of RA.

The clinical course of RA is extremely variable. The disease begines slowly and insidiously in more than half of patients, Initially there is malaise fatigue and generalized musculoskeletal pain and only after several weeks to months do the joints become involved. The patern of joint involvement varies, but generally the small joints are affected before the larger ones. Symptoms ususlly develop in the small bones of the hands and feet followed by the wrists, ankles, elbows, and knees. Uncommanly the uppore spine is involved and lumbosacral region and hips are usually spread.

The involved joints are swollen, warm, painful, and particularly stiff on arising or following inactivity. Approximately 10% of patients have an acute onset with severe symptoms and polyarticular involvement developing within a few days.In the typical patient, progressive joint involvement occurs over a period of months to years with initial minimal limitation of motion that in time becomes more severe. The disease course may be slow or rapid and fluctuate overf a period of years, with the greatest damage occuring during the first 4 or 5 years. Approximately 20% of patients enjoy periods of partial or complete remission but the symptoms inevitably return and involve previously unaffected joints