RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that may affect many tissues and organsskin, blood vessels, heart, lungs, and musclesbut principally attacks the joints, producing a nonsuppurative proliferative and inflammatory 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 afflicted by RA, women two to three times more often than men. It is most common in those age 40 to 70, but no age is immune. We first consider the morphology as a background to discuss pathogenesis. Morphology Joints. RA causes a broad spectrum of morphologic alterations; the most severe are manifested in the joints. Initially the synovium becomes grossly edematous, thickened, and hyperplastic, transforming its smooth contour to one covered by delicate and bulbous fronds ( Fig. 26-42 ). The characteristic histologic features include (1) infiltration of synovial stroma by dense perivascular inflammatory cells, consisting of B cells and CD4+ helper T cells (often forming lymphoid follicles), plasma cells, and macrophages; (2) increased vascularity owing to vasodilation and angiogenesis, with superficial hemosiderin deposits; (3) aggregation of organizing fibrin covering portions of the synovium and floating in the joint space as rice bodies; (4) accumulation of neutrophils in the synovial fluid and along the surface of synovium but usually not deep in the synovial stroma; (5) osteoclastic activity in underlying bone, allowing the synovium to penetrate into the bone forming juxta-articular erosions, subchondral cysts, and osteoporosis; and (6) pannus formationthe pannus is a mass of synovium and synovial stroma consisting of inflammatory cells, granulation tissue, and fibroblasts, which grows over the articular cartilage and causes its erosion. In time, after the cartilage has been destroyed, the pannus bridges the apposing bones, forming a fibrous ankylosis, which eventually ossifies, ultimately resulting in bony ankylosis. Inflammation in the tendons, ligaments, and occasionally the adjacent skeletal muscle frequently accompanies the arthritis. Pathogenesis. It is believed that RA is an autoimmune disease triggered by exposure of a genetically susceptible host to an unknown arthritogenic antigen. It is the continuing autoimmune reaction, with activation of CD4+ helper T cells and other lymphocytes, and the local release of inflammatory mediators and cytokines that ultimately destroys the joint[45][46] ( Fig. 26-44 ). Therefore, the key considerations in the pathogenesis of the disease are (1) the nature of the autoimmune reaction, (2) the mediators of tissue injury, (3) genetic susceptibility, and (4) the arthritogenic antigen(s). We discuss what is known about each of these. The autoimmune reaction in RA consists of activated CD4+ T cells, and probably B lymphocytes, as well. The target antigens of these lymphocytes, and how they are initially activated, are still unknown. The T cells apparently function mainly by stimulating other cells in the joint to produce cytokines that are central mediators of the synovial reaction (see below). Although the contribution of autoreactive B cells has been an issue of controversy, there is increasing evidence that immune complex deposition may also play some role in the joint destruction. Perhaps the major advances in our understanding of the disease have been a better appreciation of the actual mediators of joint injury. Cytokines are believed to play a pivotal role, and the most important of these cytokines are TNF and IL-1. Both are probably produced by macrophages and synovial lining cells that are activated by the T cells in the joint. TNF and IL-1, in turn, stimulate synovial cells to proliferate and produce various mediators of inflammation (such as prostaglandins), and matrix metalloproteinases that contribute to cartilage destruction. Activated T cells and synovial fibroblasts also produce RANKL, which activates osteoclasts and promotes bone destruction. Thus, a chain of events is set up that leads to progressive joint damage. The hyperplastic synovium rich in inflammatory cells becomes adherent to and grows

over the articular surface, forming a pannus, and stimulates resorption of the adjacent cartilage. In the end, the pannus produces sustained, irreversible cartilage destruction and erosion of subchondral bone.[47] The realization of the important roles of TNF and IL-1 is the basis for the successful use of anticytokine therapy, especially against TNF. Genetic susceptibility is a significant component of the development of RA.[48] There is a high rate of concordance between monozygotic twins and a well-defined familial predisposition. Multiple gene loci are believed to be responsible for susceptibility to the disease, but most of these have not been identified yet. One susceptibility gene that is known is in the class II HLA locus, and specifically a region of four amino acids loated in the antigen-binding cleft that is shared in the HLA DRB10401 and 0404 alleles. This HLA-DR allele may bind and display the arthritogenic antigen to T cells, although there is no formal evidence in support of this idea. The antigens that trigger autoimmunity and perpetuate the reaction are not known. There has been great interest in exploring microbial antigens as the initiating triggers, but no firm evidence has definitively identified a microbial organism as an etiologic agent in rheumatoid arthritis.[49]

The clinical course of RA is variable. The disease begins slowly and insidiously in more than half of patients. Initially, there is malaise, fatigue, and generalized musculoskeletal pain, after which the joints become clearly involved. Approximately 10% of patients have an acute onset with severe symptoms and polyarticular involvement developing more rapidly. The pattern of joint involvement varies, but generally the small joints are affected before the larger ones. Symptoms usually develop in the small bones of the hands (metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints) and feet (metatarsophalangeal (MTP) and interphalangeal (IP) joints) followed by the wrists, ankles, elbows, and knees. The cervical spine may also be involved, but the hips are usually involved only later in the disease, if at all, and the lumbosacral region is typically spared. The involved joints are swollen, warm, painful, and particularly stiff on arising or following inactivity. The disease course may be slow or rapid and fluctuates over a period of years, with the greatest damage occurring during the first 4 or 5 years. Approximately 20% of patients enjoy periods of partial or complete remission, but the symptoms inevitably return and can involve previously unaffected joints. The radiographic hallmarks are juxta-articular osteopenia and bone erosions with narrowing of the joint space from loss of articular cartilage ( Fig. 26-45 ). Destruction of tendons, ligaments, and joint capsules contribute to characteristic deformities, including radial deviation of the wrist, ulnar deviation of the fingers, and flexion-hyperextension abnormalities of the fingers (swan neck, boutonnire). The end result is deformed joints that have no stability and minimal or no range of motion. Large synovial cysts, such as the Baker cyst in the posterior knee, may develop as the increased intra-articular pressure causes outpouchings of the synovium.