Although the cause of rheumatoid arthritis remains elusive, the destructive features of the disease have been extensively documented and described. The following sections review each key element of disease pathogenesis. They include the infiltration of lymphocytes and macrophages into synovial tissue, hyperplasia of synovial cells, and the enhanced expression of multiple inflammatory mediators, such as cytokines and degradative enzymes.
FIGURE. Pathological changes in the joints of patients with rheumatoid arthritis.
Leukocyte Infiltration in the Joints. As depicted in the left side of (FIGURE. Pathological changes in the joints of patients with rheumatoid arthritis), the healthy joint consists of cartilage layered upon bone that is encased by the synovial membrane, or synovium. By contrast, in the joint of an rheumatoid arthritis patient (FIGURE. Pathological changes in the joints of patients with rheumatoid arthritis, right side), the tissue beneath the synovial lining becomes vascularized and infiltrated with T cells, B cells, and macrophages. Leukocytes also accumulate in the synovial fluid, leading to cartilage destruction and bone damage.
B cells present in the synovial fluid characteristically produce large quantities of immunoglobulin G (IgG) or IgM autoantibodies directed against the constant region of other IgG antibodies. These autoreactive antibodies are termed rheumatoid factors and form immune complexes that activate the complement cascade and phagocytic activity of macrophages. Both CD4+ and CD8+ (cytotoxic) T cells are present in the synovial fluid. Researchers note that the CD4+ subset appears to exist in an activated state, presumably owing to the abundance of IL-2 present in the synovial fluid, which also promotes the initiation of an immune response involving major histocompatibility complex (MHC) class II molecules.
Synovial Cell Hyperplasia and Tissue Destruction. Researchers believe that synovial tissue macrophages and proliferating fibroblasts are major contributors to cartilage and bone destruction because both cell populations produce degradative enzymes, such as matrix metalloproteinas. Synovial fibroblasts produce collagenase and cathepsins as well, and they demonstrate proliferative and invasive properties similar to those of transformed tumor cells.
Monocytes and macrophages may produce large quantities of pro-inflammatory cytokines, including tumor necrosis factor-alpha and IL-1β; IL-8, a potent stimulator of angiogenesis; and monocyte chemoattractant protein-1 (MCP-1). This overabundance of pro-inflammatory cytokines results in persistent inflammation. The clinical success of the tumor necrosis factor-alpha inhibitor etanercept (Amgen/Wyefh/Takeda’ s Enbrel) has resulted in an increased interest in the role of cytokines in rheumatoid arthritis. Table 1 lists some commonly detected cytokines in the synovial tissue and fluid of rheumatoid arthritis patients; TABLE.Select Cytokines Involved in the Pathogenesis of Rheumatoid Arthritis describes the pathophysiological effects of key cytokines. “Current Therapies” discusses the role of tumor necrosis factor-alpha in rheumatoid arthritis pathology.
Cytokines in Rheumatoid Arthritis
The rheumatoid arthritis synovium contains increased levels of cytokines, prominent among which are tumor necrosis factor-alpha and IL-1. Many other pro-inflammatory cytokines, including IL-6 and IL-18, are also present, as well as anti-inflammatory cytokines such as IL-10, IL-13, and transforming growth factor-beta (TGF-β), suggesting that an imbalance in favor of pro-inflammatory mediators may be a central pathogenic mechanism in rheumatoid arthritis.
An array of cytokines with pro-inflammatory activity in rheumatoid arthritis synovitis have been described that offer therapeutic potential, including IL-6, IL-12, IL-15, and IL-18. Research has demonstrated that the macrophage-produced cytokine IL-1β plays a dominant role in cartilage degradation and joint invasion by synovio-cytes. IL-1 receptor antagonist (IL-lra) expression correlates with the induction of IL-1β. Specifically, IL-lra neutralizes the ability of IL-1β to induce inflammation by binding to IL-1β receptors and inhibiting cellular activation. IL-10, a T helper (Th)2-type cytokine, also has anti-inflammatory properties; it suppresses synthesis of the pro-inflammatory Thl cytokines IL-1β and tumor necrosis factor-alpha. Elevated levels of IL-10 are detected in the synovial fluid of active rheumatoid arthritis patients, and two laboratories have reported that adenoviral transfer of the vlL-10 gene prevents arthritis development in animal models. The results of these studies suggest that IL-lra and IL-10 buffer the pro-inflammatory effects of tumor necrosis factor-alpha and IL-1/?.
IL-6, a pleiotropic cytokine, has a wide range of effects, including stimulating B cells to differentiate into plasma cells in order to produce immunoglobulin and stimulating T lymphocytes to differentiate into cytotoxic T cells. Serum IL-6 concentrations have been shown to correlate with disease activity in active rheumatoid arthritis. IL-12, and the more recently discovered IL-23 and IL-27, comprise a family of structurally related cytokines that regulate cell-mediated immune responses and Thl-type inflammatory reactions. Inhibition of IL-15 and IL-18 represent additional attractive approaches that could block Thl differentiation, inflammatory mediator production, or tumor necrosis factor-alpha expression. IL-15 is produced by endothelial cells and is a potent T-cell chemoattractant.
TABLE . Select Cytokines Detected in the Synovial Tissue of Patients with Rheumatoid Arthritis
|Cytokine||Primary Sources||Targets Activated||Degree ofAbundance in
|Degree of Effecton Inflammation
|TNF-α||Monocytes, macrophages||Macrophages, fibroblasts||High||High|
|IL-1β||Monocytes, macrophages||Fibroblasts, macrophages||High||High|
|IL-2||T lymphocytes||T lymphocytes, NK cells||Medium||Medium|
|IL-6||Monocytes, macrophages, fibroblasts||Lymphocytes||Medium||Medium|
|IL-10||Monocytes, macrophages, T lymphocytes||Lymphocytes||Medium||None|
|IL-15||Fibroblasts, monocytes, macrophages||Lymphocytes||Low||Medium|
|IL-18||T lymphocytes||Monocytes, macrophages, T lymphocytes, NK cells||Medium||Medium|
|IFN- y||T lymphocytes||NK cells||Low||Medium|
|TGF-β||Fibroblasts, monocytes, macrophages, T lymphocytes||Lymphocytes, fibroblasts||Medium||None|
|GM-CSF||: Monocytes, macrophages, T lymphocytes||Neutrophils, macrophages||Medium||Medium|
GM-CSF = Granulocyte-macrophage colony-stimulating factor; IFN = Interferon; IL = Interleukin; NK cell = Natural killer cell; TGF = Transforming growth factor; TNF = Tumor necrosis factor.
It also activates cell adhesion molecule expression on T cells. IL-17, produced by activated CD4+ T cells, is highly expressed in the diseased joint and stimulates formation of bone-resorbing osteoclasts. The pleiotropic cytokine IL-18 acts as a proinflammatory cytokine by inducing tumor necrosis factor-alpha, interferon-gamma (IFN-y), IL-8, IL-2, and prostaglandin production by macrophages and/or T cells, and elevated levels have been detected within the joints of rheumatoid arthritis patients.
Angiogenesis and Rheumatoid Arthritis
Angiogenesis occurs within the synovium early in the pathogenesis of rheumatoid arthritis. These new vessels support the growing synovial tissue, express chemokines that attract additional cells (including leukocytes), and provide an additional source of inflammatory mediators to the synovium. In 1998, researchers proposed that the rheumatoid synovium can be viewed as a rapidly dividing tumorlike structure, a view later endorsed by other researchers. Thus, inhibiting angiogenesis in rheumatoid arthritis may limit the influx of inflammatory cytokines and inhibit synovial proliferation.
TABLE . Select Cytokines Involved in the Pathogenesis of Rheumatoid Arthritis
|Mechanism||Cytokines||Role of Cytokine|
|Synovial tissue inflammation||IFN- y, IL-1β, TNF-α||Increased adherence of postcapillary venules|
|IL-8||Chemotaxis of T cells|
|IL-1β, IL-2, IL-6, TNF-α||T-cell activation and proliferation|
|IFN- y, IL-1β, IL-2, IL-6, TNF-α||B-cell differentiation and antibody formation|
|GM-CSF, IFN- y, TNF-α||Increased expression of HLA antigens|
|GM-CSF, IFN- y, IL-2||Macrophage activation|
|Synovial fluid inflammation||IFN- y, IL-1β, TNF-α||Increased adherence of postcapillary venules|
|IL-8, TNF-α||Chemotactic for PMN|
|GM-CSF, IL-8,TNF-α||Activation of PMN|
|Synovial proliferation||IL-1β,TGF-β||Fibroblast growth|
|Cartilage and bone damage||IL-1β, TNF-α||Activation of chondrocytes, fibroblasts, and osteoblasts/osteoclasts|
|Systemic manifestations||IL-1β,TNF-α||Fever, constitutional symptoms|
|IL-1β, IL-6, TNF-α||Acute-phase reactants|
GM-CSF = Granulocyte-macrophage colony-stimulating factor.
HLA = Human leukocyte antigen.
IFN = Interferon.
IL = Interleukin.
PMN = Polymorphonuclear leukocyte.
TGF = Transforming growth factor.
TNF = Tumor necrosis factor.