MECHANISMS OF DISEASE Mechanisms of Disease of cell-mediated immune responses. In genetic studies, rheumatoid arthritis is strongly linked to the major- histocompatibility-complex class II antigens HLA- F RANKLIN H. EPSTEIN, M.D., Editor DRB1*0404 and DRB1*0401.5 The main function of HLA class II molecules is to present antigenic pep- CYTOKINE PATHWAYS AND JOINT tides to CD4+ T cells, which strongly suggests that rheumatoid arthritis is caused by an unidentified ar- INFLAMMATION IN RHEUMATOID thritogenic antigen.6 The antigen could be either an ARTHRITIS exogenous antigen, such as a viral protein, or an en- dogenous protein. Recently, a number of possible ERNEST H.S. CHOY, M.D., endogenous antigens, including citrullinated protein, AND GABRIEL S. PANAYI, M.D., SC.D. human cartilage glycoprotein 39, and heavy-chain– binding protein, have been identified.7 HEUMATOID arthritis is a common chron- Cellular Mediators of Inflammation and Joint Damage ic inflammatory and destructive arthropathy that cannot be cured and that has substantial Antigen-activated CD4+ T cells stimulate mono- R cytes, macrophages, and synovial fibroblasts to pro- personal, social, and economic costs. The long-term prognosis is poor: 80 percent of affected patients are duce the cytokines interleukin-1, interleukin-6, and a disabled after 20 years,1 and life expectancy is reduced TNF- and to secrete matrix metalloproteinases (Fig. 2 1) through cell-surface signaling by means of CD69 by an average of 3 to 18 years. The medical cost of 8 rheumatoid arthritis averages $5,919 per case per year and CD11 as well as through the release of soluble g in the United States3 and approximately £2,600 per mediators such as interferon- and interleukin-17. In- a case per year in the United Kingdom.4 Current slow- terleukin-1, interleukin-6, and TNF- are the key cy- acting antirheumatic drugs have limited efficacy and tokines that drive inflammation in rheumatoid arthri- many side effects. Moreover, they do not improve the tis. Activated CD4+ T cells also stimulate B cells (Fig. long-term prognosis of rheumatoid arthritis.1 1), through cell-surface contact and through the bind- ing of a b integrin, CD154 (CD40 ligand), and The inflammatory process is usually tightly regulat- L 2 ed, involving both mediators that initiate and maintain CD28, to produce immunoglobulins, including rheu- inflammation and mediators that shut the process matoid factor. The precise pathogenic role of rheuma- down. In states of chronic inflammation, an imbalance toid factor is unknown, but it may involve the activa- between the two mediators leaves inflammation un- tion of complement through the formation of immune checked, resulting in cellular damage. In the case of complexes. Activated CD4+ T cells express osteopro- rheumatoid arthritis, this damage is manifested by the tegerin ligands that stimulate osteoclastogenesis (Fig. 1). Such activated T cells caused joint damage in an destruction of cartilage and bone. 9 Efforts to develop safer and more effective treat- animal model of rheumatoid arthritis. ments for rheumatoid arthritis that are based on an These activated macrophages, lymphocytes, and fi- improved understanding of the role of inflammatory broblasts, as well as their products, can also stimulate mediators are beginning to bear fruit. Treatments angiogenesis, which may explain the increased vascu- such as etanercept, a soluble tumor necrosis factor a larity found in the synovium of patients with rheu- (TNF-a) type II receptor–IgG1 fusion protein, and matoid arthritis. Endothelial cells in the synovium are infliximab, a chimeric (human and mouse) monoclon- activated and express adhesion molecules that promote al antibody against TNF-a, have been approved by the the recruitment of inflammatory cells into the joint. Food and Drug Administration and the European This process is enhanced by the release of chemokines, Medicine Evaluation Agency for rheumatoid arthritis. such as interleukin-8, by inflammatory cells in the These therapies could dramatically change the treat- joint. The detailed mechanisms of these complex cel- ment and outcome of the disease. lular interactions remain elusive. Soluble Mediators of Inflammation and Joint Damage PATHOGENESIS OF RHEUMATOID ARTHRITIS Monocytes, macrophages, fibroblasts, and T cells The synovial membrane in patients with rheumatoid release numerous cytokines on stimulation. Most of arthritis is characterized by hyperplasia, increased vas- these cytokines, including TNF-a and interleukin-1, can be detected in synovial fluid from patients with cularity, and an infiltrate of inflammatory cells, pri- 10 marily CD4+ T cells, which are the main orchestrator rheumatoid arthritis. Both TNF-a and interleukin-1 are likely to have primary roles in the pathogenesis of rheumatoid arthritis. The serum and synovial concen- From the Department of Rheumatology, Guy’s, King’s, and St. Thomas’ trations of both cytokines are high in patients with ac- Hospitals School of Medicine, King’s College, London. Address reprint re- 11,12 quests to Dr. Choy at the Department of Rheumatology, King’s College tive rheumatoid arthritis. Furthermore, TNF-a and Hospital, East Dulwich Grove, London SE22 8PT, United Kingdom. interleukin-1 are potent stimulators of mesenchymal N Engl J Med, Vol. 344, No. 12 · March 22, 2001 · www.nejm.org · 907 The New England Journal of Medicine Rheumatoid factor and other autoantibodies Interleukin-4 Interleukin-4 Interleukin-10 Th2 Interleukin-6 Interleukin-10 Macrophage Plasma cell Th0 Interferon-g g Interleukin-12 Interferon- B cell CD4+ T cell CD11 OPGL CD69 TNF-a, CD11 CD69 interleukin-1, Synovium and interleukin-6 Chondrocyte Osteoclast Fibroblast Production of metalloproteinases and other effector molecules Migration of polymorphonuclear cells Erosion of bone and cartilage Figure 1. Cytokine Signaling Pathways Involved in Inflammatory Arthritis. The major cell types and cytokine pathways believed to be involved in joint destruction mediated by TNF- a and interleukin-1 are shown. Th2 denotes type 2 helper T cell, Th0 precursor of type 1 and type 2 helper T cells, and OPGL osteoprotegerin ligand. cells, such as synovial fibroblasts, osteoclasts, and chon- the development of osteoclasts, which are responsible drocytes, that release tissue-destroying matrix metallo- for bone degradation.14 proteinases.13 Interleukin-1 and TNF-a also inhibit the production of tissue inhibitors of metalloprotein- TNF-a ases by synovial fibroblasts.13 These dual actions are TNF-a is a potent cytokine that exerts diverse ef- thought to lead to joint damage. Perhaps by inducing fects by stimulating a variety of cells. It is a soluble the production of interleukin-11, TNF-a stimulates 17-kd protein composed of three identical subunits. 908 · N Engl J Med, Vol. 344, No. 12 · March 22, 2001 · www.nejm.org MECHANISMS OF DISEASE It is produced mainly by monocytes and macrophages, ceptor is found in low numbers on many cells, where- but also by B cells, T cells, and fibroblasts. Newly syn- as the type II receptor is expressed primarily on neu- thesized TNF-a is inserted into the cell membrane trophils, monocytes, and B cells.30 Soluble forms of and subsequently released through the cleavage of its both types of interleukin-1 receptor compete with cell- membrane-anchoring domain by a serine metallopro- surface receptors, thereby decreasing interleukin-1– teinase.15 Thus, TNF-a secretion might be suppressed mediated activation of cells. In addition, a naturally by inhibitors of this enzyme.16 occurring antagonist, interleukin-1–receptor antago- Perhaps the best-studied aspect of TNF-a is its nist, binds the type I receptor with high affinity with- ability to promote inflammation. TNF-a is an auto- out triggering a signal, thus providing another mech- crine stimulator as well as a potent paracrine inducer anism for the inhibition of interleukin-1 activity.31 The of other inflammatory cytokines, including interleu- biologic activity of interleukin-1 is dependent on the kin-1, interleukin-6, interleukin-8, and granulocyte– precise quantities of many interacting molecules. monocyte colony-stimulating factor.17-19 TNF-a also Studies of arthritis in animals have strongly implicat- promotes inflammation by stimulating fibroblasts to ed interleukin-1 in joint damage. Injection of inter- express adhesion molecules, such as intercellular ad- leukin-1 into the knee joints of rabbits results in the hesion molecule 1.20 These adhesion molecules inter- degradation of cartilage,32 whereas the injection of act with their respective ligands on the surface of leu- antibodies against interleukin-1 ameliorates collagen- kocytes, resulting in increased transport of leukocytes induced arthritis in mice and decreases the damage into inflammatory sites, including the joints in patients to cartilage.33 Macrophages in the synovial tissue of pa- with rheumatoid arthritis. tients with rheumatoid arthritis appear to be an impor- TNF-a indirectly down-regulates inflammation by tant source of interleukin-1.34 Like TNF-a, interleu- stimulating the release of corticotropin from the pi- kin-1 may cause damage by stimulating the release of tuitary.21 This hormone stimulates the adrenal cortex matrix metalloproteinases from fibroblasts and chon- to release cortisol, which inhibits inflammation. drocytes.13,35 The concentrations of interleukin-1– As an inflammatory cytokine, TNF-a has an im- receptor antagonist are high in the synovial fluid of pa- portant — perhaps dominant — role in rheumatoid tients with