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Evolving concepts of rheumatoid arthritis

Nature volume 423, pages 356–361 (2003)Cite this article

Abstract

Rheumatoid arthritis is the most common inflammatory arthritis and is a major cause of disability. It existed in early Native American populations several thousand years ago but might not have appeared in Europe until the 17th century. Early theories on the pathogenesis of rheumatoid arthritis focused on autoantibodies and immune complexes. T-cell-mediated antigen-specific responses, T-cell-independent cytokine networks, and aggressive tumour-like behaviour of rheumatoid synovium have also been implicated. More recently, the contribution of autoantibodies has returned to the forefront. Based on the pathogenic mechanisms, specific therapeutic interventions can be designed to suppress synovial inflammation and joint destruction in rheumatoid arthritis.

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Figure 1: Synovial histology in rheumatoid arthritis.
Figure 2: Cytokine networks in rheumatoid arthritis.
Figure 3: A proposed model implicating multiple pathogenic mechanisms in RA.

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References

  1. Franklin, E. C., Molman, H. R., Muller-Eberhard, H. J. & Kunkel, H. B. An unusual protein component of high molecular weight in the serum of certain patients with rheumatoid arthritis. J. Exp. Med. 105, 425–435 (1957).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zvaifler, N. J. The immunopathology of joint inflammation in rheumatoid arthritis. Adv. Immunol. 16, 265–336 (1973).

    Article  CAS  PubMed  Google Scholar 

  3. Neumann, E. et al. Local production of complement proteins in rheumatoid arthritis synovium. Arthritis Rheum. 46, 934–945 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Ruddy, S. & Austen, K. F. Activation of the complement and properdin systems in rheumatoid arthritis. Ann. NY Acad. Sci. 256, 96–104 (1975).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Stastny, P. Mixed lymphocyte cultures in rheumatoid arthritis. J. Clin. Invest. 57, 1148–1157 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nepom, G. T. et al. HLA genes associated with rheumatoid arthritis: identification of susceptibility alleles using specific oligonucleotide probes. Arthritis Rheum. 32, 15–21 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Weyand, C. M., Hicok, K. C., Conn, D. L. & Goronzy, J. J. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann. Intern. Med. 117, 801–803 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Stern, L. J. et al. Structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 368, 215–221 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Kirschmann, D. A. et al. Naturally processed peptides from rheumatoid arthritis and non-associated HLA-DR alleles. J. Immunol. 155, 5655–5662 (1995).

    CAS  PubMed  Google Scholar 

  10. Fox, D. A. The role of T cells in the immunopathogenesis of rheumatoid arthritis: new perspectives. Arthritis Rheum. 40, 598–609 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Verheijden, G. F. et al. Human cartilage glycoprotein-39 as a candidate autoantigen in rheumatoid arthritis. Arthritis Rheum. 40, 1115–1125 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Li, N. L. et al. Isolation and characteristics of autoreactive T cells specific to aggrecan G1 domain from rheumatoid arthritis patients. Cell Res. 10, 39–49 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Oda, A. et al. Antibodies to 65Kd heat-shock protein were elevated in rheumatoid arthritis. Clin. Rheumatol. 13, 261–264 (1994).

    CAS  PubMed  Google Scholar 

  14. Rowley, M., Tai, B., Mackay, I. R., Cunningham, T. & Phillips, B. Collagen antibodies in rheumatoid arthritis. Significance of antibodies to denatured collagen and their association with HLA-DR4. Arthritis Rheum. 29, 174–184 (1986).

    Article  CAS  PubMed  Google Scholar 

  15. Courtenay, J. S., Dallman, M. J., Dayan, A. D., Martin, A. & Mosedale, B. Immunisation against heterologous type II collagen induces arthritis in mice. Nature 283, 666–668 (1980).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Firestein, G. S., Alvaro-Gracia, J. M. & Maki, R. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J. Immunol. 144, 3347–3353 (1990).

    CAS  PubMed  Google Scholar 

  17. Smeets, T. J. et al. Poor expression of T cell-derived cytokines and activation and proliferation markers in early rheumatoid synovial tissue. Clin. Immunol. Immunopathol. 88, 84–90 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Williams, R. O., Mason, L. J., Feldmann, M. & Maini, R. N. Synergy between anti-CD4 and anti-tumor necrosis factor in the amelioration of established collagen-induced arthritis. Proc. Natl Acad. Sci. USA 91, 2762–2766 (1994).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shouda, T. et al. Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J. Clin. Invest. 108, 1781–1788 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Firestein, G. S. & Zvaifler, N. J. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 33, 768–773 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Feldmann, M. & Maini, R. N. Anti-TNFα therapy of rheumatoid arthritis: what have we learned? Annu. Rev. Immunol. 19, 163–196 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Gracie, J. A. et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J. Clin. Invest. 104, 1393–1401 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Qin, S. et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J. Clin. Invest. 101, 746–754 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chabaud, M., Fossiez, F., Taupin, J. L. & Miossec, P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J. Immunol. 161, 409–414 (1998).

    CAS  PubMed  Google Scholar 

  25. Burger, D. et al. Imbalance between interstitial collagenase and tissue inhibitor of metalloproteinases 1 in synoviocytes and fibroblasts upon direct contact with stimulated T lymphocytes: involvement of membrane-associated cytokines. Arthritis Rheum. 41, 1748–1759 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Lipsky, P. E. et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N. Engl. J. Med. 343, 1594–1602 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Redlich, K. et al. Osteoclasts are essential for TNF-α-mediated joint destruction. J. Clin. Invest. 110, 1419–1427 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lubberts, E. et al. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-κB ligand/osteoprotegerin balance. J. Immunol. 170, 2655–2662 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Ziolkowska, M. et al. High levels of osteoprotegerin and soluble receptor activator of nuclear factor κB ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor α treatment. Arthritis Rheum. 46, 1744–1753 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Kong, Y. Y. et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304–309 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  31. Pettit, A. R. et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am. J. Pathol. 159, 1689–1699 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Han, Z., Boyle, D. L., Manning, A. M. & Firestein, G. S. AP-1 and NF-κB regulation in rheumatoid arthritis and murine collagen-induced arthritis. Autoimmunity 28, 197–208 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Aupperle, K. et al. NF-κB regulation by IκB kinase-2 in rheumatoid arthritis synoviocytes. J. Immunol. 166, 2705–2711 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Tak, P. P. et al. Inhibitor of nuclear factor κB kinase β is a key regulator of synovial inflammation. Arthritis Rheum. 44, 1897–1907 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Miagkov, A. V. et al. NF-κB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc. Natl Acad. Sci. USA 95, 13859–13864 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schett, G. et al. Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthritis Rheum. 43, 2501–2512 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Badger, A. M. et al. Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J. Pharmacol. Exp. Ther. 279, 1453–1461 (1996).

    CAS  PubMed  Google Scholar 

  38. Han, Z. et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J. Clin. Invest. 108, 73–81 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Han, Z., Chang, L., Yamanishi, Y., Karin, M. & Firestein, G. S. Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis. Arthritis Rheum. 46, 818–823 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Kinne, R. W. et al. Synovial fibroblast-like cells strongly express jun-B and C-fos proto-oncogenes in rheumatoid-and osteoarthritis. Scand. J. Rheumatol. Suppl. 101, 121–125 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Shiozawa, S., Shimizu, K., Tanaka, K. & Hino, K. Studies on the contribution of c-fos/AP-1 to arthritic joint destruction. J. Clin. Invest. 99, 1210–1216 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Imamura, F. et al. Monoclonal expansion of synoviocytes in rheumatoid arthritis. Arthritis Rheum. 41, 1979–1986 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Pap, T. et al. Invasiveness of synovial fibroblasts is regulated by p53 in the SCID mouse in vivo model of cartilage invasion. Arthritis Rheum. 44, 676–681 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Sen, M., Chamorro, M., Reifert, J., Corr, M. & Carson, D. A. Blockade of Wnt-5A/Frizzled 5 signaling inhibits rheumatoid synoviocyte activation. Arthritis Rheum. 44, 772–781 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Walsh, D. A., Wade, M., Mapp, P. I. & Blake, D. R. Focally regulated endothelial proliferation and cell death in human synovium. Am. J. Pathol. 152, 691–702 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Firestein, G. S. et al. Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc. Natl Acad. Sci. USA 94, 10895–10900 (1997).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  47. Reme, T. et al. Mutations of the p53 tumour suppressor gene in erosive rheumatoid synovial tissue. Clin. Exp. Immunol. 111, 353–358 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Inazuka, M. et al. Analysis of p53 tumour suppressor gene somatic mutations in rheumatoid arthritis synovium. Rheumatology 39, 262–266 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Lee, S.-H. et al. Microsatellite instability and suppressed DNA repair enzyme expression in rheumatoid arthritis. J. Immunol. 170, 2214–2220 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Yamanishi, Y. et al. Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc. Natl Acad. Sci. USA 99, 10025–10030 (2002).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kouskoff, V. et al. Organ-specific disease provoked by systemic autoimmunity. Cell 87, 811–822 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Ji, H. et al. Arthritis critically dependent on innate immune system players. Immunity 16, 157–168 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Matsumoto, I. et al. Low prevalence of antibodies to glucose-6-phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders. Arthritis Rheum. 48, 944–954 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Steiner, G. & Smolen, J. Autoantibodies in rheumatoid arthritis and their clinical significance. Arthritis Res. 4, S1–S5 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Union, A. et al. Identification of citrullinated rheumatoid arthritis-specific epitopes in natural filaggrin relevant for antifilaggrin autoantibody detection by line immunoassay. Arthritis Rheum. 46, 1185–1195 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Kim, H.-J. & Berek, C. B cells in rheumatoid arthritis. Arthritis Res. 2, 126–131 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Clausen, B. E. et al. Clonally-related immunoglobulin VH domains and nonrandom use of DH gene segments in rheumatoid arthritis synovium. Mol. Med. 4, 240–251 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lee, D. M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689–1692 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  59. Terato, K. et al. Collagen-induced arthritis in mice: synergistic effect of E. coli lipopolysaccharide bypasses epitope specificity in the induction of arthritis with monoclonal antibodies to type II collagen. Autoimmunity 22, 137–147 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Ronaghy, A. et al. Immunostimulatory DNA sequences influence the course of adjuvant arthritis. J. Immunol. 168, 51–56 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Moreland, L. W. et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N. Engl. J. Med. 337, 141–147 (1997).

    Article  CAS  PubMed  Google Scholar 

  62. Elliott, M. J. et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110 (1994).

    Article  CAS  PubMed  Google Scholar 

  63. Brennan, F. M., Chantry, D., Jackson, A., Maini, R. & Feldmann, M. Inhibitory effect of TNFα antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2, 244–247 (2001).

    Google Scholar 

  64. Lubberts, E. et al. IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion. J. Clin. Invest. 105, 1697–1710 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Smeets, T. J., Kraan, M. C., Versendaal, J., Breedveld, F. C. & Tak, P. P. Analysis of serial synovial biopsies in patients with rheumatoid arthritis: description of a control group without clinical improvement after treatment with interleukin 10 or placebo. J. Rheumatol. 26, 2089–2093 (1999).

    CAS  PubMed  Google Scholar 

  66. Matsuno, H. et al. Antirheumatic effects of humanized anti-Fas monoclonal antibody in human rheumatoid arthritis/SCID mouse chimera. J. Rheumatol. 29, 1609–1614 (2002).

    CAS  PubMed  Google Scholar 

  67. Vita, S. D. et al. Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthritis Rheum. 46, 2029–2033 (2002).

    Article  PubMed  Google Scholar 

  68. Wang, H. et al. TACI-ligand interactions are required for T cell activation and collagen-induced arthritis in mice. Nature Immunol. 2, 632–637 (2001).

    Article  CAS  Google Scholar 

  69. Banda, N. K. et al. Mechanisms of effects of complement inhibition in murine collagen-induced arthritis. Arthritis Rheum. 46, 3065–3075 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Firestein, G. S. & Zvaifler, N. J. How important are T cells in chronic rheumatoid synovitis?: II. T cell-independent mechanisms from beginning to end. Arthritis Rheum. 46, 298–308 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. van der Heijden, I. M. et al. Presence of bacterial DNA and bacterial peptidoglycans in joints of patients with rheumatoid arthritis and other arthritides. Arthritis Rheum. 43, 593–598 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Walser-Kuntz, D. R., Weyand, C. M., Fulbright, J. W., Moore, S. B. & Goronzy, J. J. HLA-DRB1 molecules and antigenic experience shape the repertoire of CD4 T cells. Hum. Immunol. 44, 203–209 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Gebe, J. A. et al. T cell selection and differential activation on structurally related HLA-DR4 ligands. J. Immunol. 167, 3250–3256 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Zanelli, E., Breedveld, F. C. & de Vries, R. R. P. HLA association with autoimmune disease: a failure to protect? Rheumatology 39, 1060–1066 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Roudier, J., Petersen, J., Rhodes, G. H., Luka, J. & Carson, D. A. Susceptibility to rheumatoid arthritis maps to a T-cell epitope shared by the HLA-Dw4 DR beta-1 chain and the Epstein-Barr virus glycoprotein gp110. Proc. Natl Acad. Sci. USA 86, 5104–5108 (1989).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  76. Aceves-Avila, F. J., Baez-Molgado, S., Medina, F. & Fraga, A. Paleopathology in osseous remains from the 16th century. A survey of rheumatic diseases. J. Rheumatol. 25, 776–782 (1998).

    CAS  PubMed  Google Scholar 

  77. Rothschild, B. M., Turner, K. R. & DeLuca, M. A. Symmetrical erosive peripheral polyarthritis in the Late Archaic Period of Alabama. Science 241, 1498–1501 (1988).

    Article  ADS  CAS  PubMed  Google Scholar 

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Acknowledgements

Supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The author also thanks N. J. Zvaifler for helpful discussions on this topic as well as two decades of instruction, collaboration and friendship.

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  1. Division of Rheumatology, Allergy and Immunology, School of Medicine, University of California, 9500 Gilman Drive, San Diego, La Jolla, 92093-0656, California, USA

    Gary S. Firestein

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Correspondence to Gary S. Firestein.

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Firestein, G. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003). https://doi.org/10.1038/nature01661

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