Current Rheumatology Reports

, Volume 3, Issue 1, pp 53–63 | Cite as

Update on synovitis

  • Zoltan Szekanecz
  • Alisa E. Koch


Rheumatoid arthritis (RA) is an inflammatory disorder associated with chronic synovitis, eventually leading to cartilage and bone destruction in the joints. Synovitis is associated with the activation of various cells in the synovium including synovial lining cells, interstitial macrophages, endothelial cells, lymphocytes, and fibroblasts. The key mechanisms underlying synovitis include inflammatory cell adhesion and activation, the production of mediators (such as cytokines, chemokines, and growth factors), angiogenesis, joint destruction, fibrosis, and bone resorption. These important events, as well as the role of inflammatory cells, cell surface molecules, and soluble mediators are updated and discussed in this review. Some aspects and strategies of current or future immunotherapy are also discussed because these animal and human trials provide information on the pathogenesis of inflammatory synovitis.


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References and Recommended Reading

  1. 1.
    Klareskog L, Ronnelid J, Holm G: Immunopathogenesis and immunotherapy in rheumatoid arthritis: an area in transition. J Int Med 1995, 238:191–206.CrossRefGoogle Scholar
  2. 2.
    Szekanecz Z, Koch AE: Cytokines. In Kelly’s Textbook of Rheumatology, edn 6. Edited by Ruddy S, Harris ED Jr, Sledge CB. Philadelphia: W.B. Saunders; 2000.Google Scholar
  3. 3.
    Szekanecz Z, Szegedi G, Koch AE: Cellular adhesion molecules in rheumatoid arthritis. Regulation by cytokines and possible clinical importance. J Invest Med 1996, 44:124–135.Google Scholar
  4. 4.
    Szekanecz Z, Strieter RM, Koch AE: Cytokines in rheumatoid arthritis: potential targets for pharmacological intervention. Drugs Aging 1998, 12:377–390.PubMedCrossRefGoogle Scholar
  5. 5.
    Szekanecz Z, Kunkel SL, Strieter RM, Koch AE: Chemokines in rheumatoid arthritis. Springer Semin Immunopathol 1998, 20:115–132.PubMedCrossRefGoogle Scholar
  6. 6.
    Dayer JM, Arend WP: Cytokines and growth factors. In Textbook of Rheumatology, edn 5. Edited by Kelley WN, Harris ED Jr, Ruddy S, Sledge CB. Philadelphia: WB Saunders; 1997:267–286. This review chapter summarizes the understanding of cytokine action. The crucial role of TNF-a and IL-1b is underscored in this chapter.Google Scholar
  7. 7.
    Szekanecz Z, Szegedi G, Koch AE: Angiogenesis in rheumatoid arthritis: pathogenic and clinical significance. J Invest Med 1998, 46:27–41.Google Scholar
  8. 8.
    Szekanecz Z, Koch AE: Endothelial cells and immune cell migration. Arthritis Res 2000, in press.Google Scholar
  9. 9.
    Breedveld FC: Future trends in the treatment of rheumatoid arthritis: cytokine targets. Rheumatology 1999, 38(Suppl 2):11–13. This is an excellent review of the current and future trends in specific immunotherapy. Primarily anticytokine treatment strategies are discussed in detail.PubMedGoogle Scholar
  10. 10.
    Muller B, Gimsa U, Mitchison NA, et al.: Modulating the Th1/Th2 balance in inflammatory arthritis. Springer Semin Immunopathol 1998, 20:181–196. The Th1/Th2 cytokine balance is important in the pathogenesis of various inflammatory and allergic diseases. The role of Th1 and Th2 cytokines and the perspectives of cytokine modulation are discussed in this paper.PubMedCrossRefGoogle Scholar
  11. 11.
    Lewis D, Harriman GR: Cells and tissues of the immune system. In Clinical Immunology Principles and Practice. Edited by Rich RR, Fleisher TA, Schwartz BD, et al.. St. Louis: Mosby-Year Book; 1996:15–38.Google Scholar
  12. 12.
    Strieter RM, Kunkel SL, Shanafelt AB, et al.: The role of C-X-C chemokines in regulation of angiogenesis. In Chemokines in Disease. Edited by Koch AE, Strieter RM. Austin: Landes Bioscience; 1996:195–209.Google Scholar
  13. 13.
    Bresnihan B: Treatment of rheumatoid arthritis with interleukin 1 receptor antagonist. Ann Rheum Dis 1999, 58(Suppl 1):196–198.Google Scholar
  14. 14.
    Hermann J, Walmsley M, Brennan FM: Cytokine therapy in rheumatoid arthritis. Springer Semin Immunopathol 1998, 20:275–288.PubMedGoogle Scholar
  15. 15.
    Robbins PD, Evans CH, Chernajovsky Y: Gene therapy for rheumatoid arthritis. Springer Semin Immunopathol 1998, 20:197–210. This is an excellent review of the concepts of gene therapy.PubMedGoogle Scholar
  16. 16.
    van den Berg WB: Joint inflammation and cartilage destruction may occur uncoupled. Springer Semin Immunopathol 1998, 20:149–164.PubMedCrossRefGoogle Scholar
  17. 17.
    Endo H, Akahoshi T, Takagishi K, et al.: Elevation of interleukin-8 (IL-8) levels in joint fluids of patients with rheumatoid arthritis and the induction by IL-8 of leukocyte infiltration and synovitis in rabbit joints. Lymphokine Cytokine Res 1991, 10:245–252.PubMedGoogle Scholar
  18. 18.
    Barnes DA, Tse J, Kaufhold M, et al.: Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J Clin Invest 1998, 101:2910–2919.PubMedGoogle Scholar
  19. 19.
    Pulsatelli L, Dolzani P, Piacentini A, et al.: Chemokine production by human chondrocytes. J Rheumatol 1999, 26:1992–2001. This paper underscores that chondrocytes, leukocytes, and endothelial cells are able to produce chemokines. These data support the role of the inflamed cartilage in maintaining synovial inflammation.PubMedGoogle Scholar
  20. 20.
    Szekanecz Z, Halloran MM, Volin MV, et al.: Temporal expression of inflammatory cytokines and chemokines in rat adjuvant-induced arthritis. Arthritis Rheum 2000, 43:1266–1277.PubMedCrossRefGoogle Scholar
  21. 21.
    Thornton S, Duwel LE, Boivin GP, et al.: Association of the course of collagen-induced arthritis with distinct patterns of cytokine and chemokine messenger RNA expression. Arthritis Rheum 1999, 42:1109–1118.PubMedCrossRefGoogle Scholar
  22. 22.
    Ogata Y, Kukita A, Kukita T, et al.: A novel role of IL-15 in the development of osteoclasts: inability to replace its activity with IL-2. J Immunol 1999, 162:2754–2760. This paper highlights a new role of IL-15 as a cytokine causing bone resorption.PubMedGoogle Scholar
  23. 23.
    Ziolkowska M, Koc A, Luszczykiewicz G, et al.: High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol 2000, 164:2832–2838.PubMedGoogle Scholar
  24. 24.
    Chabaud M, Durand JM, Buchs N, et al.: Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 1999, 42:963–970.PubMedCrossRefGoogle Scholar
  25. 25.
    Kotake S, Udagawa N, Takahashi N, et al.: IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 1999, 103:1345–1352.PubMedGoogle Scholar
  26. 26.
    Klimiuk PA, Goronzy JJ, Weyand CM: IL-16 as an antiinflammatory cytokine in rheumatoid synovitis. J Immunol 1999, 162:4293–4299. IL-16 is a recently discovered cytokine. This paper elucidates the proinflammatory and anti-inflammatory roles of IL-16.PubMedGoogle Scholar
  27. 27.
    Gracie JA, Forsey RJ, Chan WL, et al.: A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest 1999, 104:1393–1401.PubMedGoogle Scholar
  28. 28.
    Loetscher P, Uguccioni M, Bordoli L, et al.: CCR5 is characteristic of Th1 lymphocytes. Nature 1998, 391:344–345. This report suggests that different chemokine receptors may be involved in Th1 and Th2 type inflammatory machanisms, such as synovitis and allergic inflammation, respectively.PubMedCrossRefGoogle Scholar
  29. 29.
    Qin S, Rottman JB, Myers O, et al.: The chemokine receptors CXCR3 and CCR5 mark subsets of T cells with homing predilection for certain inflammatory sites. J Clin Invest 1998, 101:746–754.PubMedGoogle Scholar
  30. 30.
    Manolagas SC, Jilka RL: Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med 1995, 332:305–311.PubMedCrossRefGoogle Scholar
  31. 31.
    Croft D, McIntyre P, Wibulswas A, Kramer I: Sustained elevated levels of VCAM-1 in cultured fibroblast-like synoviocytes can be achieved by TNF-alpha in combination with either IL-4 or IL-13 through increased mRNA stability. Am J Pathol 1999, 154:1149–1158.PubMedGoogle Scholar
  32. 32.
    Volin MV, Harlow LA, Woods JM, et al.: Treatment with sulfasalazine, sulfapyridine, but not 5-aminosalicylic acid, inhibits basic fibroblast growth factor-induced endothelial cell chemotaxis. Arthritis Rheum 1999, 42:1927–1935.PubMedCrossRefGoogle Scholar
  33. 33.
    Oliver SJ, Cheng TP, Banquerigo ML, Brahn E: The effect of thalidomide and 2 analogs on collagen induced arthritis. J Rheumatol 1998, 25:964–969.PubMedGoogle Scholar
  34. 34.
    Gabay C, Arend WP: Treatment of rheumatoid arthritis with IL-1 inhibitors. Springer Semin Immunopathol 1998, 20:229–246.PubMedGoogle Scholar
  35. 35.
    Feldmann M, Charles P, Taylor P, Maini RN: Biological insights from clinical trials with anti-TNF therapy. Springer Semin Immunopathol 1998, 20:211–228.PubMedCrossRefGoogle Scholar
  36. 36.
    Rankin EC, Choy EHS, Kassimos D, et al.: The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis. Br J Rheumatol 1995, 34:334–342.PubMedCrossRefGoogle Scholar
  37. 37.
    Wendling D, Racadot E, Wijdenes J: Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. J Rheumatol 1993, 20:259–262.PubMedGoogle Scholar
  38. 38.
    Halloran MM, Szekanecz Z, Strieter RM, et al.: The role of an epithelial-neutrophil activating peptide-78-like protein in rat adjuvant arthritis. J Immunol 1999, 162:7492–7500.PubMedGoogle Scholar
  39. 39.
    Woods JM, Katschke KJ Jr, Volin MV, et al.: Adenoviral interleukin (IL)-4 gene therapy reduces rat adjuvant-induced arthritis (AIA), bony destruction, synovial leukocytosis and angiogenesis. FASEB J 2000, 14:A651.CrossRefGoogle Scholar
  40. 40.
    Woods JM, Katschke KJ Jr, Tokuhira M, et al.: Reduction of inflammatory cytokines and prostaglandin E2 by IL-13 gene therapy in rheumatoid arthritis synovium. J Immunol 2000, 165(5):2755–2763.PubMedGoogle Scholar
  41. 41.
    Woods JM, Tokuhira M, Berry JC, et al.: Interleukin-4 adenoviral gene therapy reduces production of inflammatory cytokines and prostaglandin E2 by rheumatoid arthritis synovium ex vivo. J Invest Med 1999, 47:285–292.Google Scholar
  42. 42.
    Lechman ER, Jaffurs D, Ghivizzani SC, et al.: Direct adenoviral gene transfer of viral IL-10 to rabbit knees with experimental arthritis ameliorates disease in both injected and contralateral control knees. J Immunol 1999, 163:2202–2208. This paper elucidates gene transfer with an IL-10 gene-containing vector. Interestingly, the effect of gene therapy was observed not only in the injected knee but also in the contralateral joint, suggesting a generalized effect of antiinflammatory cytokines.PubMedGoogle Scholar
  43. 43.
    Muller-Ladner U, Evans CH, Franklin BN, et al.: Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model. Arthritis Rheum 1999, 42:490–497.PubMedCrossRefGoogle Scholar
  44. 44.
    Smeets TJ, Dayer JM, Kraan MC, et al.: The effects of interferon-beta treatment of synovial inflammation and expression of metalloproteinases in patients with rheumatoid arthritis. Arthritis Rheum 2000, 43:270–274.PubMedCrossRefGoogle Scholar
  45. 45.
    Moreland LW, Baumgartner SW, Schiff MH, et al.: Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997, 337:141–147.PubMedCrossRefGoogle Scholar
  46. 46.
    Tokuhira M, Hosaka S, Volin MV, et al.: Soluble vascular cell adhesion molecule 1 mediation of monocyte chemotaxis in rheumatoid arthritis. Arthritis Rheum 2000, 43:1122–1133.PubMedCrossRefGoogle Scholar
  47. 47.
    Butcher EC: Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 1991, 67:1033–1036.PubMedCrossRefGoogle Scholar
  48. 48.
    Kavanaugh AF, Davis LS, Nichols LA, et al.: Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule-1. Arthritis Rheum 1994, 37:992–999.PubMedCrossRefGoogle Scholar
  49. 49.
    Vuorte J, Lindsberg PJ, Kaste M, et al.: Anti-ICAM-1 monoclonal antibody R6.5 (Enlimomab) promotes activation of neutrophils in whole blood. J Immunol 1999, 162:2353–2357.PubMedGoogle Scholar
  50. 50.
    Koch AE, Halloran MM, Haskell CJ, et al.: Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 1995, 376:517–519.PubMedCrossRefGoogle Scholar
  51. 51.
    Halloran MM, Carley WW, Polverini PJ, et al.: Ley/H: an endothelial-selective, cytokine-inducible, angiogenic mediator. J Immunol 2000, 164:4868–4877.PubMedGoogle Scholar
  52. 52.
    Volpert OV, Fong T, Koch AE, et al.: Inhibition of angiogenesis by interleukin 4. J Exp Med 1998, 188:1039–1046.PubMedCrossRefGoogle Scholar
  53. 53.
    Konttinen YT, Ainola M, Valleala H, et al.: Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis. Ann Rheum Dis 1999, 58:691–697.PubMedGoogle Scholar
  54. 54.
    Jackson CJ, Arkell J, Nguyen M: Rheumatoid synovial endothelial cells secrete decreased levels of tissue inhibitor of MMP (TIMP1). Ann Rheum Dis 1998, 57:158–161.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2001

Authors and Affiliations

  • Zoltan Szekanecz
  • Alisa E. Koch
    • 1
  1. 1.Department of Medicine, Division of Arthritis and Connective Tissue DiseasesNorthwestern University Medical SchoolChicagoUSA

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