Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Synovial pathology in rheumatoid arthritis

Ellen M Gravallese, MD
Ratnesh Chopra, MD
Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Deputy Editor
Paul L Romain, MD


No single histologic feature or group of features in synovium is diagnostic of rheumatoid arthritis (RA). Many of the histologic changes that are seen can also occur in other inflammatory joint diseases and even in osteoarthritis. Thus, the diagnosis of RA is made by history and physical examination of the patient, and is supported by the presence of characteristic pathologic findings in synovial tissue. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

There has been a resurgence of interest in the study of synovial tissue in RA over the past several years. Synovial tissue obtained at joint replacement surgery as well as needle and arthroscopic biopsy samples from patients with RA have been examined by molecular and immunohistochemical techniques in order to gain a better understanding of the pathogenic events in this disease. In addition, synovial biopsies are being used to assess the effects of medical interventions on the production of cytokines, joint-damaging enzymes, adhesion molecules, and other inflammatory mediators [1].

An overview of the histologic features of normal synovium and the changes that are characteristic of RA is presented first, which is followed by a discussion of the synovial response to treatment.


The synovial tissue that lines the fibrous capsule of a joint is derived from cells of the embryonic mesenchyme [2]. Three types of subintima have been described: fibrous, adipose, and areolar [3].

In the normal state, the synovium is a thin membrane that attaches to skeletal tissues at the bone-cartilage interface, and does not encroach upon the surface of articular cartilage. The synovial membrane is divided into two layers:

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Jul 29, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Pitzalis C, Kelly S, Humby F. New learnings on the pathophysiology of RA from synovial biopsies. Curr Opin Rheumatol 2013; 25:334.
  2. Caplan AI. Mesenchymal stem cells. J Orthop Res 1991; 9:641.
  3. Henderson B, Pettipher ER. The synovial lining cell: biology and pathobiology. Semin Arthritis Rheum 1985; 15:1.
  4. Lydyard PM, Edwards JC. The pathophysiology of rheumatoid arthritis. Clin Exp Rheumatol 1994; 12 Suppl 11:S55.
  5. BARLAND P, NOVIKOFF AB, HAMERMAN D. Electron microscopy of the human synovial membrane. J Cell Biol 1962; 14:207.
  6. Athanasou NA, Quinn J. Immunocytochemical analysis of human synovial lining cells: phenotypic relation to other marrow derived cells. Ann Rheum Dis 1991; 50:311.
  7. Waller HA, Butler MG, McClean JG, et al. Localisation of fibronectin mRNA in the rheumatoid synovium by in situ hybridisation. Ann Rheum Dis 1992; 51:735.
  8. Andersen RB, Gormsen J. Fibrinolytic and fibrin stabilizing activity of synovial membranes. Ann Rheum Dis 1970; 29:287.
  9. Hamann J, Wishaupt JO, van Lier RA, et al. Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue. Arthritis Rheum 1999; 42:650.
  10. Wilkinson LS, Pitsillides AA, Worrall JG, Edwards JC. Light microscopic characterization of the fibroblast-like synovial intimal cell (synoviocyte). Arthritis Rheum 1992; 35:1179.
  11. Kraan MC, Reece RJ, Smeets TJ, et al. Comparison of synovial tissues from the knee joints and the small joints of rheumatoid arthritis patients: Implications for pathogenesis and evaluation of treatment. Arthritis Rheum 2002; 46:2034.
  12. Bugatti S, Manzo A, Bombardieri M, et al. Synovial tissue heterogeneity and peripheral blood biomarkers. Curr Rheumatol Rep 2011; 13:440.
  13. Edwards JC, Willoughby DA. Demonstration of bone marrow derived cells in synovial lining by means of giant intracellular granules as genetic markers. Ann Rheum Dis 1982; 41:177.
  14. Qu Z, Garcia CH, O'Rourke LM, et al. Local proliferation of fibroblast-like synoviocytes contributes to synovial hyperplasia. Results of proliferating cell nuclear antigen/cyclin, c-myc, and nucleolar organizer region staining. Arthritis Rheum 1994; 37:212.
  15. Lalor PA, Mapp PI, Hall PA, Revell PA. Proliferative activity of cells in the synovium as demonstrated by a monoclonal antibody, Ki67. Rheumatol Int 1987; 7:183.
  16. Koch AE, Robinson PG, Radosevich JA, Pope RM. Distribution of CD45RA and CD45RO T-lymphocyte subsets in rheumatoid arthritis synovial tissue. J Clin Immunol 1990; 10:192.
  17. Weyand CM, Goronzy JJ. T-cell responses in rheumatoid arthritis: systemic abnormalities-local disease. Curr Opin Rheumatol 1999; 11:210.
  18. Wilkinson LS, Pitsillides AA, Edwards JC. Giant cells in arthritic synovium. Ann Rheum Dis 1993; 52:182.
  19. Wooley DE. Mast cells in the rheumatoid lesion--ringleaders or innocent bystanders? Ann Rheum Dis 1995; 54:533.
  20. Hale LP, Martin ME, McCollum DE, et al. Immunohistologic analysis of the distribution of cell adhesion molecules within the inflammatory synovial microenvironment. Arthritis Rheum 1989; 32:22.
  21. Koch AE, Burrows JC, Haines GK, et al. Immunolocalization of endothelial and leukocyte adhesion molecules in human rheumatoid and osteoarthritic synovial tissues. Lab Invest 1991; 64:313.
  22. Kriegsmann J, Keyszer GM, Geiler T, et al. Expression of vascular cell adhesion molecule-1 mRNA and protein in rheumatoid synovium demonstrated by in situ hybridization and immunohistochemistry. Lab Invest 1995; 72:209.
  23. Thomas R, Lipsky PE. Presentation of self peptides by dendritic cells: possible implications for the pathogenesis of rheumatoid arthritis. Arthritis Rheum 1996; 39:183.
  24. Koch AE. Angiogenesis as a target in rheumatoid arthritis. Ann Rheum Dis 2003; 62 Suppl 2:ii60.
  25. Koch AE. Review: angiogenesis: implications for rheumatoid arthritis. Arthritis Rheum 1998; 41:951.
  26. Ishikawa H, Hirata S, Andoh Y, et al. An immunohistochemical and immunoelectron microscopic study of adhesion molecules in synovial pannus formation in rheumatoid arthritis. Rheumatol Int 1996; 16:53.
  27. Shiozawa S, Tokuhisa T. Contribution of synovial mesenchymal cells to the pathogenesis of rheumatoid arthritis. Semin Arthritis Rheum 1992; 21:267.
  28. Gravallese EM, Harada Y, Wang JT, et al. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol 1998; 152:943.
  29. Pettit AR, Ji H, von Stechow D, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol 2001; 159:1689.
  30. Kotake S, Udagawa N, Hakoda M, et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum 2001; 44:1003.
  31. Schumacher HR Jr, Bautista BB, Krauser RE, et al. Histological appearance of the synovium in early rheumatoid arthritis. Semin Arthritis Rheum 1994; 23:3.
  32. Singh JA, Pando JA, Tomaszewski J, Schumacher HR. Quantitative analysis of immunohistologic features of very early rheumatoid synovitis in disease modifying antirheumatic drug- and corticosteroid-naïve patients. J Rheumatol 2004; 31:1281.
  33. Tak PP, Thurkow EW, Daha MR, et al. Expression of adhesion molecules in early rheumatoid synovial tissue. Clin Immunol Immunopathol 1995; 77:236.
  34. de Hair MJ, van de Sande MG, Ramwadhdoebe TH, et al. Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis. Arthritis Rheumatol 2014; 66:513.
  35. Soden M, Rooney M, Cullen A, et al. Immunohistological features in the synovium obtained from clinically uninvolved knee joints of patients with rheumatoid arthritis. Br J Rheumatol 1989; 28:287.
  36. Pando JA, Duray P, Yarboro C, et al. Synovitis occurs in some clinically normal and asymptomatic joints in patients with early arthritis. J Rheumatol 2000; 27:1848.
  37. Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 344:1105.
  38. 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.
  39. Chu CQ, Field M, Feldmann M, Maini RN. Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum 1991; 34:1125.
  40. Wood NC, Dickens E, Symons JA, Duff GW. In situ hybridization of interleukin-1 in CD14-positive cells in rheumatoid arthritis. Clin Immunol Immunopathol 1992; 62:295.
  41. Wood NC, Symons JA, Dickens E, Duff GW. In situ hybridization of IL-6 in rheumatoid arthritis. Clin Exp Immunol 1992; 87:183.
  42. Deleuran B, Lemche P, Kristensen M, et al. Localisation of interleukin 8 in the synovial membrane, cartilage-pannus junction and chondrocytes in rheumatoid arthritis. Scand J Rheumatol 1994; 23:2.
  43. Koch AE, Kunkel SL, Harlow LA, et al. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest 1992; 90:772.
  44. Chu CQ, Field M, Allard S, et al. Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair. Br J Rheumatol 1992; 31:653.
  45. De Groof A, Ducreux J, Humby F, et al. Higher expression of TNFα-induced genes in the synovium of patients with early rheumatoid arthritis correlates with disease activity, and predicts absence of response to first line therapy. Arthritis Res Ther 2016; 18:19.
  46. Toh ML, Miossec P. The role of T cells in rheumatoid arthritis: new subsets and new targets. Curr Opin Rheumatol 2007; 19:284.
  47. Kim KW, Kim HR, Kim BM, et al. Th17 cytokines regulate osteoclastogenesis in rheumatoid arthritis. Am J Pathol 2015; 185:3011.
  48. Franz JK, Pap T, Hummel KM, et al. Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis Rheum 2000; 43:599.
  49. Gracie JA, Forsey RJ, Chan WL, et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest 1999; 104:1393.
  50. Qin S, Rottman JB, Myers P, et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 1998; 101:746.
  51. Bradfield PF, Amft N, Vernon-Wilson E, et al. Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis Rheum 2003; 48:2472.
  52. Burman A, Haworth O, Hardie DL, et al. A chemokine-dependent stromal induction mechanism for aberrant lymphocyte accumulation and compromised lymphatic return in rheumatoid arthritis. J Immunol 2005; 174:1693.
  53. Koch AE, Polverini PJ, Kunkel SL, et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 1992; 258:1798.
  54. Koch AE, Kunkel SL, Harlow LA, et al. Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis. J Clin Invest 1994; 94:1012.
  55. Koch AE, Kunkel SL, Shah MR, et al. Growth-related gene product alpha. A chemotactic cytokine for neutrophils in rheumatoid arthritis. J Immunol 1995; 155:3660.
  56. Koch AE, Kunkel SL, Harlow LA, et al. Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest 1994; 93:921.
  57. Gravallese EM, Darling JM, Ladd AL, et al. In situ hybridization studies of stromelysin and collagenase messenger RNA expression in rheumatoid synovium. Arthritis Rheum 1991; 34:1076.
  58. Firestein GS, Paine MM, Littman BH. Gene expression (collagenase, tissue inhibitor of metalloproteinases, complement, and HLA-DR) in rheumatoid arthritis and osteoarthritis synovium. Quantitative analysis and effect of intraarticular corticosteroids. Arthritis Rheum 1991; 34:1094.
  59. McCachren SS. Expression of metalloproteinases and metalloproteinase inhibitor in human arthritic synovium. Arthritis Rheum 1991; 34:1085.
  60. Goldbach-Mansky R, Lee JM, Hoxworth JM, et al. Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis. Arthritis Res 2000; 2:145.
  61. Nawrocki B, Polette M, Clavel C, et al. Expression of stromelysin 3 and tissue inhibitors of matrix metallo-proteinases, TIMP-1 and TIMP-2, in rheumatoid arthritis. Pathol Res Pract 1994; 190:690.
  62. Müller-Ladner U, Kriegsmann J, Tschopp J, et al. Demonstration of granzyme A and perforin messenger RNA in the synovium of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38:477.
  63. Tak PP, Kummer JA, Hack CE, et al. Granzyme-positive cytotoxic cells are specifically increased in early rheumatoid synovial tissue. Arthritis Rheum 1994; 37:1735.
  64. Trabandt A, Aicher WK, Gay RE, et al. Expression of the collagenolytic and Ras-induced cysteine proteinase cathepsin L and proliferation-associated oncogenes in synovial cells of MRL/I mice and patients with rheumatoid arthritis. Matrix 1990; 10:349.
  65. Trabandt A, Gay RE, Fassbender HG, Gay S. Cathepsin B in synovial cells at the site of joint destruction in rheumatoid arthritis. Arthritis Rheum 1991; 34:1444.
  66. Hou WS, Li W, Keyszer G, et al. Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum 2002; 46:663.
  67. Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 1996; 273:1236.
  68. Handel ML, McMorrow LB, Gravallese EM. Nuclear factor-kappa B in rheumatoid synovium. Localization of p50 and p65. Arthritis Rheum 1995; 38:1762.
  69. Marok R, Winyard PG, Coumbe A, et al. Activation of the transcription factor nuclear factor-kappaB in human inflamed synovial tissue. Arthritis Rheum 1996; 39:583.
  70. Hammaker D, Sweeney S, Firestein GS. Signal transduction networks in rheumatoid arthritis. Ann Rheum Dis 2003; 62 Suppl 2:ii86.
  71. Schett G, Tohidast-Akrad M, Smolen JS, 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 2000; 43:2501.
  72. Han Z, Boyle DL, Aupperle KR, et al. Jun N-terminal kinase in rheumatoid arthritis. J Pharmacol Exp Ther 1999; 291:124.
  73. Badger AM, Griswold DE, Kapadia R, et al. Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum 2000; 43:175.
  74. Schett G, Tohidast-Akrad M, Steiner G, Smolen J. The stressed synovium. Arthritis Res 2001; 3:80.
  75. Fox DA. Kinase inhibition--a new approach to the treatment of rheumatoid arthritis. N Engl J Med 2012; 367:565.
  76. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012; 367:495.
  77. Ruderman EM, Weinblatt ME, Thurmond LM, et al. Synovial tissue response to treatment with Campath-1H. Arthritis Rheum 1995; 38:254.
  78. Verburg RJ, Flierman R, Sont JK, et al. Outcome of intensive immunosuppression and autologous stem cell transplantation in patients with severe rheumatoid arthritis is associated with the composition of synovial T cell infiltration. Ann Rheum Dis 2005; 64:1397.
  79. Tak PP, Taylor PC, Breedveld FC, et al. Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 1996; 39:1077.
  80. Haringman JJ, Kraan MC, Smeets TJ, et al. Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis 2003; 62:715.
  81. Gravallese EM, Handel ML, Coblyn J, et al. N-[4-hydroxyphenyl] retinamide in rheumatoid arthritis: a pilot study. Arthritis Rheum 1996; 39:1021.
  82. Rooney M, Condell D, Quinlan W, et al. Analysis of the histologic variation of synovitis in rheumatoid arthritis. Arthritis Rheum 1988; 31:956.
  83. Youssef PP, Triantafillou S, Parker A, et al. Effects of pulse methylprednisolone on cell adhesion molecules in the synovial membrane in rheumatoid arthritis. Reduced E-selectin and intercellular adhesion molecule 1 expression. Arthritis Rheum 1996; 39:1970.
  84. Youssef PP, Haynes DR, Triantafillou S, et al. Effects of pulse methylprednisolone on inflammatory mediators in peripheral blood, synovial fluid, and synovial membrane in rheumatoid arthritis. Arthritis Rheum 1997; 40:1400.
  85. Lindblad S, Hedfors E. The synovial membrane of healthy individuals--immunohistochemical overlap with synovitis. Clin Exp Immunol 1987; 69:41.
  86. Tak PP, Smeets TJ, Daha MR, et al. Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 1997; 40:217.
  87. Cañete JD, Celis R, Moll C, et al. Clinical significance of synovial lymphoid neogenesis and its reversal after anti-tumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis 2009; 68:751.
  88. Badot V, Galant C, Nzeusseu Toukap A, et al. Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis. Arthritis Res Ther 2009; 11:R57.
  89. Klaasen R, Thurlings RM, Wijbrandts CA, et al. The relationship between synovial lymphocyte aggregates and the clinical response to infliximab in rheumatoid arthritis: a prospective study. Arthritis Rheum 2009; 60:3217.
  90. Thurlings RM, Vos K, Wijbrandts CA, et al. Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response. Ann Rheum Dis 2008; 67:917.
  91. Kavanaugh A, Rosengren S, Lee SJ, et al. Assessment of rituximab's immunomodulatory synovial effects (ARISE trial). 1: clinical and synovial biomarker results. Ann Rheum Dis 2008; 67:402.
  92. Buch MH, Boyle DL, Rosengren S, et al. Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study. Ann Rheum Dis 2009; 68:1220.
  93. Kanbe K, Chen Q, Nakamura A, Hobo K. Inhibition of MAP kinase in synovium by treatment with tocilizumab in rheumatoid arthritis. Clin Rheumatol 2011; 30:1407.