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

Origin and utility of measurement of rheumatoid factors

Robert H Shmerling, MD
Section Editor
Mark H Wener, MD
Deputy Editor
Paul L Romain, MD


Rheumatoid factors are antibodies directed against the Fc portion of immunoglobulin G (IgG). The rheumatoid factor (RF), as initially described by Waaler and Rose in 1940 and as commonly measured in clinical practice, is an IgM RF, although other immunoglobulin types, including IgG and IgA, have been described.

Testing for RF is primarily used for the diagnosis of rheumatoid arthritis (RA); however, RF may also be present in other rheumatic diseases and chronic infections.

The origin of rheumatoid factors and the clinical utility of their measurement are reviewed here. Discussions of clinically useful biologic markers in RA, including rheumatoid factor, and of the diagnosis of RA are presented separately. (See "Biologic markers in the diagnosis and assessment of rheumatoid arthritis" and "Diagnosis and differential diagnosis of rheumatoid arthritis".)


The origin of rheumatoid factor (RF) is incompletely understood [1,2]. An abnormal immune response appears to select, via antigenic stimulation, high-affinity RF from the host's natural antibody repertoire [3]. This may occur in rheumatic diseases, such as rheumatoid arthritis (RA), and in a number of inflammatory diseases characterized by chronic antigen exposure, such as subacute bacterial endocarditis (SBE). The development of RF after such infections has suggested that they represent an antibody response to antibodies that have reacted with microbes. This possibility is supported by experimental evidence showing that mice immunized with IgM-coated vesicular stomatitis virus (VSV) develop rheumatoid factors [4].

Normal human lymphoid tissue commonly possesses B lymphocytes with RF expression on the cell surface. However, RF is not routinely detectable in the circulation in the absence of an antigenic stimulus. Modified immunoglobulin G (IgG) could be a stimulus to RF production and could be an important component of RA pathogenesis; this concept is supported by studies that observed an association of RF and more severe RA with autoantibodies to advanced glycated end-product (AGE)-damaged IgG or agalactosyl IgG [5,6].

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: Nov 2017. | This topic last updated: Oct 06, 2017.
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. Sutton B, Corper A, Bonagura V, Taussig M. The structure and origin of rheumatoid factors. Immunol Today 2000; 21:177.
  2. Westwood OM, Nelson PN, Hay FC. Rheumatoid factors: what's new? Rheumatology (Oxford) 2006; 45:379.
  3. Carayannopoulos MO, Potter KN, Li Y, et al. Evidence that human immunoglobulin M rheumatoid factors can Be derived from the natural autoantibody pool and undergo an antigen driven immune response in which somatically mutated rheumatoid factors have lower affinities for immunoglobulin G Fc than their germline counterparts. Scand J Immunol 2000; 51:327.
  4. Fehr T, Bachmann MF, Bucher E, et al. Role of repetitive antigen patterns for induction of antibodies against antibodies. J Exp Med 1997; 185:1785.
  5. Das H, Atsumi T, Fukushima Y, et al. Diagnostic value of antiagalactosyl IgG antibodies in rheumatoid arthritis. Clin Rheumatol 2004; 23:218.
  6. Newkirk MM, Goldbach-Mansky R, Lee J, et al. Advanced glycation end-product (AGE)-damaged IgG and IgM autoantibodies to IgG-AGE in patients with early synovitis. Arthritis Res Ther 2003; 5:R82.
  7. Shlomchik MJ, Zharhary D, Saunders T, et al. A rheumatoid factor transgenic mouse model of autoantibody regulation. Int Immunol 1993; 5:1329.
  8. Rifkin IR, Leadbetter EA, Busconi L, et al. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev 2005; 204:27.
  9. Hirohata S, Yanagida T, Koda M, et al. Selective induction of IgM rheumatoid factors by CD14+ monocyte-lineage cells generated from bone marrow of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38:384.
  10. Breedveld FC, Otten HG, Daha MR. Rheumatoid factor production in the joint. Scand J Rheumatol Suppl 1995; 101:183.
  11. Van Esch WJ, Reparon-Schuijt CC, Hamstra HJ, et al. Human IgG Fc-binding phage antibodies constructed from synovial fluid CD38+ B cells of patients with rheumatoid arthritis show the imprints of an antigen-dependent process of somatic hypermutation and clonal selection. Clin Exp Immunol 2003; 131:364.
  12. Perez L, Orte J, Brieva JA. Terminal differentiation of spontaneous rheumatoid factor-secreting B cells from rheumatoid arthritis patients depends on endogenous interleukin-10. Arthritis Rheum 1995; 38:1771.
  13. He X, Zhong W, McCarthy TG, et al. Increased responsiveness of rheumatoid factor-producing B cells in seronegative and seropositive rheumatoid arthritis. Arthritis Rheum 1996; 39:1499.
  14. Padyukov L, Silva C, Stolt P, et al. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum 2004; 50:3085.
  15. Halldórsdóttir HD, Jónsson T, Thorsteinsson J, Valdimarsson H. A prospective study on the incidence of rheumatoid arthritis among people with persistent increase of rheumatoid factor. Ann Rheum Dis 2000; 59:149.
  16. Nielsen SF, Bojesen SE, Schnohr P, Nordestgaard BG. Elevated rheumatoid factor and long term risk of rheumatoid arthritis: a prospective cohort study. BMJ 2012; 345:e5244.
  17. Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004; 50:380.
  18. Heinlen LD, McClain MT, Merrill J, et al. Clinical criteria for systemic lupus erythematosus precede diagnosis, and associated autoantibodies are present before clinical symptoms. Arthritis Rheum 2007; 56:2344.
  19. Symmons DP. Classification criteria for rheumatoid arthritis--time to abandon rheumatoid factor? Rheumatology (Oxford) 2007; 46:725.
  20. Youngblood K, Fruchter L, Ding G, et al. Rheumatoid factors from the peripheral blood of two patients with rheumatoid arthritis are genetically heterogeneous and somatically mutated. J Clin Invest 1994; 93:852.
  21. Duquerroy S, Stura EA, Bressanelli S, et al. Crystal structure of a human autoimmune complex between IgM rheumatoid factor RF61 and IgG1 Fc reveals a novel epitope and evidence for affinity maturation. J Mol Biol 2007; 368:1321.
  22. Thorpe SJ, Børretzen M, Bailey SW, et al. Human monoclonal rheumatoid factors: incidence of cross-reactions with tissue components and correlation with VH gene usage. Immunology 1994; 83:114.
  23. MacGregor AJ, Bamber S, Carthy D, et al. Heterogeneity of disease phenotype in monozygotic twins concordant for rheumatoid arthritis. Br J Rheumatol 1995; 34:215.
  24. Vehe RK, Nepom GT, Wilske KR, et al. Erosive rheumatoid factor negative and positive rheumatoid arthritis are immunogenetically similar. J Rheumatol 1994; 21:194.
  25. al-Jarallah KF, Buchanan WW, Sastry A, Singal DP. Seronegative rheumatoid arthritis and HLA-DR4. J Rheumatol 1994; 21:190.
  26. Tan EM, Smolen JS. Historical observations contributing insights on etiopathogenesis of rheumatoid arthritis and role of rheumatoid factor. J Exp Med 2016; 213:1937.
  27. Sokolove J, Johnson DS, Lahey LJ, et al. Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis. Arthritis Rheumatol 2014; 66:813.
  28. Shmerling RH, Delbanco TL. The rheumatoid factor: an analysis of clinical utility. Am J Med 1991; 91:528.
  29. Lichtenstein MJ, Pincus T. Rheumatoid arthritis identified in population based cross sectional studies: low prevalence of rheumatoid factor. J Rheumatol 1991; 18:989.
  30. Mikkelsen WM, Dodge HJ, Duff IF, Kato H. Estimates of the prevalence of rheumatic diseases in the population of Tecumseh, Michigan, 1959-60. J Chronic Dis 1967; 20:351.
  31. Cathcart ES, O'Sullivan JB. Rheumatoid arthritis in a New England town. A prevalence study in Sudbury, Massachusetts. N Engl J Med 1970; 282:421.
  32. Kellgren JH. Epidemiology of rheumatoid arthritis. Arthritis Rheum 1966; 9:658.
  33. Lee DM, Schur PH. Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis 2003; 62:870.
  34. Vander Cruyssen B, Peene I, Cantaert T, et al. Anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis: specificity and relation with rheumatoid factor. Autoimmun Rev 2005; 4:468.
  35. Shmerling RH. Testing for anti-cyclic citrullinated peptide antibodies: is it time to set this genie free? Arch Intern Med 2009; 169:9.
  36. Hodkinson B, Meyer PW, Musenge E, et al. The diagnostic utility of the anti-CCP antibody test is no better than rheumatoid factor in South Africans with early rheumatoid arthritis. Clin Rheumatol 2010; 29:615.
  37. Peoples C, Valiyil R, Davis RB, Shmerling RH. Clinical use of anti-cyclic citrullinated peptide antibody testing. J Clin Rheumatol 2013; 19:351.
  38. Chang PY, Yang CT, Cheng CH, Yu KH. Diagnostic performance of anti-cyclic citrullinated peptide and rheumatoid factor in patients with rheumatoid arthritis. Int J Rheum Dis 2016; 19:880.
  39. Aggarwal R, Liao K, Nair R, et al. Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis. Arthritis Rheum 2009; 61:1472.
  40. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62:2569.
  41. Gioud-Paquet M, Auvinet M, Raffin T, et al. IgM rheumatoid factor (RF), IgA RF, IgE RF, and IgG RF detected by ELISA in rheumatoid arthritis. Ann Rheum Dis 1987; 46:65.
  42. Bonagura VR, Wedgwood JF, Agostino N, et al. Seronegative rheumatoid arthritis, rheumatoid factor cross reactive idiotype expression, and hidden rheumatoid factors. Ann Rheum Dis 1989; 48:488.
  43. van Leeuwen MA, Westra J, van Riel PL, et al. IgM, IgA, and IgG rheumatoid factors in early rheumatoid arthritis predictive of radiological progression? Scand J Rheumatol 1995; 24:146.
  44. Coughlan RJ, Gordon Y, Clark B, Panayi GS. 7S IgM in the sera of patients with arthritis. Br J Rheumatol 1987; 26:108.
  45. van Zeben D, Hazes JM, Zwinderman AH, et al. Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow up study. Ann Rheum Dis 1992; 51:1029.
  46. Eberhardt KB, Truedsson L, Pettersson H, et al. Disease activity and joint damage progression in early rheumatoid arthritis: relation to IgG, IgA, and IgM rheumatoid factor. Ann Rheum Dis 1990; 49:906.
  47. Cabral D, Katz JN, Weinblatt ME, et al. Development and assessment of indicators of rheumatoid arthritis severity: results of a Delphi panel. Arthritis Rheum 2005; 53:61.
  48. Mattey DL, Hassell AB, Dawes PT, et al. Independent association of rheumatoid factor and the HLA-DRB1 shared epitope with radiographic outcome in rheumatoid arthritis. Arthritis Rheum 2001; 44:1529.
  49. Pawlotsky JM, Roudot-Thoraval F, Simmonds P, et al. Extrahepatic immunologic manifestations in chronic hepatitis C and hepatitis C virus serotypes. Ann Intern Med 1995; 122:169.
  50. Clifford BD, Donahue D, Smith L, et al. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 1995; 21:613.
  51. Pawlotsky JM, Ben Yahia M, Andre C, et al. Immunological disorders in C virus chronic active hepatitis: a prospective case-control study. Hepatology 1994; 19:841.
  52. Lienesch D, Morris R, Metzger A, et al. Absence of cyclic citrullinated peptide antibody in nonarthritic patients with chronic hepatitis C infection. J Rheumatol 2005; 32:489.
  53. Sansonno D, De Vita S, Iacobelli AR, et al. Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia. J Immunol 1998; 160:3594.
  54. Oreskes I, Siltzbach LE. Changes in rheumatoid factor activity during the course of sarcoidosis. Am J Med 1968; 44:60.
  55. Kobak S, Sever F, Sivrikoz ON, Orman M. Sarcoidois: is it only a mimicker of primary rheumatic disease? A single center experience. Ther Adv Musculoskelet Dis 2014; 6:3.
  56. Thelier N, Assous N, Job-Deslandre C, et al. Osteoarticular involvement in a series of 100 patients with sarcoidosis referred to rheumatology departments. J Rheumatol 2008; 35:1622.
  57. Brickmann K, Brezinschek RI, Yazdani-Biuki B, et al. Superior specificity of anti-citrullinated peptide antibodies in patients with chronic lymphocytic leukemia and arthritis. Clin Exp Rheumatol 2010; 28:888.
  58. Newkirk MM. Rheumatoid factors: what do they tell us? J Rheumatol 2002; 29:2034.
  59. Cammarata RJ, Rodnan GP, Fennell RH. Serum anti-gamma-globulin and antinuclear factors in the aged. JAMA 1967; 199:455.
  61. Juby AG, Davis P, McElhaney JE, Gravenstein S. Prevalence of selected autoantibodies in different elderly subpopulations. Br J Rheumatol 1994; 33:1121.
  62. Wolfe F, Cathey MA, Roberts FK. The latex test revisited. Rheumatoid factor testing in 8,287 rheumatic disease patients. Arthritis Rheum 1991; 34:951.
  63. Hsu FC, Starkebaum G, Boyko EJ, Dominitz JA. Prevalence of rheumatoid arthritis and hepatitis C in those age 60 and older in a US population based study. J Rheumatol 2003; 30:455.
  64. Kokkonen H, Mullazehi M, Berglin E, et al. Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis. Arthritis Res Ther 2011; 13:R13.
  65. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med 2007; 146:797.
  66. Shmerling RH, Delbanco TL. How useful is the rheumatoid factor? An analysis of sensitivity, specificity, and predictive value. Arch Intern Med 1992; 152:2417.
  67. Quinn MA, Green MJ, Marzo-Ortega H, et al. Prognostic factors in a large cohort of patients with early undifferentiated inflammatory arthritis after application of a structured management protocol. Arthritis Rheum 2003; 48:3039.
  68. Hülsemann JL, Zeidler H. Undifferentiated arthritis in an early synovitis out-patient clinic. Clin Exp Rheumatol 1995; 13:37.
  69. Jansen AL, van der Horst-Bruinsma I, van Schaardenburg D, et al. Rheumatoid factor and antibodies to cyclic citrullinated Peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis. J Rheumatol 2002; 29:2074.
  70. Edwards JC, Cambridge G. Prospects for B-cell-targeted therapy in autoimmune disease. Rheumatology (Oxford) 2005; 44:151.
  71. Takeuchi T, Miyasaka N, Inui T, et al. High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: a post hoc analysis of the RISING study. Arthritis Res Ther 2017; 19:194.
  72. Berendsen MLT, van Maaren MC, Arts EEA, et al. Anticyclic Citrullinated Peptide Antibodies and Rheumatoid Factor as Risk Factors for 10-year Cardiovascular Morbidity in Patients with Rheumatoid Arthritis: A Large Inception Cohort Study. J Rheumatol 2017; 44:1325.
  73. van der Heijde DM, van Riel PL, van Rijswijk MH, van de Putte LB. Influence of prognostic features on the final outcome in rheumatoid arthritis: a review of the literature. Semin Arthritis Rheum 1988; 17:284.
  74. Cats A, Hazevoet HM. Significance of positive tests for rheumatoid factor in the prognosis of rheumatoid arthritis. A follow-up study. Ann Rheum Dis 1970; 29:254.
  75. Aggarwal A, Dabadghao S, Naik S, Misra R. Serum IgM rheumatoid factor by enzyme-linked immunosorbent assay (ELISA) delineates a subset of patients with deforming joint disease in seronegative juvenile rheumatoid arthritis. Rheumatol Int 1994; 14:135.
  76. Gough A, Faint J, Salmon M, et al. Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum 1994; 37:1166.
  77. Visser K, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, et al. A matrix risk model for the prediction of rapid radiographic progression in patients with rheumatoid arthritis receiving different dynamic treatment strategies: post hoc analyses from the BeSt study. Ann Rheum Dis 2010; 69:1333.
  78. Vastesaeger N, Xu S, Aletaha D, et al. A pilot risk model for the prediction of rapid radiographic progression in rheumatoid arthritis. Rheumatology (Oxford) 2009; 48:1114.
  79. Anderson LG, Talal N. The spectrum of benign to malignant lymphoproliferation in Sjögren's syndrome. Clin Exp Immunol 1972; 10:199.
  80. Bruns A, Nicaise-Roland P, Hayem G, et al. Prospective cohort study of effects of infliximab on rheumatoid factor, anti-cyclic citrullinated peptide antibodies and antinuclear antibodies in patients with long-standing rheumatoid arthritis. Joint Bone Spine 2009; 76:248.
  81. Waaler E. On the occurrence of a factor in human serum activating the specific agglutination of sheep blood corpuscles. Acta Path Microbiol Scand 1940; 17:172.
  82. PLOTZ CM, SINGER JM. The latex fixation test. I. Application to the serologic diagnosis of rheumatoid arthritis. Am J Med 1956; 21:888.
  83. Roberts-Thomson PJ, McEvoy R, Langhans T, Bradley J. Routine quantification of rheumatoid factor by rate nephelometry. Ann Rheum Dis 1985; 44:379.
  84. Larkin JG, Sturrock RD, Stimson WH. A rapid enzyme immunoassay for the detection of IgM rheumatoid factor--a comparison of "sero-negative" and "sero-positive" rheumatoid patients. J Clin Lab Immunol 1986; 20:207.
  85. Keshgegian AA, Straub CW, Loos EF, Grenoble BK. Rheumatoid factor measured with the QM300 nephelometer: clinical sensitivity and specificity. Clin Chem 1994; 40:943.
  86. Wolfe F. A comparison of IgM rheumatoid factor by nephelometry and latex methods: clinical and laboratory significance. Arthritis Care Res 1998; 11:89.