Rheumatoid factor (RF) is the
autoantibody that was first found in
rheumatoid arthritis. It is defined as an
antibody against the
Fc portion of
IgG and different RFs can recognize different parts of the IgG-Fc.[1] RF and IgG join to form
immune complexes that contribute to the
disease process such as chronic inflammation and joint destruction at the
synovium and
cartilage.[2]
Rheumatoid factor can also be a
cryoglobulin (antibody that precipitates on cooling of a blood sample); it can be either type 2 (
monoclonalIgM to
polyclonal IgG) or type 3 (polyclonal IgM to polyclonal IgG) cryoglobulin.
Although predominantly encountered as IgM, rheumatoid factor can be of any
isotype of
immunoglobulins; i.e., IgA, IgG, IgM,[3] IgE,[4] IgD.[5]
Testing
RF is tested by collecting blood in a plain tube (5 mL is often enough). The serum is tested for the presence of RF. There are different methods available, which include
nephelometry,
turbidimetry, agglutination of gamma globulin-coated latex particles or
erythrocytes. RF is often evaluated in patients suspected of having any form of
arthritis, even though positive results can be due to other causes and negative results do not rule out disease. In combination with signs and
symptoms, it can play a role in both diagnosis and disease
prognosis. It is part of the usual disease criteria of
rheumatoid arthritis.[6]
The presence of rheumatoid factor in serum can also indicate the occurrence of suspected autoimmune activity unrelated to rheumatoid arthritis, such as that associated with tissue or organ rejection. In such instances, RF may serve as one of several
serological markers for autoimmunity.[7] The sensitivity of RF for established rheumatoid arthritis is only 60 to 70 percente with a specificity of 78 percent.[8]
Rheumatoid factor is part of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis. RF positivity combines well with
anti-CCP and/or 14-3-3η (
YWHAH) to inform diagnosis.[9] RF positivity at baseline has also been described as a good prognostic marker for future radiographic damage.[10]
Interpretation
High levels of rheumatoid factor (in general, above 20
IU/mL, 1:40, or over the 95th
percentile; there is some variation among labs) occur in rheumatoid arthritis (present in 80%) and
Sjögren's syndrome (present in 50-70% of primary forms of disease).[11] The higher the level of RF the greater the probability of destructive articular disease.[citation needed] It is also found in
Epstein–Barr virus or
Parvovirus infection and in 5–10% of healthy persons, especially the elderly.
There is an association between rheumatoid factor and more persistently active synovitis, more joint damage, greater eventual disability and
arthritis.[12][13]
Other than in
rheumatoid arthritis, rheumatoid factor may also be elevated in other conditions, including:
The test was first described by Norwegian Dr
Erik Waaler in 1940 and redescribed by Dr
Harry M. Rose and colleagues in 1948. Redescription is said to be due to the uncertainties due to World War II. It is still referred to as the Waaler–Rose test.[19][20]
^Edkins A, Cushley W (2012). "The Jekyll and Hyde nature of antibodies". Biological Sciences Review. 25 (2): 4.
^Hermann, E; Vogt, P; Müller, W (1986). "Rheumatoid factors of immunoglobulin classes IgA, IgG and IgM: Methods of determination and clinical value". Schweizerische Medizinische Wochenschrift. 116 (38): 1290–7.
PMID3775335.
^Herrmann, D; Jäger, L; Hein, G; Henzgen, M; Schlenvoigt, G (1991). "IgE rheumatoid factor. Occurrence and diagnostic importance in comparison with IgM rheumatoid factor and circulating immune complexes". Journal of Investigational Allergology & Clinical Immunology. 1 (5): 302–7.
PMID1669588.
^Banchuin, N; Janyapoon, K; Sarntivijai, S; Parivisutt, L (1992). "Re-evaluation of ELISA and latex agglutination test for rheumatoid factor detection in the diagnosis of rheumatoid arthritis". Asian Pacific Journal of Allergy and Immunology. 10 (1): 47–54.
PMID1418183.
^Rostaing, Lionel; Modesto, Anne; Cisterne, Jean Marc; Izopet, Jacques; Oksman, Françoise; Duffaut, Michel; Abbal, Michel; Durand, Dominique (1998). "Serological Markers of Autoimmunity in Renal Transplant Patients with Chronic Hepatitis C". American Journal of Nephrology. 18 (1): 50–6.
doi:
10.1159/000013304.
PMID9481439.
S2CID6941129.
^Nishimura, K; Sugiyama, D; Kogata, Y; Tsuji, G; Nakazawa, T; Kawano, S; Saigo, K; Morinobu, A; Koshiba, M; Kuntz, KM; Kamae, I; Kumagai, S (5 June 2007). "Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis". Annals of Internal Medicine. 146 (11): 797–808.
doi:
10.7326/0003-4819-146-11-200706050-00008.
PMID17548411.
S2CID6640507.
^ Zhang Y, Liang Y, Feng L, Cui L. Diagnostic performance of 14-3-3η and anti-carbamylated protein antibodies in Rheumatoid Arthritis in Han population of Northern China. Clin Chim Acta. 2020 Mar;502:102-110. doi: 10.1016/j.cca.2019.12.011. Epub 2019 Dec 17. PMID: 31862264.
^ Bukhari M, Lunt M, Harrison BJ, Scott DG, Symmons DP, Silman AJ. Rheumatoid factor is the major predictor of increasing severity of radiographic erosions in rheumatoid arthritis: results from the Norfolk Arthritis Register Study, a large inception cohort. Arthritis Rheum. 2002 Apr;46(4):906-12. doi: 10.1002/art.10167. PMID: 11953966.
^Garcia-De La Torre, Ignacio (1993). "Autoimmune phenomena in leprosy, particularly antinuclear antibodies and rheumatoid factor". The Journal of Rheumatology. 20 (5): 900–3.
PMID8336322.
^Waaler, Erik (2009). "On the Occurrence of a Factor in Human Serum Activating the Specific Agglutination of Sheep Blood Corpuscles". Acta Pathologica et Microbiologica Scandinavica. 17 (2): 172–188.
doi:
10.1111/j.1699-0463.1940.tb01475.x. reproduced in Waaler, E (2007). "On the Occurrence of a Factor in Human Serum Activating the Specific Agglutintion of Sheep Blood Corpuscles". APMIS. 115 (5): 422–38, discussion 439.
doi:
10.1111/j.1600-0463.2007.apm_682a.x.
PMID17504400.
S2CID221426678.
^Rose, HM; Ragan, C (1948). "Differential agglutination of normal and sensitized sheep erythrocytes by sera of patients with rheumatoid arthritis". Proceedings of the Society for Experimental Biology and Medicine. 68 (1): 1–6.
doi:
10.3181/00379727-68-16375.
PMID18863659.
S2CID36340687.