Last updated: October 13, 2014
Description: RFs are autoantibodies that react with the Fc portion of IgG. The major immunoglobulin classes are capable of demonstrating RF activity, but the usual routine laboratory assays detect primarily IgM RF.
Methods: Classically, IgM RF in serum is detected by agglutination of IgG-coated particles. The source of IgG may be human or rabbit because human IgM RF reacts with IgG molecules from various species. The particles may be latex beads or tanned erythrocytes. Addition of test serum in graded amounts (dilutions) may lead to agglutination of the coated particles and a positive result. The most dilute serum concentration that causes agglutination is the titer reported. The Rose-Waler test or sensitized sheep cell agglutination test was used previously. Although less sensitive, it was more specific than current assays. The specificity of the sheep cell agglutination test has been replaced by anti-CCP antibodies that are more specific than RF (for RA) but have comparable sensitivity.
Other, more quantitative techniques include measurement of complexes that form between IgM RF and IgG by rate nephelometry or by capture of IgM RF on IgG-coated plastic wells, detected using enzyme-linked reagents (e.g., enzyme immunoassay, ELISA). Results from these assays may be reported in international units using standardized reagents. Normal ranges should be supplied for each assay.
Normal Values: RF is normally not detected.
Clinical Associations: RF is found in a variety of conditions (Table 16).
—RA: Approximately 80% of patients with RA are seropositive for RF. The remaining 20% are said to be seronegative. Distinction between seropositive and seronegative RA has been considered of some importance because patients without RF are thought to have milder disease and a less severe disease course. Nonetheless, some of the more severe extraarticular manifestations of RA, such as vasculitis and nodules, occur almost exclusively in high-titer seropositive patients. Treatment with some second-line drugs, notably gold salts and penicillamine, can lower or abolish RF positivity, whereas others (e.g., cyclosporine) do not affect RF titers.
—Other conditions: RF can be detected in patients with diseases other than RA (Table 16). These disorders can be grouped into four major categories: immune system disorders, infections, malignancies, and other miscellaneous conditions. These processes suggest that long-term stimulation of the immune system may lead to production of RF.
—Normals: RF positivity is seen in 5% of healthy, young individuals and as many as 15% of elderly individuals. These “normal” individuals are not more likely to develop RA or arthritis. More sensitive techniques (radioimmunoassay, ELISA) can demonstrate RF production by mitogen-stimulated blood mononuclear cells from normal individuals, indicating that this autoantibody is part of the normal immune repertoire. Furthermore, sequences encoding immunoglobulins with RF activity exist in the normal human genome. These findings suggest that RF has an important role in the normal immune response, perhaps enhancing clearance of infectious agents or senescent cells from the circulation.
|Table 16: Conditions Associated with Rheumatoid Factor Positivity|
|Immune system disorders|
|Systemic lupus erythematosus|
|Subacute bacterial endocarditis|
|Parasitic diseases (e.g., leishmaniasis)|
|Interstitial pulmonary fibrosis|
|Chronic liver disease|
|Chronic renal disease|
Confounding Factors: Prevalence of RF positivity increases with age. Some patients with cryoglobulinemia, monoclonal paraproteinemias, or very high lipid levels may demonstrate RF activity.
Indications: RF is not specific for RA but can be seen in a wide variety of other conditions. Therefore, RF measurement should be ordered intelligently and reserved for individuals with possible RA based on the history and physical examination. Even in these situations, RF positivity should not be overinterpreted. RF should only be used as a confirmatory rather than screening test. For example, in patients with arthralgia only and a low pretest probability (i.e., 1%) of having RA, a positive RF result has a positive predictive value of 7% (only seven patients in 100 with a positive result are likely to have RA). Conversely, in patients with recent-onset symmetric polyarthritis of the knees and wrists and a moderate likelihood (pretest probability = 50%) of having RA, a positive test result has a positive predictive value of 89% (89 in 100 patients are likely to have RA).
Comment: High levels of RF somewhat increase the specificity of the RA test but do not correlate with more severe disease or with fluctuations of disease activity in an individual patient. Therefore, measurement of serial RF levels is rarely, if ever, indicated. Exceptions are during the first year of disease, when conversion from seronegativity to seropositivity may occur or with long-term use of some second-line drugs (as noted above), when conversion to seronegativity may correlate with a good therapeutic response. Some of the very highest RF titers are seen not in patients with RA but in those with other disorders such as Sjögren syndrome, macroglobulinemias, or leishmaniasis. In these patients, titers may exceed 1:10,000 using the latex-agglutination test.
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