Rheumatoid factors are antibodies directed against the Fc region of immunoglobulin G. First detected in patients with rheumatoid arthritis 70 years ago, they can also be found in patients with other autoimmune and nonautoimmune conditions, as well as in healthy subjects. Rheumatoid factors form part of the workup for the differential diagnosis of arthropathies. In clinical practice, it is recommended to measure anti-cyclic citrullinated peptide antibodies and rheumatoid factors together because anti-cyclic citrullinated peptide antibodies alone are only moderately sensitive, and the combination of the two markers improves diagnostic accuracy, especially in the case of early rheumatoid arthritis. Furthermore, different rheumatoid factor isotypes alone or in combination can be helpful when managing rheumatoid arthritis patients, from the time of diagnosis until deciding on the choice of therapeutic strategy. 1. Introduction Rheumatoid factors (RFs), a class of immunoglobulins (Igs) that have different isotypes and affinities, were first detected more than 70 years ago, but there is still much to discover about the mechanisms underlying their production, physiological role, and pathological effects [1]. Waaler described an antibody directed against serum gamma-globulins that promoted the agglutination of sheep red blood cells sensitised by subagglutinating doses of rabbit antibodies in 1940 [2], although it had actually been previously found in patients with liver cirrhosis and chronic bronchitis by Kurt Meyer in 1922. In 1948, Rose described these antibodies in patients with rheumatoid arthritis (RA) [3], and in 1952 they were finally christened RFs because of their association with RA [4]. However, although they owe their name to their first detection in RA patients, RFs are found in patients with other autoimmune and nonautoimmune diseases, as well as-in healthy subjects. The aim of this review is to describe the clinical applications of testing for RFs. 2. Methods of Detection Classic agglutination techniques were initially used because of the ability of IgMs to induce agglutination. The first RF detection assay was based on the fact that RF agglutinates sheep red blood cells sensitised with rabbit IgGs (i.e., the classic Waaler-Rose test) [2, 3], and this was followed by the development of other IgG carriers such as bentonite [5, 6] and latex particles [7, 8]. Automated techniques such as nephelometry and enzyme-linked immunosorbent assays gradually replaced the other semiquantitative methods because of their simplicity and greater reproducibility
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