Rheumatoid factor (RF) is an anti-γ-globulin antibody thought to be directed against the Fc portion of the immunoglobulins. A large portion of patients with rheumatoid arthritis (RA) are RF positive, but the role RF plays in RA is uncertain. About 25% of patients with RA are RF negative but may become positive later in their disease course. In addition to RA, RF can be seen in systemic lupus erythematosus (SLE), chronic inflammatory processes, old age, infections, liver disease, multiple myeloma, sarcoid, and Sjögren’s syndrome.

RF can involve different immunoglobulin classes, giving IgM, IgG, and IgA, and in some cases IgD and IgE as well. Different subclasses of antibody can also be involved, such as IgA1 and IgA2 rheumatoid factors. Most tests detect IgM rheumatoid factor. There is some evidence that IgA rheumatoid factor is more related to joint destruction. RF positivity goes with worse disease and poorer outcome in RA and is associated with subcutaneous nodules, vasculitis, and other extra-articular features. Osteoarthritis, gout, and psoriatic arthritis should all be negative on tests for RF. It is thus apparent that the specificity of RF in differentiating RA from some other rheumatologic conditions is poor. However, with higher titers of RF the specificity increases, and RF testing becomes a more useful laboratory tool. Higher titers are also associated with more aggressive and erosive disease. Of note, 20% to 30% of RA patients test negative for RF and yet have the clinical picture with a potentially poor prognosis when not treated. RF may appear up to several years before the onset of clinical RA.