Figure 1 IgG molecule and production of two Fab-fragments and one Fc-fragment after cleavage with papain.
Blue: heavy chains; Red: light chains; Green-yellow bars: disulfide bonds; ch, vh, cl, vL constant and variable regions of heavy and light chains, respectively. The numbers on the left indicate relevant amino acids. The rheumatoid factors bind to the Fc-fragment of IgG (lower part of Figure on the right).

Immunoglobulins which bind to the Fc region of IgG are called RF and are characteristically present in the serum of rheumatoid arthritis (RA) patients. The ”classical” RF determined by means of agglutination assays is found in about 70-90% of patients with RA and is one of the seven diagnostic criteria for RA proposed by the American Rheumatism Association (Table 4) (5)

Table 4 American rheumatism association criteria for rheumatoid arthritis classification revised in 1987

Note: For classification purposes, a patient has RA if at least 4 of these criteria are satisfied (criteria 1-4 must have been present for at least 6 weeks)

Figure 2 Diagram for monitoring the disease course in RA and documenting affected (destroyed) joints

Nevertheless, RF may also be found at lower frequency in certain other diseases (Table 4) (6, 7), whereby the highest titers of RF are often seen in patients with conditions such as Sjögren's syndrome or macroglobulinemia who have no signs of inflammatory arthritis. The absence of RF in the presence of progressive RA is seen in about 10-30% of patients who are classified as “seronegative”.
Although seronegative RA may be less severe than “seropositive” disease, many people with seronegative disease developed radiographic progression, functional decline and even premature mortality characteristic of RA. Perhaps most importantly, RF is detectable in only 33% of patients who ultimately become “seropositive” during the first 3 months of disease, and in only 60% during the first 6 months (8). Therefore, a test for RF is least likely to be positive in early disease when it might be most helpful to the clinician. This is particularly important in view of mounting evidence that patients with RA should be treated early, prior to end-organ damage, when RF is as likely to be negative as positive.
In contrast, RF has often been misinterpreted as being diagnostic for RA. However, a false-positive RF is found in many diseases, including sarcoidosis, leprosy, tuberculosis, pulmonary fibrosis, liver disease and syphilis (Table 5).

Table 5 Incidence of the classical rheumatoid factor positivity