Clinical Information

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by interactions between the environment, specific genetic risk factors, and the human immune system. It affects about 0.6% of the United States population with a global prevalence of 0.24%.(1) Clinically, RA is typified by progressive damage of synovial joints, inflammation, production of diverse autoantibodies, and variable extra-articular manifestations.(1,2) To facilitate early diagnosis, the American College of Rheumatology/European League Against Rheumatism 2010 RA classification criteria recommend testing for rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPA).(2) RF are autoantibodies directed against the Fc portion of immunoglobulin, while ACPA are directed against peptides and proteins containing citrulline, a modified form of the amino acid arginine.(3,4) In addition to the defined interpretations for anti-cyclic citrullinate peptide (CCP) and RF antibodies, the classification criteria also endorse the combination of specific clinical features and inflammatory markers for RA diagnosis.

The clinical symptoms in the early phase of RA may be nonspecific with some patients demonstrating relatively low levels of antibodies to RF or anti-CCP antibodies, which may not fulfill the diagnostic criteria for disease. In addition, some patients with clinical features of RA may test negative for criteria antibodies, a phenomenon referred to as seronegative or ACPA-negative. While alternative diagnoses may be implicated in at-risk RA patients, determination of autoantibody isotypes for RF and other RA-associated autoantibodies have been reported to improve diagnostic accuracy and/or provide prognostic clues.(5-8) Thus, determination of multiple analytes of diverse antibody isotypes in patients seropositive for RA may be useful in risk stratification for joint erosive disease and other clinical manifestations such as cardiovascular or lung involvements.(5,7,8)

In routine clinical laboratory evaluation for RA, RF antibodies are generally detected and quantified using IgM RF or total (isotype-nonspecific) RF immunoassays and CCP IgG antibodies with a variety of solid-phase immunoassays, such the enzyme linked immunosorbent assay, chemiluminescence immunoassay (CIA), fluorescent enzyme immunoassay (FEIA), multiplexed immunoassay using manual or automated platforms.(5,6,9,10) With respect to RF antibody measurements, it has been established that separate determination of RF IgA and RF IgM antibodies is important in RA evaluation, as severe joint erosive disease is seen more in patients with significantly elevated IgA RF than in those who are IgA RF negative.(5,8,9) However, IgA RF is generally less sensitive than IgM RF for RA, and double positivity for IgM RF and IgA RF has a higher specificity for RA than either IgM RF or IgA RF.(9) Both tests should be offered in a panel, which is not intended to replace RF tests that detect IgA, IgG and IgM autoantibodies. The relevance of IgG RF in addition to IgA or IgM RF is of limited clinical value and not available for testing on the CIA or FEIA platforms due to this clinical limitation.