(Study type: Blood collected in a gold-, red-, or red/gray-top tube; related body system: Immune and musculoskeletal systems.)

Rheumatoid factor (RF) is a term used for autoantibodies directed against the Fc fraction of an individual’s IgG antibodies. The RF autoantibodies that develop are usually IgM but can also be IgG or IgA antibodies. RF was the first major biomarker to be associated with rheumatoid arthritis (RA). Many musculoskeletal and chronic inflammatory conditions may also produce RF. Blood is the preferred specimen, but RF can also be detected in pericardial, pleural, and synovial fluids. Women are two to three times more likely than men to develop RA. Although RA is most likely to affect people ages 35 to 50 yr, it can affect all ages.

RA is a chronic, systemic autoimmune disease that damages the synovium or membrane surrounding the joints. Collagen, the main fibrous protein in tendons, bone, and other types of connective tissue, is gradually destroyed, narrowing the joint space. As the disease progresses, a pannus or growth of thickened synovial tissue forms and permeates the bone and cartilage, leading to permanent damage and joint deformity. Inflammation caused by autoimmune responses can affect other organs and body systems. The American College of Rheumatology’s (ACR) current criteria focus on earlier classification of newly presenting patients who have at least one swollen joint unrelated to another condition. The criteria include four determinants:

1. Joint involvement (number and size of joints involved)
2. Serological test results (RF and/or anticitrullinated protein antibody [ACPA])
3. Indications of acute inflammation (C-reactive protein [CRP] and/or erythrocyte sedimentation rate [ESR])
4. Duration of symptoms (weeks)

Each determinant includes specific criteria with assigned values (e.g., duration of symptoms less than 6 wk = 0, duration of symptoms equal to or greater than 6 wk = 1). The scores from each determinant are added together. A score of 6 of 10 or greater for the score-based algorithm defines the presence of RA. Patients with longstanding RA, whose condition is inactive, or whose prior history would have satisfied the previous classification criteria by having four of seven findings—morning stiffness, arthritis of three or more joint areas, arthritis of hand joints, symmetric arthritis, rheumatoid nodules, abnormal amounts of rheumatoid factor, and radiographic changes—should remain classified as having RA. The ACR favors the consideration of classification criteria rather than endorsement of diagnostic criteria for RA because of the difficulty in establishing a consistent set of criteria. The study of RA is complex, and it is believed that multiple genes may be involved in the manifestation of RA. The diagnosis of RA is made for patients on an individual basis by considering the ACR’s classification criteria, in the presence of additional information unique to the patient, and the patient’s genetic predisposition, lifestyle, and environment. The study of RA is complex, and it is believed that multiple genes may be involved in the manifestation of RA. Individuals with RA harbor a macroglobulin-type antibody called rheumatoid factor in their blood. Patients with other diseases (e.g., systemic lupus erythematosus [SLE] and occasionally tuberculosis, chronic hepatitis, infectious mononucleosis, and subacute bacterial endocarditis) may also test positive for RF. RF antibodies are usually immunoglobulin M (IgM) but may also be IgG or IgA. Women are two to three times more likely than men to develop RA. Although RA is most likely to affect people aged 35 to 50 yr, it can affect all ages.

Other serum markers for RA: Studies show that detection of antibodies formed against citrullinated peptides is specific and sensitive in detecting RA in both early and established disease. Numerous specificity and sensitivity studies have demonstrated strong association between anticyclic citrullinated peptide (anti-CCP) antibodies and RA. The combination of anti-CCP antibodies and RF provides even greater value for identifying both early and established RA. Anti-CCP antibodies have been detected in healthy patients years before the onset of RA symptoms and diagnosed disease. Some studies have shown that as many as 40% of patients seronegative for RF are anti-CCP positive. For additional information, refer to the study titled, “Anticyclic Citrullinated Peptide Antibody.” The 14-3-3 eta protein is a proinflammatory biomarker associated with joint erosion and RA; research studies have demonstrated that levels are elevated in both early and established RA, similar to anti-CCP antibodies.