Rheumatoid Factor

Antibodies directed against the Fc fragment of immunoglobulin G (IgG) are called rheumatoid factors (RFs). They are heterogenous and usually composed of immunoglobulin M (IgM). Because of this, most assays detect only IgM. RFs are used as a marker in individuals with suspected rheumatoid arthritis (RA) or other autoimmune conditions. ^{[1, 2, 3, 4, 5]}

Normal findings are negative (ie, < 60 U/mL by nephelometric testing). Values may be slightly higher in elderly patients. ^[6]

Rheumatoid factor (RF) is used in the diagnosis of rheumatoid arthritis (RA). RF results are positive in approximately 75% of patients with RA, although RF is not etiologically related to RA. ^[7]

High RF titers indicate a poorer prognosis, as patients with higher RF levels tend to have more severe disease. Patients with nodules or clinical evidence of vasculitis usually have positive RF results.

Low levels of RF can even be found in healthy patients, and the test is positive in up to 20% of older individuals. ^[4]

Collection details are as follows:

• Specimen type - Serum

• Container/tube - Red top, gold top or tiger top preferred (gel- bottom tube best, but any serum-type tube adequate)

• Specimen volume - 1 mL, 0.5 mL minimum ^[8]

• Reject specimens in cases of gross lipemia ^[8]

• Specimen stability – Refrigerated (preferred) 14 days, ambient 14 days, frozen 14 days

• Test often included in autoimmune panels

Rheumatoid factor (RF) has historically been measured with all the following assays: Agglutination of sheep RBCs that have been sensitized with rabbit IgG, radioimmunoassays and enzyme immunoassays, and agglutination of polystyrene latex particles coated with human IgG. No assay has been proven to be better than another, and, lack of standardization between tests leads to variability in results.

Description

Immunoglobulin M (IgM) autoantibodies against the Fc fragment of immunoglobulin G (IgG) are called rheumatoid factors (RFs). These proteins are produced by B cells and can be found circulating in the blood. Their role is unknown in both healthy individuals and in those with rheumatoid arthritis. Approximately 60-80% of individuals with rheumatoid arthritis (RA) have RF present during the course of their disease. However, RF results are positive in less than 40% of patients with early RA. RF levels vary based on disease activity, though even patients with drug-induced remissions generally retain high titers of RF.

A study by Mouterde et al indicated that in patients with early arthritis, the disease demonstrates, in those who are seronegative for rheumatoid factor (RF) and anti–citrullinated protein autoantibodies (ACPAs), less activity at baseline and, at 3-year follow-up, less radiographic progression than it does in seropositive patients. ^[9]

RF is also present with other connective-tissue diseases, autoimmune disorders, and proinflammatory states. For example, RF is found in 52% and 98% of individuals with primary or secondary Sjögren syndrome (an autoimmune disease), respectively, existing even in the absence of RA. Moreover, it has been reported that low-titer RF positivity can occur in the inflammatory disease sarcoidosis, while abnormally high RF levels can exist in the presence of leukemia, multiple myeloma, and other cancers. ^{[10, 11]}  RF is also observed in 1-5% of healthy individuals. Thus, RF is not considered specific for RA.

RF results may also be positive in patients without RA who have the following conditions:

Systemic lupus erythematosus

Polymyositis

Tuberculosis

Syphilis

Viral hepatitis

Infectious mononucleosis

Influenza

Indications/Applications

RA is a chronic, autoimmune, peripheral polyarthropathy of unknown etiogenesis. The diagnosis of RA is made via clinical, laboratory, and imaging features, as no test results are pathognomonic. For patients with suspected RA, the following studies are potentially useful:

• Erythrocyte sedimentation rate (ESR)

• C-reactive protein (CRP)

• Complete blood cell (CBC) count

• RF assay

• ANA assay

• Anticyclic citrullinated peptide antibody (anti-CCP) assay (currently used in the 2010 American College of Rheumatology/European League Against Rheumatism [ACR/EULAR] classification criteria)

• Anti-RA33 antibody assay

Considerations

False-negative and false-positive results are common in patients without RA, as well as those with RA; patients without RA have an 8% rate of false results, whereas patients with RA have a 15% rate.

RF results may be positive in patients without RA who have the following conditions:

Systemic lupus erythematosus

Polymyositis

Tuberculosis

Syphilis

Viral hepatitis

Infectious mononucleosis

Influenza

Because of its poor specificity and poor positive predictive value, RF is only one test used to diagnose RA and must be ordered judiciously and with purpose. ^[4]

A study by Jeong et al suggested that the presence of rheumatoid factor (RF) may be associated with an increased risk for critical coronavirus disease 2019 (COVID-19). Of 245 patients hospitalized for COVID-19, the investigators found that 51 (20.8%) were RF positive. Moreover, the rates of invasive mechanical ventilation and death were higher in RF-positive patients than in those who were RF negative (70.6% vs 28.4%, and 45.1% vs 18.6%, respectively). The odds ratio (OR) for critical COVID-19 in the presence of RF was 7.31. The quick COVID-19 Severity Index (qCSI) and lactate dehydrogenase (LDH) were also linked to in-hospital mortality, and the investigators stated that when combined, “RF, qCSI, and LDH showed good prognostic value … for critical COVID-19.” ^[12]