Diagnostic Evaluation of Rheumatoid Arthritis
المؤلف:
Mary Louise Turgeon
المصدر:
Immunology & Serology in Laboratory Medicine
الجزء والصفحة:
5th E, P428-429
2025-10-05
127
Low serum iron levels and a normal or low iron-binding capacity are common features in RA. The ESR is elevated to a variable degree in most RA patients and roughly parallels the level of disease activity. Serum protein electrophoresis may demonstrate elevations in the alpha-2 and gamma globulin fractions, with a mild to moderate decrease in serum albumin. The gamma globulin increase is polyclonal.
Immunologic features of RA include RF, anti–cyclic citrullinated peptide (anti-CCP), immune complexes, characteristic complement levels, and ANAs. For example, patients with Felty’s syndrome, the association of RA with splenomegaly and leukopenia, almost always develop a high-titer rheumatoid fac tor assay, a positive ANA assay, and rheumatoid nodules. In addition, these patients have a high titer of immune complex and low total serum complement levels.
Rheumatoid Factor
RFs are immunoglobulins of any isotype with antibody activity directed against antigenic sites on the Fc region of human or animal IgG. RFs have been associated with three major immunoglobulin classes, IgM, IgG, and IgA. IgM and IgG RFs are the most common.
Immunoglobulin M rheumatoid factor is manifested in approximately 70% of adults but is not specific for RA. Being RF-positive correlates with the following:
• Severity of the disease (in general)
• Nodules
• Other organ system involvement (e.g., vasculitis, Felty’s syndrome, Sjögren’s syndrome)
Agglutination tests for RF, such as the sensitized sheep cell test and latex agglutination, generally detect IgM RFs. Latex agglutination is sensitive but can produce a fairly high number of false-positive results. Because conventional procedures are semiquantitative, they may be insensitive to changes in titer and may detect only those RFs that agglutinate. Immunoturbidimetric assays and enzyme-linked immunosorbent assays (ELISAs) are automated methods of analysis. The presence of abnormal levels of all three RF isotypes—IgM, IgG, and IgA—has a specificity of 99% for RA.
Rheumatoid factor has been associated with some bacterial and viral infections, including hepatitis and infectious mononucleosis, and some chronic infections, such as tuberculosis, parasitic disease, subacute bacterial endocarditis, and cancer. Elevated values may also be observed in the normal older population. The concentration of RF tends to be highest when the disease peaks and tends to decrease during prolonged remission.
Cyclic Citrullinated Peptide Antibodies
CCP antibodies are a highly specific indicator for RA. Anti bodies to CCPs (anti-CCP1) were first described in 1998 and, following the introduction of commercial ELISA products using the so-called second-generation peptides (CCP2), there has been increased interest in using this marker in the diagnosis of RA. Anti—CCP IgG antibodies are present in about 69% to 83% of patients with RA and have specificities ranging from 93% to 95%. These autoantibodies may be present in the preclinical phase of disease, are associated with future RA development, and may predict radiographic joint destruction. Antibodies can be detected in sera from individuals up to 14 years before the first clinical symptoms of RA appear.
Compared with other assays for RF, CCP is considered to be more sensitive. This antibody is reported to have high specificity (>95%) and sensitivity (80%) for RA. Early diagnosis and effective treatment provide a window of opportunity for controlling this autoimmune disease. Anti-CCP and rheumatoid factor assays constitute a rheumatoid arthritis panel.
Autoantibodies against mutated and citrullinated vimentin (MCV), a member of the citrullinated protein family, are highly specific markers for RA. A lateral flow immunoassay (LFIA) for the qualitative detection of anti-MCV antibodies, anti MCV ELISA (ORGENTEC Diagnostics, Mainz, Germany) has been developed as a point of care test.
Other Markers
Antibodies to anti–perinuclear factor (APF) and keratin (anti keratin antibody [AKA]) are highly specific for RA. Antibodies to APF are reported to be present in the sera of 49% to 91% of RA patients, with specificity greater than 70%.
Immune Complexes
Soluble circulating immune complexes and cryoprecipitable proteins consisting of immunoglobulins, complement components, and RFs are demonstrable in the sera of some patients with RA. Anti–gamma globulin isotypes, IgM, IgG, and IgA classes, are important complexes.
The IgA, IgM, and IgG isotypes of RF are detected years before any symptoms of RA become apparent. The various vascular and parenchymal lesions of RA suggest that the lesions result from injury induced by immune complexes, especially those containing antibodies to IgG. Vasculitis is associated with complexes made up of IgG and 7S IgM RFs. A positive laboratory assay for mixed cryoglobulins indicates the presence of a large number of immune complexes and is associated with an increased incidence of extra-articular manifestations, particularly vasculitis.
Complement Levels
Serum complement levels are usually normal in patients with RA, except in those with vasculitis. Hemolytic complement levels are reduced in the serum of less than one third of patients, especially in patients with very high levels of RF and immune complexes. Levels of C4 and C2 are most profoundly depressed in these patients.
Antinuclear Antibodies
Antinuclear antibodies have been found in 14% to 28% of RA patients, who usually have advanced disease. However, disease manifestation is the same in ANA-positive and ANA-negative patients.
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