Rheumatologic Laboratory Tests
Anne R. Bass
Keith B. Elkon
The laboratory studies outlined in this chapter are helpful in the diagnosis and treatment of rheumatic diseases. They should be interpreted in the context of a careful history and physical examination.
A test should be performed only if the results of the test will likely affect the diagnosis, prognosis, or therapy, and not if the results are of clinical or academic interest. Performing a large battery of screening tests, with no guidance from the specific clinical picture, will clearly lead to false-positive results and, possibly, incorrect diagnoses and treatments. One does not “chase” or “treat” a test but, rather, the patient and his or her entire clinical presentation. Tests are designated according to the context of an individual and his or her problems.
This chapter discusses erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), autoantibody tests, complement tests, and other tests helpful in the serologic evaluation of rheumatic diseases.
I. ERYTHROCYTE SEDIMENTATION RATE
The ESR (Westergren method) is a time-honored measurement of inflammation.
Method of detection. The ESR measures the rate of fall, in mm/h, of red blood cells (RBCs) in a standard tube. Prolonged storage of the blood to be tested, or tilting of the calibrated tube, will falsely increase the ESR.
Normal Westergren ESR values are 0 to 15 mm/h for male subjects and 0 to 20 mm/h for female subjects. The ESR increases with age, and values up to 40 mm/h are not uncommon in the healthy geriatric individual. In inflammatory disorders, RBCs tend to form stacks (rouleaux), and these stacks cause the red cells to sediment more rapidly. This stacking may result from increased levels of fibrinogen.
Measurement of the ESR can be helpful in evaluating the extent or severity of inflammation and in monitoring changes in disease activity over time. This test, however, cannot be used to definitely confirm or exclude any particular disease. Falsely low ESRs are found in sickle cell disease, anisocytosis, spherocytosis, polycythemia, and heart failure. Very high levels are seen in patients with monoclonal gammopathies.
II. C-REACTIVE PROTEIN
The CRP is an acute-phase reactant serum protein that is present in low concentration in normal serum. It was originally identified by its precipitin reaction with pneumococcal C polysaccharide.
Method of detection. CRP is most commonly measured using an immunoassay or laser nephelometry.
CRP levels rise rapidly in response to an inflammatory stimulus (especially that provided by interleukin-6) and then fall when the inflammation subsides. Normal levels for healthy adults are less than 0.2 mg/dL, although levels of up to 1 mg/dL are not uncommon. Moderate elevations (1 to 10 mg/dL) in CRP levels can be seen in inflammatory conditions such as rheumatoid arthritis (RA) and giant cell arteritis. Elevations of greater than 15 to 20 mg/dL are generally seen in bacterial infections.
Although serum CRP levels are elevated in some patients with active systemic lupus erythematosus (SLE), most patients with lupus show only modest or no CRP elevation, even in the presence of active disease. Highly elevated CRP levels in patients with SLE should prompt consideration of a superimposed infection, although an elevated CRP level is not a definite proof of infection in these patients.
I. RHEUMATOID FACTOR (RF)
RFs are immunoglobulins with specificity for the Fc portion of immunoglobulin G (IgG). Multiple immunoglobulin classes have RF activity, but the RF detected by standard laboratory testing is an IgM antibody.
Method of detection. There are many methods to measure RF. Those most commonly used include the enzyme-linked immunosorbent assay (ELISA), agglutination of IgG-coated latex particles, or nephelometry.
Interpretation. Fifty percent to 75% of patients with RA have IgM RF, as do 3% to 5% of healthy subjects. RF positivity is associated with the HLA-DR4 haplotype and with more aggressive disease. Patients with extra-articular disease are invariably RF positive. IgM RFs are also commonly seen in patients with primary Sjögren’s syndrome, and mixed cryoglobulinemia, as well as in patients with chronic infections such as subacute bacterial endocarditis and chronic hepatitis (Table 4-1).
II. ANTICYCLIC CITRULLINATED PEPTIDE ANTIBODIES (ANTI-CCP)
Citrulline is formed by the deamination of the amino acid arginine. Antibodies directed against citrullinated peptides have been found in the serum of many patients with RA.
Method of detection. ELISA detection of antibodies to citrullinated antigens is the technique that is most commonly utilized.
Interpretation. The sensitivity of this test in patients with RA is 40% to 70%, but the specificity may be as high as 98%. In patients with undifferentiated arthritis, the
presence of anti-CCP antibodies is an important predictor for RA. Ninety-three percent of such patients will develop RA within 3 years. Some, but not all, patients with anti-CCP antibodies will also have a positive RF. Similarly, some, but not all, patients with a positive RF will have anti-CCP antibodies. The presence of both RF and anti-CCP best predict a poorer radiologic and functional outcome for patients with RA.
Table 4-1 Frequency of Rheumatoid Factor as Measured by Latex Agglutination
Approximate frequency (%)
Subacute bacterial endocarditis
Chronic interstitial pulmonary fibrosis
Systemic lupus erythematosus
Waldenström’s disease (macroglobulinemia)
Mixed connective tissue disease
Systemic sclerosis (scleroderma)
Elderly patients (>60 y)
Juvenile idiopathic arthritis
III. ANTINUCLEAR ANTIBODIES (ANA)
The production of antibodies to a wide array of nuclear antigens is characteristic of lupus and the other connective tissue diseases. Because the ANA test detects any antibody binding to nuclear constituents, it is extremely useful as a screening test for these diseases.
Method of detection. Indirect immunofluorescence assay (IFA) is the most common method of ANA testing. This technique employs a cellular substrate, now most commonly a human epithelial cell line (Hep-2), which is placed on a glass slide. The patient’s serum is then applied (allowing autoantibodies to bind to the Hep-2 cells) and then tagged with a fluorescent-labeled anti-Fc IgG, which can then be visualized under a microscope.
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