American Academy of Family Physicians


Journals  > American Family Physician
Vol.65/No. 6 (March 15, 2002)
<http://www.aafp.org/afp/20020315/contents.html>

American Family Physician

*Clinical Utility of Common Serum Rheumatologic Tests*

STEPHEN K. LANE, M.D., and JOSEPH W. GRAVEL, JR., M.D.
Tufts University Family Practice Residency, Malden, Massachusetts

Serum rheumatologic tests are generally most useful for confirming a
clinically suspected diagnosis. Testing for rheumatoid factor is
appropriate when rheumatoid arthritis, Sjogren's syndrome or
cryoglobulinemia is suspected. Antinuclear antibody testing is highly
sensitive for systemic lupus erythematosus and drug-induced lupus.
Anti­double-stranded DNA antibodies correlate with lupus nephritis; the
titer often corresponds with disease activity in systemic lupus
erythematosus. Testing for anti-Ro (anti-SS-A) or anti-La (anti-SS-B)
may help confirm the diagnosis of Sjogren's syndrome or systemic lupus
erythematosus; these antibodies are associated with the extraglandular
manifestations of Sjpgren's syndrome. Cytoplasmic antineutrophil
cytoplasmic antibody testing is highly sensitive and specific for
Wegener's granulomatosis. Human leukocyte antigen-B27 is frequently
present in ankylosing spondylitis and Reiter's syndrome, but the
background presence of this antibody in white populations limits the
value of testing. An elevated erythrocyte sedimentation rate (ESR) is a
diagnostic criterion for polymyalgia rheumatica and temporal arteritis;
however, specificity is quite low. ESR values tend to correlate with
disease activity in rheumatoid arthritis and may be useful for
monitoring therapeutic response. (Am Fam Physician 2002;65:1073-80.
The American Academy of Family Physicians.)

Many serum rheumatologic tests have been available for fewer than 10
years. As a result, some physicians are not fully aware of the
indications, sensitivity, specificity, cost and clinical utility of
these tests. Several studies have suggested that overuse of common serum
rheumatologic tests, including antinuclear antibody (ANA) and rheumatoid
factor (RF) measurements, leads to unnecessary referrals and further
laboratory work-ups.^1,2 Failure to use these tests in a knowledgeable
and thoughtful manner can result in diagnostic confusion and increased
costs.

Rheumatoid factor is present in approximately 80 percent of patients
with rheumatoid arthritis.

*Definition of Terms*

The essential attributes of a test are its sensitivity, specificity, and
positive and negative predictive values. Sensitivity refers to the
proportion of patients with a disease who have a positive test result.
Specificity refers to the proportion of patients without the disease who
have a negative test result.

Predictive value refers to the likelihood of disease or nondisease based
on a positive or negative test result. A positive result on a test with
a high positive predictive value indicates that the patient probably has
the disease in question. Similarly, a test with a high negative
predictive value indicates that the patient with a negative test result
most likely does not have the disease in question.

Sensitivity and specificity are independent of disease prevalence,
whereas predictive value is markedly affected by disease prevalence. For
example, the predictive value of a positive rheumatologic test in
patients with polyarthralgia is likely to be higher in a rheumatology
practice than in a family physician's office. This fact emphasizes the
importance of limiting testing to patients with a reasonable pretest
possibility of disease. As the pretest probability increases, so does
the clinical utility of a given test.

*Rheumatoid Factor*

The RF detected by standard laboratory testing is an IgM antibody
directed against the Fc (crystallizable fragment) portion of IgG.
Laboratory tests are capable of detecting other classes of rheumatoid
factors (e.g., IgG and IgA); however, these tests are not widely used
clinically.

A number of rheumatic and nonrheumatic conditions are associated with
positive RF tests /(Table 1)/. RF is present in approximately 80
percent of patients with rheumatoid arthritis. RF testing is also
commonly positive in patients with Sjogren's syndrome or
cryoglobulinemia. Nonrheumatic conditions frequently associated with the
presence of RF include bacterial endocarditis, tuberculosis, sarcoidosis
and malignancies. The prevalence of RF in healthy elderly patients may
be as high as 10 percent, although the titer is usually low (1:40 or
lower).

TABLE 1
*Conditions Associated with a Positive Rheumatoid Factor Test*

------------------------------------------------------------------------

*Rheumatic conditions          (prevalence)*
Rheumatoid arthritis            (50 to 90%)
Systemic lupus erythematosus    (15 to 35%)
Sjogren's syndrome              (75 to 95%)
Systemic sclerosis              (20 to 30%)
Cryoglobulinemia                (40 to 100%)
Mixed connective tissue disease (50 to 60%)

*Nonrheumatic conditions*
Aging
Infection: bacterial endocarditis, liver disease, tuberculosis,
syphilis, viral infections (especially mumps, rubella and influenza),
parasitic diseases

Pulmonary disease: sarcoidosis, interstitial pulmonary fibrosis,
silicosis, asbestosis

Miscellaneous diseases: primary biliary cirrhosis, malignancy
(especially leukemia and colon cancer)

------------------------------------------------------------------------
/Adapted with permission from Shmerling RH, Delbanco TL. The rheumatoid
factor: an analysis of clinical utility. Am J Med 1991;91:528-34./
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TABLE 2
*Conditions Associated with a Positive Antinuclear Antibody Test*

------------------------------------------------------------------------
/Condition /                    /Sensitivity (%)*/
Drug-induced lupus                  100
Systemic lupus erythematosus         99
Scleroderma                          97
Sjögren's syndrome                  96
Mixed connective tissue disease      93
Polymyositis and dermatomyositis     78
Rheumatoid arthritis                 40
Systemic vasculitis                  15
Healthy old age                       5

------------------------------------------------------------------------
/*--Percentage of patients with a positive test./

/Adapted with permission from Peng SL, Hardin JA, Craft J. Antinuclear
antibodies. In: Kelley WN, et al, eds. Textbook of rheumatology. 5th ed.
Philadelphia: Saunders, 1997:250-66./

RF testing may be appropriate in patients suspected of having rheumatoid
arthritis. The test is most useful when there is a moderate level of
suspicion for rheumatoid arthritis. If clinical suspicion is low
(i.e., absence of joint inflammation), RF testing is unlikely to be
helpful because of the high incidence of false-positive results in the
general population. Even when clinical suspicion is high, 20 percent of
patients with rheumatoid arthritis are seronegative. Furthermore, up
to 40 percent of patients with rheumatoid arthritis may be seronegative
early in the course of the disease. RF testing in these circumstances
may influence the physician away from the true diagnosis.

In patients with rheumatoid arthritis, the RF titer generally correlates
with extra-articular manifestations and disease severity. RF testing may
have prognostic value in these patients. However, RF titers are not
helpful in following disease progression. Once a patient has a positive
RF result, repeating the test is of no value.

The specificity of RF for rheumatoid arthritis ranges from 80 to 95
percent, depending on the age and health of the population studied.
The sensitivity of RF ranges from approximately 10 percent in patients
with polymyositis to more than 90 percent in those with Sjögren's
syndrome or cryoglobulinemia.

RF testing is a useful screening tool when Sjogren's syndrome or
cryoglobulinemia is suspected. Serial RF measurements can be helpful in
patients with Sjogren's syndrome because the disappearance of RF may
herald the onset of lymphoma.

*Antinuclear Antibody*

Antinuclear antibody (ANA) testing involves the use of indirect
immunofluorescence to detect antibodies that bind to various nuclear
antigens. Most laboratories employ a HEp-2 cell line (a line of human
epithelial cells) as the substrate for this test. The sensitivity of ANA
tests can differ when other animal-based substrates are used.

ANAs are reported as titers, and higher values (greater than 1:320) are
more likely to represent true-positive results. Although titers of 1:20
or 1:40 are commonly reported as positive, patients with rheumatologic
syndromes rarely have such low titers.

ANA tests are frequently positive in patients with connective tissue
diseases /(Table 2)/. In systemic lupus erythematosus and drug-induced
lupus, the sensitivity of ANA testing approaches 100 percent; the
specificity for systemic lupus erythematosus is approximately 90 percent.

In systemic lupus erythematosus and drug-induced lupus, the sensitivity
of antinuclear antibody testing approaches 100 percent; the specificity
for systemic lupus erythematosus is approximately 90 percent.

ANA tests can be false-positive in many conditions, including rheumatoid
arthritis, subacute bacterial endocarditis, human immunodeficiency virus
infection, liver disease, malignancy, type 1 diabetes, pulmonary
fibrosis and multiple sclerosis. False-positive tests also occur in
patients with silicone gel implants, pregnant women and the elderly.

When an ANA test is positive, the nuclear staining pattern is frequently
reported. This pattern reflects the intracellular target of ANA. The
most commonly described nuclear staining patterns are homogeneous and
rim (both specific for systemic lupus erythematosus), speckled
(associated with Sjogren's syndrome and mixed connective tissue
disease), diffuse (nonspecific), nucleolar (associated with diffuse
scleroderma) and anti-centromere (highly specific for CREST syndrome
[*/c/*alcinosis cutis, */R/*aynaud's phenomenon, */e/*sophageal
dysmotility, */s/*clerodactyly and */t/*elangiectasias]). With more
specific autoantibody tests now available, nuclear staining patterns are
clinically less useful.

ANA testing is done primarily when systemic lupus erythematosus or
drug-induced lupus is suspected. In patient populations with a low
prevalence of systemic lupus erythematosus (i.e., the elderly), ANA
testing is unlikely to be useful because of its low positive predictive
value. ANA titers correlate poorly with disease activity; hence, serial
measurements are not recommended.

In rheumatoid arthritis, the erythrocyte sedimentation rate tends to
correlate with clinical disease activity, although joint examination is
far more useful in assessing synovitis.

Despite high sensitivity, a negative ANA test does not rule out systemic
lupus erythematosus. Rarely, patients with isolated anti-Ro (anti-SS-A)
antibodies or anti-single-stranded DNA (anti-ssDNA) have a negative ANA
test. Also, patients with the systemic lupus erythematosus­like
antiphospholipid syndrome may be ANA negative. Conversely, ANA results
are positive in 5 percent of tested women and older patients. In these
patients, the ANA titer is generally less than 1:320.

*Chromatin-Associated Antibodies*

*ANTI-DOUBLE-STRANDED DNA*

High titers of anti-double-stranded DNA (anti-dsDNA) antibodies are
highly specific for systemic lupus erythematous. However, only about 60
percent of patients with the disease have high anti-dsDNA titers.
Hence, absence of anti-dsDNA should not be used to exclude the diagnosis
of systemic lupus erythematous.

TABLE 3
*Factors That May Influence the Erythrocyte Sedimentation Rate**
------------------------------------------------------------------------

*Increase in erythrocyte sedimentation rate*
Old age
Female gender
Pregnancy
Anemia
Macrocytosis
Technical factors: dilutional problem, increased specimen temperature,
tilted tube
Elevated fibrinogen level: infection, inflammation, malignancy

*Decrease in erythrocyte sedimentation rate*
Extreme leukocytosis
Polycythemia
Sickle cell disease
Anisocytosis
Spherocytosis
Acanthocytosis
Microcytosis
Technical factors: dilutional problem, inadequate mixing, clotting of
blood sample, short tube, vibration during testing
Protein abnormalities: hypofibrinogenemia, hypogammaglobulinemia,
dysproteinemia with hyperviscosity state

------------------------------------------------------------------------
/*--Factors with no clinically significant effect or a questionable
effect include obesity, body temperature, recent meal and use of aspirin
or other nonsteroidal anti-inflammatory drugs./

/Adapted from Brigden ML. Clinical utility of the erythrocyte
sedimentation rate. Am Fam Physician 1999;60:1443-50./

Low titers of anti-dsDNA can be present in normal persons and in
patients with Sjogren's syndrome, rheumatoid arthritis and other
disorders. The presence of anti-dsDNA tends to correlate with lupus
nephritis, and the anti-dsDNA level often correlates with disease
activity in systemic lupus erythematosus.

Testing for anti-dsDNA may be useful in patients with a positive ANA
test and clinical suspicion (i.e., skin and/or joint involvement) for
systemic lupus erythematosus. Testing is not recommended in patients
with a negative ANA test.

Anti-ssDNA antibodies are nonspecific and have little clinical utility.

*ANTI-HISTONE*

Anti-histone antibodies are sensitive but nonspecific for drug-induced
lupus. Because these antibodies may also be present in patients with
systemic lupus erythematosus, testing has limited diagnostic utility.
However, anti-histone antibody testing may be useful in patients with a
positive ANA test and a history of exposure to medications associated
with drug-induced lupus, such as procainamide (Pronestyl) and isoniazid
(INH).

*Ribonucleoproteins*

*ANTI-SMALL NUCLEAR RIBONUCLEOPROTEINS*

Several autoantibodies against small nuclear ribonucleoproteins
(anti-snRNPs) have been described. Anti-Sm (anti-Smith) antibodies are
specific for systemic lupus erythematosus, although they are detected in
only 20 to 30 percent of such patients.

Anti-U1 snRNP is present in 30 to 40 percent of patients with systemic
lupus erythematosus and is associated with disease activity, myositis,
esophageal hypomotility, sclerodactyly, Raynaud's phenomenon,
arthralgias and arthritis. In addition, mixed connective tissue
disease is frequently defined by the presence of anti-U1 snRNP in
patients with features of multiple overlapping autoimmune diseases.
Testing for anti-U1 snRNP should be limited to patients with a positive
ANA test who are suspected of having systemic lupus erythematosus or
mixed connective tissue disease.

*ANTI-RO AND ANTI-LA*

Anti-Ro and anti-La (anti-SS-B) are commonly identified in patients with
Sjogren's syndrome, and their presence is associated with extraglandular
manifestations of the disease. Anti-Ro activity is also found in
approximately 40 percent of patients with systemic lupus erythematosus
and is associated with photosensitive skin rash, pulmonary disease and
lymphopenia. Anti-La activity is detected in 10 to 15 percent of
patients with systemic lupus erythematosus and is associated with
late-onset disease, secondary Sjogren's syndrome and neonatal lupus
syndrome.

Anti-Ro and anti-La testing may help to confirm the diagnosis of
Sjogren's syndrome. These tests may also be useful in patients with
a positive ANA test and suspected systemic lupus erythematosus.

*ANTI-RIBOSOME*

Anti-ribosome antibody is highly specific for systemic lupus
erythematosus, although it is present in only 10 to 20 percent of
patients with the disease. The antibody is also associated with lupus
psychosis. Testing, however, is rarely useful in diagnosing
central-nervous-system systemic lupus erythematosus.

*Scleroderma Antibodies*

*ANTI-CENTROMERE*

Anti-centromere antibodies are found in 22 to 36 percent of patients
with scleroderma. Their presence is correlated with Raynaud's
phenomenon, CREST syndrome and limited skin involvement.
Anti-centromere antibodies are also present in some patients with
primary biliary cirrhosis. Testing may be helpful when scleroderma is
suspected.

*ANTI-TOPOISOMERASE I*

Anti-topoisomerase I (or anti-Scl-70) is highly specific and is found in
22 to 40 percent of patients with scleroderma. Its presence is
correlated with diffuse cutaneous disease, pulmonary fibrosis, cardiac
involvement and longer disease duration. Testing for
anti-topoisomerase I may be useful in patients with suspected scleroderma.

*Other Antibody Tests*

*ANTI-JO1*

Anti-Jo1 (histidyl-tRNA synthetase) antibody is found in 30 percent of
patients with polymyositis or dermatomyositis. It is associated with
pulmonary fibrosis and Raynaud's phenomenon.

*ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES*

Antineutrophil cytoplasmic antibodies (ANCAs) are directed against a
number of antigens located in the cytoplasm of neutrophils. ANCA testing
currently distinguishes between cytoplasmic ANCA (cANCA) and perinuclear
ANCA (pANCA).

A positive cANCA test result indicates the presence of antibodies to the
enzyme proteinase 3. The cANCA test has high specificity and sensitivity
for the detection of Wegener's granulomatosis. However, the test has
limited clinical utility in primary care settings, where the prevalence
of this condition is quite low. Testing for cANCA should be limited to
patients in whom Wegener's granulomatosis is strongly suspected.

The pANCA test targets myeloperoxidase, an antigen frequently associated
with microscopic polyangiitis and necrotizing glomerulonephritis.^16
However, the sensitivity of pANCA for these diseases is quite low.
Although pANCA has been identified in several rheumatic autoimmune
diseases, the sensitivity and specificity are quite low.

*Human Leukocyte Antigen B27*

The human leukocyte antigen-B27 (HLA-B27) allele is associated with
spondyloarthropathies, especially ankylosing spondylitis. HLA-B27 has a
sensitivity of approximately 95 percent for ankylosing spondylitis, 80
percent for Reiter's syndrome, 70 percent for spondylitis with
psoriasis, and 50 percent for spondylitis associated with inflammatory
bowel disease. However, the usefulness of HLA-B27 is limited by its
background prevalence in approximately 6 to 10 percent of white
populations. Testing is rarely useful and is only recommended when
spondylitis is strongly suspected.

*Erythrocyte Sedimentation Rate*

The erythrocyte sedimentation rate (ESR) is a measurement of the height
of the layer of red blood cells that settle in a tube of anticoagulated
blood in a specific unit of time, most commonly one hour.  The upper
limit of normal for persons 50 years of age and younger is 15 mm per
hour in men and 20 mm per hour in women. Over the age of 50, the upper
limit of normal for the ESR is 20 mm per hour in men and
30 mm per hour in women. Factors that may increase or decrease ESR
values are summarized in /Table 3/.9

The ESR is a diagnostic criterion in polymyalgia rheumatica and temporal
arteritis. An elevated ESR value has a sensitivity of approximately
80 percent for polymyalgia rheumatica and greater than 95 percent for
temporal arteritis.

The ESR is a means for staging rheumatoid arthritis, rather than a major
diagnostic criterion. The ESR value tends to correlate with clinical
disease activity and to parallel such symptoms as morning stiffness and
fatigue, although joint examination is far more useful in assessing
synovitis.^21 The sensitivity of an elevated ESR value is approximately
50 percent in patients with signs of rheumatoid arthritis. However,
the specificity of an elevated ESR is quite low, limiting its use as a
diagnostic test.

*Final Comment*

Selective ordering can improve the clinical usefulness and
cost-effectiveness of serum rheumatologic tests /(Table 4)/. These
tests should be ordered and interpreted cautiously--and only within the
context of the patient's clinical situation. The practice of ordering a
rheumatologic panel or an arthritis panel is discouraged. Such panels
often include tests that have little or no sensitivity for the suspected
condition. Physicians are often perplexed about how to interpret
abnormal results within the panels.

In general, rheumatologic tests are most helpful in confirming a
clinical diagnosis. Several tests are also useful for prognostic
purposes. As with all tests, physicians need to be familiar with the
predictive value and implications of a positive result.

In addition to the serum immunologic tests reviewed in this article,
more routine tests, including urinalysis and synovial fluid analysis,
are often useful in the diagnosis of rheumatologic disease. These tests
should be performed when clinically appropriate.

/The authors thank Robert Pastan, M.D., Stoneham, Mass., for reviewing
the manuscript./

/The authors indicate that they do not have any conflicts of interest.
Sources of funding: none reported./

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The Authors

STEPHEN K. LANE, M.D., is currently in private practice at Jordan
Primary Care of Marshfield, Marshfield, Mass., and is a clinical
instructor in family medicine and community health at Tufts University
School of Medicine, Boston. Previously, he was academic chief resident
at the Tufts University Family Practice Residency, Malden, Mass. Dr.
Lane received his medical degree from the University of Massachusetts
Medical School, Worcester.

JOSEPH W. GRAVEL, JR., M.D., is program director for the Tufts
University Family Practice Residency and assistant clinical professor
of family medicine and community health at Tufts University School of
Medicine, Boston, Mass., where he also earned his medical degree. Dr.
Gravel completed a family medicine residency and served as chief
resident at Fairfax (Va.) Family Practice Residency (Virginia
Commonwealth University School of Medicine).

/Adress correspondence to Stephen K. Lane, M.D., Jordan Primary Care
of Marshfield, 1000 Plain St., Marshfield, MA 02050 (e-mail:
sklane@massmed.org <mailto:sklane@massmed.org>).
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