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Diagnosing SLE:
what UPCMD.com says
June 2001
Here is a shortened version of what visitors to UPCMD.com will find on the subject of systemic lupus erythematosus. The author is Charles T. Lutz, MD, PhD, professor of pathology, director of molecular pathology laboratory, assistant director of immunopathology laboratory, University of Iowa College of Medicine, Iowa City.
Diagnostic testing for systemic
lupus erythematosus
ICD9: 710.0
DISEASE DEFINITION
- Disease of unknown etiology in which tissues are damaged by antibodies to self proteins and immune complexes.
- Disease affects the kidneys, joints, skin, blood vessels, nervous system, blood cells, heart, lungs, and other tissues.
- Highest prevalence in child-bearing-age women. All other ages and genders are affected.
- Diagnosis established when at least four of 11 clinical and laboratory criteria are satisfied.
CRITERIA FOR DIAGNOSIS
This 1982 system was developed to identify patients for clinical studies. An individual must have four or more of 11 criteria, serially or simultaneously, during any interval of observation to establish the diagnosis of systemic lupus erythematosus.
| Criterion |
Definition |
Malar
rash |
Fixed erythema, flat or raised, over rash the malar eminences, tending to spare the nasolabial folds |
Discoid
rash |
Erythematous raised patches with rash adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions |
| Photosensitivity |
Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation |
| Oral Ulcers |
Oral or nasopharyngeal ulceration, ulcers usually painless, observed by a physician |
| Arthritis |
Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion |
| Serositis |
• Pleuritis: convincing history of pleuritic pain or rub heard by physician or evidence of pleural effusion
• Pericarditis: documented by electrocardiogram or rub or evidence of pericardial effusion |
Renal
disorder |
• Persistent proteinuria >0.5 g disorder per day or >3+ if quantitation not performed
• Cellular casts: may be red cell, hemoglobin, granular, tubular, or mixed |
| Neurological disorder |
• Seizures: in the absence of offending drugs or known metabolic derangements, e.g. uremia, ketoacidosis, or electrolyte imbalance
• Psychosis: in the absence of offending drugs or known metabolic derangements, e.g. uremia, ketoacidosis, or electrolyte imbalance |
| Hematologic disorder |
• Hemolytic anemia: with reticulo-cytosis disorder
• Leukopenia: <4,000/mm3 total on two or more occasions
• Lymphopenia: <1,500/mm3 on two or more occasions
• Thrombocytopenia: <100,000/mm3 in the absence of offending drugs |
| Immunologic disorder |
• Positive LE cell preparation
• Anti-DNA: antibody to native DNA in abnormal titer
• Anti-Sm: presence of antibody to Sm nuclear antigen
• False-positive serologic test for syphilis known to be positive for at least six months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test |
| Anti-nuclear antibody |
An abnormal titer of antinuclear anti-body by immunofluorescence or an antibody equivalent assay at any point in time and in the absence of drugs known to be associated with “drug-induced lupus” syndrome |
RECOMMENDED TESTING
Initial testing
Antinuclear antibody
(ANA) [CPT 86039]
Method: Immunofluorescence technique, which detects patient serum antibodies that react with cell nuclei components, is used. Most sensitive and most commonly used substrate is human HEp-2 epithelial tumor. Cell line with rodent liver or kidney tissue sections is sometimes used.
Diagnostic sensitivity and specificity: Using HEp-2 substrate, ANA detects >95 percent of patients with SLE and drug-induced lupus. Test is nonspecific and positive in a wide variety of autoimmune diseases, the elderly, and many other diseases.
Confirmatory testing
Anti-double-stranded DNA (dsDNA) antibody
[CPT 86225]
Method: Multiple testing methods—see “Controversies,” page 31.
Diagnostic sensitivity and specificity:
- ~ 50 percent SLE patients have antibody that reacts at high titer with native double-stranded DNA. Patients with quiescent disease may test negatively.
- Anti-dsDNA antibodies not found in drug-induced lupus.
- 95 percent specificity anti-dsDNA when test properly conducted.
- Antibodies to single-stranded DNA (ssDNA) is much less specific for SLE. False positives may occur as ssDNA contaminates the dsDNA assay preparation. Any low titer antibody dsDNA result should be viewed with suspicion.
Monitoring testing (two tests)
24-hour urine protein, quantitative
[CPT 84155]
Method: Protein in timed 24-hour collection measured by turbidimetry. Important to collect urine without acid or preservative. Have patient discard the first morning urine sample, then collect urine for next 24 hours.
Use in monitoring: Disease index assessed in SLE patients using a panel of clinical findings and urine protein amounts.
Complete blood count, hemogram and platelet count, automated, with automated WBC differential [85025]
Method: Impedence or laser-based quantitation of red cells, white cells, and platelets.
Use in monitoring: Monitor disease activity by changes in hemogram components.
Other monitoring tests
Anti-dsDNA antibody titer and complement levels.
INTERPRETATION
Initial testing
Antinuclear antibody
Results reported as negative or positive; if positive, a titer is reported.
Positive
- Criteria for positive result vary among immunopathology laboratories.
- 1:40 or 1:80 titers using HEp-2 substrate considered positive.
- A positive ANA is consistent with SLE.
- In nonselected populations, fewer than 20 percent of ANA-positive patients may have SLE.
- Incidence of positive result increases with age among healthy people.
Negative
- A negative ANA virtually rules out active SLE.
- Testing for anti-Ro/SS-A antibody has been advocated as a diagnostic test for SLE among rare patients with highly suggestive symptoms and persistently negative ANA testing results.
Confirmatory testing
Anti-double-stranded
DNA antibody
Results reported as negative or positive; if positive, a titer or level is reported. Some laboratories report equivocal levels.
Positive
- A positive result is highly specific for SLE.
- High titer anti-dsDNA antibody is highly specific for SLE.
- Antibody titers indicate the degree of lupus nephritis but do not reflect other aspects of SLE.
- Anti-dsDNA antibody may be used as a monitor or predictor of disease flares.
Negative
- Up to 50 percent of SLE patients may lack anti-dsDNA antibody, especially those with quiescent disease.
- 58 percent of ANA-positive, anti-dsDNA-negative SLE patients have antibody to Ro/ SS-A.
Monitoring testing
24-hour urine protein
Results are reported as protein excreted/24 hours.
- >3.5 g per 24 hours indicates severe, progressive renal damage; rising levels indicate increasing renal damage.
Complete blood count
Results reported as quantitative levels of erythrocytes, platelets, and leukocytes.
- Low erythrocyte, leukocyte, lymphocyte, and platelet counts correlate with disease activity.
- Normal hemogram values consistent with quiescent disease.
ALTERNATIVE TESTS
These tests have all been advocated for use in testing for SLE:
- Anti-Smith (Sm) antibody [CPT 86235]
- Anti-Ro/SS-1 antibody [CPT 86235]
- Anti-phospholipid antibody [CPT 86147]
- Complement levels [CPT 86160 (C3 and C4), 86162 (CH50)]
- Urinalysis [CPT 81000]
- Renal biopsy [CPT 50200, 88305]
CONTROVERSIES
1. Are medical laboratory tests useful in monitoring or predicting SLE disease activity?
Arguments for using laboratory testing
- Increases in anti-dsDNA antibody levels often precede systemic lupus erythematosus disease exacerbation.
- Anti-dsDNA antibody levels correlate specifically with exacerbation of renal disease.
- Decrease in complement C3 levels appeared to predict vasculitis flare in an otherwise negative study.
Arguments against using laboratory testing
- Common monitoring tests failed to predict SLE disease flares in several reported studies.
- Monitoring tests may identify patients at risk for certain complications but do not predict if or when disease exacerbation will occur.
2. Which is the best anti-dsDNA antibody test method? Three tests are widely available:
Arguments for Farr assay
- Classical radioimmunoassay test for anti-dsDNA antibody
- Detects high avidity antibody
- Good sensitivity and specificity
Arguments for ELISA
- Simple and inexpensive
- Less cumbersome than Farr assay and radioisotopes not required
- High specificity reported in some studies (but not in others)
Arguments for Crithidia luciliae assay
- Performed rapidly
- Highly specific
- Good sensitivity reported in some studies (but not in others)
MEDICAL ARTICLES AND WEB SITES OF INTEREST
- Amoura Z, Piette JC, Bach JF, Koutouzov S. The key role of nucleosomes in lupus. Arthritis Rheum. 1999; 42(5):833-843. Reviews evidence for a new theory on the pathogenesis of SLE.
- Hahn BH. Antibodies to DNA. N Engl J Med. 1998;338(19):1359-1368. Reviews the pathological role of anti-DNA antibodies in SLE.
- Vyse TJ, Kotzin BL. Genetic susceptibility to systemic lupus erythematosus. Annu Rev Immunol. 1998;16:261- 292. An excellent discussion of the genetics of SLE in humans and in animal models.
- www.lupusnet.ucalgary.ca/lhnet/index.htm—Web site of Lupus Healthnet, a collaborative project between the University of Calgary and the Lupus Society of Alberta, Canada. The site offers a variety of information for patients about SLE, including laboratory testing.
- www.lupus.org—Web site of the Lupus Foundation of America. The site offers a variety of information for patients about SLE, including laboratory testing.
- www.mtio.com/lupus/—Web site of Lupus Around the World. The site offers a variety of information, including lists of books and articles.
UPCMD.com: PEER AND EDITORIAL REVIEW
Associate editor, Immunologic Disease: John Kemp, MD
Editor: Kenneth Sims, MD
Managing editor: Elizabeth Redmon, MA
Copyeditor-programmer: Joette Maskew
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