Systemic Lupus Erythematosus (SLE) Workup

  • Author: Christie M Bartels, MD, MS; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: Jan 18, 2012
 

Approach Considerations

The diagnosis of systemic lupus erythematosus (SLE) must be based on the proper constellation of clinical findings and laboratory evidence. Familiarity with the diagnostic criteria helps clinicians to recognize SLE and to subclassify this complex disease based on the pattern of target-organ manifestations.

The 1982 American College of Rheumatology (ACR) criteria summarize features necessary to diagnose SLE.[52, 53] The presence of 4 of the 11 criteria yields a sensitivity of 85% and a specificity of 95% for SLE. Keep in mind that individual features are variably sensitive and specific. Patients with SLE may present with any combination of clinical features and serologic evidence of lupus.

The following are the ACR diagnostic criteria in SLE, presented in the "SOAP BRAIN MD" mnemonic:

  • Serositis - Pleurisy, pericarditis on examination or diagnostic electrocardiogram (ECG) or imaging
  • Oral ulcers - Oral or nasopharyngeal, usually painless; palate is most specific
  • Arthritis - Nonerosive, two or more peripheral joints with tenderness or swelling
  • Photosensitivity - Unusual skin reaction to light exposure
  • Blood disorders - Leukopenia (< 4 × 103 cells/µL on more than one occasion), lymphopenia (< 1500 cells/µL on more than one occasion), thrombocytopenia (< 100 × 103 cells/µL in the absence of offending medications), hemolytic anemia
  • Renal involvement - Proteinuria (>0.5 g/d or 3+ positive on dipstick testing) or cellular casts
  • Antinuclear antibodies (ANAs) - Higher titers generally more specific (>1:160); must be in the absence of medications associated with drug-induced lupus
  • Immunologic phenomena - dsDNA; anti-Smith (Sm) antibodies; antiphospholipid antibodies (anticardiolipin immunoglobulin G [IgG] or immunoglobulin M [IgM] or lupus anticoagulant); biologic false-positive serologic test results for syphilis, lupus erythematosus (LE) cells (omitted in 1997 revised criteria)
  • Neurologic disorder - Seizures or psychosis in the absence of other causes
  • Malar rash - Fixed erythema over the cheeks and nasal bridge, flat or raised
  • Discoid rash - Erythematous raised-rimmed lesions with keratotic scaling and follicular plugging, often scarring

In patients with high clinical suspicion and/or high ANA titers, additional testing is indicated. This commonly includes evaluation of antibodies to dsDNA, complement, and ANA subtypes such as Sm, SSA, SSB, and ribonucleoprotein (RNP) (often called the ENA panel), as well as screening anticardiolipin antibodies, lupus anticoagulant +/- beta 2 glycoprotein.

Screening laboratory studies to diagnose possible SLE should include the following:

  • Complete blood count (CBC) with differential
  • Serum creatinine
  • Urinalysis with microscopy

The CBC count may help to screen for leukopenia, lymphopenia, anemia, and thrombocytopenia. Urinalysis and creatinine studies may be useful to screen for kidney disease.

The following are autoantibody tests used in the diagnosis of SLE[54] :

  • ANA - Screening test; sensitivity 95%; not diagnostic without clinical features
  • Anti-dsDNA - High specificity; sensitivity only 70%; level variable based on disease activity
  • Anti-Sm - Most specific antibody for SLE; only 30-40% sensitivity
  • Anti-SSA (Ro) or Anti-SSB (La) - Present in 15% of patients with SLE and other connective-tissue diseases such as Sjögren syndrome; associated with neonatal lupus
  • Anti-ribosomal P - Uncommon antibodies that may correlate with risk for CNS disease, including increased hazzards of psychosis in a large inception cohort, although the exact role in clinical diagnosis is debated[55]
  • Anti-RNP - Included with anti-Sm, SSA, and SSB in the ENA profile; may indicate mixed connective-tissue disease with overlap SLE, scleroderma, and myositis
  • Anticardiolipin - IgG/IgM variants measured with enzyme-linked immunoassay (ELISA) are among the antiphospholipid antibodies used to screen for antiphospholipid antibody syndrome and pertinent in SLE diagnosis
  • Lupus anticoagulant - Multiple tests (eg, direct Russell viper venom test) to screen for inhibitors in the clotting cascade in antiphospholipid antibody syndrome
  • Direct Coombs test - Coombs test–positive anemia to denote antibodies on RBCs
  • Anti-histone - Drug-induced lupus ANA antibodies are often of this type (eg, with procainamide or hydralazine; perinuclear antineutrophil cytoplasmic antibody [p-ANCA]–positive in minocycline-induced drug-induced lupus)

Laboratory studies

The following laboratory tests may also be used in the diagnosis of SLE:

  • Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
  • Complement levels
  • Liver function tests
  • Creatine kinase assay

levels of inflammatory markers, including the ESR and CRP, may be elevated in any inflammatory condition, including SLE. CRP levels change more acutely, and the ESR lags behind disease changes.

Measurement of complement may be useful because C3 and C4 levels are often depressed in patients with active SLE as a result of consumption by immune complex–induced inflammation. In addition, some patients have congenital complement deficiency that predisposes them to SLE.

Liver test results may be mildly elevated in acute SLE or in response to therapies such as azathioprine or nonsteroidal anti-inflammatory drugs (NSAIDS). Creatinine kinase levels may be elevated in myositis or overlap syndromes.

Imaging studies

Joint radiography often provides little evidence of SLE, even in the presence of Jaccoud arthropathy with deformity or subluxations. The most common radiographs in SLE show periarticular osteopenia and soft-tissue swelling without erosions.

Chest radiography and chest CT scanning can be used to monitor interstitial lung disease and to assess for pneumonitis, pulmonary emboli, and alveolar hemorrhage.

Brain MRI/magnetic resonance angiography (MRA) is used to evaluate CNS lupus for white-matter changes, vasculitis, or stroke, although findings are often nonspecific and may be absent in as many as 42% of cases with neuropsychiatric symptoms.[56]

Echocardiography is used to assess for pericardial effusion, pulmonary hypertension, or verrucous Libman-Sacks endocarditis.

Lumbar puncture

Lumbar puncture may be performed to exclude infection with fever or neurologic symptoms. Nonspecific elevations in cell count and protein level and decrease in glucose level may be found in the cerebrospinal fluid of patients with CNS lupus.

Renal and skin biopsies

Renal biopsy is used to identify the specific type of glomerulonephritis, to aid in prognosis, and to guide treatment. Another benefit of renal biopsy is in distinguishing renal lupus from renal thrombosis, which may complicate antiphospholipid antibody syndrome and require anticoagulation rather than immunomodulatory therapy.

Skin biopsy can help to diagnose SLE or unusual rashes in patients with SLE. Many different rashes may herald SLE, making review by a dermatopathologist important.

Arthrocentesis

Arthrocentesis may be performed in patients with joint effusions. Effusions can be inflammatory or noninflammatory. Cell count may range from less than 25% polymorphonuclear neutrophils (PMN) in noninflammatory effusions or more than 50% in inflammatory effusions. Viscosity will be high in noninflammatory effusions and low in inflammatory effusions. Gross appearance will be straw-colored/clear in noninflammatory cases and cloudy/yellow in inflammatory ones.

Histologic findings

Lupus skin rash often demonstrates inflammatory infiltrates at the dermoepidermal junction and vacuolar change in the basal columnar cells. Discoid lesions demonstrate more-significant skin inflammation, with hyperkeratosis, follicular plugging, edema, and mononuclear cell infiltration at the dermoepidermal junction. In many SLE rashes, immunofluorescent stains demonstrate immunoglobulin and complement deposits at the dermoepidermal basement

Next

Diagnostic Criteria for SLE

The American College of Rheumatology last updated the diagnostic criteria for SLE in 1997. The most current criteria are listed below.[52, 53]

Table 1. American College of Rheumatology Diagnostic Criteria (Open Table in a new window)

CriterionDefinition
1. Malar rashFixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
2. Discoid rashErythematous raised patches with adherent keratotic scaling and follicular plugging (Atrophic scarring may occur in older lesions)
3. PhotosensitivitySkin rash as a result of unusual reaction to sunlight, by patient history or physician observation
4. Oral ulcersOral or nasopharyngeal ulceration, usually painless, observed by a physician
5. ArthritisNonerosive arthritis involving ≥2 peripheral joints, characterized by tenderness, swelling, or effusion
6. Serositis(A) Pleuritis: Convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion



or



(B) Pericarditis: Documented by ECG or rub or evidence of pericardial effusion
7. Renal disorder(A) Persistent proteinuria >0.5 g/d or >3+ if quantitation not performed



or



(B) Cellular casts: May be red blood cell, hemoglobin, granular, tubular, or mixed
8. Neurologic disorder(A) Seizures: In the absence of offending drugs or known metabolic derangements (eg, uremia, ketoacidosis, electrolyte imbalance)



or



(B) Psychosis: In the absence of offending drugs or known metabolic derangements (eg, uremia, ketoacidosis, electrolyte imbalance)
9. Hematologic disorder(A) Hemolytic anemia: With reticulocytosis



or



(B) Leukopenia: < 4000/mm3 total on ≥2 occasions



or



(C) Lymphopenia: < 1500/mm3 on ≥2 occasions



or



(D) Thrombocytopenia: < 100,000/mm3 in the absence of offending drugs
10. Immunologic disorder(A) Anti-DNA: Antibody to native DNA in abnormal titer



or



(B) Anti-Sm: Presence of antibody to Sm nuclear antigen



or



(C) Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption tests
11. Antinuclear antibodyAn abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome
SLE can be diagnosed if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation.
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Renal Biopsy

Renal biopsy is used to confirm the presence of lupus nephritis, to aid in classification of SLE nephritis, and to guide therapeutic decisions. The World Health Organization classification for lupus nephritis is based on light microscopy, electron microscopy, and immunofluorescence findings. (See Table 2, below.)

Table 2. International Society of Nephrology 2003 Revised Classification of SLE Nephritis[57] (Open Table in a new window)

ClassClassificationFeatures
Class IMinimal mesangialNormal light microscopy findings; abnormal electron microscopy findings
Class IIMesangial proliferativeHypercellular on light microscopy
Class IIIFocal proliferative< 50% of glomeruli involved
Class IVDiffuse proliferative>50% of glomeruli involved; classified segmental or global; treated aggressively
Class VMembranousPredominantly nephrotic disease
Class VIAdvanced sclerosingChronic lesions and sclerosis
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Contributor Information and Disclosures
Author

Christie M Bartels, MD, MS  Assistant Professor of Rheumatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health

Christie M Bartels, MD, MS is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American College of Rheumatology

Disclosure: Nothing to disclose.

Coauthor(s)

Richard S Krause, MD  Senior Clinical Faculty/Clinical Assistant Professor, Department of Emergency Medicine, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Richard S Krause, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Viraj S Lakdawala, MD  Clinical Instructor of Emergency Medicine, University of California, San Francisco, School of Medicine; Attending Physician, San Francisco General Hospital

Viraj S Lakdawala, MD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians

Disclosure: Nothing to disclose.

Mark J Leber, MD, MPH  Assistant Professor of Emergency Medicine in Clinical Medicine, Weill Cornell Medical College; Attending Physician, Lincoln Medical and Mental Health Center

Mark J Leber, MD, MPH is a member of the following medical societies: American College of Emergency Physicians and American College of Physicians

Disclosure: Nothing to disclose.

Daniel Muller, MD, PhD  Associate Professor of Rheumatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health

Daniel Muller, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American College of Rheumatology, and American Holistic Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Carlos J Lozada, MD  Director of Rheumatology Fellowship Program, Professor, Department of Medicine, Division of Rheumatology and Immunology, University of Miami, Leonard M Miller School of Medicine

Carlos J Lozada, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Pfizer Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Elliot Goldberg, MD  Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Gino A Farina, MD, FACEP, FAAEM  Associate Professor of Clinical Emergency Medicine, Albert Einstein College of Medicine; Program Director, Department of Emergency Medicine, Long Island Jewish Medical Center

Gino A Farina, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD  Adjunct Professor of Medicine, Division of Rheumatology, University of Pittsburgh School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa

Disclosure: Merck Ownership interest Other; Smith Kline Ownership interest Other; Zimmer Ownership interest Other

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Julie Hildebrand, MD, and Anuritha Tirumani, MD, to the development and writing of the source articles.

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In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-antibody responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate autoimmunity.
The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.
Photosensitive systemic lupus erythematosus (SLE) rashes typically occur on the face or extremities, which are sun-exposed regions. Photo courtesy of Dr. Erik Stratman, Marshfield Clinic.
This axial, T2-weighted brain MRI demonstrates an area of ischemia in the right periventricular white matter of a 41-year-old woman with long-standing systemic lupus erythematosus (SLE). She presented with headache and subtle cognitive impairments but no motor deficits. Faintly increased signal intensity was also seen on T1-weighted images, with a trace of enhancement following gadolinium that is too subtle to show on reproduced images. Distribution of the abnormality is consistent with occlusion of deep penetrating branches, such as may result from local vasculopathy, with no clinical or laboratory evidence of lupus anticoagulant or anticardiolipin antibody. Cardiac embolus from covert Libman-Sacks endocarditis remains less likely due to distribution.
Table 1. Drugs Associated With Lupus Erythematosus
Definite Association
ChlorpromazineMethyldopa
HydralazineProcainamide
IsoniazidQuinidine
Possible Association
Beta-blockersMethimazole
CaptoprilNitrofurantoin
CarbamazepinePenicillamine
CimetidinePhenytoin
EthosuximidePropylthiouracil
HydrazinesSulfasalazine
LevodopaSulfonamides
LithiumTrimethadione
Unlikely Association
AllopurinolPenicillin
ChlorthalidonePhenylbutazone
Gold



salts



Reserpine
GriseofulvinStreptomycin
MethysergideTetracyclines
Oral contraceptives
*Data from Tierney et al.[51]
Table 1. American College of Rheumatology Diagnostic Criteria
CriterionDefinition
1. Malar rashFixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
2. Discoid rashErythematous raised patches with adherent keratotic scaling and follicular plugging (Atrophic scarring may occur in older lesions)
3. PhotosensitivitySkin rash as a result of unusual reaction to sunlight, by patient history or physician observation
4. Oral ulcersOral or nasopharyngeal ulceration, usually painless, observed by a physician
5. ArthritisNonerosive arthritis involving ≥2 peripheral joints, characterized by tenderness, swelling, or effusion
6. Serositis(A) Pleuritis: Convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion



or



(B) Pericarditis: Documented by ECG or rub or evidence of pericardial effusion
7. Renal disorder(A) Persistent proteinuria >0.5 g/d or >3+ if quantitation not performed



or



(B) Cellular casts: May be red blood cell, hemoglobin, granular, tubular, or mixed
8. Neurologic disorder(A) Seizures: In the absence of offending drugs or known metabolic derangements (eg, uremia, ketoacidosis, electrolyte imbalance)



or



(B) Psychosis: In the absence of offending drugs or known metabolic derangements (eg, uremia, ketoacidosis, electrolyte imbalance)
9. Hematologic disorder(A) Hemolytic anemia: With reticulocytosis



or



(B) Leukopenia: < 4000/mm3 total on ≥2 occasions



or



(C) Lymphopenia: < 1500/mm3 on ≥2 occasions



or



(D) Thrombocytopenia: < 100,000/mm3 in the absence of offending drugs
10. Immunologic disorder(A) Anti-DNA: Antibody to native DNA in abnormal titer



or



(B) Anti-Sm: Presence of antibody to Sm nuclear antigen



or



(C) Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption tests
11. Antinuclear antibodyAn abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome
SLE can be diagnosed if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation.
Table 2. International Society of Nephrology 2003 Revised Classification of SLE Nephritis[57]
ClassClassificationFeatures
Class IMinimal mesangialNormal light microscopy findings; abnormal electron microscopy findings
Class IIMesangial proliferativeHypercellular on light microscopy
Class IIIFocal proliferative< 50% of glomeruli involved
Class IVDiffuse proliferative>50% of glomeruli involved; classified segmental or global; treated aggressively
Class VMembranousPredominantly nephrotic disease
Class VIAdvanced sclerosingChronic lesions and sclerosis
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