Systemic Lupus Erythematosus - SLE

Diagnosis

Indications for Testing

• Multisystem disease presentation

Criteria for Diagnosis (American College of Rheumatology, 1997)

• Diagnosis requires ≥4 of the following criteria to be present, serially or simultaneously, during any interval of observation
  • Malar rash
  • Discoid rash
  • Photosensitivity
  • Oral ulcers
  • Arthritis (nonerosive)
  • Pleuritis or pericarditis
  • Renal disorder (persistent proteinuria or cellular casts)]
  • Hematologic disorder (hemolytic anemia, leukopenia, lymphopenia, or recurrent thrombocytopenia)
  • Immunologic disorder
  • Antinuclear antibody (ANA) positive

Laboratory Testing

• Initial testing – not disease-specific but may be helpful in determining organ involvement
  • CBC – anemia, thrombocytopenia, leukopenia
  • Urinalysis – hematuria; indicates renal disease
  • Liver transaminases – may be elevated
  • BUN/creatinine – may be elevated; indicates renal disease
  • ANCA – rule out vasculitis
  • Complement 3 and 4 (C3, C4) – elevated levels may be predictive for glomerulonephritis in SLE
  • ESR/CRP – high elevations unusual in SLE
• ANA test – useful as initial screen for SLE although not disease-specific; positive samples should be further tested to identify antibodies specific for SLE
  • dsDNA >1:10 detected by immunofluorescence assay (IFA) – 50-60% of SLE
    • Presence of high antibody titers to native dsDNA is specific and diagnostic for SLE
  • High avidity dsDNA – more specific but less sensitive for SLE than the low-affinity anti-dsDNA (LA dsDNA) IgG antibody
    • More often associated with renal involvement (lupus nephritis)
  • Extractable nuclear antigens
    • Smith (Sm) antibodies – highly specific for SLE but occur in only 30-35% of cases
    • Ribonucleic protein (RNP) antibodies – not specific for SLE
    • SSA and SSB antibodies  – not specific for SLE
  • Histone and ssDNA antibodies – not specific for SLE
  • Anti-ribonuclear P (anti-P) – associated with neurolupus
  • Chromatin antibodies
    • Mainly used to diagnosis drug-induced lupus
    • 50-90% of SLE patients have these antibodies
    • Linked to proteinuria, glomerulonephritis, and disease activity
    • May be found in Sjögren syndrome and APS
• Biomarkers of lupus nephritis
  • Anti-C1q antibodies – high negative predictive value if absent; correlates with renal activity and flares, but no better than anti-dsDNA and complement
• Consider the following testing to rule out other diseases
  • Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-beta-2 glycoprotein 1 IgG and IgM assays)
  • Cryoglobulin
• Neurolupus
  • CSF for cells, glucose, oligoclonal bands, culture
    • Cell count – mild elevations with mononuclear cells
    • Glucose – usually normal, but may be decreased in myelopathy
    • Oligoclonal bands
    • Interleukin 6, 8, 10 (if available) – very high, decreased with remission
• Other testing
  • EEG – frequently abnormal

Imaging Studies

• MRI/CT of brain and/or spine
• MR angiography – if vascular involvement considered

Differential Diagnosis

• Other autoimmune diseases
  • Mixed connective tissue disease
  • Sjögren syndrome
  • Dermatomyositis
• Fibromyalgia
• Vasculitis
• Sarcoidosis
• Infection
  • Endocarditis
  • M. tuberculosis
• Glomerulonephritis
• Malignancy
• Drug-induced lupus
• Hematologic/minocycline diseases
  • Idiopathic thrombocytopenic purpura
  • Thrombotic thrombocytopenic purpura 
• APS

Monitoring

Clinical Background

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of several autoantibodies, formation of immune complexes, and inflammation in different organs.

Epidemiology

• Incidence – 1/2,000 in the U.S. (1/2,500 in northern Europeans; 2/1,000 in African Americans)
• Age – peak onset is 15-40 years
• Sex – M<F 1:12 (ages 15-45); 1:2 other age groups
• Ethnicity – greater incidence in African Americans, Asian Americans, and Hispanics than in Caucasians (3:1)

Risk Factors

• Genetics – possible association with deletion of long arm of chromosome 1
• Sun exposure
• Drugs – hydralazine, procainamide, quinidine, penicillamine, acebutolol, and methyldopa
• Epstein-Barr virus infection
• Occupational exposure
  • Crystalline silica
  • Pesticides
  • Mercury

Pathophysiology

• Pathophysiology of SLE is not completely understood; however, the following have been implicated
  • Apoptosis (programmed cell death) leading to loss of immune tolerance
  • Interferon-alpha (IFN-α) and plasmacytoid dendritic cells (PDCs)
  • Toll-like receptors through the induction of IFN-α by PDCs
• Multiple pathogenic antibodies have been discovered
  • Double-stranded DNA (dsDNA)
  • Ro (anti-SSA)
  • Smith (Sm)
  • Antiphospholipid antibodies (anticardiolipin and beta-2 glycoprotein 1)
  • Lupus anticoagulant
  • C1q
  • Nucleosome
  • La (anti-SSB)

Clinical Presentation

• Dermatologic – malar discoid rash, photosensitivity, skin eruptions, alopecia
• Musculoskeletal – arthritis, arthralgia, myalgia
• Serositis – pleuritis, pericarditis
• Renal – nephritis
• Neurologic 
  • Central nervous system – meningitis, demyelinating disease, seizures, psychosis, mood disorder, stroke, chorea, myelopathy, headache, transient ischemic attack
  • Peripheral nervous system – autonomic disorder, mononeuropathy, myasthenia gravis, cranial neuropathy, plexopathy, polyneuropathy
• Hematologic – hemolytic anemia, leukopenia, thrombocytopenia, antiphospholipid syndrome symptoms
• Cardiovascular – vasculitis, Libman-Sachs endocarditis
• Ocular – sicca syndrome
• Complications
  • Osteoporosis – probably a combination of disease inflammation and steroids used in treatment
  • Malignancy
    • Increased risk of hematologic cancer and non-Hodgkin lymphoma
    • Hepatobiliary cancers increased in men
    • Early coronary heart disease
  • Adverse pregnancy outcomes
    • Higher risk of miscarriage
    • Higher rate of low birth weight infants

Treatment

• Immunosuppressives are currently the mainstay of therapy
• Newer biologics hold promise

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Smith (ENA) Antibody, IgG 0050085 Method: Semi-Quantitative Multiplex Bead Assay	Order as secondary screen based on results of ANA
Lupus Comprehensive Reflexive Panel 0050119 Method: Quantitative Immunoturbidimetry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Quantitative Chemiluminescent Immunoassay/Semi-Quantitative Multiplex Bead Assay
Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflexes to ANA, IgG by IFA and to dsDNA, RNP, Smith, SSA, and SSB Antibodies, IgG 0050317 Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay	Recommend if high suspicion of SLE or Sjögren syndrome If ELISA screen is positive, then IFA using HEp-2 substrate will be added; if confirmed by IFA, titer and pattern will be reported and testing for dsDNA antibody and ENA antibodies will be added
RNP (U1) (Ribonucleic Protein) (ENA) Antibody, IgG 0050470 Method: Semi-Quantitative Multiplex Bead Assay	Helpful in detecting central nervous system SLE (somewhat rare)
Scleroderma (Scl-70) (ENA) Antibody, IgG 0050599 Method: Semi-Quantitative Multiplex Bead Assay
Extractable Nuclear Antigen Antibodies (RNP, Smith, SSA, & SSB) 0050652 Method: Semi-Quantitative Multiplex Bead Assay
Extractable Nuclear Antigen Antibodies (RNP, Smith, Scleroderma, SSA, & SSB) 0050653 Method: Semi-Quantitative Multiplex Bead Assay	Clarify pattern result from ANA May help differentiate SLE from mixed connective tissue disease, rheumatoid arthritis, scleroderma, Sjögren syndrome
SSA (Ro) (ENA) Antibody, IgG 0050691 Method: Semi-Quantitative Multiplex Bead Assay	Order as secondary screen based on results of ANA testing
SSB (La) (ENA) Antibody, IgG 0050692 Method: Semi-Quantitative Multiplex Bead Assay	Order as secondary screen based on results of ANA testing
Centromere Antibody, IgG 0050714 Method: Semi-Quantitative Multiplex Bead Assay
Extractable Nuclear Antigen Antibodies (SSA & SSB) 0050791 Method: Semi-Quantitative Multiplex Bead Assay
Histone Antibody, IgG 0050860 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Neutrophil-Associated Antibodies 0055506 Method: Qualitative Flow Cytometry
Ribosomal P Protein Antibody 0099249 Method: Semi-Quantitative Multiplex Bead Assay	Helps in detecting central nervous system SLE (somewhat rare)
ssDNA Antibody, IgG 0099528 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Order as secondary screen based on results of ANA testing
Jo-1 Antibody, IgG 0099592 Method: Semi-Quantitative Multiplex Bead Assay	Helps in detecting inflammatory myopathies
C1q Binding Assay 0050301 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Antiphospholipid Syndrome Reflexive Panel 2003222 Method: Clotting/Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Preferred initial panel for strong suspicion of APS Reflex panel detects lupus anticoagulant (LA), IgG and IgM anticardiolipin (aCL), and IgG and IgM anti-beta-2-glycoprotein 1 (anti-β2GP1) antibodies Due to false-positive rate, persistent positivity must be demonstrated at least 12 weeks from initial testing For LA, high concentrations of heparin or warfarin, or the presence of direct thrombin inhibitors, specific factor inhibitors, or other anticoagulant medications may lead to false-positive results LA is a reflex test – panel includes LA-sensitive PTT and dilute Russell viper venom (dRVVT) for screening, followed by mixing studies and confirmatory tests, as indicated
Cryoglobulin, Qualitative with Reflex to IFE Typing and Quantitative IgA, IgG, and IgM 2002403 Method: Qualitative Cold Precipitation/Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry	If qualitative is positive, Immunofixation Electrophoresis Typing and Quantitative IgA, IgG and IgM will be added
Cell Count, CSF 0095018 Method: Cell Count/Differential
Protein, Total, CSF 0020514 Method: Reflectance Spectrophotometry	May be helpful in differentiating bacterial from viral etiology
Glucose, CSF 0020515 Method: Enzymatic	May be helpful in differentiating bacterial from viral etiology Usually low (<10 mg//dL) in bacterial meningitis and tuberculous disease
Glucose, Plasma or Serum 0020024 Method: Quantitative Enzymatic	Quantifies glucose to match CSF glucose values
Albumin, Serum or Plasma by Spectrophotometry 0020030 Method: Quantitative Spectrophotometry
Interleukin 6 by MAFD 0051537 Method: Quantitative Multiplex Bead Assay
Interleukin 8 by MAFD 0051538 Method: Quantitative Multiplex Bead Assay
Interleukin 10 by MAFD 0051534 Method: Quantitative Multiplex Bead Assay

Diagnostic Algorithm

  Connective Tissue Disease Testing Algorithm