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 sensitive for lupus nephritis than intermediate or low affinity anti-dsDNA antibodies
  • 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 1IgG 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 I)
  • 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 Antibody (ANA), IgG by ELISA with Reflexes to ANA by IFA and to dsDNA, RNP, Smith, SSA, and SSB Antibodies 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
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
Glucose, Plasma or Serum 0020024 Method: Quantitative Enzymatic
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