Systemic Lupus Erythematosus - SLE

Diagnosis

Indications for Testing

  • Multisystem disease presentation

Criteria for Diagnosis

  • American College of Rheumatology criteria (1997)

    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
    Systemic Lupus International Collaborating Clinics (SLICC) classification criteria (Petri, 2012)

    Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria

    (Petri, 2012)

    Diagnosis requires ≥4 of the following criteria, serially or simultaneously; at least one criterion must be clinical and one must be immunologic

    CLINICAL CRITERIA

    Disorder/System

    Symptoms

    Acute cutaneous lupus

    Subacute cutaneous lupus

    Bullous lupus

    Lupus malar rash

    Maculopapular lupus rash

    Photosensitive lupus rash

    Toxic epidermal necrolysis variant of systemic lupus erythematosus

    OR

    Psoriaform and/or annular polycyclic lesions

    Chronic cutaneous lupus

    Chilblains lupus

    Classic discoid rash (localized and generalized)

    Discoid lupus/lichen planus overlap

    Hypertrophic lupus

    Lupus erythematosus tumidus

    Lupus panniculitis

    Mucosal lupus

    Head

    Nasal ulcers

    Oral ulcers

    AlopeciaNon-scarring alopecia
    JointsSynovitis involving two or more joints and at least 30 minutes of morning stiffness
    Serous tissuesSerositis
    Renal

    Urine protein-to-creatinine ratio (or 24-hour urine protein) representing 500 mg protein/24 hours

    OR

    Red blood cell casts

    Neurological

    Acute confusional state

    Mononeuritis multiplex

    Myelitis

    Peripheral and cranial neuropathy

    Psychosis

    Seizures

    Red blood cellsHemolytic anemia

    Leukopenia

    Lymphopenia

    <4,000 cells/µL at least once

    OR

    <1,000 cells/µL at least once

    Thrombocytopenia<100,000 cells/µL at least once

Laboratory Testing

  • Nonspecific testing – may be helpful in determining organ involvement
    • CBC – anemia, thrombocytopenia, leukopenia
    • Urinalysis – hematuria indicates renal disease
    • Liver transaminases – may be elevated
    • Blood urea nitrogen (BUN)/creatinine – may be elevated; indicates renal disease
    • Anti-neutrophil cytoplasmic antibody (ANCA) – rule out vasculitis
    • Complement 3 and 4 (C3, C4) – elevated levels may be predictive for glomerulonephritis in systemic lupus erythematosus (SLE)
    • SLE
    • C-reactive protein (CRP)
  • Anti-nuclear antibodies (ANA) – useful as initial screen (not disease-specific); positive specimens should be further tested to identify antibodies specific for SLE
    • Double-stranded DNA (dsDNA) >1:10 detected by immunofluorescence assay (IFA) – 50-60% of patients with SLE
      • Presence of high antibody titers to native dsDNA is specific and diagnostic for SLE
    • 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
      • Anti-Sjögren’s syndrome antigen A (SSA, or Ro) and anti-Sjögren syndrome antigen B (SSB, or La) antibodies – not specific for SLE
    • Histone an dsingle-stranded DNA (ssDNA) antibodies – not specific for SLE
    • Anti-ribonuclear P (anti-P) – associated with neurolupus
    • Chromatin antibodies
      • Primary use – diagnose drug-induced lupus
      • 50-90% of SLE patients have these antibodies
      • Associated with proteinuria, glomerulonephritis, and disease activity
      • Not specific for SLE
  • Biomarkers of lupus nephritis/disease severity
    • Anti-C1q antibodies – assess risk for SLE global activity and lupus nephritis
      • SLE
        • Presence of antibodies – predicts higher risk for developing severe manifestations of disease
      • Renal disease
        • Presence of antibodies - correlates with renal activity and flares
        • Absence of antibodies - high negative predictive value
  • Consider the following testing to rule out other diseases
  • Neurolupus
    • CSF for cell count, 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
    • Collagen type VII antibody IgG by ELISA – may be positive in bullous lupus erythematosus

Imaging Studies

  • MRI/CT of brain and/or spine
  • Magnetic resonance angiography – if vascular involvement is suspected

Differential Diagnosis

Monitoring

  • European League Against Rheumatism (EULAR) 2010 recommendations
    • Re-evaluation of previously negative antiphospholipid antibodies prior to pregnancy, surgery, transplant, or use of estrogen-replacement therapy in the presence of new neurologic event
      • Anti-Ro and anti-La antibodies prior to pregnancy
      • Anti-dsDNA, C3, C4 to support remission
    • Other nonspecific testing every 6-12 months
      • CBC, C-reactive protein (CRP), albumin, creatinine or estimated glomerular filtration rate (EGFR), urinalysis (UA), and urine protein level
    • Other monitoring based on toxicities of prescribed therapies
    • Evaluation of cardiac risk factors
    • Osteoporosis evaluation
    • Cancer screening – follow society-specific recommendations for screening and surveillance

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)
    • Anti-Sjögren syndrome antigen A (SSA, or Ro) (anti-SSA)
    • Smith (Sm)
    • Antiphospholipid antibodies (anticardiolipin and beta-2 glycoprotein 1)
    • Lupus anticoagulant
    • C1q
    • Nucleosome
    • Anti-Sjögren syndrome antigen B (SSB, or 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

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
Test Name and Number Recommended Use Limitations Follow Up
Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, IgG by IFA 0050080
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Initial screen for connective tissue diseases

Detects antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, snRNP/Sm, Scl-70, Jo-1, centromere, and an extract of lysed HEp-2 cells

ELISA results reported as “Detected” are further evaluated by IFA

Low titer ANAs common with advancing age; certain drugs may also cause low titer ANAs

ANA ELISA assays have lower sensitivities for antibodies associated with nucleolar and specked ANA-IFA patterns

Recommend cutaneous direct immunofluorescence testing of active edge of new lesion (lesional biopsy) if dermatologic manifestations are present

Connective Tissue Diseases Profile 0051668
Method: Semi-Quantitative Multiplex Bead Assay

Aid in identifying the specific connective tissue disease

Panel includes ribosomal P protein, centromere antibodies, and the following IgG antibodies: Smith, RNP (U1), scleroderma (Scl-70), SSA (Ro), SSB (La), Jo-1

   
Double-Stranded DNA (dsDNA) Antibody, IgG by ELISA with Reflex to dsDNA Antibody, IgG by IFA 0050215
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Order as secondary screen based on results of ANA testing

dsDNA antibodies are screened using an ELISA assay

Reflex pattern – if dsDNA antibodies are detected, dsDNA antibody IgG by IFA (using Crithidia luciliae) is performed

Some patients with early or inactive SLE may be positive for anti-dsDNA IgG by ELISA but negative by CLIFT

If the patient is negative by CLIFT but positive by ELISA and clinical suspicion remains, consider antinuclear antibody (ANA) testing by IFA

Chromatin Antibody, IgG 2005287
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Evaluate risk for lupus nephritis

   
Anti-C1q Antibody, IgG 2007601
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Assess risk for lupus nephritis and global SLE disease activity

   
Complement Components 3 and 4 0050149
Method: Quantitative Immunoturbidimetry

Monitor disease activity

   
Complement Component 4 0050155
Method: Quantitative Immunoturbidimetry

Screen for lupus nephritis

   
C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Preferred test to detect inflammatory processes

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Initial testing in SLE

Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Evaluate renal disease

Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Use to assess inflammation

Bilirubin, Direct and Total, Serum or Plasma 0020426
Method: Quantitative Spectrophotometry

Evaluate hepatocellular function

Urea Nitrogen, Serum or Plasma 0020023
Method: Quantitative Spectrophotometry

Evaluate renal function

Creatinine, Serum or Plasma 0020025
Method: Quantitative Enzymatic

Elevated levels indicate renal disease

Anti-Neutrophil Cytoplasmic Antibody with Reflex to Titer and MPO/PR-3 Antibodies 2002068
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Rule out vasculitis

If screen is positive, titer and MPO/PR-3 antibodies testing is added to aid in antibody determination

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

Reflex pattern – if antibodies are detected, then an IFA titer will be added; if confirmed by IFA, then specimen will be tested for TPO antibody, anti-Scl-70 (ENA), EIA, RNP antibody, IgG, Smith antibody, IgG, SSA 52 and 60 (Ro) antibodies, IgG, SSB (La) antibody, IgG and double-stranded DNA (dsDNA) antibody, IgG by ELISA; if dsDNA antibody, IgG by ELISA result is detected, then dsDNA antibody, IgG by IFA (using Crithidia luciliae) is added

Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflexes to ANA, IgG by IFA and to dsDNA, RNP, Smith, SSA 52, SSA 60, 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

Reflex pattern – if ANA IgG is detected by ELISA, then ANA IgG by IFA (using HEp-2 substrate) will be added; if ANA, IgG by IFA is confirmed positive with a titer of 1:40 or greater, then a titer and pattern will be reported; in addition, samples positive for ANA, IgG by IFA will reflex to double-stranded DNA (dsDNA) antibody, IgG by ELISA, RNP (U1) (Ribonucleic Protein) (ENA) antibody, IgG, Smith (ENA) antibody, IgG, SSA 52 and 60 (Ro) (ENA) antibodies, IgG, and SSB (La) (ENA) antibody, IgG. If double-stranded DNA (dsDNA) antibody, IgG by ELISA is detected, then double-stranded DNA (dsDNA) antibody, IgG by IFA (using Crithidia luciliae) will be added

RNP (U1) (Ribonucleic Protein) (ENA) Antibody, IgG 0050470
Method: Semi-Quantitative Multiplex Bead Assay

Aids in detecting somewhat-rare central nervous system SLE

Scleroderma (Scl-70) (ENA) Antibody, IgG 0050599
Method: Semi-Quantitative Multiplex Bead Assay
Extractable Nuclear Antigen Antibodies (RNP, Smith, SSA 52, SSA 60, and SSB) 0050652
Method: Semi-Quantitative Multiplex Bead Assay
Systemic Sclerosis Panel 2012057
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay/ Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use to evaluate systemic sclerosis

Components include anti-nuclear antibody (ANA); scleroderma (Scl-70); and RNA polymerase III

SSA 52 and 60 (Ro) (ENA) Antibodies, IgG 2012074
Method: Semi-Quantitative Multiplex Bead Assay

Order as secondary screen based on results of ANA test or if there is strong suspicion for Sjögren syndrome, SLE or myositis and ANA IFA is negative

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 52, SSA 60, and 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: Electromagnetic Mechanical Clot Detection/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

Cryoglobulin, Qualitative with Reflex to IFE Typing and Quantitative IgA, IgG, and IgM 2002403
Method: Qualitative Cold Precipitation/Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

Reflex pattern – 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 0051537
Method: Quantitative Multiplex Bead Assay
Interleukin 8 0051538
Method: Quantitative Multiplex Bead Assay
Interleukin 10 0051534
Method: Quantitative Multiplex Bead Assay
Collagen Type VII Antibody IgG by ELISA  2010905
Method: Enzyme-Linked Immunosorbent Assay