Antinuclear Antibody

Aka: Antinuclear Antibody, Anti-Nuclear Antibody Test, Antinuclear Antigen, ANA

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II. Causes: Negative

  1. Normal titer less than 1:20 dilution
  2. See interpretation below regarding titers

III. Causes: Positive

  1. Normal patient without underlying abnormality: 3-30%
    1. More common in older women
  2. Rheumatologic Conditions
    1. Systemic Lupus Erythematosus
    2. Rheumatoid Arthritis
    3. Mixed Connective Tissue Disease
    4. Sjogren's Syndrome
    5. Necrotizing Vasculitis
  3. Infection
    1. Tuberculosis
    2. Chronic active hepatitis (e.g. Hepatitis C)
    3. Subacute Bacterial Endocarditis
    4. HIV Infection
  4. Miscellaneous Conditions
    1. Type I Diabetes Mellitus
    2. Hashimoto Thyroiditis
    3. Multiple Sclerosis
    4. Pulmonary fibrosis
    5. Silicone gel implants
    6. Pregnant women
    7. Elderly patients
  5. Medications (Drug induced Lupus Erythematosus)
    1. Phenytoin
    2. Ethosuximide
    3. Primidone
    4. Methyldopa
    5. Hydralazine
    6. Penicillamine
    7. Carbamazepine
    8. Procainamide
    9. Thiazides
    10. Griseofulvin
    11. Chlorpromazine
    12. Isoniazid
    13. Quinidine
    14. Gold Salts
    15. Minocycline

IV. Mechanism

  1. IgG or IgM Antinuclear Antibody (ANA)
  2. Antibody binds to nuclei or nuclear components

V. Precautions

  1. Almost all patients with Systemic Lupus Erythematosus (SLE) have a positive ANA titer
  2. Most patients with a positive ANA titer do not have Systemic Lupus Erythematosus (SLE)
    1. High False Positive Rate (esp. low titers) and in Autoimmune Conditions (see above)
  3. ANA Levels fluctuate and do not correlate with response to therapy or with disease activity
    1. Once ANA test is positive, repeat testing is rarely indicated

VI. Labs: Indirect Immunofluorescence Assay (IIF) Slide test

  1. Uses fixed and permeabilized human epithelial cells (HEp-2 cells)
  2. Labor intensive
  3. Most accurate ANA Test
    1. Test Sensitivity: 93%
    2. Test Specificity: 57%
    3. Positive Likelihood Ratio (LR+) for SLE: 2.2
    4. Negative Likelihood Ratio (LR-) for SLE: 0.1
  4. Measures direct binding
    1. Patient's serum antibodies to cell nuclei
    2. Specific components of cell nucleus are also bound
      1. See ANA subunits below

VII. Labs: Enzyme-Linked Immunosorbent Assay (ELISA)

  1. Less labor intensive and less costly than Indirect Immunofluorescence Assay (IIF) Slide Test
  2. Less accurate than Indirect Immunofluorescence Assay (IIF) Slide Test
    1. Test Sensitivity: 81.9%
    2. Test Specificity: 79.6%
    3. Positive Likelihood Ratio (LR+) for SLE: 2.97
    4. Negative Likelihood Ratio (LR-) for SLE: 0.25

VIII. Interpretation: Titer (Dilution)

  1. Pretest probability affects interpretation
    1. Primary Care Setting: 2% SLE probability
    2. Rheumatology Setting: 30% SLE probability
  2. Low Positive (1:160 or lower): Low significance
    1. SLE Likelihood: <2% (<26% for rheumatologists)
  3. High Positive (1:320 or higher): Higher significance
    1. SLE Likelihood: 2-17% (32-81% for rheumatologists)
  4. References
    1. Malleson (1997) Arch Dis Child 77:299-304 [PubMed]

IX. Interpretation: ANA Staining Patterns

  1. Systemic Lupus Erythematosus specific patterns
    1. ANA Rim Pattern
    2. ANA Homogenous Pattern (ANA Diffuse Pattern)
  2. Sjogren Syndrome
    1. ANA Speckled Pattern
  3. Scleroderma Specific Patterns
    1. ANA Nucleolar Pattern
  4. CREST Syndrome Specific Patterns
    1. ANA Centromere Pattern

X. Interpretation: ANA Subunits

  1. Systemic Lupus Erythematosus
    1. Anti-dsDNA (SLE Test Sensitivity: 60%)
      1. Specific for lupus erythematosus
      2. Associated with Lupus Nephritis
      3. Associated with Lupus CNS Involvement
    2. Anti-Smith or Anti-Sm (SLE Test Sensitivity: 20-30%)
      1. Highly specific for lupus erythematosus
    3. Anti-ribosomal P (SLE Test Sensitivity: 20-30%)
      1. Highly specific for lupus erythematosus
      2. Associated with Lupus Psychosis
    4. Anti-RNP (SLE Test Sensitivity: 30-40%)
      1. Associated with lupus disease activity
      2. Seen in all cases Mixed Connective Tissue Disease
    5. Anticardiolipin Antibody
    6. Lupus Anticoagulant
    7. Consider Sjogren Antibodies (Anti-SSA and Anti-SSB)
  2. CREST and Scleroderma
    1. Anti-centromere
      1. Sensitivity for Scleroderma: 22-36%
    2. Scl-70 kD kinetochore (Anti-Topoisomerase I)
      1. Sensitivity for Scleroderma: 22-40%
  3. Polymyositis and Dermatomyositis
    1. Anti-Jo1 (sensitivity: 30%)
      1. Also in Raynaud's Phenomenon, pulmonary fibrosis
    2. Anti-Ku
    3. Anti-Mi2
  4. Sjogren Syndrome
    1. Anti-Ro (Anti-SSA)
      1. Sjogren's SyndromeTest Sensitivity: 75%
      2. Systemic Lupus ErythematosusTest Sensitivity: 40%
    2. Anti-La (Anti-SSB)
      1. Sjogren's SyndromeTest Sensitivity: 40%
      2. Systemic Lupus ErythematosusTest Sensitivity: 10-15%
  5. Drug Induced Lupus
    1. Anti-histone
      1. Drug-induced LupusTest Sensitivity: 95%
      2. Drug-induced LupusTest Specificity: >90%
      3. Systemic Lupus ErythematosusTest Sensitivity: 50%
  6. Non-specific
    1. Anti-ssDNA
      1. Non-specific and rarely indicated

XI. References

  1. Gladman in Klippel (1997) Rheumatic Diseases p. 255-6
  2. Peng in Ruddy (2001) Kelley's Rheumatology, p. 161-72
  3. Ali (2018) Am Fam Physician 98(3): 164-70 [PubMed]
  4. Callegari (1995) Postgrad Med, 97(4):65-74 [PubMed]
  5. Lane (2002) Am Fam Physician 65(6):1073-80 [PubMed]

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