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

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 Lupus Test Sensitivity: 95%
      2. Drug-induced Lupus Test Specificity: >90%
      3. Systemic Lupus Erythematosus Test 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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Ontology: Antibodies, Antinuclear (C0003243)

Definition (NCI) An autoimmune antibody that is directed against structures within the nucleus of the cell.
Definition (MSH) Autoantibodies directed against various nuclear antigens including DNA, RNA, histones, acidic nuclear proteins, or complexes of these molecular elements. Antinuclear antibodies are found in systemic autoimmune diseases including systemic lupus erythematosus, Sjogren's syndrome, scleroderma, polymyositis, and mixed connective tissue disease.
Definition (CSP) autoimmune, pathological antibodies against histones, DNA, nuclear RNA, or other components of the cell nucleus.
Concepts Amino Acid, Peptide, or Protein (T116) , Immunologic Factor (T129)
MSH D000974
SnomedCT 165849001, 45530001
English Antibodies, Antinuclear, Antibody, Antinuclear, Antinuclear Antibodies, Antinuclear Antibody, Antinuclear Factor, Antinuclear Factors, Factor, Antinuclear, Factors, Antinuclear, antinuclear autoantibody, ANTINUCLEAR FACTOR, antinuclear antibody, antiDNA autoantibody, antinuclear factor, Antinuclear Autoantibody, Antibodies, Antinuclear [Chemical/Ingredient], antinuclear antibody (ANA), anti-nuclear antibody, antinuclear factors, antinuclear antibodies, antinuclear antibody ana, ana, Anti-nuclear factor, Anti nuclear factor, Antinuclear factors, ANF, ANA, ANA - Anti-nuclear antibody, ANF - Anti-nuclear factor, Anti-nuclear antibody, Antinuclear antibody, Antinuclear factor, Antinuclear antibody (substance)
Swedish Antinukleära antikroppar
Finnish Tumavasta-aineet
Italian Fattore antinucleare, Anticorpo antinucleare, Fattori antinucleari, Anticorpi antinucleari
Russian ANTINUKLEARNYE FAKTORY, ANTI-DNK ANTITELA, ANTITELA ANTI-DNK, ANTITELA ANTINUKLEARNYE, FLIUORESTSENTNYE ANTINUKLEARNYE ANTITELA, ANTINUKLEARNYE ANTITELA, АНТИ-ДНК АНТИТЕЛА, АНТИНУКЛЕАРНЫЕ АНТИТЕЛА, АНТИНУКЛЕАРНЫЕ ФАКТОРЫ, АНТИТЕЛА АНТИ-ДНК, АНТИТЕЛА АНТИНУКЛЕАРНЫЕ, ФЛЮОРЕСЦЕНТНЫЕ АНТИНУКЛЕАРНЫЕ АНТИТЕЛА
French ANTICORPS ANTINUCLEAIRES, Facteurs lupiques, Anticorps anti-nucléaires, Anticorps antinucléaires, Facteurs antinucléaires, Facteurs anti-nucléaires, Anticorps antinucléaire, Anticorps anti-nucléaire, ACAN, FAN (Facteur AntiNucléaire)
Portuguese FACTOR ANTINUCLEAR, Anticorpos Antinucleares, Fatores Antinucleares
Japanese 抗体-抗核, 抗DNA抗体, 抗核因子, 蛍光抗核抗体, 抗核抗体
Croatian ANTITIJELA, ANTINUKLEARNA
Polish Przeciwciała przeciwjądrowe, Czynniki przeciwjądrowe
Czech antinukleární protilátky, antinukleární faktory, protilátky antinukleární, antinukleární faktor
Spanish FAN, anticuerpo antinuclear (sustancia), anticuerpo antinuclear, factor antinuclear, Anticuerpos Antinucleares, Factores Antinucleares
German Antikörper, antinukleäre, Antinukleäre Antikörper, Antinukleäre Faktoren

Ontology: Anti-nuclear antibody measurement (C0587178)

Definition (NCI_CDISC) A measurement of the antinuclear antibodies (antibodies that attack the body's own tissue) in a biological specimen.
Definition (NCI) The determination of the amount of antinuclear antibodies present in a sample.
Concepts Laboratory Procedure (T059)
SnomedCT 359788000, 390280009, 79404001, 269837009, 389548001
CPT 86038, 1014272
English ANA, Antinuclear antibodies (ANA), Antinuclear antibody, Antinuclear factor, ANA measurement (procedure), Antinuclear antibody (ANA) measurement, Nuclear antibody, Antinuclear Antibody Measurement, Test;anti nuclear antibodies, antinuclear antibody (ANA) test, anti nuclear antibodies test, anti antibody nuclear test, ANTINUCLEAR ANTIBODIES ANA, Antinuclear antibody measurement (procedure), Antinuclear antibody measurement, Antinuclear antibody (ANA) measurement (procedure), Measurement of antinuclear antibodies (ANA), Anti-nuclear factor level, Anti-nuclear antibody measurement (procedure), Anti-nuclear factor level (procedure), Antinuclear Antibodies, ANA - Anti-nuclear antibody level, Anti-nuclear antibody level, ANA measurement, Anti-nuclear antibody measurement, Anti-nuclear antibody measurement, NOS, ANA measurement, NOS, ANTINUCLEAR ANTIBODIES, Antinuclear antibodies, Anti-nuclear antibody measurement (procedure) [Ambiguous]
Italian Anticorpo antinucleo, Anticorpi antinucleo, Anticorpo nucleare, Fattore antinucleare
Spanish dosaje de anticuerpos antinucleares, dosaje de AAN, ANA, Factor antinuclear, medición de anticuerpos antinucleares, dosaje de anticuerpos antinucleares (procedimiento), medición de anticuerpos antinucleares (procedimiento), medición de AAN, medición de ANA, medición de anticuerpos anti - ácido desoxirribonucleico, medición de anticuerpos antinucleares (concepto no activo), Anticuerpos antinucleares
Dutch antinucleaire factor, ANA, nucleaire antistof, antinucleaire antistof
French Anticorps anti-nucléaire, Facteur antinucléaire, ANA, Anticorps anti-nucléaires
German nukleaerer Antikoerper, ANA, antinukleaerer Faktor, antinukleaerer Antikoerper
Portuguese ANA, Factor antinuclear, Anticorpo nuclear, Anticorpos antinucleares
Japanese 抗核抗体, 抗核因子, ANA, 核抗体, コウカクコウタイ, カクコウタイ, コウカクインシ, ANA
Czech Antinukleární protilátky, Nukleární protilátky, ANA, Antinukleární faktor
Hungarian Antinukleáris antitest, ANA, Antinukleáris faktor, Nukleáris antitest