Hospital Medicine

ANA and rheumatologic tests

I. Problem/challenge

Many constellations of symptoms and physical exam findings can provoke a suspicion for a connective tissue disease and prompt antinuclear antibody (ANA) testing. A clinical suspicion of systemic rheumatic disease is at times supported by well-characterized features of the patient's presentation, but at other times an ANA test may be sent when a clinician is exploring an unlikely diagnosis, or atypical or early presentations of a connective tissue disease.

Sending an ANA test under these exploratory circumstances has many pitfalls. The challenge for a clinician is to order the test discriminately, so that a positive or negative result can yield clinically useful information to make a diagnosis or guide decision-making, and rationally interpret tests sent in other circumstances.

II. Objectives

  • Establish a differential diagnosis for systemic rheumatic diseases before sending an ANA test.

  • Understand whether the test will be useful in that particular context

  • Interpret the ANA result appropriately.

III. Approach to deciding whether to order an antinuclear antibody test

Step 1: Which systemic rheumatic process do you suspect?

When a history and examination findings raise clinical suspicion for one or more rheumatic disease, serologic testing can then increase or decrease the pre-test probability of the disease. Before ordering an ANA test, consider whether the patient you are evaluating has groups of features that might guide you toward a particular diagnosis. Diagnostic criteria for connective tissue diseases are often helpful in creating a differential diagnosis in this situation.

  • Systemic sclerosis: sclerodactyly, Raynaud's phenomenon, telangiectasias, esophageal dysmotility, lung disease, renal dysfunction

  • Systemic lupus erythematosus (SLE): polyarthritis/arthralgia, butterfly rash, photosensitivity, renal dysfunction, drug exposure -- hydralazine, minocycline, anti-tumor necrosis factor (anti-TNF), procainamide

  • Polymyositis or dermatomyositis: muscle weakness, polyarthralgias, heliotrope rash (purple discoloration of eyes, periorbital edema), mechanic's hands

  • Mixed connective tissue disease (MCTD): features of SLE, systemic sclerosis and/or polymyositis; swollen hands; Raynaud's phenomenon is often an initial presenting symptom

  • Sjögren's syndrome: dry eyes, dry mouth

  • Rheumatoid arthritis (RA): inflammatory polyarthritis, ulcers or rheumatoid nodules, lung disease

  • None of the above: autoimmune hepatitis, thyroid disease, fibromyalgia, or another condition

Step 2: Decide whether to order the test based on which systemic rheumatic disease you suspect and the pre-test probability of that diagnosis

Likelihood ratios for a positive ANA test have been established for several rheumatic conditions. A likelihood ratio of 1 means the test does not change the probability that the patient has the disease. The likelihood ratios range from 2.2 for SLE to near 1 for RA and Sjögren's syndrome. In comparison, the likelihood ratio for a positive troponin in diagnosing a myocardial infarction is 24. As a result, if the pre-test probability for SLE or another condition is low, the ANA result will not have a significant impact on likelihood of disease, and a positive result may be misleading.

Clinical suspicion should strongly influence your decision about whether to order an ANA test.

The following lists are guides to assist in determining whether to order an ANA test when there is a reasonable clinical suspicion for a particular rheumatic diagnosis (sensitivity, specificity and likelihood ratios are included below).

Suspected diagnoses in which an ANA result is likely to be useful:

  1. SLE

  2. Systemic sclerosis

  3. Drug-induced SLE

  4. MCTD

  5. Autoimmune hepatitis*

(*While a positive ANA test is part of the definition of autoimmune hepatitis, the presence of a positive ANA test should not preclude investigation for other causes of hepatic disease. In addition to the high rate of positivity among normal individuals, ANA titers may be elevated in other forms of hepatic disease, particularly hepatitis C and tuberculosis.)

Situations in which a result could potentially be helpful:

  1. Diagnosis of polymyositis and dermatomyositis

  2. Diagnosis of Sjögren's syndrome

  3. Patients with Raynaud's phenomenon only*

(*The ANA test in Raynaud's phenomenon is useful in predicting the chance of development of a systemic disease. A positive ANA test in patients with Raynaud's phenomenon increases the risk of developing a systemic rheumatologic disease from 19% to 30%, whereas a negative test decreases that chance from 19% to 7%.)

An ANA test is unlikely to be useful for:

  1. Diagnosis or monitoring of RA

  2. Diagnosis of multiple sclerosis

  3. Diagnosis of fibromyalgia

  4. Diagnosis of thyroid disease

Approach to monitoring

Although an ANA titer is sometimes suggested for use as a measure of disease activity, in most cases disease activity does not correlate well with an ANA titer.

ANA titers have not been shown to be useful in the following situations:

  1. Monitoring of SLE activity (anti-double stranded deoxyribonucleic acid (Anti-dsDNA) may have clinical significance)

  2. Monitoring of systemic sclerosis activity (Scl-70, anti-centromere may have clinical/prognostic significance)

  3. Monitoring of polymyositis or dermatomyositis

  4. Monitoring of Sjögren's

  5. Monitoring of RA

  6. Monitoring of drug-induced SLE

Sensitivities, specificities and likelihood ratios for selected rheumatic diseases

  1. SLE: sensitivity 93%, specificity 57%, +LR 2.2, -LR 0.11

  2. Systemic sclerosis: sensitivity 85%, specificity 54%, +LR 1.86, -LR 0.27

  3. Polymyositis/dermatomyositis: sensitivity 61%, specificity 63%, +LR 1.67, -LR 0.61

  4. Sjögren's: sensitivity 48%, specificity 52%, +LR .99, -LR 1.01

  5. RA: sensitivity 41%, specificity 56%, +LR .93, -LR 1.06

Approach to interpretation of a positive antinuclear antibody test

Step 1: Is the ANA test positive?

Many labs will provide information about the percentage of patients without ANA-associated disease with positive results at each titer. As a general guideline:

  • 25-30% of the population will have a titer positive at 1:40

  • 10% of the population will have a titer positive at 1:80

  • 5% of the population will have a titer positive at 1:160

  • 3% of the population will have a titer positive at 1:320

A titer of 1:160 or above is commonly considered a positive test result.

Step 2: Interpret the result

If an ANA test is positive in the context of a low pre-test probability of disease or if it is negative in the context of a high pre-test probability, interpret the result in light of the prevalence of the titer in healthy controls and the frequency of positive tests in particular populations. The prevalence of a positive ANA in selected conditions are listed below:

Rheumatic diseases:

  • SLE: 93%

  • Drug-induced lupus: greater than 95%

  • Mixed connective tissue disease: 93%

  • Systemic sclerosis: 85%

  • Polymyositis/dermatomyositis: 30-80%

  • Sjögren's syndrome: 48%-80%

  • RA: 30-50%

Other conditions:

  • Autoimmune hepatitis: 63-91%

  • Hashimoto's thyroiditis: 46%

  • Primary biliary cirrhosis: 10-40%

  • Graves' disease: 50%

  • Idiopathic pulmonary arterial hypertension: 40%

  • Idiopathic thrombocytopenic purpura: 10-30%

  • Multiple sclerosis: 25%

  • Fibromyalgia: 15-25%

  • Relatives of patients with SLE or scleroderma: 5-25%

  • Other conditions with ANA associations include Crohn's disease, mononucleosis, subacute bacterial endocarditis, tuberculosis, and lymphoproliferative diseases.

If a positive ANA result is felt to be unrelated to an active rheumatic diagnosis but there remains a risk for development of rheumatic disease, the patient may be monitored. Otherwise, monitoring is not indicated for an isolated positive ANA.

Step 3: Consider follow-up tests

A positive ANA may prompt additional serologic testing targeted to the suspected disease:

  • SLE: anti-dsDNA, anti-Sm, anti U1 snRNP, anti Ro

  • Scleroderma: anti Scl-70, anticentromere

  • Sjögren's syndrome: anti Ro, anti La

  • Polymyositis, dermatomyositis: anti-Jo

  • Drug induced lupus: antihistone

  • MCTD: anti nRNP

IV. Common Pitfalls

Intermediate or high ANA titers can be seen in unaffected relatives of patients with connective tissue disease, elderly patients, pregnant women, patients with chronic infections, malignancy, and as noted above, in healthy individuals.

V. National Standards, Core Indicators and Quality Measures

The American Society for Rheumatology has published a position statement on the methodology of measurement of ANA.

The British Colombia Ministry of Health has a guideline for indications for ANA testing.

VI. What's the evidence?

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Adams, B, Mutasim, D. "The diagnostic value of anti-nuclear antibody testing". International Journal of Dermatology. vol. 39. 2000. pp. 887-891.

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Luggen, M, Belhorn, L, Evans, T. "The evolution of Reynaud's phenomenon. A long-term prospective study". J Rheumatol. vol. 22. 1995. pp. 2226-2232.

Waits, J. "Rational use of laboratory testing in the initial evaluation of soft tissue and joint complaints". Prim Care Clin Office Pract. vol. 37. 2010. pp. 673-689.

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Clifford, BD, Donahue, D, Smith, L. "High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C". Hepatology. vol. 21. 1995. pp. 613.

Czaja, AJ, Nishioka, M, Morshed, SA, Hachiya, T. "Patterns of nuclear immunofluorescence and reactivities to recombinant nuclear antigen in autoimmune hepatitis". Gastroenterology. vol. 107. 1994. pp. 200.

Bonnet, F, Pineau, JJ, Taupin, JL. "Prevalence of cryoglobulinemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: a cross-sectional study of 97 patients". J Rheumatol. vol. 30. 2003. pp. 2005.

Petri, M, Karlson, EW, Cooper, DS, Ladenson, PW. "Autoantibody tests in autoimmune thyroid disease: a case-control study". J Rheumatol. vol. 18. 1991. pp. 1529.

Reichlin, M, Arnett, FC. "Multiplicity of antibodies in myositis sera". Arthritis Rheum. vol. 27. 1984. pp. 1150.

Rosenburg, AM. "The clinical associations of antinuclear antibodies in juvenile rheumatoid arthritis". Clin Immunol Immunopathol. vol. 49. 1988. pp. 19.

Seiner, M, Klein, E, Klein, G. "Antinuclear reactivity of sera in patients with leukemia and other neoplastic diseases". Clin Immunol Immunopathol. vol. 4. 1975. pp. 374.

Solomon, DH, Kavanaugh, AJ, Schur, PH. "American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines. Evidence-based guidelines for the use of immunologic tests: antinuclear antibody testing". Arthritis Rheum. vol. 47. 2002. pp. 434.

Agmon-Levin, N, Damoiseaux, J, Kallenberg, C. "International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies". Ann Rheum Dis. vol. 73. 2014. pp. 17.

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