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Clinical Review
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When an ANA test is
positive – what next?
More selective ordering of ANA can decrease anxiety of patients,
write Nick Malone, Claire-Louise Murphy and Paul O’Connell
What do you do when faced with a positive ANA (antinuclear antibodies) test? This is a common question
encountered by GPs and a frequent cause for referral to
rheumatology services. In the course of this article we aim
to answer the following:
• What’s the meaning of a positive ANA test?
• When should an ANA test be ordered?
• What questions should be asked when faced with a positive ANA?
• When and who to refer?
Antinuclear antibody
Antinuclear antibodies are autoantibodies directed
against a variety of components of the cell nucleus. Most
healthy people have a low ANA titre (defined as < 1:80
in Irish laboratories). However, unfortunately about 3% of
the healthy population has a positive ANA and this poses a
dilemma and difficulty for doctors, especially when the test
is ordered indiscriminately. The most common autoimmune
disease associated with a positive ANA is connective tissue
disease (CTD).
What is the meaning of a positive ANA test?
A positive ANA reading does not alone indicate autoimmune disease. The prevalence of ANAs in healthy
individuals is about 3-15%.1 The production of these antibodies is strongly age-dependent, and increases to about
10-35% in healthy individuals over the age of 65.1
Even healthy patients with viral infections such as infectious mononucleosis can have a positive ANA for a short
while. Furthermore, patients with cancer, or patients taking
common medications such as beta blockers, can have a
positive ANA. It is therefore crucial to take a positive result
in the context of clinical history and examination. Some
autoimmune diseases are strongly associated with a positive ANA to the extent whereby the test is an intrinsic part
of diagnosis as indicated in Table 1.
ANAs present different ‘patterns’ depending on the staining of the cell nucleus following immunofluorescent lab
preparation and can have a diagnostic value.
Speckled and homogenous patterns tend to be nonspecific, while a nucleolar and centromere pattern is specific
for scleroderma and CREST syndrome respectively (see
Figure 1 and 2).
When should an ANA test be ordered?
The likelihood that a positive test will provide useful
information is proportional to the probability that CTD is
present.2 ANA testing is recommended in patients who show
signs and symptoms of CTD consistent with systemic lupus
Table 1
Conditions associated with
a positive ANA
Frequency
Diseases for which ANA is
very useful for diagnosis:
SLE (systemic lupus erythematosus)
95-100%
Scleroderma
60-80%
Diseases for which ANA is somewhat
useful for diagnosis:
Sjögren’s syndrome
40-70%
Dermatomyositis-polymyositis
30-80%
Diseases for which ANA is an intrinsic
part of diagnosis:
Drug-induced SLE
100%
Mixed connective tissue disease (MCTD)
100%
Autoimmune hepatitis
100%
erythematosus (SLE), scleroderma, Sjögren’s syndrome or
polymyositis/dermatomyositis. The list below outlines the
important questions to ask in search of an underlying CTD
and in general a patient with CTD will have two or more
symptoms:
• Symmetrical small joint inflammatory arthritis
• Recurrent mouth ulcers
• Malar rash/photosensitive rash
• Severe cold sensitivity of the digits with tri-phasic colour
change (Raynaud’s, see Figure 3). If positive for Raynaud’s ask about: dysphagia, heartburn, tight skin, finger
tip ulcers
• Sicca (dry eyes and dry mouth)
• Proximal muscle weakness
• Alopecia
• History of other autoimmune disease (thyroid disease,
ITP).
Rates of positive ANA are affected by the prevalence of
CTD in the population. Specifically, false positive rates will
be higher in populations with a low prevalence of CTD, such
as in primary care.3 Therefore, ANA should only be obtained
in patients with suspicious symptoms as outlined above. It
should also be noted that back pain, fatigue and nonspecific musculoskeletal pain alone do not merit an ANA test.
ANA is also not useful in diagnosing osteoarthritis.
Positive ANA tests do not usually need to be repeated and
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Clinical Review
Figure 1. Stained
ANA (speckled and
homogenous)
Figure 2. Stained
ANA (nucleolar and
centromere pattern)
Figure 3. Raynaud’s
changes in ANA titre do not correlate with disease activity.
Only if there is a strong suspicion that the patient may have
an evolving CTD should a repeat ANA be considered.
When and who to refer?
Under the majority of circumstances, an ANA titre of
≤ 1:100 is enough to rule out connective tissue disease and
can be disregarded.4 Titres < 1:160 outside of liver disease
is rarely significant and unless signs and symptoms suggest
CTD, can be disregarded.
Titres between 1:200 and 1:320 require clinical assessment for CTD. Only if clinical assessment is positive for
CTD is further testing necessary. Should further testing
subsequently reveal signs and symptoms of CTD, referral
should be made to a rheumatologist. Titres of > 1: 400 are
significant and need careful evaluation for CTD followed by
further blood testing.
A positive ANA is rarely an emergency and there is time
to complete further blood work prior to referral. A renal,
bone, liver, thyroid, complete blood count and inflammatory marker screen is necessary to assess the extent of
organ involvement.
Double-stranded DNA should be considered as it is highly
specific for SLE. ENA (extractable nuclear antigen) serology
are also useful; these are nuclear and cytoplasmic components that are antibody targets. They include Anti-Ro,
Anti-La, Anti-RNP, Anti-Sm, Anti-Scl 70 and Anti Jo-1 antibodies all of which are helpful in sub-classifying patients
with an established diagnosis of autoimmune disease.
It is worth noting that ANA titres are included in the
diagnostic criteria for autoimmune hepatitis. The IAHG
(International Autoimmune Hepatitis Group) includes an
ANA ≥ 1:80 in its scoring system. Therefore, in the context
of abnormal LFTs, the presence of raised IgG and absence
of viral hepatitis, this is also a possibility and should be
kept in mind when faced with a positive ANA.
Selective ordering
To conclude, many diseases cause a positive ANA and
many healthy patients have a positive ANA. The higher the
ANA, the more significant it becomes.
Patients should be evaluated for signs and symptoms
of connective tissue disease before ordering an ANA. A
positive clinical assessment for CTD with a positive ANA
requires referral.
A negative ANA with signs and symptoms of CTD should
prompt evaluation for another diagnosis and consultation
with a rheumatologist can be considered. More selective
ordering of ANA can decrease anxiety among patients with
a positive result and reduce the chances of misdiagnosis.
Nick Malone is rheumatology house officer, Claire-Louise
Murphy is rheumatology SpR and Paul O’Connell is consultant
rheumatologist at Beaumont Hospital, Dublin
References
1. American College of Rheumatology Practice Management: ANA. 2010
2. Thomas C, Robinson JA. The antinuclear antibody test. When is a positive result clinically relevant? Postgrad Med 1993; 94(2): 55-66
3. Gill J, Quisel A, Rocca P, Walters D. Diagnosis of Systemic Lupus Erythematosis, American Family Physician, Dec 2003
4. Tan E, Cohen A, Fries J, Masi A, McShane D, Rothfield N. The 1982
revised critieria for the classification of SLE. Arthritis Rheumatology
1982; 25: 1271-7127
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