Pediatric rheumatology clinics are overwhelmed by patients with nonspecific symptoms and positive antinuclear antibody (ANA) tests, but studies show few of these patients are diagnosed with rheumatic disease.
In a recent study, 23% of patients newly referred to a large pediatric rheumatology center were diagnosed with rheumatic disease. Within this cohort, rheumatic disease was diagnosed in only 7% of ANA positive referrals (Reiff DD, et al. Pediatr Rheumatol Online J. 2023;21:120).
Given the shortage of pediatric rheumatologists nationally, large volumes of such referrals can result in significant delays for patients with inflammatory disorders. General pediatricians can help reduce inappropriate referrals by knowing when to use and how to interpret ANA tests in children.
Clinical suspicion key to diagnosis
ANAs are autoantibodies that target the nuclei of cells. Their presence is a feature of various autoimmune disorders. However, they also are present in 20%-30% of the healthy pediatric population, which can lead to confusion and frustration for patients, families and general pediatricians (Meier HCS, et al. Front Immunol. 2022;13:789379).
Clinical suspicion of autoimmune disease is the key to making a diagnosis, not the ANA.
An ANA is unlikely to be clinically relevant in the absence of symptoms suggestive of an autoimmune disorder such as nontraumatic joint effusion, limited range of motion of joints, malar or heliotrope rash, sclerodactyly, Raynaud’s phenomenon or cytopenia.
An ANA test can be helpful in diagnosing pediatric systemic lupus erythematous, scleroderma, mixed or undifferentiated connective tissue disease, dermatomyositis or Sjogren’s syndrome, since most children with these conditions have a positive ANA test. A negative ANA, however, does not rule out autoimmune disease if clinical suspicion remains high.
Given the high prevalence of ANA in the healthy population, the test has an extremely limited utility in the evaluation of symptoms such as chronic fatigue or arthralgia unless an aforementioned rheumatic disease is suspected. The likelihood that someone with these symptoms and a positive test result has a rheumatic disease is only 10% (Malleson PN, et al. Arch Dis Child. 1997;77:299-304).
Rheumatologists frequently order ANA tests for children with juvenile idiopathic arthritis (JIA), since patients younger than 7 years with a positive test are at higher risk of developing uveitis. ANA positivity guides recommendations for ophthalmologic monitoring in these children. The presence of the ANA has no other impact on the diagnosis or subsequent management of JIA.
A positive ANA also can be seen with viral infections, use of certain medications, celiac disease, autoimmune thyroid disease and/or malignancies without clinical implications for those scenarios.
Interpreting positive tests
If a patient has a positive ANA test, a primary care physician can consider additional factors to help interpret the finding before offering reassurance or referral. This interpretation includes understanding the patternidentified by immunofluorescence and the titer of the ANA.
While the majority of patterns can be seen in both the healthy population and in children with rheumatic disease, two patterns are noteworthy (see table). Centromere patterns are strongly associated with autoimmune diseases, specifically scleroderma. On the contrary, isolated nuclear dense fine speckled patterns rarely are associated (1%) with underlying connective tissue disorders such as lupus.
Other patterns, such as homogenous, nucleolar, peripheral and speckled, have low specificity for any particular autoimmune disease and are found in healthy individuals. Therefore, they are not of specific concern.
The titer of an ANA indicates the highest dilution of the serum that produces detectable fluorescence.
High titers (≥1:640) are strongly associated with autoimmune disease. Therefore, ordering more specific testing such as for anti-dsDNA, anti-Smith, anti-RNP, anti-SSA and anti-SSB antibodies can be considered to expedite and direct further evaluation.
Moderate titers (1:160-1:320) require careful clinical correlation as they can be seen in a multitude of conditions, including infection or autoimmune disease.
Low titers (1:40-1:80) can be found in healthy individuals and are considered nonspecific.
If no titer is provided with results, then the test was not completed using an immunofluorescence assay, which is the standard in pediatric rheumatology.
ANA testing is complex, and clinicians must consider the complete clinical picture, including patient history, physical examination and other basic laboratory findings when interpreting results.
In the absence of specific signs of autoimmune disease, judicious use of ANA testing can improve patient care by reducing false-positive results, unnecessary parental and patient anxiety, and overmedicalization.
Dr. Kung and Dr. Ostrov are members of the AAP Section on Rheumatology.
