Antinuclear Antibody (ANA) Testing

Testing for the presence of antinuclear antibody (ANA) should be undertaken in a patient for whom relevant connective tissue or rheumatologic disorders are credible diagnostic considerations. It can serve as a laboratory marker that supports confirmation of a disease already suspected based on the child’s history and physical examination (such as in systemic lupus erythematosus [SLE]) or to subcategorize a condition at risk for complications (such as the presence of ANA in the setting of oligoarticular juvenile arthritis). In the case of the former, further assay for antibody specificity is necessary to determine which nuclear autoantigens are targeted, leading to greater accuracy in determining whether SLE or some other autoimmune disorder is present. Because ANA can be present in children and adolescents who are without disease, the test can be misleading if used for screening in the absence of a consistent clinical picture.An ANA-related phenomenon initially was reported in 1948 by Hargraves and was labeled the “LE” cell. The authors described obtaining concentrated bone marrow specimens from patients who had SLE and demonstrating the phagocytosis of antibody-sensitized nuclei by polymorphonuclear leukocytes. The cause of the LE cell mechanism was found later to be due to plasma autoantibody directed against deoxyribonucleoprotein.Although still occasionally available as a laboratory assay, the LE cell test has given way to the indirect immunofluorescence ANA test (FANA), which is a much more sensitive technique for detecting antinuclear antibodies. The FANA test involves incubation of serial dilutions of the patient’s sera with substrate cells. If antibody to nuclear elements is present, binding to the substrate is detected by fluorescein conjugated antihuman immunoglobulin, which attaches to the antibody and is visualized by using a fluorescence microscope. The most sensitive and commonly used cell substrate is the human epithelial tumor line HEp-2. In addition to reporting the highest dilution titer at which binding is still present, laboratories also describe the pattern of staining. The latter is expressed as homogeneous, rim, or speckled and can be detailed further in the case of speckled nucleolar patterns as discrete or grainy. Although there are some consistencies between ANA pattern and disease (eg, homogeneous or rim seen in SLE, anticentromere/kinetochore in systemic sclerosis), testing for specific ANAs (eg, anti-double-stranded DNA, anti-Smith, anti-topoisomerase I) is more reliable than the aforementioned qualitative immunofluorescent patterns.The details and subtleties of ANA testing are much more extensive than previously summarized and are of utility to the pediatric rheumatologist, but the general pediatrician more appropriately is concerned with the questions of who should be tested and how positive and negative results should be interpreted. As noted previously, looking for ANA in a patient who does not have signs or symptoms characteristic of connective tissue diseases that are known to be associated with ANA is potentially more confusing than elucidating. Because healthy children and adolescents (especially females and those whose family members have ANA) can test positive for ANA, the clinician is ill-advised to use this as a screening tool to rule out connective tissue or autoimmune disease.Various reports of the ANA frequency in normal, healthy children using the sensitive HEp-2 substrate (and including low titers) have described prevalences between 2% and 6%. Among 108 children who had musculoskeletal pain but no identifiable disease at presentation and were referred to several pediatric rheumatology clinics in Canada for ANA testing, 24 (23 girls) had positive results, and 21 of these children continued to have positive results over a mean of 61 months without developing inflammatory, autoimmune, or malignant disease. In a similar study in our rheumatology clinic, we observed that 72 of 113 patients (64%) who had positive ANA test results at the time of initial referral were diagnosed as having a related autoimmune condition at the first subspecialty evaluation. The remaining 41 patients had no connective tissue disease diagnosis. Over time, 10 of these 41 patients could not be located for ongoing monitoring, but with a mean follow-up of 37 months, 30 of the remaining 31 patients did not develop a disease related to ANA. The one patient who became ill with autoimmune hepatitis was diagnosed at her second clinic visit. These studies highlight that without clinical findings of connective tissue diseases (eg, fever, rash, photosensitivity, alopecia, mucous membrane lesions, serositis, arthritis), ANA is not useful in identifying an otherwise occult pathologic process. It also does not represent a meaningful risk factor for later disease development.Appropriate application of ANA testing, therefore, is based on an understanding of which illnesses are associated with ANA and how they present. SLE is the connective tissue disease in which ANA is almost universal (very high sensitivity), but the anti-double-stranded DNA and anti-Smith autoantibodies are very specific for SLE, unlike the ANA. In some patients who have SLE, the level of anti-ds DNA correlates with the risk and severity of renal disease. Many other autoantibodies are detected in SLE, including anti-Ro/SS-A, anti-La/SS-B, anti-RNP, and anti-Ku. Drug-induced SLE (which can occur with hydralazine, procainamide, isoniazid, phenytoin, and other medications) is virtually eliminated from consideration if ANA is not detected. Anti-histone antibodies are the typical ANA specificity of drug-induced SLE. Other conditions in which greater than 90% of patients are found to have ANA include: systemic sclerosis (anti-topoisomerase I or anti-SCL-70), dermatomyositis (anti-tRNA synthetases such as anti Jo-1), mixed connective tissue disease (anti-ribonuclear protein), and Sjögren syndrome (anti-Ro/SS-A, anti-La/SS-B). The presence of SS-A, SS-B, or both in pregnant women who have SLE also is associated with the neonatal lupus syndrome or complete congenital heart block in the neonate. In a patient who has a thromboembolic event or a young woman who has a history of serial spontaneous miscarriages, the anti-phospholipid antibody syndrome should be investigated because this can be a complication of SLE. Thus, along with the ANA, lupus anticoagulant and anticardiolipin antibody should be assayed.In addition to the previously noted ANA-associated systemic illnesses, ANA can be found in patients who have juvenile arthritis. Among those who have oligoarticular disease complicated by uveitis (most often in young girls), ANA is detected in 65% to 85% of patients. Thus, the ANA test in this context serves as an indication for periodic slitlamp examination of the eyes and offers an opportunity for earlier diagnosis and therapy if iridocyclitis is detected. Rheumatoid factor-positive polyarticular juvenile arthritis is associated with ANA in some patients, but this finding does not carry specific clinical implications.ANA is detected in many diseases that do not belong to the connective tissue or rheumatologic categories, and it is important to recognize this phenomenon so as not to misinterpret a potentially false-positive result. Children and adolescents who have viral illnesses may develop ANA that can persist for up to 8 weeks following the acute illness. Other infections associated with ANA include tuberculosis, subacute bacterial endocarditis, chronic osteomyelitis, and malaria. Psoriasis, idiopathic thrombocytopenic purpura, autoimmune hepatitis, autoimmune thyroiditis, multiple sclerosis, and diabetes mellitus also have been reported in association with ANA, as have lymphoma and leukemia.

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