The antinuclear antibody test: Last or lasting gasp?

Autoantibodies have been regarded as a serologic hallmark of systemic autoimmune rheumatic diseases (ARDs) for more than half a century. Two years following the landmark discovery of the lupus erythematosus (LE) cell and the LE cell phenomenon by Hargraves and colleagues at the Mayo Clinic in 1948 (1), Coons and Kaplan described indirect immunofluorescence (IIF) as a useful approach to the detection of serum autoantibodies directed against intracellular antigens (2). This led to IIF applications designed to detect antinuclear antibodies (ANAs) as a key approach to the laboratory diagnosis of systemic lupus erythematosus (SLE) and eventually other systemic ARDs (3). After more than 50 years of widespread use, the ANA test and other IIF applications have enjoyed a favored position in diagnostic medicine, although they have been plagued by limitations and are now being challenged by newer diagnostic platforms and technologies (4). The advent and acceptance of the newer technologies has also been predicated on the appreciation that the ANA IIF test is not well suited to high-volume and high-throughput laboratories where the containment of medical health care costs has been a determining factor. Nevertheless, it has been recognized that many of these high-throughput technologies have limitations, most notably falsenegative results, in the detection of ANAs (5). To address these issues and concerns, the American College of Rheumatology (ACR) convened a committee to undertake an analysis and provide recommendations with respect to ANA testing as an approach to diagnosing systemic ARDs. In May 2010, a summary of the committee’s findings and recommendations was published; among these was the recommendation that the ANA IIF test using cell substrates should be considered the “gold standard” assay to screen for autoantibodies in sera from patients with systemic ARDs (5). For several decades, it has been well known that the ANA IIF test is compromised by the lack of universal standardization and by false-positive tests that lead (in some clinicians’ opinions) to “unnecessary” referrals or even to inappropriate diagnoses. An interesting case in point are autoantibodies that produce a staining pattern referred to as nuclear dense fine speckled, and in this issue of Arthritis & Rheumatism, Mariz and colleagues elaborate on the nuclear dense fine speckled pattern and provide timely and provocative observations about its usefulness as a screening test for systemic ARDs (6). However, unlike the case with other ANAs, Mariz et al suggest that the detection of the nuclear dense fine speckled staining pattern can be used as a biomarker to rule out the diagnosis of SLE and/or other systemic ARDs. Two key points need to be made: first, it should not be concluded that all sera demonstrating the nuclear dense fine speckled staining pattern are from healthy individuals; second, before the observations and conclusions reached by Mariz and colleagues can be widely accepted and applied in clinics, a number of issues should be addressed.