ARTHRITIS & RHEUMATISM Vol. 63, No. 1, January 2011, pp 19–22 DOI 10.1002/art.30078 © 2011, American College of Rheumatology EDITORIAL The Antinuclear Antibody Test: Last or Lasting Gasp? Marvin J. Fritzler Autoantibodies have been regarded as a serologic hallmark of systemic autoimmune rheumatic diseases (ARDs) for more than half a century. Two years follow- ing 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 autoanti- bodies 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 diagnos- tic medicine, although they have been plagued by limi- tations and are now being challenged by newer diagnos- tic 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 false- negative results, in the detection of ANAs (5). To address these issues and concerns, the Amer- ican College of Rheumatology (ACR) convened a com- mittee to undertake an analysis and provide recommen- dations 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 consid- ered the “gold standard” assay to screen for autoanti- bodies 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 univer- sal 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 col- leagues 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. False-negative or false-positive ANA test results: which are worse? The primary concern of the ACR committee alluded to above (5) was the problem of false-negative results generated by newer high-throughput (i.e., enzyme- linked immunosorbent assay [ELISA] and microarray) ANA screening tests, the allegation being that false- negative screening tests could delay or lead to an erroneous diagnosis and/or dismissal of the patient as having no disease when in fact the patient had a systemic ARD. In the committee’s conclusion that the ANA IIF test should remain the “gold standard,” little commen- tary was devoted to the limitations of the ANA IIF test, particularly false-positive results that might also lead to Marvin J. Fritzler, MD, PhD: University of Calgary, Calgary, Alberta, Canada. Dr. Fritzler has received consulting fees and/or honoraria from Bio-Rad and Inova Diagnostics (less than $10,000 each) as well as from Immuno Concepts (more than $10,000). Address correspondence to Marvin J. Fritzler, MD, PhD, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. E-mail: fritzler@ucalgary.ca. Submitted for publication September 8, 2010; accepted in revised form September 30, 2010. 19