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To the Editor:

We thank Dr. Nordal and colleagues for their interest in our work, but disagree with their criticisms. They argue that the method used in our study to determine the ANA status (i.e., IIF on rat liver or HEp-2 cells) is not reliable. In support, they cite 2 recent editorials on ANA testing in systemic autoimmune rheumatic diseases (ARDs) (1, 2). However, Drs. Meroni and Schur report in their editorial, the recent recommendations of the American College of Rheumatology (ACR) task force with respect to ANA determination in systemic ARDs, which state that the “immunofluorescence ANA test should remain the gold standard for ANA testing” (1). That task force also concluded that solid-phase immunoassays may not currently be appropriate as a replacement for IIF as a screening test for the detection of ANA. Although Dr. Fritzler highlights the limitations of the IIF ANA test in his editorial (2), he also emphasizes the unacceptably high rates of false-negative results from newer ANA screening technologies, such as ELISA and microarray. In their letter, Nordal and colleagues mention their previous study, which showed that ELISA for ANA has no clinical value as a diagnostic test or a marker of iridocyclitis in JIA (3). Therefore, based on the available information, IIF testing remains the best method to detect ANAs in patients with JIA.

In all of our ANA-positive patients, the presence of ANAs was confirmed by repeated testing. Furthermore, the minimum cutoff titer for ANA positivity was set at 1:160. We chose this strict definition for positive ANA status in order to minimize the rate of false-positive results (that is, to make sure that patients included in the ANA-positive group really had a positive ANA status). To date, an agreed-upon definition for ANA positivity in children with JIA does not exist. We have chosen the above cutoff on the basis of 20 years of our own clinical observation that virtually all JIA patients with the “ANA-positive phenotype” have a titer above that threshold in most determinations.

To further emphasize the inadequacy of IIF ANA testing, Nordal and colleagues state that the rates of IIF-determined ANA positivity vary between different cohorts worldwide and attribute this variability to the operator dependency of the test and the lack of reproducibility and a uniformly accepted cutoff titer. This argument is surprising, as it has long been known that there are disparities in the frequency of the various JIA subsets in different ethnic populations. Several studies have shown that early-onset, ANA-positive, iridocyclitis-associated JIA, which is the most frequently observed subtype in Western countries, is rare in some areas of the world, including Costa Rica, India, New Zealand, and South Africa (for review, see ref.4). A recent epidemiologic study of JIA in a multiethnic cohort in the Toronto area showed that European ancestry can be a predisposing factor for a combination of JIA characteristics including young age at diagnosis and ANA positivity and, in the presence of these characteristics, the development of JIA-related uveitis (5). Overall, these reports suggest that the geographic differences in the prevalence of the ANA-positive JIA subgroups are largely related to diversity in genetic background rather than to a lack of standardization of ANA assays across laboratories.

  • 1
    Meroni PL, Schur PH. ANA screening: an old test with new recommendations. Ann Rheum Dis 2010; 69: 14202.
  • 2
    Fritzler MJ. The antinuclear antibody test: last or lasting gasp? [editorial]. Arthritis Rheum 2011; 63: 1922.
  • 3
    Nordal EB, Songstad NT, Berntson L, Moen T, Straume B, Rygg M. Biomarkers of chronic uveitis in juvenile idiopathic arthritis: predictive value of antihistone antibodies and antinuclear antibodies. J Rheumatol 2009; 36: 173743.
  • 4
    Martini A. Are the number of joints involved or the presence of psoriasis still useful tools to identify homogeneous entities in juvenile idiopathic arthritis? J Rheumatol 2003; 30: 19003.
  • 5
    Saurenmann RK, Rose JB, Tyrrell P, Feldman BM, Laxer RM, Schneider R, et al. Epidemiology of juvenile idiopathic arthritis in a multiethnic cohort: ethnicity as a risk factor. Arthritis Rheum 2007; 56: 197484.

Angelo Ravelli MD*, Alberto Martini MD*, * Università degli Studi di Genova, Istituto di Ricovero e Cura a Carattere, Scientifico G. Gaslini, Genoa, Italy.