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Antiperinuclear Factor Test Is More Useful than Anti-Sa Assay When Used with Anti-Cyclic Citrullinated Peptide Test in Diagnosis of Rheumatoid Arthritis

To the Editor:

We read with interest the article by Lopez-Longo, et al regarding anti-cyclic citrullinated peptide (anti-CCP) versus anti-Sa antibodies in diagnosis of rheumatoid arthritis (RA)¹. The authors insisted that the sensitivity of the anti-Sa test (43.6%) is lower than that of the anti-CCP test (72.4%), but since 12% of patients with RA showed anti-CCP test negatives with anti-Sa test positives, performing the anti-Sa test in RA patients with anti-CCP-negative results can aid in the diagnosis of patients with RA. Instead of the anti-Sa, we used the antiperinuclear factor (APF) test simultaneously with the anti-CCP test and found interesting results.

We analyzed the results of patients from the outpatient clinic of Hanyang University Hospital for Rheumatic Diseases who underwent both tests. The disease distributions of patients were as follows: 56 patients with RA, 65 with non-RA connective tissue diseases, and 139 with osteoarthritis. APF test was performed by the indirect immunofluorescent method using a commercial kit (IT-APF^TM; ImmunoThink Co., Seoul, Republic of Korea). The anti-CCP test was referred to a commercial reference laboratory, and a second-generation enzyme immunoassay kit was used (Diastat^TM Anti-CCP; Axis-Shield Diagnostics Limited, Dundee, UK). Each test was performed such that the result of the other test is not known. In addition, a comprehensive autoimmune antibody screening test, the "autoimmune target" (AIT) test, was performed using an indirect immunofluorescent test kit (IT-AIT^TM; ImmunoThink Co.).

Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratio for each test are shown in Table 1. Although there were no big differences between the 2 tests, the sensitivity was higher in the anti-CCP test, while the specificity and predictive value were similar. The likelihood ratios for positive findings were also similar — 8.30 and 7.69, respectively. If we define positives as cases in which both tests are positive, specificity increases to 98.5% and the likelihood ratio for positive findings increases to 38.86, suggesting significant usefulness in the diagnosis of RA. Cases showing discrepant results between the 2 tests are shown in Table 2. The concordance rate of the 2 tests was 82.7%, while the kappa value, the barometer of concordance rate, was 0.498 (p < 0.01). In 15 RA patients with negative anti-CCP test results, 6 patients (40%) were positive in the APF test.

Table 1. Diagnostic performance of antiperinuclear factor (APF) test and anti-cyclic citrullinated peptide (anti-CCP) test for the diagnosis of RA.

Table 2. Discrepancy between antiperinuclear factor (APF) test and anti-cyclic citrullinated peptide (anti-CCP) test results in patients with RA.

The APF test was essential in the diagnosis of RA for a long time, but since then, various problems regarding commercialization of the test led to only limited use in certain specialized rheumatic disease laboratories. In Korea, however, a commercial APF kit was developed to be readily used in the general laboratory², and it is actively in use with the approval of the Korean Food and Drug Administration for in vitro diagnostic purposes. In addition, the external quality control program is adopted under the supervision of the Korean Society for Laboratory Medicine to standardize the test³. The anti-CCP test was developed as an enzyme immunoassay method using the recombinant peptide that is similar with part of the APF target antigen. The early first-generation kit showed a low sensitivity rate, around 50%, but the current second-generation kit shows an improved average sensitivity rate of 70%⁴. As a consequence, use of the anti-CCP test is growing worldwide, and some researchers have insisted that the anti-CCP test can replace the APF test⁵. However, according to the results of this study, these 2 tests are in a complementary relationship, and since 40% of those patients with clinically suspected RA who were negative for the anti-CCP test showed positive APF test results, replacing the APF test by the anti-CCP test would be inappropriate. On the other hand, 33% of those patients with RA who were negative for both tests showed positive results in the AIT test, and we think it would be diagnostically helpful when the AIT test is performed upon those patients who are clinically suspected of RA.

The AIT test is a comprehensive autoimmune antibody screening test, using macrophage cell line (IT-1 cell) as substrate for the antinuclear antibody (ANA) test. The AIT test is more reliable and more easily interpreted than the ANA test performed with the customary HEp-2 cell line⁶. In addition, the AIT test can detect anti-MTOC and anti-GiM, which are the marker antibodies for RA^7,8.

DUCK-AN KIM, MD; LA-HE JEARN, MD; THINK-YOU KIM, MD, Department of Early Arthritis, Hospital for Rheumatic Diseases, Hanyang University Medical Center, Seoul, Republic of Korea. Address reprint requests to Dr. Kim. E-mail: dukim@hanyang.ac.kr

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