Abstract
The diagnosis of rheumatoid arthritis (RA) is based on a combined approach that includes serological markers such as rheumatoid factor (RF) and anti-citrullinated peptide/protein antibodies (ACPA). The goal of this study was to evaluate the clinical performance of several RF and ACPA immunoassays for the diagnosis of RA, as well as the diagnostic value of a combinatory approach with these markers. The study cohort included 1,655 patients from the Swiss Clinical Quality Management registry with sera from 968 patients with RA and 687 disease controls, including patients with axial spondyloarthritis (n = 450) and psoriatic arthritis (n = 237). ACPA were determined by anti-CCP2 IgG enzyme-linked immunosorbent assay (ELISA), QUANTA Flash® CCP3 IgG [chemiluminescent immunoassay (CIA)], and QUANTA Lite® CCP3 IgG ELISA. RF was determined by ELISA (QUANTA Lite® RF IgM, RF IgA, and RF IgG) and with two research use only CIAs (QUANTA Flash® RF IgM and RF IgA). All three ACPA assays showed good discrimination between RA patients and controls and good clinical performance. Overall, CCP3 performed better than CCP2. More pronounced differences were observed between the RF assays. We observed that CIA platforms for both RF IgM and RF IgA showed better performance than the ELISA platforms. Excellent and good total agreements were found between ELISA and CIA for CCP3 (total agreement 95.3%, kappa = 0.90), and between CCP2 and CCP3 ELISA (total agreement 86.6%, kappa = 0.73), respectively. RF IgM CIA and ELISA had a good qualitative agreement (86.5%, kappa = 0.73); RF IgA CIA and ELISA showed a moderate total agreement (78.5%, kappa = 0.53). When combinatory analyses were performed, the likelihood of RA increased with dual positivity and triple positivity and combining different markers resulted in higher odds ratio than the individual markers in all cases. ACPA and RF showed good clinical performance in this large Swiss cohort of RA patients and controls. Overall, the performance of CCP3 was superior to CCP2. The combination of these biomarkers in an interval model represents a potential tool for the diagnosis of RA patients.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by pain, inflammation, and joint destruction and affects up to 1.0% of the general population (1, 2)
At the cutoff values provided by the manufacturer, the CCP2 Enzyme-linked immunosorbent assay (ELISA) showed a high sensitivity (71.1%) and a moderately high specificity (86.9%) with a corresponding odds ratios (OR) of 16.3
At the cutoffs provided by the manufacturer for the ELISAs and at the preliminary cutoffs established for the chemiluminescent immunoassay (CIA), the sensitivities ranged from 35.6% (RF IgG ELISA) to 67.1% (RF IgM CIA), and the specificities were between 77.9% (RF IgA ELISA) and 96.9% (RF IgA CIA)
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by pain, inflammation, and joint destruction and affects up to 1.0% of the general population (1, 2). Diagnosis and treatment in RA is crucial as it can prevent disease progression and irreversible joint damage (3–5). Rheumatoid factor IgM, the main isotype identified by RF assays, is found in approximately 70–80% of patients with confirmed RA (6–8). Elevated levels of RF IgA and IgG have been reported in patients with RA (9, 10). Studies suggest that elevated levels of RF IgG are highly specific for RA diagnosis (10, 11). It has been proposed that the detection of all three RF isotypes improves the specificity and predictive value of RF testing (12)
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