Comparison of Serological Biomarkers in Rheumatoid Arthritis and Their Combination to Improve Diagnostic Performance

Abstract

IntroductionThe 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.MethodsThe 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).ResultsAll 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.ConclusionACPA 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.

Immunoglobulin A antibodies to oxidized collagen type II as a potential biomarker for the stratification of spondyloarthritis from rheumatoid arthritis

“…Our data confirm previous reports where ACPA positivity was detected in about 1% to 13% of PsA and axSpA patients, depending if second or third generation anti-cyclic citrullination peptide antibody assay were used (35). This alone does not rule out the involvement of a humoral immune response, as it should be appreciated that back in the 1990s, a number of studies demonstrated reactivity to fibrocartilage proteins, including aggrecan, suggesting that an autoimmune antibody response may underlie enthesitis and spondylitis pathology (36).…”

Third‐Generation Anti–Cyclic Citrullinated Peptide Antibodies Improve Prediction of Clinical Arthritis in Individuals at Risk of Rheumatoid Arthritis

“…In previous studies, the agreement between the 2 tests has been evaluated almost exclusively in patients with RA, with conflicting results. In fact, some studies demonstrated good agreement between anti‐CCP2 and anti‐CCP3 antibodies (23,24,35–38), whereas other studies showed a significant discrepancy between the 2 tests (39,40). The lack of agreement was attributed to several factors, such as borderline results, interassay discrepancy, the fact that anti‐CCP3 assays may include additional epitopes not present in the anti‐CCP2 antigen sequence, and intertest variability depending on other components of the kits (i.e., standards, secondary antibody, or the cutoff used).…”

“…In 2 studies (22,23), anti‐CCP3 was found to discriminate better than anti‐CCP2 between RA and non‐RA in patients negative for rheumatoid factor (RF). Interestingly, the combination of these 2 assays was shown to have higher specificity for the identification of RA patients than the individual assays (24,25).…”

Potential clinical biomarkers in rheumatoid arthritis with an omic approach

“…Considered useful in early stages of the disease to predict the development of erosions and the presence of the IgA isotype is associated with extra-articular manifestations. Aggressive development of the disease and decreased response to anti-TNF therapy have been reported at high levels [ 42 , 53 , 57 , 68 , 74 , 75 , 99 , 109 , 121 , 124 ] PHASE 1 Anti-citrullinated protein antibodies (ACPA) Non-omics Biomarker more sensitive (60–80%) and specific (95–98%) for the diagnosis of RA than RF. ACPA + patients develop a more aggressive and erosive progressive disease clinical phase compared to ACPA- patients; Positivity has been associated with a better response to treatment in early stages but medication-free remission is less frequent.…”

“…Baseline levels can be predictive for the response to methotrexate and ACPA + subjects are associated with a better response to abatacept independent of disease activity. It has been detected in healthy patients therefore increases the risk of developing RA by 5% in the next 5 years [ 42 , 51 , 53 – 57 , 65 , 68 , 74 , 75 , 99 , 109 , 110 , 112 , 121 ] PHASE 1 Anticarbamylated protein (anti-CarP) antibodies Non-omics Association with rapid radiological damage and severe course of the disease independent of the ACPA value. In patients ACPA—it is associated with the development of arthralgias [ 57 , 65 , 74 , 109 , 112 ] PHASE 1 Regulatory B lymphocytes (Breg) Non-omics Protective role in RF + patients (Lower T2/Breg levels) [ 62 ] PHASE 1 Erythrocyte Sedimentation Rate (ESR) Non-omics Nonspecific indicator of the amount of inflammation in the elevated body in patients with RA.…”