Relationship Between Rheumatoid Factor Isotypes and IgG Anti-Cyclic Citrullinated Peptide Antibodies

Abstract

Objective.To validate in a general patient population (GPP) the clinical value of measuring rheumatoid factor (RF) isotypes in relationship to IgG anti-cyclic citrullinated peptide (CCP) antibodies (CCP2 and CCP3).Methods.Serum samples were obtained as follows: 1021 GPP, for whom RF was ordered for diagnosis, 137 with rheumatoid arthritis (RA), 100 healthy blood donors (HBD), and 50 with systemic lupus erythematosus. Turbidimetry and ELISA were utilized for RF screening, and individual RF isotypes and IgG anti-CCP antibodies were measured by ELISA; RF IgG was measured after pepsin digestion.Results.We validated the generally accepted 90%–98% positive predictive value (PPV) and about 68% sensitivity of the anti-CCP2 test on our diagnosed cohorts as 96% (95% CI 89–99) and 65% (95% CI 56–73), respectively. The 282 RF IgM+ specimens identified in the GPP were subdivided into 3 subsets: (1) 83 as RF IgM+ IgG+ IgA+ with 63% (95% CI 51–73) anti-CCP2+ (i.e., sensitivity similar to the RA cohort); (2) 50 as RF IgM+ IgG− IgA+ with significantly fewer anti-CCP2+ (22%; 95% CI 12–36); and (3) about half as IgM+ IgG− IgA− with just 3% (95% CI 1–8) anti-CCP2+, i.e., not significantly different from the 1% (95% CI 0–5) in HBD. Thus, the chance for a specimen in the GPP to be anti-CCP2+ (i.e., to come from an RA patient) was increased by 7- and 21-fold, respectively, by identifying RF IgA and IgG in addition to IgM. About one-third of anti-CCP− RA patients in our cohort were RF IgM+ IgG+ IgA+, reflected as 3.4% in the anti-CCP2− GPP. The agreement between anti-CCP2 and anti-CCP3 was significantly higher for RF+ RA and GPP patients, 86% (95% CI 78–93) and 83% (95% CI 73–91), respectively, than for the RF− RA (27%; 95% CI 6–61), RF− GPP (4%; 95% CI 0–19), and non-RA controls. Anti-CCP2 but not anti-CCP3 significantly distinguished the HBD from the GPP (95% CI).Conclusion.Measurement of the 3 isotypes of RF may increase by 7- to 21-fold the chance of making the serologic diagnosis of RA; a testing algorithm is proposed. The anti-CCP antibody response appears significantly less peptide-specific in the presence of IgM RF than in its absence.

Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide 2 antibody and anti-cyclic citrullinated peptide 3 antibody in rheumatoid arthritis

“…We identified 797 articles, of which 17 met the inclusion criteria [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. There were 1952 RA patients selected from Europe, Americas and Asia in the remaining 17 articles that were eventually available for this meta-analysis (see Table 1).…”

Anti-citrullinated protein antibodies in the diagnosis of rheumatoid arthritis (RA): diagnostic performance of automated anti-CCP-2 and anti-CCP-3 antibodies assays

“…A study performed by Jaskowski et al [20] found no statistically significant difference in sensitivity and specificity between anti-CCP3 and anti-CCP2. Instead, they showed that anti-CCP3 antibodies were more prevalent than anti-CCP2 antibodies in RF-negative RA patients.…”

Clinical validation of surface-enhanced Raman scattering-based immunoassays in the early diagnosis of rheumatoid arthritis

“…Various serum biomarkers were studied with regard to diagnosing RA. Anti-CCP autoantibodies are currently considered to be the best biomarkers in the early diagnosis of RA [30][31][32][33]. Specifically, we demonstrated that the SERS-based immunosensor is more sensitive at detecting human anti-CCP than is the commercially available enzymelinked immunosorbent assays (ELISA).…”