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

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.