Abstract
IntroductionRecently, arrays have become available that allow the simultaneous analysis of several anti-citrullinated protein antibody (ACPA) reactivities using distinct citrullinated peptides. Such assays are designed for exploratory studies. The interpretation of positive antibody reactivities can best be made if the diagnostic and prognostic value of a multiplex array in an early arthritis setting is known and if the multiplex-positive patients who are negative according to three commonly used commercial ACPA assays are characterized.MethodsUsing Thermo Scientific’s ImmunoCap ISAC (Immuno Solid-phase Allergen Chip) system, a multiplexed array that determines reactivities to 11 citrullinated peptides, we analysed serum/plasma of 195 healthy controls and 1282 early arthritis patients from two independent cohorts: the Leiden Early Arthritis Clinic (n = 1013) and the IMPROVED (n = 269) cohort. Findings were compared with results primarily of the anti-citrullinated cyclic peptide 2 (anti-CCP-2) assay but also with anti- CCP-3 and anti-mutated citrullinated vimentin (anti-MCV) assays. The associations between ACPA reactivities and patient characteristics, risk factors (shared epitope, smoking) and disease outcomes (progression of undifferentiated arthritis to rheumatoid arthritis (RA) and severity of joint destruction) were assessed.ResultsThirty-one percent of anti-CCP-2-negative RA patients displayed reactivity toward citrullinated peptides in the multiplex assay. These patients had a positive signal toward a more restricted peptide repertoire than anti-CCP-2-positive RA patients (median of 1 versus 5). Within anti-CCP-2-negative patients, ACPA reactivity as detected by multiplex array was not significantly associated with known risk factors or clinical or prognostic parameters. The frequency of sera from anti-CCP-2-negative RA patients who were positive for the multiplexed peptides was comparable to the frequency in non-RA arthritic patients (27 %).ConclusionsAdditive citrulline peptide reactivities detected by the current multiplex system did not reach significant power to be RA-specific. The presence of residual citrulline reactivities detected by this multiplex system in arthritis patients who are negative in commercial ACPA assays needs to be interpreted with caution.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0786-z) contains supplementary material, which is available to authorized users.
Highlights
Arrays have become available that allow the simultaneous analysis of several anti-citrullinated protein antibody (ACPA) reactivities using distinct citrullinated peptides
Presence of citrulline reactivities by multiplex assay in patients with Rheumatoid arthritis (RA) Before embarking on determining the diagnostic value of a prototype multiplex array in an early arthritis setting, we wished to validate the assay by comparing the results in the Leiden population of patients with RA with previously published data by using other sets of patients with RA
The frequency of anti-Cyclic citrullinated peptide (CCP)-2-positive RA patients is higher in the IMPROVED than in the Early Arthritis Clinic (EAC) (65 % versus 51 %) and this is probably explained by the different inclusion criteria
Summary
Arrays have become available that allow the simultaneous analysis of several anti-citrullinated protein antibody (ACPA) reactivities using distinct citrullinated peptides. Such assays are designed for exploratory studies. The interpretation of positive antibody reactivities can best be made if the diagnostic and prognostic value of a multiplex array in an early arthritis setting is known and if the multiplex-positive patients who are negative according to three commonly used commercial ACPA assays are characterized. Patients with RA frequently present with autoantibodies, of which the anti-citrullinated protein antibodies (ACPAs) are of particular interest. These autoantibodies are highly specific for RA and target proteins that have undergone a post-translational modification that converts arginine to citrulline residues. These subsets differ substantially in clinical outcome and with regard to underlying genetic and environmental risk factors [4,5,6]
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