Profiling of IgG antibodies targeting unmodified and corresponding citrullinated autoantigens in a multicenter national cohort of early arthritis in Germany

Abstract

Objective: To assess the diagnostic potential of IgG antibodies to citrullinated and corresponding native autoantigens in early arthritis. Methods: IgG autoantibodies to 390 distinct unmodified and corresponding in vitro citrullinated recombinant proteins were measured by a multiplex assay in baseline blood samples from a German multicenter national cohort of 411 early arthritis patients (56.5 ± 14.6 years, 62.8% female). The cohort was randomly split into a training cohort (n = 329, 28.6% ACPA positive) and a validation cohort (n = 82, 32.9% ACPA pos.). The diagnostic properties of candidate antibodies to predict a subsequent diagnosis of rheumatoid arthritis (RA) as opposed to a non-RA diagnosis were assessed by receiver operating characteristics analysis and generalized linear modeling (GLM) with Bonferroni correction in comparison to clinically determined IgM rheumatoid factor (RF) and citrullinated peptide antibody (ACPA) status. Results: Of 411 patients, 309 (75.2%) were classified as RA. Detection rates of antibody responses to citrullinated and uncitrullinated forms of the proteins were weakly correlated (Spearman's r = 0.13 (95% CI 0.029-0.22), p = 0.01). The concentration of 34 autoantibodies (32 to citrullinated and 2 to uncitrullinated antigens) was increased at least 2-fold in RA patients and further assessed. In the training cohort, a significant association of citrullinated "transformer 2 beta homolog" (cTRA2B)-IgG with RA was observed (OR 5.3 × 10 3 , 95% CI 0.8 × 10 3-3.0 × 10 6 , p = 0.047). Sensitivity and specificity of cTRA2B-IgG (51.0%/82.9%) were comparable to RF (30.8%/91.6%) or ACPA (32.1%/94.7%). Similar results were obtained in the validation cohort. The addition of cTRA2B-IgG to ACPA improved the diagnostic performance over ACPA alone (p = 0.026 by likelihood ratio test). Conclusions: cTRA2B-IgG has the potential to improve RA diagnosis in conjunction with RF and ACPA in early arthritis.

Human antibody profiling technologies for autoimmune disease

“…Another emerging protein array is ImmunoINSIGHTS (formally known as Serotag (Oncimmune)), which differs from the prior examples based on planar solid surfaces, as the over 8000 human proteins are immobilised on Luminex bead-based suspension arrays enabling solution phase antigen binding. Although a relatively new technology, it has been utilised (Table 1) in rheumatoid arthritis [21,22] and SLE [23].…”

Perspektiven für die rheumatologische Versorgungsforschung am Deutschen Rheuma-Forschungszentrum

“…Dieser Limitation wird in mehreren Kooperationsprojekten des Programmbereichs Rechnung getragen. Bestehende Kooperationsprojekte mit den Universitäten Düsseldorf und Granada, der Universität Münster und der Universität von Calgary in Canada haben zu kennzeichnenden und prognostischen Markern der juvenilen idiopathischen Arthritis [ 22 – 24 ] und frühen Arthritis bei Erwachsenen in der CAPEA-Kohorte [ 25 , 26 ] beigetragen. In RABBIT wurden anhand der Response auf verschiedene Therapieprinzipien gezielt unterschiedliche Patientengruppen identifiziert, von denen in Kooperation mit der Universität Düsseldorf Biomaterial gesammelt wurde, das im Hinblick auf Biomarkerprofile und Risikogene bei multiplen Non-Respondern untersucht werden wird.…”