Anticitrullinated protein/peptide antibody multiplexing defines an extended group of ACPA-positive rheumatoid arthritis patients with distinct genetic and environmental determinants. Issue 2 (25th October 2017)

• Record Type: Journal Article
• Authors: Rönnelid, Johan; Hansson, Monika; Mathsson-Alm, Linda; Cornillet, Martin; Reed, Evan; Jakobsson, Per-Johan; Alfredsson, Lars; Holmdahl, Rikard; Skriner, Karl; Serre, Guy; Lundberg, Karin; Klareskog, Lars
• Is Part Of: Annals of the rheumatic diseases. Volume 77:Issue 2(2018)
• Page Start: 203
• Page End: 211
• Publication Date: 2017-10-25
• Subjects: ant-ccp -- autoantibodies -- rheumatoid arthritis; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2017-211782
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Introduction: The second generation anticycliccitrullinated peptide (anti-CCP2) assay detects the majority but not all anticitrullinated protein/peptide antibodies (ACPA). Anti-CCP2-positive rheumatoid arthritis (RA) is associated with HLA-DRB1* shared epitope (SE) alleles and smoking. Using a multiplex assay to detect multiple specific ACPA, we have investigated the fine specificity of individual ACPA responses and the biological impact of additional ACPA reactivity among anti-CCP2-negative patients. Methods: We investigated 2825 patients with RA and 551 healthy controls with full data on anti-CCP2, HLA-DRB1* alleles and smoking history concerning reactivity against 16 citrullinated peptides and arginine control peptides with a multiplex array. Results: The prevalence of the 16 ACPA specificities ranged from 9% to 58%. When reactivity to arginine peptides was subtracted, the mean diagnostic sensitivity increased by 3.2% with maintained 98% specificity. Of the anti-CCP2-negative patients, 16% were found to be ACPA positive. All ACPA specificities associated with SE, and all but one with smoking. Correction for arginine reactivity also conveyed a stronger association with SE for 13/16 peptides. Importantly, when all ACPA specificities were analysed together, SE and smoking associated with RA in synergy among ACPA positive, but not among ACPA-negative subjects also in the anti-CCP2-negative subset. Conclusions: Multiplexing detects an enlarged group of ACPA-positive but anti-CCP2-negative patients with genetic and environmental attributes previously assigned to anti-CCP2-positive patients. The individual correction for arginine peptide reactivity confers both higher diagnostic sensitivity and stronger association to SE than gross ACPA measurement.