PT  - JOURNAL ARTICLE
AU  - Rönnelid, Johan
AU  - Hansson, Monika
AU  - Mathsson-Alm, Linda
AU  - Cornillet, Martin
AU  - Reed, Evan
AU  - Jakobsson, Per-Johan
AU  - Alfredsson, Lars
AU  - Holmdahl, Rikard
AU  - Skriner, Karl
AU  - Serre, Guy
AU  - Lundberg, Karin
AU  - Klareskog, Lars
TI  - Anticitrullinated protein/peptide antibody multiplexing defines an extended group of ACPA-positive rheumatoid arthritis patients with distinct genetic and environmental determinants
AID  - 10.1136/annrheumdis-2017-211782
DP  - 2018 Feb 01
TA  - Annals of the Rheumatic Diseases
PG  - 203--211
VI  - 77
IP  - 2
4099  - http://ard.bmj.com/content/77/2/203.short
4100  - http://ard.bmj.com/content/77/2/203.full
SO  - Ann Rheum Dis2018 Feb 01; 77
AB  - 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.