Anticitrullinated protein/peptide antibody multiplexing defines an extended group of ACPA-positive rheumatoid arthritis patients with distinct genetic and environmental determinants.
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.
['Rönnelid|Johan|J|', 'Hansson|Monika|M|', 'Mathsson-Alm|Linda|L|', 'Cornillet|Martin|M|', 'Reed|Evan|E|', 'Jakobsson|Per-Johan|PJ|', 'Alfredsson|Lars|L|', 'Holmdahl|Rikard|R|', 'Skriner|Karl|K|', 'Serre|Guy|G|', 'Lundberg|Karin|K|', 'Klareskog|Lars|L|']
D000293:Adolescent D000328:Adult D000368:Aged D000483:Alleles D000075422:Anti-Citrullinated Protein Antibodies D001120:Arginine D001172:Arthritis, Rheumatoid D016022:Case-Control Studies D005260:Female D020022:Genetic Predisposition to Disease D005838:Genotype D059811:HLA-DRB1 Chains D006801:Humans D008297:Male D008875:Middle Aged D040081:Protein Array Analysis D012680:Sensitivity and Specificity D012907:Smoking D055815:Young Adult
rheumatoid arthritis ant-ccp autoantibodies