Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity.
BACKGROUND
Antibodies targeting citrullinated antigens are specific for rheumatoid arthritis (RA). Citrullination is catalysed by the peptidylarginine deiminase (PAD) enzyme family. Critical enzymes are often targeted by disease-specific antibodies in complex immune-mediated diseases. Here, we have tested for autoantibodies against human recombinant PAD4 (hPAD4) in Caucasian RA patients.


METHODS
A time-resolved fluorometric immunoassay based on hPAD4 was developed to analyse sera from two RA cohorts (n = 237 and n = 177), one systemic lupus erythaematosus (SLE) cohort (n = 84) and 148 healthy controls. Simple and multiple analyses were performed to examine possible associations between anti-hPAD4 and disease variables.


RESULTS
Raised levels of anti-hPAD4 IgG were found in both RA cohorts compared to the controls, and 23% of the RA patients were anti-hPAD4 IgG positive. Anti-hPAD4 was associated with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF), as well as increased physical disability. Anti-hPAD4 was also associated with higher longitudinal radiographic damage scores and increased clinical joint pathology, but weaker than anti-CCP. No associations were found between anti-hPAD4 and selected Human leukocyte antigen (HLA)-DRB1 variants.


CONCLUSIONS
Approximately 23% of Caucasian RA patients have serum IgG antibodies against hPAD4. The presence of serum anti-hPAD4 IgG was in simple analyses associated with a more severe disease phenotype, and the association with physical disability was maintained in multiple analyses.
Halvorsen
E H
EH
Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, 0027 Oslo, Norway. eirikhha@medisin.uio.no
Pollmann
S
S
Gilboe
I-M
IM
van der Heijde
D
D
Landewé
R
R
Ødegård
S
S
Kvien
T K
TK
Molberg
Ø
Ø
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D005470:Fluorometry; D006801:Humans; D006867:Hydrolases / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011859:Radiography; D011994:Recombinant Proteins / Q000276:immunology; D012217:Rheumatoid Factor / Q000097:blood; D012720:Severity of Illness Index
D001323:Autoantibodies; D007074:Immunoglobulin G; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases