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.