associations with disease severity deiminase 4 in rheumatoid arthritis and Serum IgG antibodies to peptidylarginine

ABSTRACTBackground: Antibodies targeting citrullinated antigensare specific for rheumatoid arthritis (RA). Citrullination iscatalysed by the peptidylarginine deiminase (PAD)enzyme family. Critical enzymes are often targeted bydisease-specific antibodies in complex immune-mediateddiseases. Here, we have tested for autoantibodies againsthuman recombinant PAD4 (hPAD4) in Caucasian RApatients.Methods: A time-resolved fluorometric immunoassaybased on hPAD4 was developed to analyse sera from twoRA cohorts (n=237 and n=177), one systemic lupuserythaematosus (SLE) cohort (n=84) and 148 healthycontrols. Simple and multiple analyses were performed toexamine possible associations between anti-hPAD4 anddisease variables.Results: Raised levels of anti-hPAD4 IgG were found inboth RA cohorts compared to the controls, and 23% ofthe RA patients were anti-hPAD4 IgG positive. Anti-hPAD4was associated with anti-cyclic citrullinated peptide (CCP)and rheumatoid factor (RF), as well as increased physicaldisability. Anti-hPAD4 was also associated with higherlongitudinal radiographic damage scores and increasedclinical joint pathology, but weaker than anti-CCP. Noassociations were found between anti-hPAD4 andselected Human leukocyte antigen (HLA)-DRB1 variants.Conclusions: Approximately 23% of Caucasian RApatients have serum IgG antibodies against hPAD4.Thepresence of serum anti-hPAD4 IgG was in simple analysesassociated with a more severe disease phenotype, andthe association with physical disability was maintained inmultiple analyses.Rheumatoid arthritis (RA) has a multifactorialaetiology, and is typically classified as a compleximmune-mediated disorder. The distinct immuno-logical features of RA include clear Humanleukocyte antigen (HLA)-associations, T cell infil-tration of the target organ and disease-specificantibodies against citrullinated proteins generatedin vivo by the peptidylarginine deiminase (PAD)enzyme family.