Background: Antibodies targeting citrullinated antigens are specific for rheumatoid arthritis (RA). Citrullination is catalyzed 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 auto-antibodies against human recombinant PAD4 (hPAD4) in Caucasian RA patients.
Methods: A time-resolved fluorometric immunoassay based on hPAD4 was developed to analyze sera from two RA cohorts (n=237 and n=177), one 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-CCP and 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 HLA-DRB1 variants.
Conclusion: 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.
- peptidylarginine deiminase 4
- rheumatoid arthritis
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Supplementary figure 1
Dose-dependent inhibition of serum anti-hPAD4 IgG binding to solid-phase hPAD4 by incubation with liquid-phase hPAD4. Human albumin was used as a control inhibitor. A pool of five anti-hPAD4 positive RA sera diluted 1:2000 in TBS-T was incubated for 1 hour at 37�C with equal volumes of hPAD4 (▲) or human albumin (▼) in increasing concentrations. Serum pools were then applied to the microtiter plate after the blocking of the plate with 1% BSA.
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