Background/Purpose:  The mechanisms that drive clinical heterogeneity and outcomes in patients with rheumatoid arthritis (RA) are poorly understood, but precise biomarkers may identify clinically unique subgroups with distinct underlying disease mechanisms. In a subset of patients with RA, autoantibodies that activate the peptidylarginine deiminase (PAD) 4 enzyme have been identified. These antibodies are associated with severe joint and lung disease, highlighting the potential importance of functional autoantibodies in disease pathogenesis. The PAD enzymes are central players in RA due to their ability to generate the citrullinated targets of anti-citrullinated protein antibodies (APCAs). Although PAD4 has garnered the most attention, PAD2 is also strongly implicated in RA pathogenesis, but antibodies to PAD2 have not been reported.

Methods:  In this study, sera from 184 patients in the ESCAPE RA cohort and 37 healthy controls were screened for the presence of antibodies to human PAD2 by ELISA. The frequency of anti-PAD2 antibodies and associated clinical features were determined.

Results:  The frequency of anti-PAD2 antibodies in patients with RA was 18.5%, compared with 5.4% of healthy controls (p=0.001). Interestingly, the clinical characteristics of anti-PAD2 positive patients were distinct from those previously observed for anti-PAD4 antibodies. While antibodies to PAD4 are associated with APCAs, the HLA-DRβ1 shared epitope (SE), and severe joint and lung disease, anti-PAD2 antibodies were negatively associated with SE (p=0.014) and swollen joint count (p<0.05) and were not associated with APCAs (p=0.94). Significantly higher anti-PAD2 antibody titers were observed in RA patients who were female (p=0.013) or on biologic therapies (p=0.036), while significantly lower antibody titers were observed in patients with SE (p=0.02) or interstitial lung disease (p=0.039). In a multi-variable model adjusted for C-reactive protein, adiponectin, and baseline radiographic joint damage, anti-PAD2 antibodies were significantly protective against radiographic progression with a 9% lower odds of progression per log unit of anti-PAD2 antibody (OR=0.91; p=0.021) (Figure).

Conclusion: Anti-PAD2 antibodies represent a novel biomarker in RA that is not associated with the traditional risk factors linked to disease severity such as SE and ACPAs. Instead, patients with antibodies to PAD2 are protected against radiographic progression and have less interstitial lung disease. This novel biomarker has potential implications for disease monitoring and highlights an unappreciated role of PAD2 in RA pathogenesis. The less aggressive disease phenotype observed in patients with anti-PAD2 antibodies suggests that they may target a pathogenic function of PAD2 in patients with RA. The effect of anti-PAD2 antibodies on PAD2 enzyme activity is currently under investigation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoantibodies-to-peptidylarginine-deiminase-2-protect-against-radiographic-progression-in-patients-with-rheumatoid-arthritis/