Background/Purpose: Over the past years, novel biomarkers have been described in rheumatoid arthritis (RA) patients, including autoantibodies to the protein-arginine deiminase (PAD) enzymes. Anti-PAD4 IgG are associated with anti-citrullinated protein antibodies (ACPA), worse baseline radiographic joint damage and a better response to treatment escalation. These data suggest that anti-PAD antibodies might play a role in RA pathogenesis. The objective of this study was to evaluate the presence of anti-PAD4 IgG and IgA in the sera of RA patients and to investigate their association with joint erosion and biological treatment use. 

Methods: All the samples included in this study were tested for anti-PAD4 IgG and IgA using the novel particle-based multi-analyte technology (PMAT, research use only, research use only). In a first phase, sera from RA patients (n=70) and controls (n=155) were included (Figure 1). Next, anti-PAD4 IgG and IgA were measured in a second cohort of RA patients (n=40) for whom information on erosion status and biological treatment was available. ACPA IgG was also measured in these patients by QUANTA Flash CCP3 (Inova Diagnostics, CA, US). 

Results: Anti-PAD4 IgA but not IgG levels were significantly higher in RA patients vs. controls (p=0.0080 and p=0.2740, respectively) (Figure 1). Receiver operating characteristics (ROC) analysis showed significant discrimination in the clinically relevant area (high specificity) for both IgG and IgA (Figure 2). Using the 95^th percentile of the controls as cut-offs, anti-PAD4 IgG reported a sensitivity and specificity of 17.1%/94.8% for IgG and 20.0%/94.8% for IgA. Significantly higher levels of anti-PAD4 IgA but not anti-PAD4 IgG or ACPA were found in the RA patients with erosive disease vs. individuals without erosions (p=0.0419, p=0.2126, and p=0.7417, respectively) (Figure 3A), and in patients under biological treatment vs. those that were not on biologics (p=0.0240, p=0.1261, and p=0.8202, respectively) (Figure 3B).

Conclusion: Our study is the first to report anti-PAD4 IgA as a highly specific marker for RA showing strong association with erosive disease as well as biological treatment, suggesting a more severe phenotype. Anti-PAD4 antibodies of the IgA isotype represent a novel biomarker for RA patient stratification and prediction of prognosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-protein-arginine-deiminase-pad-4-iga-are-present-in-the-sera-of-rheumatoid-arthritis-patients-and-are-associated-with-joint-erosion-and-biological-treatment-use/