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Antibodies targeting protein-arginine deiminase 4 (PAD4) demonstrate diagnostic value in rheumatoid arthritis
  1. Laura Martinez-Prat1,
  2. David Lucia1,
  3. Claudia Ibarra2,
  4. Michael Mahler1,
  5. Thierry Dervieux3
  1. 1 Research and Development, Inova Diagnostics, San Diego, California, USA
  2. 2 Laboratory Operations, Exagen Diagnostics, Vista, California, United States
  3. 3 Research and Development and Laboratory Operations, Exagen Diagnostics, Vista, California, USA
  1. Correspondence to Michael Mahler, Research and Development, Inova Diagnostics, San Diego, CA 92131, USA; mmahler{at}

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Although anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are widely used as part of the diagnosis of patients with rheumatoid arthritis (RA), they leave a serological gap.1 Recently, several novel autoantibodies have been described in RA including antibodies targeting protein-arginine deiminases (PAD).2 3 Similar to ACPA and RF, anti-PAD4 antibodies also precede the clinical onset of RA.4 A subset of autoantibodies cross-reactive to PAD3 and PAD4 decrease the enzyme’s calcium requirement into the physiologic range, thereby increasing the catalytic efficiency of PAD4.5 Here we aim to evaluate the diagnostic relevance of anti-PAD3/4 antibodies in a large cohort (n=1473) of patients with RA and relevant controls (details in figure 1, table 1).

Figure 1

Distribution and diagnostic performance of anti-PAD3 and anti-PAD4 antibodies in patients with RA and controls. The prevalence and titres of both anti-PAD3 (A) and anti-PAD4 (B) antibodies were significantly higher in RA versus controls. Both anti-PAD3 and anti-PAD4 antibodies were found in ACPA+ and in ACPA− patients as well as in early RA. Cut-off values are indicated by the dotted red line (200 MFI for PAD3 and 1000 MFI for PAD4). Receiver operating characteristic (ROC) …

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  • Handling editor Josef S Smolen

  • Contributors LM performed the anti-PAD3 and anti-PAD4 testing, helped in the data analysis and to draft the manuscript. DL helped optimise the anti-PAD3 and anti-PAD4 assays. CI contributed to the design of the study. MM and TD designed the study, performed the statistical analysis and helped write the manuscript. All authors read, reviewed and approved the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests MM, LMP and DL are employed at Inova Diagnostics selling autoimmune diagnostic assays. TD and CI are employed at Exagen Diagnostics offering clinical testing.

  • Patient consent Not required.

  • Ethics approval The samples were collected in concordance with local ethical review standards and the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.