Autoantibodies to protein-arginine deiminase (PAD) 4 in rheumatoid arthritis: immunological and clinical significance, and potential for precision medicine

ABSTRACT

Introduction: The protein-arginine deiminase (PAD) 4 enzyme plays an important role in the pathogenesis of rheumatoid arthritis (RA) and also represents an antigenic target. Anti-PAD4 antibodies can be present in RA and are associated with specific clinical features.

Areas covered: This review aims to analyze the current knowledge and recent findings on anti-PAD4 antibodies in RA and their clinical and immunological significance.

Expert opinion: Anti-PAD4 antibodies are not currently used in clinical practice for the management of RA. Nevertheless, there is growing evidence of their relevance in RA, and of their potential utility to improve diagnosis, patient stratification, and prognosis.

KEYWORDS:

• Rheumatoid arthritis
• RA
• autoantibodies
• protein-arginine deiminase
• anti-PAD
• PAD4
• anti-PAD4
• precision medicine
• citrullination

Article highlights

• Five members of the PAD family have been described in humans, and three of them, PAD2, 3 and 4, have been identified as autoantigens in RA.

• Anti-PAD4 antibodies are found in 30–40% of the RA patients with specificity of >95%, and in 2-18% of the RF and ACPA seronegative individuals.

• Anti-PAD4 antibodies are associated with joint erosions and a more severe disease phenotype.

• Testing for anti-PAD4 antibodies might provide diagnostic and prognostic value.

Declaration of interest

L Martinez-Prat and M Mahler are employees of Inova Diagnostics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Inova Diagnostics, University of Florence and Stanford University.