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  • Review Article
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PAD enzymes in rheumatoid arthritis: pathogenic effectors and autoimmune targets

Nature Reviews Rheumatology volume 16, pages 301–315 (2020)Cite this article

Subjects

Abstract

Peptidylarginine deiminases (PADs) have an important role in the pathogenesis of rheumatoid arthritis (RA) owing to their ability to generate citrullinated proteins — the hallmark autoantigens of RA. Of the five PAD enzyme isoforms, PAD2 and PAD4 are the most strongly implicated in RA at both genetic and cellular levels, and PAD inhibitors have shown therapeutic efficacy in mouse models of inflammatory arthritis. PAD2 and PAD4 are additionally targeted by autoantibodies in distinct clinical subsets of patients with RA, suggesting anti-PAD antibodies as possible biomarkers for RA diagnosis and prognosis. This Review weighs the evidence that supports a pathogenic role for PAD enzymes in RA as both promoters and targets of the autoimmune response, as well as discussing the mechanistic and therapeutic implications of these findings in the wider context of RA pathogenesis. Understanding the origin and consequences of dysregulated PAD enzyme activity and immune responses against PAD enzymes will be important to fully comprehend the pathogenic mechanisms involved in this disease and for the development of novel strategies to treat and prevent RA.

Key points

  • Peptidylarginine deiminase (PAD) enzymes catalyse the deimination of arginine residues, generating the citrullinated protein targets of anti-citrullinated protein antibodies (ACPAs).

  • PAD2 and PAD4 are the most strongly implicated PAD enzymes in rheumatoid arthritis (RA) pathogenesis on the basis of genetic, histological and animal studies.

  • Anti-PAD4 antibodies are associated with severe joint damage, and anti-PAD2 antibodies are associated with less severe joint and lung disease in patients with RA.

  • A subset of patients with RA who have the most severe joint and lung disease have anti-PAD4 antibodies that cross-react with PAD3 and can activate PAD4 enzyme function.

  • ACPAs and anti-PAD4 antibodies can both develop preclinically, but development of ACPAs typically precedes that of anti-PAD4 antibodies.

  • Dysregulated PAD enzyme activity and the development of citrullination-associated autoantibodies can promote three important features of RA: citrullination, pro-inflammatory cytokine production and bone destruction.

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Fig. 1: Rheumatoid arthritis-associated single nucleotide polymorphisms in PADI4 and PADI2.
Fig. 2: Evolution of anti-PAD antibodies and epitope spreading in rheumatoid arthritis.
Fig. 3: Citrullination-associated immune response mechanisms in rheumatoid arthritis.

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Acknowledgements

The work of A.M.C. and E.D. is supported by a Rheumatology Research Foundation Innovative Research Award.

Review criteria

A search for original articles was performed in PubMed using the following terms alone and in combination: “deiminase”, “rheumatoid”, “arthritis”, “antibodies” and “citrullination”. References cited in selected articles were also traced back to the primary sources.

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Authors and Affiliations

  1. Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ashley M. Curran, Pooja Naik & Erika Darrah

  2. Division of Rheumatology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA

    Jon T. Giles

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A.M.C., P.N. and E.D. researched data for the article. All authors substantially contributed to discussions of content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Erika Darrah.

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Competing interests

E.D. and J.T.G. declare that they are authors on licensed patent no. 8,975,033 entitled “Human autoantibodies specific for PAD3 which are cross-reactive with PAD4 and their use in the diagnosis and treatment of rheumatoid arthritis and related diseases”. E.D. declares that she is an author on provisional patent no. 62/481,158 entitled “Anti-PAD2 antibody for treating and evaluating rheumatoid arthritis”. E.D. has received grants from Bristol-Myers Squibb, Celgene and Pfizer, and personal fees from Celgene that are not related to this article. A.M.C. and P.N. declare no competing interests.

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Nature Reviews Rheumatology thanks J. Roudier, P. Venables and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Curran, A.M., Naik, P., Giles, J.T. et al. PAD enzymes in rheumatoid arthritis: pathogenic effectors and autoimmune targets. Nat Rev Rheumatol 16, 301–315 (2020). https://doi.org/10.1038/s41584-020-0409-1

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