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  • Review Article
  • Published:

The case for periodontitis in the pathogenesis of rheumatoid arthritis

Nature Reviews Rheumatology volume 13, pages 606–620 (2017)Cite this article

Subjects

Key Points

  • Periodontitis and rheumatoid arthritis (RA) are closely linked, and periodontitis often precedes the development of RA

  • Periodontitis correlates with levels of anti-citrullinated protein antibodies in healthy individuals, suggesting that periodontitis could trigger the autoimmune response that leads to RA

  • Hypercitrullination of proteins at chronically inflamed sites of periodontitis could constitute the mechanistic link between periodontitis and RA

  • The major periodontal pathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans are directly implicated in the breakdown of immune tolerance to citrullinated epitopes

  • Further well-designed mechanistic and epidemiological studies into the links between periodontitis and RA are needed to elucidate the mechanisms involved

Abstract

Rheumatoid arthritis (RA), an autoimmune disease that affects ∼1% of the human population, is driven by autoantibodies that target modified self-epitopes, whereas ∼11% of the global adult population are affected by severe chronic periodontitis, a disease in which the commensal microflora on the tooth surface is replaced by a dysbiotic consortium of bacteria that promote the chronic inflammatory destruction of periodontal tissue. Despite differences in aetiology, RA and periodontitis are similar in terms of pathogenesis; both diseases involve chronic inflammation fuelled by pro-inflammatory cytokines, connective tissue breakdown and bone erosion. The two diseases also share risk factors such as smoking and ageing, and have strong epidemiological, serological and clinical associations. In light of the ground-breaking discovery that Porphyromonas gingivalis, a pivotal periodontal pathogen, is the only human pathogen known to express peptidylarginine deiminase, an enzyme that generates citrullinated epitopes that are recognized by anti-citrullinated protein antibodies, a new paradigm is emerging. In this Review, the clinical and experimental evidence supporting this paradigm is discussed and the potential mechanisms involved in linking periodontitis to RA are presented.

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Figure 1: Clinical and microbiological aspects of periodontitis.
Figure 2: Protein citrullination catalysed by human peptidylarginine deiminases.
Figure 3: Proposed mechanisms underlying the links between periodontal disease and the pathogenesis of rheumatoid arthritis.
Figure 4: C-Terminal protein citrullination catalysed by Porphyromonas gingivalis peptidylarginine deiminase (PPAD).

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Acknowledgements

The authors would like to acknowledge financial support in the form of grants from the National Institute of Dental and Craniofacial Research (R01 DE022597 to J.P.), the European Commission's 7th Framework Programme (FP7-HEALTH-2012-306029-2 'TRIGGER' to P.M. and J.P.), the Polish Ministry of Science and Higher Education (MNiSW) (2975/7.PR/13/2014/2 to J.P.), and the Polish National Science Centre (2016/22/E/NZ6/00336 to J.K.). The Faculty of Biochemistry, Biophysics and Biotechnology at Jagiellonian University in Krakow, Poland is a partner of the Leading National Research Center (KNOW) supported by the Polish Ministry of Science and Higher Education.

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Authors and Affiliations

  1. Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, 501 South Preston Street, Louisville, 40202, Kentucky, USA

    Jan Potempa

  2. Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7 Gronostajowa Street, Krakow, 30–387, Poland

    Jan Potempa, Piotr Mydel & Joanna Koziel

  3. Department of Clinical Science, Broegelmann Research Laboratory, University of Bergen, The Laboratory Building, 5th floor, Haukeland University Hospital, Bergen, N-5021, Norway

    Piotr Mydel

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All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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Potempa, J., Mydel, P. & Koziel, J. The case for periodontitis in the pathogenesis of rheumatoid arthritis. Nat Rev Rheumatol 13, 606–620 (2017). https://doi.org/10.1038/nrrheum.2017.132

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