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
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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Listl, S., Galloway, J., Mossey, P. A. & Marcenes, W. Global economic impact of dental diseases. J. Dent. Res. 94, 1355–1361 (2015).
Kassebaum, N. J. et al. Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression. J. Dent. Res. 93, 1045–1053 (2014).
Eke, P. I. et al. Update on prevalence of periodontitis in adults in the United States: NHANES. J. Periodontol. 86, 611–622 (2015).
Kobayashi, T. & Yoshie, H. Host responses in the link between periodontitis and rheumatoid arthritis. Curr. Oral Health Rep. 2, 1–8 (2015).
Zenobia, C. & Hajishengallis, G. Basic biology and role of interleukin-17 in immunity and inflammation. Periodontol. 2000 69, 142–159 (2015).
Paraskevas, S., Huizinga, J. D. & Loos, B. G. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J. Clin. Periodontol. 35, 277–290 (2008).
Rhodes, B., Fürnrohr, B. G. & Vyse, T. J. C-Reactive protein in rheumatology: biology and genetics. Nat. Rev. Rheumatol. 7, 282–289 (2011).
de Pablo, P., Chapple, I. L., Buckley, C. D. & Dietrich, T. Periodontitis in systemic rheumatic diseases. Nat. Rev. Rheumatol. 5, 218–224 (2009).
Wegner, N. et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 62, 2662–2672 (2010).
Rosenstein, E. D., Greenwald, R. A., Kushner, L. J. & Weissmann, G. Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. Inflammation 28, 311–318 (2004).
Hajishengallis, G. Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response. Trends Immunol. 35, 3–11 (2014).
Hajishengallis, G. & Lamont, R. J. Beyond the red complex and into more complexity: the polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology. Mol. Oral Microbiol. 27, 409–219 (2012).
Gomes, M. S. et al. Can apical periodontitis modify systemic levels of inflammatory markers? A systematic review and meta-analysis. J. Endod. 39, 1205–1217 (2013).
Hajishengallis, G., Chavakis, T., Hajishengallis, E. & Lambris, J. D. Neutrophil homeostasis and inflammation: novel paradigms from studying periodontitis. J. Leukoc. Biol. 98, 539–548 (2016).
Silman, A. J. & Pearson, J. E. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 4 (Suppl. 3), S265–S272 (2002).
Mikuls, T. R., Payne, J. B., Deane, K. D. & Thiele, G. M. Autoimmunity of the lung and oral mucosa in a multisystem inflammatory disease: The spark that lights the fire in rheumatoid arthritis? J. Allergy Clin. Immunol. 137, 28–34 (2016).
Rosenbaum, J. T. & Asquith, M. J. The microbiome: a revolution in treatment for rheumatic diseases? Curr. Rheumatol. Rep. 18, 62 (2016).
Mankia, K. & Emery, P. Is localized autoimmunity the trigger for rheumatoid arthritis? Unravelling new targets for prevention. Discov. Med. 20, 129–135 (2015).
Smolen, J. S., Aletaha, D. and McInnes, I. B. Rheumatoid arthritis. Lancet 388, 2023–2038 (2016).
Klareskog, L., Lundberg, K. & Malmström, V. Autoimmunity in rheumatoid arthritis: citrulline immunity and beyond. Adv. Immunol. 118, 129–158 (2013).
Viatte, S., Plant, D. & Raychaudhuri, S. Genetics and epigenetics of rheumatoid arthritis. Nat. Rev. Rheumatol. 9, 141–153 (2013).
Muller, S. & Radic, M. Citrullinated autoantigens: from diagnostic markers to pathogenetic mechanisms. Clin. Rev. Allergy Immunol. 49, 232–239 (2015).
Trouw, L. A., Rispens, T. & Toes, R. E. M. Beyond citrullination: other post-translational protein modifications in rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 331–339 (2017).
Wang, S. & Wang, Y. Peptidylarginine deiminases in citrullination, gene regulation, health and pathogenesis. Biochim. Biophys. Acta 1829, 1126–1135 (2013).
Baka, Z. et al. Citrullination: a posttranslational modification in health and disease. Int. J. Biochem. Cell Biol. 38, 1662–1677 (2006).
Vossenaar, E. R., Zendman, A. J., van Venrooij, W. J. & Pruijn, G. J. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays 25, 1106–1118 (2003).
Arita, K. et al. Structural basis for Ca2+-induced activation of human PAD4. Nat. Struct. Mol. Biol. 11, 777–783 (2004).
Robertson, W. G. et al. Ionised calcium in body fluids. Crit. Rev. Clin. Lab. Sci. 15, 85–125 (1981).
Darrah, E. et al. Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity. Sci. Transl. Med. 5, 186ra65 (2013).
Auger, I., Martin, M., Balandraud, N. & Roudier, J. Rheumatoid arthritis-specific autoantibodies to peptidyl arginine deiminase type 4 inhibit citrullination of fibrinogen. Arthritis Rheum. 62, 126–131 (2010).
Makrygiannakis, D. et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann. Rheum. Dis. 67, 1488–1492 (2008).
Nesse, W. et al. The periodontium of periodontitis patients contains citrullinated proteins which may play a role in ACPA (anti-citrullinated protein antibody) formation. J. Clin. Periodontol. 39, 599–607 (2012).
Bennike, T. B. et al. Proteome analysis of rheumatoid arthritis gut mucosa. J. Proteome Res. 16, 346–354 (2017).
Konig, M. F. et al. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci. Transl. Med. 8, 369ra176 (2016).
Scher, J. U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2, e01202 (2013).
Teng, F. et al. Gut microbiota drive autoimmune arthritis by promoting differentiation and migration of Peyer's Patch T follicular helper cells. Immunity 44, 875–888 (2016).
Maeda, Y. et al. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol. 68, 2646–2661 (2016).
Zhang, X. et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat. Med. 21, 895–905 (2015).
Suzuki, A. et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402 (2003).
Heasman, L. S. F., Preshaw, P. M., McCracken, G. I., Hepburn, S. & Heasman, P. A. The effect of smoking on periodontal treatment response: a review of clinical evidence. J. Clin. Periodontol. 33, 241–253 (2006).
de Pablo, P., Dietrich, T. & McAlindon, T. E. Association of periodontal disease and tooth loss with rheumatoid arthritis in the US population. J. Rheumatol. 35, 70–76 (2008).
Marotte, H. et al. The association between periodontal disease and joint destruction in rheumatoid arthritis extends the link between the HLA-DR shared epitope and severity of bone destruction. Ann. Rheum. Dis. 65, 905–909 (2006).
Berthelot, J. M. & Le Goff, B. Rheumatoid arthritis and periodontal disease. Joint Bone Spine 77, 537–541 (2010).
Detert, J., Pischon, N., Burmester, G. R. & Buttgereit, F. The association between rheumatoid arthritis and periodontal disease. Arthritis Res. Ther. 12, 218 (2010).
Mikuls, T. R. et al. Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis Rheum. 66, 1090–1100 (2014).
Eriksson, K. et al. Prevalence of periodontitis in patients with established rheumatoid arthritis: a Swedish population based case-control study. PLoS ONE 11, e0155956 (2016).
Kharlamova, N. et al. Antibodies to Porphyromonas gingivalis indicate interaction between oral infection, smoking, and risk genes in rheumatoid arthritis etiology. Arthritis Rheum. 68, 604–613 (2016).
Mikuls, T. et al. Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis. Int. Immunopharmacol. 9, 38–42 (2009).
Hitchon, C. et al. Antibodies to Porphyromonas gingivalis are associated with anticitrullinated protein antibodies in patients with rheumatoid arthritis and their relatives. J. Rheumatol. 37, 1105–1112 (2010).
Shimada, A. et al. Expression of anti-Porphyromonas gingivalis peptidylarginine deiminase immunoglobulin G and peptidylarginine deiminase-4 in patients with rheumatoid arthritis and periodontitis. J. Periodontal. Res. 51, 103–111 (2016).
Kobayashi, T. et al. Serum immunoglobulin G levels to Porphyromonas gingivalis peptidylarginine deiminase affect clinical response to biological disease-modifying antirheumatic drug in rheumatoid arthritis. PLoS ONE 11, e0154182 (2016).
Johansson, L. et al. Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis. Arthritis Res. Ther. 18, 201 (2016).
Bello-Gualtero, J. M. et al. Periodontal disease in individuals with a genetic risk of developing arthritis and early rheumatoid arthritis: a cross-sectional study. J. Periodontol. 87, 346–356 (2016).
Terao, C. et al. Significant association of periodontal disease with anti-citrullinated peptide antibody in a Japanese healthy population - The Nagahama study. J. Autoimmun. 59, 85–90 (2015).
Golub, L. M., Payne, J. B., Reinhardt, R. A. & Nieman, G. Can systemic diseases co-induce (not just exacerbate) periodontitis? A hypothetical “two-hit” model. J. Dent. Res. 85, 102–105 (2006).
Maresz, K. J. et al. Porphyromonas gingivalis facilitates the development and progression of destructive arthritis through its unique bacterial peptidylarginine deiminase (PAD). PLoS Pathog. 9, e1003627 (2013).
Marchesan, J. T. et al. Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis. Arthritis Res. Ther. 15, R186 (2013).
Chukkapalli, S. et al. Periodontal bacterial colonization in synovial tissues exacerbates collagen-induced arthritis in B10. RIII mice. Arthritis Res. Ther. 18, 161 (2016).
Sandal, I. et al. Bone loss and aggravated autoimmune arthritis in HLA-DRβ1-bearing humanized mice following oral challenge with Porphyromonas gingivalis. Arthritis Res. Ther. 18, 249 (2016).
Gully, N. et al. Porphyromonas gingivalis peptidylarginine deiminase, a key contributor in the pathogenesis of experimental periodontal disease and experimental arthritis. PLoS ONE 9, e100838 (2014).
Yamakawa, M. et al. Porphyromonas gingivalis infection exacerbates the onset of rheumatoid arthritis in SKG mice. Clin. Exp. Immunol. 186, 177–189 (2016).
de Aquino, S. G. et al. Periodontal pathogens directly promote autoimmune experimental arthritis by inducing a TLR2- and IL-1-driven Th17 response. J. Immunol. 192, 4103–4111 (2014).
Eriksson, K. et al. Effects by periodontitis on pristane-induced arthritis in rats. J. Transl Med. 14, 311 (2016).
de Aquino, S. G. et al. The aggravation of arthritis by periodontitis is dependent of IL-17 receptor A activation. J. Clin. Periodontol. http://dx.doi.org/10.1111/jcpe.12743 (2017).
Corrêa, M. G. et al. Periodontitis increases rheumatic factor serum levels and citrullinated proteins in gingival tissues and alter cytokine balance in arthritic rats. PLoS ONE 12, e0174442 (2017).
Cirano, F. R. et al. Effect of resveratrol on periodontal pathogens during experimental periodontitis in rats. Braz. Oral Res. 30, e128 (2016).
Sakaguchi, S., Takahashi, T., Hata, H., Nomura, T. & Sakaguchi, N. SKG mice, a new genetic model of rheumatoid arthritis. Arthritis Res. Ther. 5 (Suppl. 3), 10 (2003).
Schwenzer, A. et al. Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis. Ann. Rheum. Dis. 75, 1876–1883 (2016).
Di Benedetto, A., Gigante, I., Colucci, S. & Grano, M. Periodontal disease: linking the primary inflammation to bone loss. Clin. Dev. Immunol. 2013, 503754 (2013).
Uehara, A., Imamura, T., Potempa, J., Travis, J. & Takada, H. Gingipains from Porphyromonas gingivalis synergistically induce the production of proinflammatory cytokines through protease-activated receptors with Toll-like receptor and NOD1/2 ligands in human monocytic cells. Cell. Microbiol. 10, 1181–1189 (2008).
Akitsu, A. et al. IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2+Vγ6+γδ T cells. Nat. Commun. 6, 7464 (2015).
Schett, G., Dayer, J. M. & Manger, B. Interleukin-1 function and role in rheumatic disease. Nat. Rev. Rheumatol. 12, 14–24 (2016).
Gaffen, S. L. & Hajishengallis, G. A new inflammatory cytokine on the block: re-thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. J. Dent. Res. 87, 817–828 (2008).
Quirke, A. M., Fisher, B. A., Kinloch, A. J. & Venables, P. J. Citrullination of autoantigens: upstream of TNFα in the pathogenesis of rheumatoid arthritis. FEBS Lett. 585, 3681–3688 (2011).
Harvey, G. P. et al. Expression of peptidylarginine deiminase-2 and -4, citrullinated proteins and anti-citrullinated protein antibodies in human gingiva. J. Periodontal. Res. 48, 252–261 (2013).
Opdenakker, G. & Van Damme, J. Cytokine-regulated proteases in autoimmune diseases. Immunol. Today 15, 103–107 (1994).
Van den Steen, P. E. et al. Cleavage of denatured natural collagen type II by neutrophil gelatinase B reveals enzyme specificity, post-translational modifications in the substrate, and the formation of remnant epitopes in rheumatoid arthritis. FASEB J. 16, 379–389 (2002).
Nazar Majeed, Z., Philip, K., Alabsi, A. M., Pushparajan, S. & Swaminathan, D. Identification of gingival crevicular fluid sampling, analytical methods, and oral biomarkers for the diagnosis and monitoring of periodontal diseases: a systematic review. Dis. Markers. 2016, 1804727 (2016).
Opdenakker, G., Proost, P. & Van Damme, J. Microbiomic and posttranslational modifications as preludes to autoimmune diseases. Trends Mol. Med. 22, 746–757 (2016).
Guentsch, A. et al. Cleavage of IgG1 in gingival crevicular fluid is associated with the presence of Porphyromonas gingivalis. J. Periodontal. Res. 48, 458–465 (2013).
Lundberg, K. et al. Antibodies to citrullinated α-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis. Rheum. 58, 3009–3019 (2008).
Kinloch, A. J. et al. Immunization with Porphyromonas gingivalis enolase induces autoimmunity to mammalian α-enolase and arthritis in DR4-IE-transgenic mice. Arthritis Rheum. 63, 3818–3823 (2011).
Jeong, E., Lee, J. Y., Kim, S. J. & Choi, J. Predominant immunoreactivity of Porphyromonas gingivalis heat shock protein in autoimmune diseases. J. Periodontal. Res. 47, 811–816 (2012).
Quirke, A. M. et al. Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. Ann. Rheum. Dis. 73, 263–269 (2014).
Bicker, K. L. & Thompson, P. R. The protein arginine deiminases: Structure, function, inhibition, and disease. Biopolymers 99, 155–163 (2013).
Laugisch, O. et al. Citrullination in the periodontium - a possible link between periodontitis and rheumatoid arthritis. Clin. Oral Investig. 20, 675–683 (2016).
Guentsch, A. et al. Comparison of gingival crevicular fluid sampling methods in patients with severe chronic periodontitis. J. Periodontol. 82, 1051–1060 (2011).
Konig, M. F. et al. Defining the role of Porphyromonas gingivalis peptidylarginine deiminase (PPAD) in rheumatoid arthritis through the study of PPAD biology. Ann. Rheum. Dis. 74, 2054–2061 (2015).
McGraw, W. T., Potempa, J., Farley, D. & Travis, J. Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. Infect. Immun. 67, 3248–3256 (1999).
Bielecka, E. et al. Peptidyl arginine deiminase from Porphyromonas gingivalis abolishes anaphylatoxin C5a activity. J. Biol. Chem. 289, 32481–33247 (2004).
Pyrc, K. et al. Inactivation of epidermal growth factor by Porphyromonas gingivalis as a potential mechanism for periodontal tissue damage. Infect. Immun. 81, 55–64 (2013).
Gawron, K. et al. Peptidylarginine deiminase from Porphyromonas gingivalis contributes to infection of gingival fibroblasts and induction of prostaglandin E2-signaling pathway. Mol. Oral Microbiol. 29, 321–332 (2014).
Corsiero, E., Pratesi, F., Prediletto, E., Bombardieri, M. & Migliorini, P. NETosis as source of autoantigens in rheumatoid arthritis. Front. Immunol. 7, 485 (2016).
Konig, M. F. & Andrade, F. A. Critical reappraisal of neutrophil extracellular traps and NETosis mimics based on differential requirements for protein citrullination. Front. Immunol. 7, 461 (2016).
Pratesi, F. et al. Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 contained in neutrophils extracellular traps. Ann. Rheum. Dis. 73, 1414–1422 (2014).
Alemán, O. R., Mora, N., Cortes-Vieyra, R., Uribe-Querol, E. & Rosales, C. Differential use of human neutrophil Fcγ receptors for inducing neutrophil extracellular trap formation. J. Immunol. Res. 2016, 2908034 (2016).
Hirschfeld, J. et al. Neutrophil extracellular trap formation in supragingival biofilms. Int. J. Med. Microbiol. 305, 453–463 (2015).
Vitkov, L., Klappacher, M., Hannig, M. & Krautgartner, W. D. Neutrophil fate in gingival crevicular fluid. Ultrastruct. Pathol. 34, 25–30 (2010).
Fullerton, J. N., O'Brien, A. J. & Gilroy, D. W. Pathways mediating resolution of inflammation: when enough is too much. J. Pathol. 231, 8–20 (2013).
Davidovich, P., Kearney, C. J. & Martin, S. J. Inflammatory outcomes of apoptosis, necrosis and necroptosis. Biol. Chem. 395, 1163–1171 (2014).
Nefla, M., Holzinger, D., Berenbaum, F. & Jacques, C. The danger from within: alarmins in arthritis. Nat. Rev. Rheumatol. 12, 669–683 (2016).
Malcolm, J. et al. IL-33 exacerbates periodontal disease through induction of RANKL. J. Dent. Res. 94, 968–975 (2015).
Charoonpatrapong, K. et al. HMGB1 expression and release by bone cells. J. Cell. Physiol. 207, 480–490 (2006).
Luo, L. et al. Expression of HMGB1 and HMGN2 in gingival tissues, GCF and PICF of periodontitis patients and peri-implantitis. Arch. Oral Biol. 56, 1106–1111 (2011).
Theoharides, T. C., Petra, A. I., Taracanova, A., Panagiotidou, S. & Conti, P. Targeting IL-33 in autoimmunity and inflammation. J. Pharmacol. Exp. Ther. 354, 24–31 (2015).
Xu, D. et al. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc. Natl Acad. Sci. USA 105, 10913–10918 (2008).
Tada, H. et al. Porphyromonas gingivalis gingipain-dependently enhances IL-33 production in human gingival epithelial cells. PLoS ONE 11, e0152794 (2016).
Rosier, B. T., De Jager, M., Zaura, E. & Krom, B. P. Historical and contemporary hypotheses on the development of oral diseases: are we there yet? Front. Cell. Infect. Microbiol. 4, 92 (2014).
Theilade, E. The non-specific theory in microbial etiology of inflammatory periodontal diseases. J. Clin. Periodontol. 13, 905–911 (1986).
Loesche, W. J. Chemotherapy of dental plaque infections. Oral Sci. Rev. 9, 65–107 (1976).
Slots, J. & Genco, R. J. Black-pigmented Bacteroides species. Capnocytophaga species, and Actinobacillus actinomycetemcomitans in human periodontal disease: virulence factors in colonization, survival, and tissue destruction. J. Dent. Res. 63, 412–421 (1984).
Loesche, W. J. The antimicrobial treatment of periodontal disease: changing the treatment paradigm. Crit. Rev. Oral Biol. Med. 10, 245–275 (1999).
Socransky, S. S. Microbiology of periodontal disease – present status and future considerations. J. Periodontol. 48, 497–504 (1977).
Socransky, S. S., Haffajee, A. D., Cugini, M. A., Smith, C. & Kent, R. L. Jr. Microbial complexes in subgingival plaque. J. Clin. Periodontol. 25, 134–144 (1998).
Rickard, A. H., Gilbert, P., High, N. J., Kolenbrander, P. E. & Handley, P. S. Bacterial coaggregation: an integral process in the development of multi-species biofilms. Trends Microbiol. 11, 94–100 (2003).
Socransky, S. S. & Haffajee, A. D. Periodontal microbial ecology. Periodontol. 2000 38, 135–187 (2005).
Griffen, A. L. et al. Distinct and complex bacterial profiles in human periodontitis and health revealed by 16S pyrosequencing. ISME J. 6, 1176–1185 (2012).
Hajishengallis, G. et al. Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell. Host Microbe. 10, 497–506 (2011).
Lamont, R. J. & Hajishengallis, G. Polymicrobial synergy and dysbiosis in inflammatory disease. Trends Mol. Med. 21, 172–183 (2015).
Goulas, T. et al. Structure and mechanism of a bacterial host-protein citrullinating virulence factor. Porphyromonas gingivalis peptidylarginine deiminase. Sci. Rep. 5, 11969 (2015).
Schmickler, J. et al. Cross-sectional evaluation of periodontal status, microbiological and rheumatoid parameters in a large cohort of patients with rheumatoid arthritis. J. Periodontol. 88, 368–379 (2017).
Khare, N. et al. Nonsurgical periodontal therapy decreases the severity of rheumatoid arthritis: a case-control study. J. Contemp. Dent. Pract. 17, 484–488 (2016).
Kurgan, Ş. et al. Gingival crevicular fluid tissue/blood vessel-type plasminogen activator and plasminogen activator inhibitor-2 levels in patients with rheumatoid arthritis: effects of nonsurgical periodontal therapy. J. Periodontal. Res. 52, 574–581 (2017).
Äyräväinen, L. et al. Periodontitis in early and chronic rheumatoid arthritis: a prospective follow-up study in Finnish population. BMJ Open 7, e011916 (2017).
Romero-Sanchez, C. et al. Is the treatment with biological or non-biological DMARDS a modifier of periodontal condition in patients with rheumatoid arthritis? Curr. Rheumatol. Rev. http://dx.doi.org/10.2174/1573397113666170407161520 (2017).
Kirchner, A. et al. Active matrix metalloproteinase-8 and periodontal bacteria depending on periodontal status in patients with rheumatoid arthritis. J. Periodontal. Res. http://dx.doi.org/10.1111/jre.12443 (2017).
Janssen, K. M. J. et al. Autoantibodies against citrullinated histone H3 in rheumatoid arthritis and periodontitis patients. J. Clin. Periodontol. http://dx.doi.org/10.1111/jcpe.12727 (2017).
Reichert, S. et al. Association of levels of antibodies against citrullinated cyclic peptides and citrullinated α-enolase in chronic and aggressive periodontitis as a risk factor of rheumatoid arthritis: a case control study. J. Transl Med. 13, 283 (2015).
Seror, R. et al. Association of anti-Porphyromonas gingivalis antibody titers with nonsmoking status in early rheumatoid arthritis: Results from the prospective French cohort of patients with early rheumatoid arthritis. Arthritis Rheumatol. 67, 1729–1737 (2015).
Silosi, I. et al. Significance of circulating and crevicular matrix metalloproteinase-9 in rheumatoid arthritis-chronic periodontitis association. J. Immunol. Res. 2015, 218060 (2015).
Kurgan, Ş. et al. The effects of periodontal therapy on gingival crevicular fluid matrix metalloproteinase-8, interleukin-6 and prostaglandin E2 levels in patients with rheumatoid arthritis. J. Periodontal. Res. 51, 586–955 (2016).
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.
The authors declare no competing financial interests.
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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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