Periodontal Disease and Rheumatoid Arthritis

The Evidence Accumulates for Complex Pathobiologic Interactions

Clifton O. Bingham III; Malini Moni

Disclosures

Curr Opin Rheumatol. 2013;25(3):345-353. 

In This Article

Discussion

Research in the area of periodontal disease and rheumatoid arthritis in the last 2 years has confirmed long-standing observed associations between the two disease processes. New observations have demonstrated that periodontal disease is present, and severe, early in the rheumatoid arthritis disease process providing further evidence toward a causal or permissive event. Studies from cohorts at high risk for rheumatoid arthritis have provided additional evidence of periodontal bacterial exposure in the prerheumatoid arthritis state and evidence for differential bacterial colonization in those with early rheumatoid arthritis, including species beyond P. gingivalis. Recent animal studies support bidirectional relationships between periodontal bacteria, inflammation, periodontal bone destruction, and joint disease, mediated at least in part through TNF.

There is growing interest in better understanding of citrullination in periodontal disease, and the function of Pg-PAD in this process. Although Pg-PAD can citrullinate its own proteins that cross-react with human citrullinated peptide homologues, in the case of enolase, it is unclear whether citrullination is necessary for arthritis induction. The descriptions of ubiquitous citrullination in normal oral mucosa, and its increase in periodontal disease with concomitantly expressed PAD-2 and PAD-4, demonstrate the likely participation of microenvironmental inflammation in citrullinating events. Moreover, protein citrullination may have other functional and regulatory consequences through activation and inactivation of proteins.

The growing appreciation for oral bacteria interactions and their effects alone and in concert emphasizes the complex interplay among different species in amplifying local inflammatory and immunoregulatory pathways. Although the unique contribution to periodontal disease propagation by Pg as a single species may be considerable, the likelihood for considerable redundancies of function with other bacteria seems likely. In light of emerging research, the initial emphasis on Pg as a single bacterial species to explain the associations between periodontal disease and rheumatoid arthritis may be inadequate to explain the multiple intersecting pathobiologic pathways in these diseases.

As is evident from the studies that continue to emerge, collaborations among immunologists, oral pathologists, microbiologists, periodontists, rheumatologists, and systems biologists are increasingly needed to fully understand the relationships between rheumatoid arthritis and periodontal disease. The area is ripe for further clinical and translational research, grounded in studies in which the oral and rheumatologic conditions are clinically well characterized using uniform outcome measures, as well as biomarker analyses from different relevant sites. Complementary basic research is needed to dissect the complex biochemistry, immunology, molecular, and cell biology that provide the mechanistic underpinnings.

Based on the present research, a number of clinical questions have been posed: Will treatment of clinical or subclinical periodontal disease in individuals at risk for rheumatoid arthritis succeed in preventing rheumatoid arthritis development? Will specific treatment of periodontal disease lead to improvement in rheumatoid arthritis parameters? These questions begin to raise logistical and ethical issues: How large and how long must a study be to demonstrate primary prevention? Can a secondary treatment study be done in isolation, or should it be done as an adjunct to other DMARDs? What would be the expected magnitude of response? If prevalent periodontal disease is identified, can that patient be randomized to receive suboptimal or no treatment for the dental condition, with tooth loss a known outcome of treatment delay? Although some have proposed that eradication or immunization against Pg could improve the periodontal condition, and thus reduce arthritis, will this be adequate to prevent or sufficiently decrease localized oral inflammation? And although a strategy of inhibiting Pg-PAD may be attractive, the redundancies in function of individual PAD enzymes and their substrates raise questions related to specificity.

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