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

Animal Studies of Periodontal Disease and Arthritis

A number of animal studies have been conducted to evaluate interactions between periodontal disease and arthritis. In an adjuvant arthritis model, killed Pg organisms within sponges were implanted under the back skin of rats;[80] arthritis was induced using varying adjuvant doses. The threshold for arthritis induction was lower in animals with Pg exposure, suggesting a priming effect of Pg that augmented arthritis development. Although previous rat adjuvant arthritis studies reported periodontal bone loss with arthritis suggesting reciprocal interactions,[81] this was not seen in the recent report. In studies[82,83] using a mouse antigen-induced arthritis (AIA) model, mice with bacterially-induced periodontitis were compared with those without, and groups were treated with anti-TNF therapy and/or antimicrobials. Several findings were reported: first, early bone loss around teeth was seen in AIA mice without bacterial exposure at a severity similar to that with direct bacterial installation; second, clearing oral bacteria with antiseptic prevented periodontal bone loss, but had no effect on arthritis; third, the presence of AIA exacerbated bacterially induced periodontal disease; finally, both arthritis and alveolar bone loss were reduced in the presence of anti-TNF therapy. Another important observation was that a non-Pg species of oral bacteria, Aggregatibacter actinomycetemcomitans, could worsen arthritis. Another group recently reported that, in the type II collagen-induced arthritis (CIA) model, mice with prior periodontal disease induction from oral Pg installation had more severe arthritis, based on inflammation and bony changes.[84] Moreover, they demonstrated that mice with Pg-induced periodontal disease, but without CIA, had bony destruction in peripheral joints, without concomitant inflammation. In another recent CIA study,[85] alveolar bone destruction was worsened in CIA mice compared with controls, mediated through both increased osteoclast activity and a reduced osteoblastic bone formation.

Based on their earlier reports that Pg enolase was homologous to human enolase, and susceptible to CEP-1 citrullination,[73,74] Kinloch et al.[86] recently tested whether Pg-derived peptides could participate in the generation of rheumatoid arthritis-related, HLA-DR4-restricted autoantigen responses and arthritis development. Using the DR4-IE-transgenic mouse arthritis model,[87] animals were immunized using Pg-enolase and human [alpha]-enolase, in both native and citrullinated forms. Interestingly, rapid arthritis induction was seen with both enolase forms, with either bacterial or human protein. Animals immunized with Pg-enolase also generated antibodies that recognized human enolase. Although not showing that citrullinated enolases were more reactive in the DR4-restricted model, the study demonstrated that a Pg protein could induce arthritis and propagate an immune response against citrullinated peptides. Another group conducted a similar series of experiments using citrullinated and noncitrullinated forms of human enolase in several arthritis-susceptible mouse strains.[88] Although antibodies developed against both forms, arthritis did not develop, clinically or histologically, in any of their experiments. The reasons for the discordant findings between the two groups are unclear, but merit additional exploration.

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