Update on "Two-Hit" Model of RA, From Two Perspectives


Reviews by a rheumatologist and an oral health specialist spell out the evidence that links periodontal disease and rheumatoid arthritis. Can effective treatment of teeth and gums alter the course of the rheumatic disease?

Payne JB, Golub LM, Thiele GM, Mikuls TR. The Link Between Periodontitis and Rheumatoid Arthritis: A Periodontist’s PerspectiveCurrent Oral Health Reports. 2015; 2:20-29.  doi 10.1007/s40496-014-0040-9

Rosenstein ED, Kushner LJ, and Kramer N. Rheumatoid Arthritis and Periodontal Disease: A Rheumatologist's PerspectiveCurrent Oral Health Reports 2015; 2: 9-19. doi: 10.1007/s40496-014-0038-3

These articles in a special issue of Current Oral Health Reports on the relationship of periodontal disease (PD) and rheumatoid arthritis (RA) discuss the topic from two perspectives.

According to the “two-hit” model, which the authors of the first article above originally proposed in 2006, a systemic disease like RA can exacerbate or initiate PD, and vice versa. The first hit is at the periodontal microbial biofilm, where the local bacteria induce a systemic inflammation. The second hit is a disease like RA, which also induces systemic inflammation. 

Does treating periodontal disease alter the course of RA? The two authors ponder that question, with slightly different conclusions.

Each article separately reviews the evidence for the model, first the association between RA and PD in case-controlled studies, and second the common mechanism of citrullination, which suggests that PD may cause RA. The major pathogen responsible for PD, Porphyromonas gingivalis, has an enzyme that citrullinates proteins. This could trigger ACPA, the antibody response to citrullinated proteins, in both the oral cavity and the synovium.

RA existed in native American groups thousands of years ago, but only appeared in Europe in the late 1780s after, according to Rosenstein's theory, the sugar and molasses that promoted PD and then RA among Native Americans began being exported across the Atlantic.

PD may be treated with mechanical debridement, with adjunctive host modulation therapy, or both. Adjunctive host modulation therapy uses subantimicrobial dose doxycycline (SDD) and non-steroidal anti-inflammatory drugs (NSAIDs). At this dose, SSDs act as a matrix metalloproteinase inhibitor.

If the two-hit model is correct, then SDD and NSAID treatment of PD should improve RA as well. It does, in some studies. Table 1 in Payne et al. summarizes the results of seven studies, three of them randomized, showing that SDD and NSAID treatment reduces markers of disease activity and systemic inflammation.

Taken together, though, the cited studies don’t show a clear clinical benefit. As Bartold (the section editor for this issue of the journal) concluded in an earlier meta-analysis in Seminars in Arthritis and Rheumatism,1 non-surgical periodontal treatment was associated with significant reductions in erythrocyte sedimentation rate and a trendtowards reduction in tumor necrosis factor-α titers and Disease Activity Scores. There was no evidence of any effect on anti–citrullinated protein antibody or other markers. Larger, and longer-term, studies are needed, that analysis concludes.

Bartold and Payne are optimistic. These studies support the hypothesis that control of PD can reduce clinical and biochemical markers of RA. They agree that this needs assessment in larger, longer, better-designed clinical trials, they agree.

Rosenstein is even more optimistic. He thinks the existing evidence is strong enough to justify recommending the early dental referral of RA patients. His article concludes with general guidance for managing RA, including dietary changes, exercise, weight loss-and effective management of periodontal disease.



1. Kaur S, Bright R, Proudman SM, Bartold PM. Does periodontal treatment influence clinical and biochemical measures for rheumatoid arthritis? A systematic review and meta-analysis. Seminars in Arthritis and Rheumatism. 2014;44:113-22. doi: 10.1016/j.semarthrit.2014.04.009. Epub 2014 Apr 28.

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