Periodontal disease (PD) is a multifactorial chronic inflammatory disorder that progresses beyond an initial stage of gingivitis to a chronic inflammatory process, causing destruction of the alveolar bone and periodontal connective tissue, and ultimately resulting in tooth loss. Epidemiologic and case-control studies have provided evidence that individuals with PD are at significantly greater risk for a wide variety of systemic diseases, including gastrointestinal and pancreatic cancers, type 2 diabetes, cardiovascular disease, and inflammatory rheumatologic diseases, particularly rheumatoid arthritis (RA).1-3 Results from a 2016 meta-analysis showed that individuals with RA had a 13% greater risk for periodontitis compared with non-RA control patients.4

Although no definitive causal or permissive link between PD and systemic inflammatory disease has been established, it has been hypothesized that in patients with PD, local periodontal pathogens and inflammatory mediators may spill into the circulatory system via the damaged sulcular epithelium, increasing the level of systemic inflammation and thus raising the risk for the development of systemic inflammatory diseases.5 The association between PD and systemic inflammatory diseases is likely also grounded in their shared risk factors, which include age, tobacco use, lifestyle, and socioeconomic status.2

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Similar to PD, RA involves damage to connective tissue and bone. Although PD is an immuno-inflammatory disease of bacterial origin, and RA is an inflammatory autoimmune disease, researchers have observed that both conditions share similarities in their cellular and molecular pathobiology.1,6 In both conditions, cell infiltration with T lymphocytes, macrophages, and polymorphonuclear leukocytes leads to progressive hard and soft tissue destruction. The inflammatory process of both diseases is mediated by pro-inflammatory cytokines, particularly tumor necrosis factor-alpha and interleukin 6.1,7,8

Citrullination has been proposed as a mechanism that links RA and PD. Porphyromonas gingivalis, a prominent pathogen involved in the development and propagation of PD, has the unique ability among oral bacteria to release peptidyl arginine deiminase, a microbial enzyme that mediates posttranslational conversion of arginine into citrulline. As RA is characterized by the presence of disease-specific autoantibodies against citrullinated proteins, the enzymatic conversion of arginine to citrulline presents a plausible link between PD and RA.9 Genetic factors may also be involved. Research has demonstrated that including the human leukocyte antigen-DR shared epitope is related to the pathogenesis of both RA and PD.10

For more background on the relationship between PD and RA and its clinical implications, Rheumatology Advisor interviewed Nidhi Sofat, MBBS, PhD, from the Center for Infection and Immunity Research at St George’s University of London, United Kingdom. Dr Sofat was co-author of a 2016 meta-analysis on the association between RA and PD.

Rheumatology Advisor: The relationship between RA and PD has been investigated for many years. Why is it of enduring interest? What are the potential outcomes of more knowledge on this topic?

Dr Sofat: Historically, the link between PD and RA was of interest because of anecdotal evidence of people with gum disease and poor dentition being at higher risk for RA. In more recent years, the scientific link between PD and RA has been better established, with larger studies investigating the association of PD with RA from different populations around the world. There are also some data to suggest that chronic infection arising from PD may be a risk factor for RA.

Rheumatology Advisor: What are the treatment implications of this relationship for rheumatologists caring for patients with RA? Should the presence of PD affect treatment approaches?

Dr Sofat: In our clinics, we assess the dental health of patients, using questionnaires, and recommend further review by a dentist/periodontal specialist if the patient is at higher risk. It has been shown in some small studies that better control of PD can affect improved outcomes in RA.

Rheumatology Advisor: How does treatment for PD influence the disease course in RA, and vice versa?

Dr Sofat: Early detection, diagnosis, and treatment of PD is likely to reduce the infection burden and help maintain patients in remission. Other studies have suggested that some of the enzymes that cause development of autoimmunity in RA (antibodies to citrullinated peptides) may arise from pathogens in the oral cavity; therefore, maintaining good oral hygiene and dental health in the first place may prevent the development of autoimmunity. Larger longitudinal studies are needed to determine this.

Rheumatology Advisor: What recommendations would you have for further research on this topic, based on your review?

Dr Sofat: Future research is needed in which interventions for PD are best for improved RA outcomes, and more studies in people with PD who have not yet developed RA, so we can identify which risk factors (eg, genetic and environmental) predispose them to developing RA.

References

1. Thilagar DS. Rheumatoid arthritis and chronic periodontitis – a disease link. J Pharm Sci. 2017;9:4.

2. Nagpal R, Yamashiro Y, Izumi Y. The two-way association of periodontal infection with systemic disorders: an overview. Mediators Inflamm. 2015;2015:793898.

3. de Pablo P, Chapple ILC, Buckley CD, Dietrich T. Periodontitis in systemic rheumatic diseases. Nature Reviews Rheumatology. 2009;5:218.

4. Fuggle NR, Smith TO, Kaul A, Sofat N. Hand to mouth: a systematic review and meta-analysis of the association between rheumatoid arthritis and periodontitis. Front Immunol. 2016;7:80.

5. Donley TG. Time to put periodontal disease on the list of chronic inflammatory diseases contributing to premature atherosclerosis. CMAJ. 2019;191(2):E52-E52.

6. Araújo VMA, Melo IM, Lima V. Relationship between periodontitis and rheumatoid arthritis: review of the literature. Mediators Inflamm. 2015;2015:259074.

7. Corrêa MG, Sacchetti SB, Ribeiro FV, et al. Periodontitis increases rheumatic factor serum levels and citrullinated proteins in gingival tissues and alter cytokine balance in arthritic rats. PLoS One. 2017;12(3):e0174442.

8. Kobayashi T, Yoshie H. Host responses in the link between periodontitis and rheumatoid arthritis. Curr Oral Health Rep. 2015;2:1-8.

9. Olsen I, Singhrao SK, Potempa J. Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and alzheimer’s disease. J Oral Microbiol. 2018;10(1):1487742.

10. Li R, Tian C, Postlethwaite A, et al. Rheumatoid arthritis and periodontal disease: what are the similarities and differences? Int J Rheum Dis. 2017;20(12):1887-1901.