Bi-Directional Links Between Rheumatoid Arthritis and Periodontal Disease

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Improved dental hygiene throughout life, with regular dental monitoring for the detection of early PD, along with special attention to preventative treatment is recommended in patients with RA.
Improved dental hygiene throughout life, with regular dental monitoring for the detection of early PD, along with special attention to preventative treatment is recommended in patients with RA.

A common comorbidity in rheumatoid arthritis (RA) is periodontal disease (PD). More than one-third of adults older tnan age 35 in the United States are estimated to be afflicted with periodontal disease, and approximately 20% of the world's population suffers from PD severe enough to result in tooth loss.1,2

The link between RA and PD has been well-established for more than a century, starting with an article by Kenneth Goadby, DPH,3 that appeared in a 1911 issue of The Lancet, and which has been confirmed by many studies since.4-7 The conditions are both primarily mediated by inflammatory mechanisms with involvement of cytokines such as interleukin 1, tumor necrosis factor alpha, and prostaglandin E2 in the destruction of bone tissue, including teeth and joints.8-10

PD in Patients with RA

It has been observed that people with RA have double the risk of PD, compared with the general population,4-7 and the risk of having PD increases as the course of RA continues.10,11 A 1997 study of 50 patients with RA of long duration demonstrated higher rates of gingival bleeding, greater probing depth and attachment loss, and greater number of missing teeth, which were each increased by 50%, 26%, 173%, and 29%, respectively, compared with controls.11

In 2016, a large scale prospective study in Finland looked at the comorbidity of PD in early RA (ERA).11 Using a cohort of 124 participants — 53 with ERA, 28 with chronic RA (CRA) who did not respond to disease-modifying antirheumatic drugs (DMARDS), and 43 controls — the investigators found moderate PD was already present in 63.7% of patients with ERA and 64.3% of patients with CRA, compared with only 39.5% of the controls (P =0.001), a difference that was not attributed to the use of (DMARDs).11

Citrullination

A large body of evidence from epidemiological studies strongly supports a role for autoimmunity against citrulline in mechanisms of RA.10,12-21 The link between RA and periodontal disease appears to be mediated via similar pro-inflammatory immune responses that drive periodontal and synovial joint tissue and bone destruction.21,22

The mechanisms are not yet clear, but the pathway appears to be quite direct: PD is an inflammatory gateway for citrullination, a process that alters the structural integrity of proteins and their ultimate function through mechanisms that may be both causal and non-causal. Non-causal mechanisms include shared environmental risk factors such as smoking and possible genetic links via expression of the MHC class II HLA-DRB1 allele.23-27 Several studies, however, have pointed to an important potential causal mechanism, in which PD leads to RA.

The main precipitating factor in many cases of RA is now believed to be a destructive autoimmune response to anticitrullinated protein antibodies (ACPA) triggered by PD. In susceptible individuals who have lower tolerance to citrullinated proteins, the antibody response is increased and may also attack synovial tissue.10,28-30

Mechanisms Tied to RA

The key pathogen in the development of PD is the bacterium porphyromonas gingivalis, which is known to colonize dental plaque as part of the initiation of the inflammatory citrullination process.31

Citrullination of dental plaque triggers an autoimmune response by creating anti-cyclic cirtrullinated (anti-CCP) antibodies, which at higher concentrations are associated with more severe RA. The specificity of ACPA in RA was found to be high, even in early studies.

A 1998 investigation by Schellekens, et al 32 detected serum ACPA in 76% of their participants, with a specificity of 96%, which the investigators stated was “indicative for a possible role of citrulline-containing epitopes in the pathogenesis of RA.”

A 2016 study by Karmalova, et al33 found that the antibody response to P gingivalis virulence factor arginine gingipainB (RgpB) levels was significantly elevated in patients with PD and RA compared with controls, and in cases of ACPA-positive RA compared with ACPA-negative RA.

The researchers reported that “the previously reported link between PD and RA could be accounted for by P gingivalis infection, and we conclude that P gingivalis is a credible candidate for triggering and/or driving autoimmunity and autoimmune disease in a subset of RA.”33

Bi-directional Influences

The question that challenges researchers today is where the link begins: does RA cause PD, as was previously believed, or does PD cause RA, as many studies now indicate?

A “two-hit” hypothetical model by Golub et al34 suggested that a first inflammatory assault via chronic PD in the presence of a second arthrogenic inflammatory attack could combine to produce an over-response by the immune system that initiates RA. A second theory suggested that altered proteins such as those caused by citrullination trigger exaggerated and destructive immune responses.35 In their published results of a 2014 meta-analysis, Kaur and colleagues36 suggested that the mechanisms may be bi-directional, allowing for either disorder to trigger the other.

Summary and Clinical Applicability

Bi-directional mechanisms linking periodontal disease to the development of RA may offer biomarkers for the development of RA and treatment objectives that influence the courses of both inflammatory conditions. A 2014 study by Koziel, et al10 found that the release of peptidyl-arginine deiminases (PADs) by P gingivalis increases citrullination, and may provide a good target for future therapies for RA.

Improved dental hygiene throughout life, with regular dental monitoring for the detection of early PD, along with special attention to preventative treatment, is recommended in patients with RA, and highlights the importance of proper dental care in the general population as well.

References

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