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Review
, 20 (18)

Linkage of Periodontitis and Rheumatoid Arthritis: Current Evidence and Potential Biological Interactions

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Review

Linkage of Periodontitis and Rheumatoid Arthritis: Current Evidence and Potential Biological Interactions

Rafael Scaf de Molon et al. Int J Mol Sci.

Abstract

The association between rheumatoid arthritis (RA) and periodontal disease (PD) has been the focus of numerous investigations driven by their common pathological features. RA is an autoimmune disease characterized by chronic inflammation, the production of anti-citrullinated proteins antibodies (ACPA) leading to synovial joint inflammation and destruction. PD is a chronic inflammatory condition associated with a dysbiotic microbial biofilm affecting the supporting tissues around the teeth leading to the destruction of mineralized and non-mineralized connective tissues. Chronic inflammation associated with both RA and PD is similar in the predominant adaptive immune phenotype, in the imbalance between pro- and anti-inflammatory cytokines and in the role of smoking and genetic background as risk factors. Structural damage that occurs in consequence of chronic inflammation is the ultimate cause of loss of function and disability observed with the progression of RA and PD. Interestingly, the periodontal pathogen Porphyromonas gingivalis has been implicated in the generation of ACPA in RA patients, suggesting a direct biological intersection between PD and RA. However, more studies are warranted to confirm this link, elucidate potential mechanisms involved, and ascertain temporal associations between RA and PD. This review is mainly focused on recent clinical and translational research intends to discuss and provide an overview of the relationship between RA and PD, exploring the similarities in the immune-pathological aspects and the possible mechanisms linking the development and progression of both diseases. In addition, the current available treatments targeting both RA and PD were revised.

Keywords: alveolar bone loss; bone; bone resorption; periodontal disease; periodontitis; rheumatoid arthritis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Possible biological intersections between rheumatoid arthritis (RA) and periodontal disease (PD): Common risk/predisposing factors and reciprocal biological influences. The exposure to certain environmental factors, e.g., smoking, genetic background (HLA-DRB1-SE), gut microbiome, infection with P. gingivalis and more recently with A. actinomycetemcomitans (microbial dysbiosis) leads to local protein alteration by citrullination. In combination with an inflammatory process stimulated by macrophages, dendritic cells, and T cells, a host response to citrullinated proteins in predisposed patients will occur. Immune cells will produce proinflammatory mediators (Interleukins (ILs), Prostaglandins (PGs), Tumor Necrosis Factor (TNF), and metalloproteinases (MMPs), which also contribute to the aggravation of the immune response. IL-17, an important cytokine of the Th17 induces the production of CXC chemokines, MMPs, and reactive oxygen species (ROS), as well as the osteoblast expression of the receptor activator of the factor nuclear kappa B ligand (RANK-L) that stimulate osteoclast activation. Stimulated lymphocytes (B and T cells, specifically Th1 and Th17) play an important function during bone resorption by means of the RANKL-dependent mechanism in both conditions. P. gingivalis infection lead to the activation of proteases and peptidylarginine deiminase (PPADs) that generates citrullinated proteins and triggers the synthesis of anti-citrullinated proteins antibodies (ACPAs). A resultant signal against citrullinated epitopes in the joints resulting in enhanced expression of the rheumatoid factor (RF) and ACPAs, assisting in the formation of immune complexes. A. actinomycetemcomitans lead to the hypercitrullination of neutrophils and result in the activation of citrulline enzymes, which are also involved in the breakdown of the immune tolerance to the host molecules. These immune complexes enhance the host inflammatory development, which may aggravate RA. In addition, the autoantibodies produced during this process might contribute to the inflammatory process by directly activating osteoclast and resulting in the bone and cartilage damage. Thus, citrullination may represent a biological mechanism bridging reciprocal influences between RA and PD.
Figure 2
Figure 2
The pathogenesis of the periodontal disease. A dysbiotic microbiome localized in the enamel surface of the tooth, below the gingival margin, initiate the innate immunity by stimulating resident cells (epithelial cells, periodontal ligament fibroblast, and gingival fibroblast and dendritic cells) to produce mediators of inflammation in response to bacterial lipopolysaccharide (LPS) (via the toll-like receptor). Resident cells located in the connective tissue and alveolar bone produce proinflammatory cytokines and chemokines, including (Tumor Necrosis Factor- α (TNF-α), Interleukin-1 β (IL-1β), IL-6, IL-8, IL-12, IL-17 and the receptor activator of the factor nuclear kappa B ligand (RANK-L). Microorganisms located in the biofilm can reach the connective tissue and goes toward the alveolar bone, leading to the expression of RANK-L by osteoblasts, which can be accounted for the bone resorption seen during the disease process. If the infection fails to resolve, the release of pro-inflammatory mediators will continue and the activation of the B and T cells initiates the adaptive immunity. In this stage, the connective tissue become infiltrated by lymphocytes with predominantly more B cells (RANK-L) than T cells. The T cells will produce TNF-α, RANK-L and IL-17 which lead to increased osteoclastogenesis and bone resorption. This will result in the clinical signs of the disease characterized by increased clinical attachment loss (CAL.).
Figure 3
Figure 3
The pathogenesis of rheumatoid arthritis. The innate immune process is characterized by the infiltration of several inflammatory cells, chemokines, as well as other inflammatory mediators into the joint. Rheumatoid factor (RF) and anti-citrullinated proteins antibodies (ACPAs), the two most important autoantibodies, are typically produced by plasma cells. The coordinated production of proinflammatory cytokines and chemokines play crucial role in the orchestration of the inflammatory responses that ultimately result in the cartilage and bone destruction. Macrophages, synovial fibroblast, and dendritic cells produce several pro-inflammatory mediators such as Interleukins (IL-1, IL-2, IL-6, IL-10, IL-13, IL-15, IL-17, IL-18, Tumor Necrosis Factor- α (TNF-α), Granulocyte macrophage colony-stimulating factor (GM-CSF), and metalloproteinases (MMPs). In addition, the T cells activation leads to overproduction of inflammatory cytokines, including TNF-a, IL-1b, and IL-6 by macrophages. The overexpression of inflammatory cytokines enhances the capacity to induce the production of RANKL, which is the main regulator of osteoclastogenesis. These cells of the innate immune system hold extensive proinflammatory, destructive, and remodeling capacities, and substantially contribute to inflammation and joint destruction in RA.
Figure 4
Figure 4
Potential initiators of immune-mediated inflammatory conditions at distant sites. A briefly description of the extra-articular potential initiators that might account for the pathogenesis of rheumatic diseases. Patients at high risk to develop autoimmune arthritis are more prone to infections due to endogenous (dysfunctional immune system) and external factors, i.e., periodontal disease and the presence of P. gingivalis and A. actinomycetemcomitans that trigger citrullinated peptides; exposure to risk factors such as smoke and pollutants might lead to the production of neutrophils extracellular traps (NEToses) and anti-citrullinated proteins antibodies (ACPA) in the lung; and the gut dysbiosis that also lead to the ACPA production. For patients at high risk to develop rheumatoid arthritis (RA), meticulous examining for infectious foci, particularly in the intestine and mouth, should be advocated in order to allow their early recognition and eradication.

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