Relationship between Periodontitis and Rheumatoid Arthritis: Review of the Literature

Periodontitis (PD) and rheumatoid arthritis (RA) are immunoinflammatory diseases where leukocyte infiltration and inflammatory mediators induce alveolar bone loss, synovitis, and joint destruction, respectively. Thus, we reviewed the relationship between both diseases considering epidemiological aspects, mechanical periodontal treatment, inflammatory mediators, oral microbiota, and antibodies, using the keywords “periodontitis” and “rheumatoid arthritis” in PubMed database between January 2012 and March 2015, resulting in 162 articles. After critical reading based on titles and abstracts and following the inclusion and exclusion criteria, 26 articles were included. In the articles, women over 40 years old, smokers and nonsmokers, mainly constituted the analyzed groups. Eight studies broached the epidemiological relationship with PD and RA. Four trials demonstrated that the periodontal treatment influenced the severity of RA and periodontal clinical parameters. Nine studies were related with bacteria influence in the pathogenesis of RA and the presence of citrullinated proteins, autoantibodies, or rheumatoid factor in patients with PD and RA. Five studies investigated the presence of mediators of inflammation in PD and RA. In summary, the majority of the articles have confirmed that there is a correlation between PD and RA, since both disorders have characteristics in common and result from an imbalance in the immunoinflammatory response.


Introduction
Periodontitis (PD) is a chronic inflammatory disease where resident cells and preformed mediators induce leukocyte infiltration and progressive destruction of the tooth supporting tissues as a result of interaction between bacterial products, cell populations, and mediators in disease-susceptible individuals [1,2]. This is also influenced by genetic and environmental risk factors and is characterized as a complex disease with multifactorial etiology [3,4]. In this context, environmental factors, including oral hygiene/bacterial plaque, smoking, and stress, play an important role in the expression of PD [3]. Furthermore, it has been evidenced by some authors that there is a joint influence of polymorphisms in multiple genes [5], such as the genes of IL-10 [6] and IL-6 [7].
Polymorphonuclear neutrophils (PMNs) represent the first line of defense to protect the host from periodontal pathogens in the gingival sulcus and junctional epithelium. Data on the role of the pathogenesis of periodontitis are mixed. PMNs are a critical arm of defense against periodontitis, but bacterial evasion of the neutrophil microbicidal machinery coupled with delayed neutrophil apoptosis may transform the neutrophil from defender to perpetrator [8]. Actually, these cells can release a variety of factors, such as reactive oxygen species, collagenases, and other proteases, [1,9], such as stimulation from a wide range of cytokines. In this scenario, macrophages can act as antigen-presenting cells, promoting the activation of lymphocytes [1]. Therefore, the cellular concentration of neutrophils in the inflammatory infiltrates decreases during the transition between gingivitis and periodontitis, in which there is a predominance of lymphocytes [9].
It has been described that proinflammatory cytokines, prostaglandin E 2 , matrix metalloproteinase (MMP), nitric oxide (NO), and other inflammatory mediators play a crucial role in the pathogenesis of PD [10][11][12]. Moreover, an increase of TNF-, IL-1 , IL-6, IL-11, and IL-17 can induce osteoclastogenesis by increasing the expression of Receptor Activator of NF-B Ligand (RANKL) and by reducing the osteoprotegerin (OPG) production in osteoblasts and stromal cells [13]. In fact, it was demonstrated that IL-17 and RANKL were overregulated and IL-10, an anti-inflammatory cytokine, and TGF-1 were downregulated in active periodontal lesions compared with inactive lesions [14,15] (Figure 1(a)).
Considering that an imbalance between bone formation and resorption is also linked to various diseases, studies suggest that PD may be a risk factor for other diseases [16], such as rheumatoid arthritis (RA) [17], but without consensus. Although pathogenesis of RA is not completely understood, it is recognized that the activation of the complement system is important in disease development [18], the abnormal response of circulating lymphocytes from patients, and an alteration in the structure of these cells, which contribute to the autoimmunity, immunosuppression, and the genesis of the disease [19]. Studies report there is a correlation between both PD and RA since the mechanisms for the development of RA have consonance with the pathogenesis of chronic PD. In fact, RA is defined as an inflammatory and autoimmune disease characterized by accumulation of leukocyte inflammatory infiltrate in the synovial membrane, as well as mediators such as PGE 2 , TNF-, IL-1 , IL-6, IL-12, IL-17, IL-18, IL-33, granulocyte macrophage colony-stimulating factor (GM-CSF), Monocyte Colony-Stimulating Factor (M-CSF), RANKL, MMPs, and NO, all being found in the synovial fluid [20][21][22][23][24], and leading to synovitis and joint architecture destruction.
Some studies have suggested that the susceptibility of RA may be associated with genetic or environmental factors [25]. One of the most important genetic factors is the human leukocyte antigen (HLA) class II. Certain alleles of this antigen are often associated with the development of rheumatoid arthritis (HLA-DRB1 * 0101, HLA-DRB1 * 0102, HLA-DRB1 * 0401, HLA-DRB1 * 0404, HLA-DRB1 * 0405, HLA-DRB1 * 0408, HLA-DRB1 * 0410, HLA-DRB1 * 1001, and HLA-DRB1 * 1402) [14]. Other factors include the allele of 620W of PTPN22 (protein tyrosine phosphatase nonreceptor type   Mediators of Inflammation   3 22), a gene encoding tyrosine phosphatase that is involved in controlling the intracellular signaling triggered through T and B receptors [26]; C5-TRAF1, which can interfere with disease susceptibility and severity of the alteration in the structure, function, and levels of complement component c5/factor 1 associated with the TNF receptor [27]; gene encoding the CTLA4 (cytotoxic T lymphocyte antigen-4), the protein responsible for the regulation of T lymphocyte activation [28]; peptidylarginine deiminase (PAD2), the enzyme responsible for the generation of citrullinated proteins, which are related to the formation of anticyclic citrullinated peptide autoantibodies [29] (Figure 1(b)). With regard to environmental factors, smoking is a risk factor that duplicates the risk of developing RA, but its effect is limited to those with antibodies to citrullinated peptides [30,31]. Other factors refer to the excessive consumption of coffee (more than 10 cups daily) which can be related to the development of the disease [32] and bacterial microbiota, including oral bacterial species which can participate in the etiopathogenesis of RA [33]. On the other hand, the intake of alcohol may exert a protective effect in rheumatoid arthritis in a dose-dependent manner [32]. The literature shows that the basic difference between both diseases is that RA is an inflammatory autoimmune disease, while PD is an immunoinflammatory disease of bacterial origin [9]. However, it is noteworthy that many epidemiological studies seem to dilute the subtle differences expressed by some parameters, though clinically important. Indeed, analyses of inflammatory mediators and other molecular markers are examples where the differences found in a trial with few participants could disappear in a large and diverse sample. In this sense, this review is a critical appraisal of studies that address potential associations of periodontitis with RA and with an overall comprehensive approach.

Methods
For this review, the US National Library of Medicine National Institutes of Health PubMed was searched by two independent researchers who agreed with the search criteria of studies with patients with both PD and RA and checked by a third researcher separately. The keywords periodontitis and rheumatoid arthritis were used and 367 articles published in English were found. The time period was limited from January 2012 to March 2015, and 162 references were found. Then, a critical reading based on titles and abstracts was made and 136 papers were excluded, such as reviews, assays in vitro and animal studies, articles that were not in English, studies not related to both PD and RA, case study, workshop, or unavailable and incomplete articles. Then, 26 articles were finally included for this review, which related to PD and RA, considering epidemiological aspects, mechanical periodontal treatment, mediators of inflammation, oral microbiota, and antibodies as seen in Figure 2 Table 1 shows demographic data, such as gender, age and habits, comorbidities and medications, and the relationship  between both diseases investigated through clinical and epidemiological associations, presence of oral bacterial DNA in patients with RA, proinflammatory mediators, antibodies against bacteria, and autoantibodies, as well as the effects of mechanical periodontal treatment, related to the 26 selected articles.
Among the selected trials, eight studies broached the epidemiological and clinical relationship of patients with PD and RA [38,41,44,45,49,54,56,59], indicating a higher prevalence of PD in patients with RA, which have worse periodontal parameters. The effect of mechanical removal of foci of infection in the oral cavity on the severity of RA and periodontal clinical parameters were shown by four    studies [37,42,46,51], which demonstrated the beneficial effects of the mechanical treatment in the improvement of clinical parameters of RA. Two studies were related to the oral bacteria influence of the pathogenesis of RA [40,52]. Seven trials highlighted the presence of citrullinated proteins and their antibodies, antibodies to P. gingivalis in patients with RA and periodontitis, and also the association between anti-P. gingivalis and periodontal parameters, and the titers of rheumatoid factor and antibodies anticyclic citrullinated peptide, which were also related to the severity of PD [35,36,39,50,53,55,57]. Regarding the inflammation in both diseases, five trials considered the mediators of inflammation to the PD and RA [34,43,47,48,58], such as MMP-9, TNF-, IL-17, RANKL, and OPG. Considering the relationship between rheumatoid arthritis and periodontitis, only two articles showed no statistical significant association, while 24 studies have established this association, either by descriptive (3 studies) or statistical analysis (21 studies).

Discussion
In this review, demographic data and other aspects that can modify one or both diseases were presented, as well as the relationship between both diseases investigated through clinical and epidemiological associations, effects of mechanical periodontal treatment, presence of oral bacterial DNA in patients with RA, proinflammatory mediators, antibodies against bacteria, and autoantibodies.
The articles showed higher prevalence of female patients. This aspect was interesting, as a possible relationship between female sex hormones and susceptibility of rheumatoid arthritis had been reported in the literature, so that low levels of those hormones at menopause promote the risk of developing the disease early [60]. However, a protective role of oral contraceptives on the risk for rheumatoid arthritis in women is still controversial [61][62][63]. On the other hand, there is strong evidence that estrogen deficiency influences the severity of periodontitis, since worse periodontal parameters were observed as bleeding on probing, gingival recession, and clinical attachment loss in postmenopausal women with osteoporosis [64].
The smoking status was also recorded in the selected studies. Cigarette smoking is considered an important risk factor for the development of rheumatoid arthritis, since it was demonstrated that lifelong cigarette smoking was positively associated with the risk of RA even among smokers with a low lifelong exposure [65]. Moreover, it has been related that smoking interacts with HLA-DR SE genes and increases the risk of anti-CCP antibodies in patients with rheumatoid arthritis [66]. Regarding the periodontium, it was shown that smokers presented greater probing depths, when compared to the probing depths of patients who never smoked [67].
The literature shows that PD does not usually require pharmacological treatment, except for mechanical periodontal treatment as routine. In this review, this fact was also observed, while half of the studies had shown that rheumatoid arthritis involved some pharmacological approach. The use of disease-modifying antirheumatic drugs (DMARDs) aims to reverse the symptoms of the disease, reduce the progression of joint damage, and consequently improve the quality of life of patients [68]. The conventional synthetic DMARDs include methotrexate, sulfasalazine, and leflunomide; the available tumor necrosis factor inhibitors (adalimumab, etanercept, and infliximab), the T cell costimulation inhibitor (abatacept), the anti-B cell agent (rituximab), and the interleukin-6 receptor blocking monoclonal antibody are included in biological DMARDs [69]. These medications may be associated with glucocorticoids (GC) or nonsteroidal antiinflammatory drugs (NSAIDs). The long-term, low-dose glucocorticoid and NSAIDs therapy were shown to reduce joint symptoms, pain, and other systemic manifestations [70,71]. Although these benefits are present, the long-time treatment with GC and methotrexate decreased immune response and promoted oral changes, such as candidiasis, periodontitis, and oral ulceration besides impaired saliva secretion [72]. Indeed the literature demonstrated that patients on corticosteroids exhibited higher levels of candidiasis, clinical attachment loss, and probing pocket depth [73]. These aspects, at least in part, may contribute to the worse periodontal status of RA patients when compared to healthy patients. Moreover, the use of medications referred to in half of the articles could compromise the evaluation of this review. However, it is noteworthy that the other half of the articles did not use any medication [35-37, 40, 41, 44, 45, 49, 50, 52, 53, 55, 58].
Analysing the articles, it was observed that most patients with RA showed a significant increase in the incidence of PD as compared to healthy individuals, while only few articles concluded the opposite, probably due to the lack of standardization of parameters in evaluating the different types of periodontitis. Although epidemiological studies outlined by Dev et al. (2013) [45] have not observed a significant RA incidence in subjects with periodontitis where these authors suggested that periodontitis is an independent factor for RA, several other studies have shown that patients with RA were more susceptible to the development of periodontitis [38,44], since these patients had worse periodontal parameters, such as clinical attachment level [37,56], alveolar bone loss [56,59], probing depth [37,49], plaque index, and bleeding on probing [37,41,54]. Indeed, the mechanical periodontal treatment as scaling and root planning in the control of periodontal infection interfered not only with the severity of RA but also with the periodontal clinical parameters [74]. This result can be explained by a reduction in the foci of oral bacteria, and therefore the low levels of inflammation demonstrated a decrease of DAS28 (disease activity score in 28 joints) and serum levels of IL-1 , TNF-, C-reactive protein, and erythrocyte rate sedimentation [37,42,46,51]. In this sense, studies have defended the hypothesis that oral infections play an important role in the pathogenesis of RA, promoting the citrullination of proteins, which can be based on the detection of bacterial DNA using the techniques of DNA isolation (PCR and DNA-DNA hybridization) and high titers of antibodies against bacteria in synovial fluid and serum samples from patients with RA [40,51,52]. Most of the studies have shown the presence of oral bacteria in patients with RA, highlighting P. gingivalis and F. nucleatum [40,52]. Markedly, P. gingivalis is the most elucidated in the development of RA, and studies using animal models have demonstrated the potential of this proinflammatory bacterium promoting the development of experimental arthritis and increased serum levels of C-reactive protein, TNF-, IL-1 , IL-17, MMP-13, and RANKL [75]. Furthermore, RA is an autoimmune disease characterized by autoantibodies specific for citrullinated peptide antigen (anticyclic citrullinated peptide), which are synthetized by peptidylarginine deiminase and characterized as the most specific markers for the diagnosis of the disease [76,77]. Considering that the P. gingivalis is regarded as being capable of expressing this enzyme (PAD), it is suggested that infection with this microorganism could influence the pathogenesis of RA [78,79]. These citrullinated proteins were also found in periodontal tissues, indicating a link between these peptides generated in the oral cavity and those observed in articular tissues [36,80].
Additionally, the presence of antibodies to P. gingivalis was investigated. Although Seror et al. (2015) [57] have not detected this, antibody titres significantly differ between early rheumatoid arthritis and healthy controls. Other studies observed the antibodies to P. gingivalis in patients with RA and severe periodontitis [39] and were associated with probing depth and clinical attachment level and the titers of rheumatoid factor and anticyclic citrullinated peptide autoantibodies [35,50], which may be found in patients with RA and related to the severity of periodontitis [55]. In summary, the studies suggested that P. gingivalis might play a role in the pathogenesis of RA. The response in periodontitis was related to uncitrullinated peptide, suggesting that these peptides break tolerance and can be involved in pathogenesis of RA [53] (Figure 1(c)).
Inflammatory conditions and mechanisms for bone destruction in PD and RA have many similarities. Most of the studies have found high levels of proinflammatory cytokines and other mediators of inflammation, such as MMP-9 [58], TNF- [48], IL-17, RANKL, and OPG [47]. Moreover, it was demonstrated that the hypomethylated status, a single region of the IL-6, may contribute to elevated serum levels of this cytokine, implying a role in the pathogenesis of these diseases [34], while the anti-inflammatory cytokines in the GCF, such as IL-4 and IL-10, showed no consensus among studies regarding the differences observed among individuals with PD and RA [43]. In addition, hypotheses have been proposed to explain the relationship between periodontitis and systemic diseases, such as rheumatoid arthritis. In the literature, studies have suggested that chronic periodontitis generates local constant high levels of microparticles, which have been considered inflammatory biomarkers or mediators responsible for distant cell signalling and regulation [81]. Moreover, it has been reported that these microparticles play an important role in thrombosis and angiogenesis and mediate cellular communication by transferring mRNAs and microR-NAs from the cell of origin to target cells [82]. Thus, the microparticle participation and its spread into the bloodstream could constitute the explanation to the increased risk for systemic disease in patients with periodontitis [83].
Despite these evidences showing a link between rheumatoid arthritis and periodontitis, the exact mechanisms involving this association have not been fully elucidated. Thus, welldesigned longitudinal multicentre clinical trials and further studies with sufficient sample sizes are required to determine the biochemical processes and clinical relationships between these chronic inflammatory conditions. Moreover, these studies should consider other potential confound factors such as the drugs administered for the treatment for each disease or differences in oral hygiene or smoking habits in these patients.

Conclusion
The majority of the articles have confirmed that there is a correlation between PD and RA, since both disorders have characteristics in common and result from an imbalance in the immunoinflammatory response. Although it is necessary to highlight the importance of the mechanical treatment for periodontitis and pharmacological treatments mainly for RA patients, more research is needed to assess whether the coexistence of both diseases can affect the clinical signs of periodontitis and systemic markers of rheumatoid arthritis and strengthen the capacity of oral bacteria to stimulate an autoimmune response, thus establishing that cell constituents or mediators could share common pathophysiological pathways for both diseases and therefore define the best therapy.