Rheumatoid Arthritis and Periodontal Disease Association and Effect of Disease Modifying Anti-Rheumatic Drugs: A Narrative Review

— Associations between periodontal disease (PD) and other diseases, including rheumatoid arthritis (RA), respiratory disease, and chronic kidney disease, have been reported. Patients with moderate to severe periodontitis have a high risk of suffering from RA and vice versa. This bidirectional relationship could be due to genetic (HLA-DR), dysregulation of the inflammatory response, and the role of Porphyromonas gingivalis ( P. gingivalis ), which stimulates anti-cyclic citrullinated peptide antibodies via citrullination. This review aims to identify associated factors that contribute to RA and PD relationship and to explore the effects of disease-modifying anti-rheumatic drugs (DMARDs) on PD. A literature search was performed using PubMed and Google Scholar to identify related articles published from the year 1990 to 2020 within the research interest using keyword combinations. Thirty-one articles that fit the research interest and address the research questions for both objectives were selected. As a result, the associated factors for RA and PD relationship, including genetic predisposition, immunoregulatory imbalance, and the role of P. gingivalis in the citrullination process as a risk factor of RA. Significant improvement was found in periodontal parameters in RA patients treated with biologic and synthetic DMARDs. This review reported common factors contributing to the RA and PD relationship and the benefits of DMARDs on periodontitis.


I. INTRODUCTION
Periodontal diseases are among the most common oral health problems in adults of most populations all over the world.They are induced by bacteria and bacterial products of dental plaque, which are characterised by inflammatory destruction of periodontal tissues and alveolar bone.Scientific evidence has shown that severe periodontitis may enhance susceptibility to systemic diseases such as cardiovascular disease, diabetes mellitus, adverse pregnancy outcomes, RA, and pulmonary infections [1].Microbial dental plaque is the initiator of the disease, but the progression and form of the disease will depend on the host's susceptibility and immune response.Thus, systemic health will play a role in initiating or modifying PD, explaining the bidirectional relationship between PD and systemic diseases.
RA is a chronic and progressive autoimmune inflammatory disease that primarily affects joints.It is characterized by uncontrolled proliferation of synovial tissue and a wide array of multi-system co-morbidities [2].The etiology of RA is mainly due to genetics, and it is accompanied by a number of risk factors.Certain environmental triggers, such as stress, smoking, and infectious agents, can precipitate posttranslational modification of proteins as a physiological process.However, the modified proteins may break the immune tolerance in genetically susceptible individuals, leading to autoantibody production [3].
An association between RA and PD has been evidenced by various studies over the past decades.According to those studies, the association between PD and RA had been reported in terms of genetic factors, chronic inflammatory events with immunoregulatory imbalances, bacterial factors, and citrullination.Other than that, the usage of DMARDs as one of the standard therapies in the treatment of RA may influence the progression of periodontitis and vice-versa [4][5][6].This has been suggested in many studies, thus stipulating the potential advantage of host-modulating therapy to control both disorders [7].
Despite that, the association between RA and PD relationship and the effect of DMARDs on periodontitis were still not extensively studied.Therefore, this review will compile the data from previous research regarding the factors contributing to the PD and RA relationship and the effects of RA treatment on periodontitis, specifically with the use of DMARDs.This narrative review will contribute to a better understanding of the association between RA and PD, and their pathogenesis, as well as to improve the management of periodontitis in RA patients.

II. METHODOLOGY
The literature search was performed using PubMed and Google Scholar to identify related articles that are within the research interest using multiple keyword combinations; "rheumatoid arthritis", "periodontal disease", "periodontitis", "anti-cyclic citrullinated peptide", "citrullination", "disease modifying anti-rheumatic drugs", "Porphyromonas gingivalis".Searches were limited to articles that have the keywords of interest, published in English from the year 1990 to 2020, articles regarding RA and PD relationship, and benefits of DMARDs on periodontitis.Editorials, case reports, and articles published before 1990 and in other languages were excluded.Thirty-one articles that fit the research interest and address the research questions for both objectives were selected.Twelve articles that did not fulfil the criteria were excluded (Figure 1).

III. RESULTS AND DISCUSSIONS
Thirty-one articles were compiled regarding the factors contributing to the PD and RA relationship and the effects of RA treatment on periodontitis, specifically with the use of DMARDs in the following Table 1 & Table 2.In this review, the associated factors that relate to PD and RA were investigated through clinical, epidemiological associations and serological studies on the presence of oral bacterial DNA in RA patients, the prevalence of periodontitis in RA patients and vice versa, the role of P. gingivalis in associating PD and RA, as well as the effect of citrullination process.Apart from that, this review also investigated the effects of DMARDs on periodontitis.Based on data analysis, two articles mentioned the presence of oral bacterial DNA in the synovial fluid of RA patients.This might explain the fact that the periodontal pathogens may translocate from the periodontal tissue to the synovium, as what had been found in a study conducted by Témoin and colleagues.The study revealed bacterial DNA was detected in the synovial fluid samples from 5 out of 36 patients [8].The direct translocations of oral microbiota from gingiva to synovium might occur during transient bacteremia, which may result in bacterial colonization in remote sites.This might also explain the increased risk of cardiovascular disorders in patients with RA [9].Another study also reported that the systemic diffusion of bacterial lipopolysaccharide (LPS), a cell wall compound of gramnegative bacteria, positively correlated with joint inflammatory response and the severity of joint degradation [10].Despite the presence of bacterial DNA, the high levels of IgG antibodies in samples of synovial fluid of patients with RA were also detected [11][12][13].
Another important factor that might explain the relationship between PD and RA is Porphyromonas gingivalis.It has a unique ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and drive the citrullination process, which converts arginine to citrulline [14,15].Our result is comparable with a study by Engström and colleagues, where they discovered that citrullinated proteins were present in most of the gingival tissues of individuals with periodontitis while only in a few of the healthy group [16].Another study also found that in RA patients, the mean CAL, mean PI, and the number of pockets ≥ 5 mm in severe periodontal conditions were linearly associated with both levels of anti-CCP antibodies [17].Citrullinated antigens in the periodontal tissues may selectively activate the adaptive immune response and break the self-tolerance, leading to severe aggressive periodontitis and the formation of ACPA [18].ACPAs encourage the perpetuation of synovial inflammation via binding to citrullinated proteins positioned in the cellular membrane [19].HLA-DRB1 genetic locus is strongly associated with susceptibility to RA through citrullinated selfpeptides binding to HLA-DR molecules [20].One of the key inherited risk factors that contribute to ACPA-positive RA is the human leukocyte antigen (HLA) class II loci, namely HLA-DRB1, which encodes the HLA class II antigen-presenting molecules [15].
MJoSHT Vol. 9, No. 2 (2023) 92 The hypomethylated status of a single promoter region in the IL-6 promoter may lead to increased levels of serum IL-6, implicating a role in the pathogenesis of PD and RA.
Increased levels of IL-6 may play a role in the pathogenesis of PD and RA.

Dysregulation of the inflammatory response
There was a high prevalence of mild to moderate periodontitis in the RA patients' group, and statistically significant differences were present in the periodontal parameters of the RA group compared to the non-RA group.
An association exists between PD and an underlying dysregulation of the molecular pathways in the inflammatory response.

PubMed [29]
Case-control clinical study 31 patients with new-onset RA; 34 chronic RA patients; 18 healthy controls

Role of P.gingivalis
Patients with new-onset RA exhibited a high prevalence of PD at disease onset, and their subgingival microbiota was similar to that in patients with chronic RA and healthy subjects whose PD was of comparable severity.
PD may represent a risk factor for RA development independent of smoking status.P. gingivalis may serve as a shared causal pathway in some cases of RA.

6.
Google Scholar [30] Cross-sectional clinical, microbiological, and serological study 95 RA patients; 44 non-RA controls; 36 healthy controls Citrullination A higher prevalence of severe periodontitis was observed in RA patients in comparison to matched non-RA controls.
Higher antibody titers against P. gingivalis in RA patients with severe periodontitis compared to severe periodontitis patients without RA.
The severity of periodontitis is related to the severity of RA Higher antibody titers may be due to the hyperinflammatory state of RA patients with periodontitis and ACPAs directed to citrullinated peptides of P. gingivalis.

7.
Google Synovial inflammation in RA and PsA may favor the trapping of oral bacterial DNAs, which suggests a perpetuating effect of oral pathogens in joint disease.10.PubMed [34] Case-control study 13779 newly diagnosed RA patients; 137790 healthy controls There is a statistically significant association between a history of periodontitis and newly diagnosed RA.
There is an association between PD and RA; however, it is weak and limited to a lack of individual smoking status.
11. PubMed [35] Cross-sectional study 852 PD patients; 668 healthy controls In patients referred for periodontal treatment, the prevalence of RA in females and subjects over 50 years showed a significantly higher prevalence than their counterparts.
Individuals with moderate to severe PD are at higher risk of suffering from RA and vice versa.
12. PubMed [36] Clinical study 66 RA patients -No patients were periodontally healthy.Twenty-four patients were classified as having periodontitis, 18 had moderate periodontitis, 23 had severe periodontitis, and one was toothless.
Most patients with RA in this study showed moderate-to-severe periodontitis and the presence of periodontal pathogens.13.PubMed [37] Serological study 80 RA patients; 44 PD patients; 82 healthy volunteers

PPAD and auto citrullination
Recombinant PPAD was a potent citrullinating enzyme.Antibodies to PPAD were elevated in the RA sera compared with controls.
The peptidyl citrulline-specific immune response to PPAD supports the hypothesis that it might break tolerance in RA.

PubMed [38]
Case-control clinical study 100 RA patients; 112 healthy volunteers Genetic predisposition , the role of the periodontal pathogen, dysregulations of the host immunoinfla mmatory response There was a statistically significant difference in periodontal parameters, ESR, and CRP levels between the RA and non-RA groups.
The occurrence of periodontitis in the RA group is also higher, and RA subjects are three times more likely to have moderate to severe chronic periodontitis than non-RA subjects.However, among subjects with RA, there was no significant association between rheumatoid disease activity and the severity of PD.
The prevalence and severity of periodontitis are higher in RA patients.This may be due to common genetic predisposition, the role of the periodontal pathogen, as well as dysregulations of the host immunoinflammatory response.15.PubMed [39] Case-control study 39 RA patients; 36 healthy controls Citrullination Untreated periodontitis patients had higher anti-cyclic citrullinated peptide (CCP) antibody titters than healthy controls.
Periodontitis patients who smoked demonstrated lower anti-P.gingivalis, but similar to anti-CCP in non-smoking periodontitis patients.
There is a statistically significant reduction in anti-CCP titters following periodontal treatment.
Smoking and the presence of P. gingivalis may modulate anti-CCP circulating antibodies.

16.
Google Scholar [40] Case-control clinical study 17 RA patients; 30 healthy controls Immunoregul atory imbalance (increased TNF-α) Patients with high levels of time-averaged TNF-α from repeated plasma samples had a higher frequency of BOP as well as increased CAL and PD compared to those with low levels.
Gingivitis and periodontitis are related to high levels of circulating TNF-α in patients with RA.

Presence of oral bacteria DNA in synovial fluid
In patients with RA, DNA of P. gingivalis was detected in both oral plaque and synovial fluid more often than in controls.
Among the patients' group, the number of missing teeth was correlated with the number of joints with movement restrictions caused by RA.
DNA of periodontopathogens can be found in synovial fluid, and oral bacteria may play a role in the pathogenesis of arthritis.

PubMed [41] 196 RA patients
There is a high percentage of moderate and severe periodontitis in subjects.
Higher age, male gender, previous or current smoking, and high level of plaque score were associated with severe PD.
There is a high prevalence of periodontitis in Thai patients with RA.However, there was no association between RA parameters and periodontal conditions.
However, no differences in RA parameters were found between groups of patients who had moderate and severe periodontitis.19.PubMed [42] Case-control clinical study 287 RA patients; 330 osteoarthritis patients as control

Role of P.gingivalis
The presence of PD was more common in patients with RA and patients with anti-citrullinated protein antibody (ACPA) positive.
The presence of PD was associated with increased swollen joint counts and greater disease activity.Specific antibodies for ACPA were higher in patients with P. gingivalis and subgingival plaque.
PD and P. gingivalis appear to shape the autoreactivity of RA and the independent relationship between PD and RA.20.PubMed [43] Case-control study 16 PD patients; 15 non-PD controls; 1974 RA patients; 377 healthy controls Genetic predisposition,

Role of P.gingivalis
There was a significant association between anti-RgpB (P.gingivalis virulence factor) IgG and RA, which was even stronger than the association between smoking and RA.
In ACPA-positive RA, there were interactions between anti-RgpB antibodies and both smoking and the HLA-DRB1 SE.
P. gingivalis is a credible candidate for triggering and/or driving autoimmunity and autoimmune disease in a subset of RA patients.

Role of PPAD in citrullination
The serum levels of anti-CCP IgG and anti-PPAD IgG were significantly higher in the RA group than in the non-RA group.
This suggests an association between anti-PPAD IgG and anti-CCP IgG responses, implicating a role for PPAD in protein citrullination in patients with RA and periodontitis.

PubMed [45]
Epidemiological cross-sectional study 22 early RA patients: 22 healthy controls More advanced forms of periodontitis were found in ERA patients compared with controls, where they had a greater missing number of teeth, deeper periodontal pocket, and greater BOP.The characteristic pathogen in early RA is Tannerella forsythia subgingivally, while Streptococcus anginosus supragingivally.
There is an increased loss of periodontal attachment and alveolar bone loss in early RA patients, suggesting an association between RA and PD.

Role of P.gingivalis
Anti-P.gingivalis antibody titers did not significantly differ between early RA patients and healthy, sicca, or PD controls.
The results suggest that the association of periodontitis and RA could be linked to other bacterial species than P. gingivalis or a mechanism other than citrullination.

Dysregulation of the inflammatory response
There are statistically significant differences in serum MMP-9 between patient groups and control.Serum levels of MMP-9 were similar in RA and RA-PDassociated patients.Gingival crevicular fluid (GCF) recorded increased MMP-9 levels in RA-PD association subjects compared to PD.
MMP-9 may play a role in the pathogenesis of RA-CP association.Therefore, it is a sensitive tool in diagnosing and managing patients affected by PD and RA.25.PubMed [48] Case-control clinical study 287 RA patients; 330 osteoarthritis patients Citrullination ACPA-positive patients with RA had a significantly higher mean percentage of sites with alveolar bone loss compared with patients with OA.Alveolar bone loss was significantly associated with higher serum ACPA concentration.
Greater alveolar bone loss is associated with higher ACPA.Children who take anti-TNFα had a lower frequency of sites with BOP compared to the 24 patients not taking anti-TNFα The similarities in pathological and immunological characteristics between PD and RA are increased infiltration of inflammatory and immune cells, including neutrophils, monocytes, and T and B lymphocytes, increased release of proinflammatory mediators, such as the tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and matrix-degrading enzymes (MMPs, Cathepsin) [21].There is also an increased activation of the receptor activator of the factor nuclear kappa B (NF-κB) ligand (RANK-L) pathway induced by soluble mediators released by immune cells, with subsequent osteoclast differentiation and maturation [22].
Our literature search found that there is a significant improvement in periodontal parameters in RA patients treated with biologic and synthetic DMARDs.This result is comparable with a study conducted by Kobayashi and colleagues, where it was found that there is a significant decrease in periodontal parameter measurements after treatment with biologic DMARDs.This might be related to the differences in serum protein profiles before and after the DMARDs therapy [23].Systematic DMARDs may ameliorate PD burden in RA patients with periodontitis, where they can decrease gingival inflammation and periodontal destruction [23].However, there is only one study that found that there is no statistically significant difference in the response to nonsurgical periodontal treatment in multiple conventional synthetic DMARDs therapies and the addition of NSAIDs and/or steroids to conventional synthetic DMARDs in the RA group [24].

IV. CONCLUSION AND LIMITATIONS
The associated factors for RA PD relationship include genetic predisposition, immunoregulatory imbalance, and the role of P. gingivalis as a key pathogen involved in the citrullination process as a risk factor of RA.Significant improvement was also found in periodontal parameters in RA patients treated with biologic and synthetic DMARDs.A similar study can be conducted with a larger sample size in the future to obtain more convincing findings.
This review was performed in a limited period due to time constraints.A comparison of the study findings was done on a specific area or topic in the related articles.A larger number of articles can be reviewed in a longer stipulated time and may yield better results or more conclusive findings.

Figure 1 :
Figure 1: Flowchart of search strategy and selection process.

TABLE I .
SELECTED STUDIES ASSESSING THE ASSOCIATED FACTORS OF PD-RA RELATIONSHIP

TABLE 2 .
STUDIES ON THE EFFECT OF DMARDS ON PERIODONTITIS.