Association of Rheumatoid Arthritis with Dental Health-A Mini Review

Autoimmune disorders represent a cluster of diseases related to dysregulation of the immune system or misrecognition of self from non-self. Rheumatoid arthritis (RA) is a chronic in lammatory condition involving the joints. It is one of the most common forms of in lammatory arthritis reported globally. The incidence rate of RA is found to be the highest among middle-aged women. There happens to be a close relationship between RA and dental health. The in lammatory processes triggered bymicrobes and other endogenous factors affects the bone health resulting in the resorption of bones. This condition is observed in aggressive and chronic periodontitis. Themain objective of the present literature reviewwas to evaluate the association of rheumatoid arthritis with dental health such as gingivitis, tooth loss and periodontitis. Furthermore, the present literature review throws light on the common markerswhichmight be associatedwith both the disease conditions. The current review identi ied novel markers that were associated with rheumatoid arthritis which were implicated in dental health also. Hence management of rheumatoid arthritis might as well reduce the damage caused by bone resorption and could aid in the prevention of premature tooth loss.

Rheumatoid arthritis, pain, biological markers, Mediterranean diet, antirheumatic drugs ABSTRACT Autoimmune disorders represent a cluster of diseases related to dysregulation of the immune system or misrecognition of self from non-self. Rheumatoid arthritis (RA) is a chronic in lammatory condition involving the joints. It is one of the most common forms of in lammatory arthritis reported globally. The incidence rate of RA is found to be the highest among middle-aged women. There happens to be a close relationship between RA and dental health. The in lammatory processes triggered by microbes and other endogenous factors affects the bone health resulting in the resorption of bones. This condition is observed in aggressive and chronic periodontitis. The main objective of the present literature review was to evaluate the association of rheumatoid arthritis with dental health such as gingivitis, tooth loss and periodontitis. Furthermore, the present literature review throws light on the common markers which might be associated with both the disease conditions. The current review identi ied novel markers that were associated with rheumatoid arthritis which were implicated in dental health also. Hence management of rheumatoid arthritis might as well reduce the damage caused by bone resorption and could aid in the prevention of premature tooth loss.

INTRODUCTION
Autoimmune disorders are a form of disease wherein the self molecules of the system are recognized as non-self, eventually leading to the destruction of tissues. The in lammatory process is considered to be a "double-edged" sword (Lin and Kazmierczak, 2017). Although a protective mechanism against invading microbes, at times a chronic exposure to a pool of in lammatory molecules causes severe damage to the tissues. Rheumatoid arthritis (RA) is one such autoimmune disease characterised by systemic in lammation, persistent synovitis and development of autoantibodies. Genetic factors play a very important role in the aetiology of RA, along with other factors, including smoking. The prevalence of RA is found to be in the range of 0.5 -1% with an occurrence more common in women. RA can damage joints causing life-long disability and is responsible for aggravating several other co-morbid conditions (Scott et al., 2010).

Effect of rheumatoid arthritis in dental health
Periodontitis is a common disorder experienced by tissue damage due to failure of the immune system to control infectious microbial pathogens and immune response associated with it. Periodontal pathogens such as Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis contributes to the production of RA related antibodies by either directing the post-translational modi ication of proteins or neo-epitope generation mediated by neutrophils. The invasion of oral pathogens into the blood might also result in chronic in lammatory responses triggering the production of auto antibodies (Cheng et al., 2017;Eriksson et al., 2019). A study conducted by recruiting Danish patients with RA reported a signi icant proportion of them suffering from periodontal or gingival diseases (Radwan-Oczko et al., 2019). Another study has pointed out the fact that patients with RA more often exhibit the symptoms of periodontitis than patients without RA. The study demonstrated that RA groups were more affected with moderate to severe forms of caries than the control group. The Decayed, Missing and Filled Teeth (DMFT) index was higher in the RA patients indicating the need for dental attention and prompt treatment. In addition, the count of Streptococcus mutans, the organism commonly associated with dental caries was signi icantly more in the RA group (Martinez-Martinez et al., 2019;Ceccarelli et al., 2019). Hence, these reports justify the role of rheumatologist and dentists in management of the disease.

Common biological markers associated with both rheumatoid arthritis and periodontitis
The process of NETosis has been implicated in various autoimmune diseases. Deployment of neutrophils to the site of injury or infection is considered to be the irst line of defence for containment of infections by microbial pathogens. The process of NETosis results in the formation of neutrophil extracellular traps (NETs), which includes enzymes and decondensed chromatin embedded with granular material extruded from the neutrophils. Citrullinated histone proteins along with primary and secondary granules such as myeloperoxidase, elastase, gelatinase, proteinase 3, peptidoglycan binding proteins, cathepsin G, lactoferritin are a few components of the NET milieu proven to possess antibacterial activity. The bio-mesh entrap microbes, eventually leading to the clearance of pathogens from the system. Reports on the association of NETosis with autoimmune diseases (Frangou et al., 2019) and other non-communicable (Jayaseelan and Paramasivam, 2020) diseases are well documented. Citrullinated histones were found in the periodontal tissues of patients with RA and periodontitis. A study reported the highest frequency of NETosis associated proteins PAD4 (peptidylarginine deiminases) in 93%, CD68 (cluster of differentiation 68) is 87% and citrullinated histone H3 in 60% of patients. Furthermore, anti-citrullinated H3 antibodies auto antibodies were also identi ied in about 39% of RA patients with periodontitis (Janssen et al., 2017).
Microbial factors have also shown a signi icant association with both diseases. A study conducted by Bello-Gualtero and colleagues analyzed several bio markers related to the process of in lammation viz., CRP (C-reactive protein), rheumatoid factor, ESR (erythrocyte sedimentation rate), ACAs (anticitrullinated antibodies). Individuals with pre-RA conditions presented with greater levels of plaque index, bleeding on probing and severity of the periodontal disease. The pre-RA individuals had a signi icant measure of bio markers when compared to those with early RA. Interestingly, the IgG2 antibody was found to be speci ic for P.gingivalis (Bello-Gualtero et al., 2016). Another study reports the bio markers in serum and saliva of RA patients with periodontal problems. Chronic RA patients showed an elevated concentration of MMP-8 (matrix metalloproteinases 8) and IL-6 (Interleukin-6) which is considered to be the re lection of joint in lammation, whilst early RA patients showed elevated concentrations of MMP-8 in saliva (Äyräväinen et al., 2018). A very recent study identi ied the glutaminyl cyclases (QC and is QC) from human and bacterial sources (P.gingivalis). Human QC, ISOQC and PgQC were found to regulate in lammatory responses. The expression of QC, ISOQC and PgQC was measured in patients with chronic periodontitis (CP) and RA. The QC protein was found to be signi icantly increased in peripheral blood and GCF (gingival crevicular luid) in CP patients when compared to controls (Bender et al., 2019).
Apart from the common biochemical markers, genetic polymorphisms common for both RA and periodontitis were also assessed.
Schulz and team studied the impact of genetic polymorphisms in 13 anti and pro-in lammatory cytokines using sequence-speci ic PCR. Several markers showed independent as well as combined associations with both the diseases. The G allele of rs1801275 of IL4Ralpha gene and the G allele of rs361525 of TNFalpha gene was found to be RA associated risk factors. On the other hand, the A allele rs2430561 of IFN-gamma produced signi icant association with periodontitis in RA patients. A binary logistic regression analysis con irmed rs2430561 as an independent risk factor for both RA and periodontitis (Schulz et al., 2019).

Treatment and management of RA and periodontitis
Several pharmacological interventions have been used in the treatment of RA. Glucocorticoids, non-steroidal anti-in lammatory drugs, diseasemodifying anti-rheumatic drugs (DMARDs), TNF-alpha inhibitors, Interleukin -1 beta and interleukin one receptor antagonist, Janus Kinase inhibitors are the commonly prescribed medications for RA. These drugs are found to ameliorate the symptoms by reducing in lammation and progression of the disease, thereby improving the quality of life. Continuous usage of anti-in lammatory drugs and glucocorticoids leads to immunosuppression. This condition has been found to be associated with various changes in the oral cavity leading to candidiasis, xerostomia etc., Despite the fact that studies have demonstrated both bene icial and worse outcomes of periodontitis treatment in RA patients, early diagnosis and prompt treatment of these diseases is sure to slow down the progression of the diseases (de Molon et al., 2019). Researchers have identi ied phytocompounds which can be used in the treatment of in lammatory conditions (M et al., 2019). The formulations incorporating herbal components have also been tested against oral pathogens which are involved in caries and deepseated lesions (Shahana and Muralidharan, 1991;Vaishali and Geetha, 2018) Intracanal medicaments and herbal mouthwashes have been recently tested to prove their ef icacy towards potential dental pathogens (Marickar et al., 2014;Selvakumar and Np, 2017).
Several in silico approaches have been developed to effectively manage PD (Ushanthika et al., 2019;Sivakumar et al., 2020). Since the process of vaccination involves the activation of the immune system, any adverse reactions associated with the process should be addressed if the individual is diagnosed with autoimmune disease state (Pratha and Geetha, 2017). Moreover, eradication of emerging pathogens of the oral cavity (Ashwin and Muralidharan, 2015;Girija et al., 2019) and drug-resistant organisms (Smiline et al., 2018;Priyadharsini et al., 2018b) might also help in alleviating the disease. The eradication of fungal pathogens in the oral cavity is also required to reduce the in lammation (Shahzan et al., 2019). Early diagnosis of co-morbid conditions such as metabolic disorders, hypertension could also have a great impact in modifying the disease state (Priyadharsini et al., 2018a). Hence, Management of chronic metabolic disorders such as diabetes, hypertension, etc., could also reduce the incidence of autoimmune conditions . The treatment of periodontitis is usually carried out by the mechanical debridement of plaque, which is the microbial bio ilm accumulated at the site of infection. The treatment modality used not only helps in reducing the in lammation but also maintains the hostmicrobe homeostasis. Clinical and experimental studies have proved that the treatment process had reduced potential bio markers such as MMP-8, Il-6, etc., in RA patients.

CONCLUSIONS
The present mini-review throws light on the vital roles to be played by rheumatologist and dentist in controlling the autoimmune conditions. More research into these converging ields of medicine and dentistry would bene it patients to lead a healthy lifestyle. Focusing on the early diagnosis of RA with the signs and symptoms associated with dental disorders is sure to reduce the pain and progression of such debilitating diseases. Lifestyle modi ications are also suggested to avoid the exposure of tissues to chronic in lammatory markers.