Dental Caries in Adult Patients with Rheumatoid Arthritis—A Systematic Review

Patients suffering from rheumatoid arthritis (RA) are repeatedly affected by oral diseases or complaints, including xerostomia, periodontitis and dental caries. The aim of this systematic review was the evaluation of caries prevalence and/or incidence in patients with RA. Within this review, there is a systematic search of the literature based on PubMed, Web of Science and Scopus. Two independent researchers performed the search in February 2023. The search terms were “dental caries” AND “rheumatoid arthritis”. Additionally, a manual search completed the review process. Studies on adult patients (age ≥ 18 years) only suffering from RA were included. Studies had to explicitly report on the prevalence or incidence of dental caries. The respective studies were checked regarding suitability and, if they were eligible, analyzed qualitatively. A quality appraisal was performed for all of the analyzed studies. A total of 336 studies were detected, of which 16 studies met the in- and exclusion criteria. The sample sizes of the clinical investigations ranged between 13 and 1337 participants. Twelve studies evaluated a healthy control group. In 8/12 studies, a significant difference in the prevalence/incidence of caries was found between RA patients and controls. The majority of the studies applied the decayed (DT), missing and filled teeth index (DMFT) for the diagnosis of caries. On average (mean value), 0.8 to 5.79 carious teeth per patient were reported across the studies. There was no information on the stadium, activity or location of caries (e.g., root caries) in any study. Quality appraisal revealed a moderate quality for most studies. In conclusion, caries prevalence was heterogeneous across studies, while a higher caries prevalence was repeatedly reported in RA patients against controls. Further research regarding dental caries in RA appears recommendable; multidisciplinary, patient-centered dental care for patients with RA should be fostered to improve patients’ dental health status.


Introduction
Globally, dental caries is highly prevalent and, therefore, one of the most frequently occurring chronic diseases [1,2], potentially affecting people in any age group. From childhood to retirement age, caries develops in different areas of the teeth. Children and (young) adults often develop caries at the crowns of teeth, while elderly individuals are concerned by root caries lesions [3]. Caries can present itself as anything from a small white spot to a deep cavity in the tooth surface, potentially leading to tooth decay, pain, acute exacerbation and tooth loss [3]. Its progression lasts several years and needs the accumulation of biofilm on teeth. Furthermore, there is a complex interaction between potentially cariogenic bacteria and fermentable carbohydrates, as well as various host factors including the quantity and quality of saliva [4]. A wide range of risk factors is known for the development of caries lesions. These include oral hygiene and carbohydrate intake, but several systemic diseases and associated symptoms can also be related to caries development and progression [5].
In this context, dry mouth/xerostomia, in particular, is an important factor influencing the occurrence of dental caries [6]. For example, it is generally known that especially patients with rheumatoid arthritis suffer from xerostomia [7]. Rheumatoid arthritis (RA) is comparably frequent among rheumatic diseases and clinically relevant with a global prevalence of 0.5-1% [8][9][10]. It is already known that patients with RA have a higher risk for developing infections [11]. Therefore, untreated dental diseases can be risk factors for systemic infections, where RA patients are particularly at risk due to their immunosuppressive medication [12]. Some studies in the existing literature show an association between dental caries and RA [13,14]. Moreover, patients with RA often suffer from more severe periodontitis [15]. The exposition of root surfaces caused by periodontal recession might, therefore, be an additional risk factor for the manifestation of caries in those individuals.
The evidence accumulated in this area of research in recent years shows some heterogeneity. Similarly, it remains unclear whether patients with RA suffer from root caries or specific lesions. Additionally, the assessment of caries or its diagnostic in the different studies appears different. Hence, the current systematic review aimed to evaluate the prevalence and/or incidence of dental caries in adults with RA. In the course of this, characteristics and results of the available studies were evaluated. Furthermore, a comparison of the caries prevalence between patients with RA and healthy control individuals was considered, if available. Moreover, an appraisal of the quality of the included studies was applied. It was hypothesized that patients with rheumatoid arthritis show a higher caries prevalence and/or incidence than healthy (non-RA) individuals.

Methods
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16].

Central Issue of the Systematic Review
The PICO question of this review (patients, intervention, comparison, and outcome) was if adults with RA have a higher prevalence and/or incidence of caries than healthy individuals. For this, patients were only adults with diagnosed RA. There was no assessment of an intervention. If applicable, a healthy (non-RA) control group was used for comparison. In the end, the respective caries assessments were recorded as outcomes. It was hypothesized that adults with RA would present a higher caries prevalence and/or incidence than healthy individuals.

Eligibility Criteria
As inclusion criteria for the current systematic review, the exclusive examination of adult patients (age >18 years) suffering from RA was formulated. Therefore, the RA diagnosis was required to have been confirmed by a specialized physician, considering the respective diagnosis criteria. If data of population-based cohort studies or registers were reported, it was assumed that a qualified specialist had checked and approved the RA diagnoses in those patients. Another mandatory criterion was the clinical assessment of dental caries (prevalence or incidence), e.g., decayed teeth (DT) or decayed-missingfilled-teeth index (DMFT). An experienced examiner was required to have made the caries diagnosis. Studies without an English full text were excluded from the analysis. Further inand exclusion criteria did not exist.

Search Strategy
Two independent individuals performed the literature search based on the databases of PubMed, Web of Science and Scopus in February 2023. The search terms used were "dental caries" AND "rheumatoid arthritis". A manual search completed the process, whereby citations of the included articles were checked based on their respective reference lists. Grey literature was not explicitly searched within the systematic review process. After the systematic search, the studies were verified for their eligibility.

Data Extraction
From the included studies, several pieces of information were extracted during the review process: • Two independent reviewers conducted the systematic search, study selection and qualitative analysis. If any disputes occurred during the process, they were discussed with the senior author first and afterwards, if necessary, discussed and resolved among all the authors.

Quality Appraisal
A checklist, containing 11 items to evaluate the quality of included studies, i.e., the list for cross-sectional investigations by the Agency for Healthcare Research and Quality (AHRQ) [17], was used in this systematic review. "No" and "unclear" answers were scored 0 points and "yes" answers were scored 1 point for each question to determine a total score for the assessment. Sum scores of 0-3 indicated low quality, and 4-7 points implied moderate quality, while 8-11 points indicated high quality of the respective study. The appraisal was conducted independently by the first authors (D.K. and B.E.) and the senior author (G.S.). Disagreements were discussed and resolved among the authors.

Systematic Search Results
According to the PRISMA statement [16], Figure 1 illustrates the search findings. The systematic search, supplemented by the manual search, identified 336 studies. Due to duplication, 50 studies were excluded, and another 224 studies were excluded during the subsequent screening. A total of 198 studies were off-topic, and in 26 cases, the studies were systematic reviews. After screening the records, 62 full texts were assessed for eligibility. A total of 46 of these studies were excluded, whereby 10 studies were also found to be off-topic, and in 26 studies, the participants were under 18 years of age. Moreover, in nine cases there was no English full text available. In total, 16 studies were included in the qualitative analysis ( Figure 1).

Study Characteristics
The included studies were performed in 11 different countries. The sample sizes of the clinical investigations ranged between 13 and 1337 RA participants. Twelve studies examined a healthy control group for comparison. The study type, as well as the mean age, sex and disease duration of the participants, is shown in Table 1.

Study Characteristics
The included studies were performed in 11 different countries. The sample sizes of the clinical investigations ranged between 13 and 1337 RA participants. Twelve studies examined a healthy control group for comparison. The study type, as well as the mean age, sex and disease duration of the participants, is shown in Table 1.

Quality Assessment
Quality appraisal according to AHRQ criteria showed that the majority of the included studies were evaluated as being of moderate quality (Table 4).

Discussion
A total of 16 studies from 12 different countries were qualitatively analyzed in the current review. These studies had a range in sample size between 13 and 1337 RA participants, indicating a heterogeneity across the investigations. A total of 12 of those 16 studies had a control group, and 8/12 showed a significant difference in caries prevalence between the RA patients and the control group. The majority of the studies investigated the presence of caries with DMFT or DT. In several studies, the caries prevalence was indicated by the investigators, and in one study, caries was detected only with a panoramic dental x-ray.
The hypothesis was formed that patients with RA would present a higher caries prevalence and/or incidence compared to healthy controls. After evaluation of the 16 studies, it was shown that the hypothesis can be confirmed because of the seven studies which demonstrated a significantly increased caries prevalence in RA patients. Only one study showed the opposite. Actually, a higher caries prevalence was displayed in the healthy control group [30]. However, it must be highlighted that there were several studies comparing RA and control patients which had a low sample size, and, therefore, their statistical power remains questionable (see Table 3). Mostly, the included studies appropriated the DMFT-index for clinical examinations. This index is regularly and repeatedly used in clinical studies for swift dental check-ups. Therefore, DT is applied to document carious lesions with cavitation of the tooth surfaces [31]. The disadvantage of this index is that early lesions (white spots or brown spots) are not recorded. Furthermore, the location and extent, or even the activity, of carious lesions are not taken into account. Similarly, as for RA patients, the literature shows that individuals with different rheumatic diseases suffer from a high oral disease burden, leading to an increased need of attention in dental practice and preventive measures [32]. Children and adolescents with juvenile idiopathic arthritis were found to suffer from different oral complaints, although an increased caries prevalence was not confirmed within a multilevel analysis [33]. Rheumatically diseased patients with oral symptoms, especially reduced salivary flow such as in Sjogren syndrome, have a high caries burden [34]. Additionally, patients with diffuse cutaneous systemic sclerosis show an increased caries prevalence, which is correlated with disease characteristics [35]. Overall, patients with rheumatic disease appear to show a high caries burden, although this differs between the various entities. In this context, a high caries prevalence in individuals with RA seems plausible.
One explanation for the increased incidence and prevalence of caries in patients with RA appears to be physical dysfunction and associated problems with oral hygiene. A study from 1992 already showed that patients with RA suffered from reduced physical function in their arms and hands. Participants of this study reported that hand problems would affect oral hygiene [19]. However, no correlation was found between physical dysfunctions and tooth loss by the investigators [19]. Another study from the working group of Mehdipour confirmed those findings and, additionally, mentioned that reasons for higher DMFT could be decreased salivary flow, increased salivary acidity, emergence of microorganisms and generalized osteoarthritis, specifically in the fingers and arms [14]. The study by Äyräväinen et al. in 2018 compared patients with early untreated RA (EURA) and patients with chronic RA (CRA), as well as a healthy control group [13]. The investigators showed that the oral health of RA patients was worse compared with the control group, and caries indices were associated with the activity of RA. Patients with a higher activity of RA showed increasing caries scores (DMFT, DT) [13]. This was the only study which carried out an intervention and a follow-up. The group of Äyräväinen also showed that EURA patients brushed their teeth less often than chronic RA patients did at the baseline, while after 16 months a significant improvement in the oral hygiene of the EURA patients was determined [13]. Furthermore, the activity of DAS-28 increased with higher caries indices, which might indicate an association between disease activity and caries [13]. Accordingly, the relationship between dental caries and RA-related parameters could be of certain interest. An Iranian study which was included in the current systematic review showed that caries was in an inverse relationship with the rheumatoid factor (RF) [23]. Taken together, disease severity, activity and disease-related disability might be one plausible explanation for the increased caries burden on individuals with RA.
Another potential issue is the saliva of patients with RA. The study of Risheim et al. investigated salivary flow and oral sugar clearance in patients suffering from RA and dry mouth. The study group demonstrated that rheumatic patients presented a decreased salivary flow (median unstimulated: 0.09 mL/min and stimulated: 0.9 mL/min). On the other hand, those patients with a long oral sugar clearance revealed more root caries lesions, lower resting salivary flow and higher salivary counts of mutans streptococci [36]. Furthermore, patients with RA have repeatedly shown xerostomia [7], which is an important risk factor for caries, as it reduces the potential of remineralization [6]. Additionally, a case-control study investigated salivary immunoglobulin A in RA patients and controls without finding a statistical significance between those two groups [37]. Altogether, the quantity and quality of saliva appears to affect caries in individuals with RA. However, only a minority of the studies which were included in this systematic review performed salivary analyses [13,18,26,29].
Another issue of potential relevance is the patient's perspective; therefore, the oral health-related quality of life (OHRQoL) could play a potential role. A recent systematic review found a reduced OHRQoL in RA patients; however, this was often caused by disease-related and psychosocial factors [38]. In this context, it has been explained that chronically diseased patients can undergo a kind of response shift, while the perception of the burden of their general disease is so high that other issues, such as oral hygiene and oral health, might be upstaged [39]. Accordingly, a neglect of oral health behavior by individuals with RA could be an additional explanation for their increased caries prevalence.
Generally, it must be stated that several issues require consideration with regard to the included studies. The vast majority used DMFT, which is well-established for clinical studies [31]. However, this index does not include any information on the caries localization (crown or root) or the caries stadium (initial lesion, large lesion affecting the pulp chamber, etc.). As described previously in a systematic review on dental caries in patients with renal replacement therapy, improved caries diagnostics should be applied in such cohorts of at-risk patients, for example, by using extended clinical or adjunctive diagnostics [40]. Additionally, the heterogeneity and quality of the studies, which was moderate in most cases, underline the need for improvements in the research on dental caries in RA patients.
As a further issue, it is well-documented that RA is in a bidirectional relationship with periodontitis [15,41,42]. Therefore, host factors (the immune system) and bacteria were documented to link both diseases; the potential periodontal pathogen Porphyromonas gingivalis was especially found to increase RA-related inflammation, especially via citrullination of proteins [43]. Similarly, Aggregatibacter actinomycetemcomitans, another potential periodontal pathogenic bacterium, can be involved in the interplay between periodontitis and RA [44]. Additionally, RA can lead to changes in the jawbone and temporomandibular joint [45]. All of these issues could also affect caries development and progression. In this context, common acquired risk factors exist between caries and periodontitis, which might support the increased caries risk in patients with RA [46].
The strengths and limitations of this study are as follows. The current systematic review followed the PRISMA guidelines, while a clear PICO question was also formulated. Two independent reviewers performed the systematic search and the quality appraisal. Nevertheless, there are certain limitations, which are discussed in the following sentences. Studies from a variety of countries with various patient populations were reviewed. Therefore, dental examinations were performed under different conditions. No separate new examination took place when the results from national health studies were used. Hence, this limits the generalizability of the data. Besides this limitation, studies with and without a healthy control group were included. While for a definitive confirmation of the hypothesis of this review, a control group would be needed, it was decided to include studies without a control group to increase the number of included studies and, thus, the ability to draw conclusions. This was performed similarly to previous studies [40,47]. Most studies showed a moderate quality (Table 4). It should be mentioned that none of the studies except one conducted an intervention or follow-up. Only half of the studies included laboratory values or saliva examinations in their investigations. Considering the lack of differentiated caries diagnostics or any RA-related parameters, the available evidence remains limited. Therefore, in summary, there is a lack of homogeneity regarding the study designs, methods and populations. Additionally, a couple of studies examined a small sample. Furthermore, there is a lack of explanation for bias across the studies. Therefore, further well-performed clinical studies appear to be needed in the field to strengthen the body of evidence. The missing registration of this systematic review must be seen as another limitation.

Conclusions
In patients with RA, caries prevalence was heterogeneous across the studies, while an increased caries prevalence in RA patients against controls was repeatedly reported, indicating a higher prevalence of dental caries in individuals with RA. Different reasons appear probable, including salivary flow and composition, disease activity and physical disability. There still appears to be a lack of evidence and heterogeneity of the literature. Nevertheless, multi-disciplinary dental care of RA patients needs to be fostered to improve their oral situation.
Author Contributions: D.K. and B.L.V.E. performed the data curation and analysis and wrote the manuscript. T.E., R.H. and D.Z. participated in data interpretation and revised the manuscript. G.S. was the head of the study; participated in data curation, analysis and interpretation; and revised the manuscript. All authors have read and agreed to the published version of the manuscript. Data Availability Statement: All data generated or analyzed during this study are included in this published article.

Acknowledgments:
The authors acknowledge support from Leipzig University for Open Access Publishing.

Conflicts of Interest:
The authors declare no conflict of interest.