Periodontitis is a microbially-associated, host-mediated hyperinflammatory condition that leads to the destruction of structures supporting the teeth, including the alveolar bone, periodontal ligament, and cementum (1–3). If not addressed, periodontitis can lead to early tooth loss, affecting one’s ability to chew, self-confidence, and overall well-being (4–6). Furthermore, periodontitis has been linked to broader health implications, contributing to conditions such as cardiovascular disease, type 2 diabetes mellitus, and adverse outcomes in pregnancy (7). The global prevalence of periodontitis is 20-50%, and together with gingivitis, its precursor, they collectively constitute the 11^th most prevalent condition worldwide (8). Its impact is substantial, accounting for 3.5 million years of disability and causing an estimated productivity loss of around USD$54 billion annually (4). Recent studies have also shown significant associations between rheumatoid arthritis (RA) and, to a smaller degree, systemic lupus erythematosus (SLE), with periodontitis (9–11). However, these associations remain underappreciated and warrant further investigations (12).

Rheumatoid arthritis is a chronic autoimmune disease that has both joint-specific and systemic manifestations (13). Its global prevalence, as estimated by the Global Burden of Disease 2010 Study, stands at approximately 0.24% (14, 15). SLE is a potentially fatal, chronic autoimmune disease that affects multiple systems. It primarily affects women, with the highest incidence during childbearing years (16). The global prevalence of SLE has been on the rise over the years, escalating from 40 cases per 100,000 individuals in the 1970s to 100 cases per 100,000 individuals since the 2000s (17).

The exact aetiopathogenesis of RA and SLE is complex, with multiple genetic, epigenetic, immunological, and environmental factors involved. These factors often culminate in immune dysregulation and autoantibody production (18–20). Moreover, evidence suggests that infections may contribute to the development of these diseases through mechanisms such as molecular mimicry and uncontrolled immune cell activation (21). The relationship between RA and periodontitis is better established than that between SLE and periodontitis, partly due to the process of citrullination. Citrullination involves the modification of arginine residues to citrulline by peptidyl arginine deiminases. Porphyromonas gingivalis, a key organism in periodontitis, is the sole prokaryotic organism that secretes Porphyromonas gingivalis-derived peptidyl arginine deiminase (PPAD) (11, 22). Prolonged exposure to citrullinated proteins in the oral cavity may trigger the production of anti-cyclic citrullinated peptide (CCP) antibodies, potentially leading to the onset of RA in susceptible individuals (23). The associations between (i) periodontitis and anti-CCP seropositivity and (ii) periodontitis severity and presence of anti-CCP antibodies in patients with RA provide further support for this hypothesis (24, 25). In addition, disease-modifying antirheumatic drugs ameliorate both RA and periodontitis, suggesting shared inflammatory pathways (26). In contrast, while a connection between SLE and periodontitis is emerging, it is still in the early stages of recognition, and the relationship has not been confirmed (10, 27, 28). Despite the high prevalence of Porphyromonas gingivalis, this pathogen appears to have minimal involvement in the onset of periodontitis in SLE patients. Additionally, anti-CCP antibodies are infrequently detected in individuals with SLE (29, 30). Nonetheless, both RA and SLE may overlap, causing a syndrome termed “rhupus” whereby features of both diseases appear in the same patient (31). Furthermore, a positive association between anti-CCP antibodies and erosive arthritis has been reported in rhupus (31). Consequently, while periodontitis might contribute to the onset of RA, a similar association may ostensibly also occur for SLE.

Considering the overlap between RA and SLE, the magnitude of the burden of periodontitis in SLE compared to RA patients has not been explored. Therefore, the aim of this meta-analysis and network meta-analysis (NMA) is to compare: (i) the prevalence of periodontitis in SLE patients compared to versus those with RA and (ii) the odds of developing periodontitis in controls, RA, and SLE to evaluate the magnitude of this comorbidity in SLE.

To the best of our knowledge, this meta-analysis and NMA represent the first attempt to compare the prevalence and odds of periodontitis in SLE compared to RA. The principal findings of our meta-analysis and NMA include: (i) the prevalence of periodontitis in patients with SLE was comparable to that of RA, afflicting more than 60% of both patient groups; (ii) both RA and SLE patients exhibited higher odds of having periodontitis compared to controls and (iii) SLE patients were more likely to have periodontitis (1.49-fold higher odds) compared to RA. Similar to previously conducted meta-analyses on periodontitis in patients with RA and SLE, our study showed significantly increased odds of periodontitis in both patient groups compared to controls (9, 10, 46, 76). RA is the most widely recognised rheumatic disease associated with periodontitis, partly because of the key role of citrullination induced by Porphyromonas gingivalis and the induction of anti-CCP antibodies that are specific for this disease (22). As a result, the association between RA and periodontitis, as well as dental care considerations specific to RA, have been extensively studied (46, 76, 77). However, the association between SLE and periodontitis is not well recognised by the dental and rheumatology communities (S.H.T., personal communication). Although our study established that there was no statistically significant difference in the prevalence of periodontitis between SLE and RA, it demonstrated that SLE patients have an increased odds of developing periodontitis. Therefore, awareness of the association between SLE and periodontitis is warranted.

The difference in awareness between the associations of periodontitis with RA and SLE may stem from variations in our understanding of their immunopathogenesis. Following the discovery that Porphyromonas gingivalis secretes PPAD (22), it was hypothesized that periodontitis may accelerate the process of citrullination within the mouth and lead to increased exposure to citrullinated proteins. Consequently, anti-CCP antibodies are produced, which have been linked to more severe RA and joint destruction (78). Additionally, smoking is known to increase the formation of citrullinated proteins, potentially leading to autoimmunity and the development of RA in susceptible individuals (78). These lines of evidence provided a clear link between periodontitis and RA. While most observational studies do not fully establish this relationship, the axiomatic understanding that periodontitis and RA share a causal relationship may have provided greater awareness of this association. On the other hand, while the possibility of a bidirectional association between periodontitis and SLE has been proposed, the evidence supporting it remains relatively weak (79). Several lines of preclinical evidence explanation have supported the association between periodontitis and SLE. First, increased expression of Toll-like receptors 2 and 4, which are involved in innate immune responses, has been observed in both periodontal disease and SLE (80). Second, the innate immune dysregulation in SLE patients with overactive phagocytic cells leads to elevated production of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18, which are implicated in the pathogenesis of periodontitis (81, 82). Third, in patients with periodontitis, B lymphocytes and plasma cells are increased in the periodontal tissues. These cells are also the adaptive immune cells implicated in the immunopathogenesis of SLE (82, 83). Fourth, periodontal bacteria may stimulate antiphospholipid antibody production through the process of molecular mimicry between bacterial peptides and β2-glycoprotein I (41). Fifth, a recent Mendelian randomization analysis indicated that periodontitis is associated with a weak causal association with SLE (84). Lastly, immunosuppression using corticosteroids and steroid sparers leads to a reduction in host immunity and consequently repeated oral infections (85, 86).

The most common oral manifestation observed in SLE is painless ulcers typically found in the lip and buccal mucosa (87). While oral manifestations of SLE have been estimated to vary from 9-45% (87), owing to the lack of awareness that periodontitis may be associated with SLE, its suspicion may not be entertained, resulting in delayed diagnosis and intervention (88). Consequently, this delay contributes to poorer dental outcomes, tooth loss, and diminished quality of life among SLE patients (4–6). Despite the burden of periodontitis in SLE, there is a dearth of literature on the awareness of medical professionals on this comorbidity. In contrast, the level of awareness regarding the relationship between periodontitis and RA has been documented in medical literature. Afilal et al. conducted a cross-sectional survey revealing that only 6% of rheumatologists routinely examined the oral cavity, while 11% acknowledged the negative impact of poor oral hygiene on RA, and 10% recommended dental consultation for RA patients (89). Similarly, Nazir et al. found that 36.2% of dentists were aware of the association between periodontal disease and rheumatoid arthritis (90). There is a pressing need for studies to explore the level of awareness regarding the association between SLE and periodontitis within the rheumatology and dental communities.

Numerous studies have demonstrated an association between disease activity in RA/SLE and the severity of periodontitis. RA patients with periodontitis categorized as level 0 or 1 exhibited significantly lower mean DAS28-CRP compared to those with level 2 periodontitis (62). Similarly, SLE patients with higher SLEDAI scores were shown to have more severe periodontal disease (91, 92). Furthermore, a randomised controlled trial by Fabbri et al. found that treatment for periodontitis led to a notable reduction in SLEDAI scores (93). Within 3 months of treatment initiation, a notable decrease in both SLE disease activity and periodontal disease parameters was observed. In contrast, the group without treatment had persistent SLE disease activity and half of the periodontal disease parameters unchanged from baseline (93). Hence, these findings underscore the importance of raising awareness among clinicians about the association between SLE and periodontitis, as managing this modifiable comorbidity might help to modulate SLE disease activity.

The similar prevalence but increased odds of periodontitis for SLE compared to RA in our analysis deserves discussion. One possible explanation is that SLE patients included in the NMA had relatively higher disease activity compared to RA and therefore had more cases of periodontitis as a result of the bidirectional association (79). In addition, the lower pooled prevalences of periodontitis in the controls of SLE (45.0%, 95% CI 33.0-57.0%) compared to RA (52.0%, 95% CI 41.0-64.0%) ( Supplementary Figure 1 ) would have contributed to an increased odds of periodontitis for SLE compared to RA.

Rheumatoid arthritis and SLE share several risk-associated loci (e.g., HLA-DRB1, BLK, UBE2L3, PTPN22, STAT4, TNFAIP3, FCGR2A, PRDM1, IRF5, PXK and COG6) and are characterized by the presence of autoantibodies that recognize self-antigens (15, 16, 31, 94). Environmental triggers such as tobacco smoking have also been described in both diseases, although the prevalence of smoking in both RA and SLE is not well described in epidemiological studies (15, 16). Both diseases, however, differ in many aspects such as immunopathogenesis whereby type I interferons in response to viral factors and tumor necrosis factor in relation to microbiota are operational in SLE and RA, respectively (15, 16). Specific class II major histocompatibility molecules contain the shared epitope, a specific amino acid motif associated with the risk of developing RA (15). This epitope facilitates the presentation of arthritogenic peptides to CD4⁺ T cells, particularly those containing citrulline, thereby promoting the development of anti-CCP antibodies (31). The interaction between the shared epitope and smoking has been extensively studied and its interplay with Porphyromonas gingivalis in arthritis-prone B6.DR1 mice leading to increased anti-CCP production makes periodontitis an even more compelling risk factor for RA (95). RA is considered a continuum that begins with a high-risk or susceptibility state influenced by genetic factors and progresses through preclinical, early, and established disease, where environmental factors contribute to the inflammatory and destructive synovial response (15). Preclinical and early RA are different from rhupus, a disease with features that overlap between RA and SLE (31). The progression of arthritis in rhupus mirrors a pattern similar to RA, potentially advancing to typical inflammatory erosions. However, the SLE-related aspects in rhupus tend to be milder, primarily manifesting as hematological and mucocutaneous involvement. (31).

This study has several limitations that should be considered. First, a high heterogeneity was observed. However, in this analysis, heterogeneity was estimated from the I² statistic and it is common for proportional meta-analyses to have a high I², possibly because of the nature of the proportional data (96). The high heterogeneity could also be attributed to variability in the case definition and classification of periodontitis (1, 97). Consistent case definition and classification of periodontitis would contribute to reduced heterogeneity. Of note, prevalence of periodontitis decreased in RA patients after the 2017 World Workshop Classification of Periodontal and Peri-implant Diseases and Conditions was published ( Table 2 ), which may reflect reduced heterogeneity in the ascertainment of this odontogenic infection (1). The other possibility is the improvement of RA treatment over time resulting in decreased periodontitis due to a bidirectional effect. Diagnostic criteria for RA and SLE have not been endorsed by major rheumatology societies and only classification criteria have been developed to recruit homogenous populations for research (15, 16). These classification criteria are not intended for use in clinical practice as the basis for establishing the diagnoses of RA and SLE. As such, some RA and SLE patients in the studies that did not specify the classification criteria used were diagnosed clinically. In addition, specific endotypes of RA (e.g., seropositive and seronegative) and SLE (e.g., organ-dominant, lupus with antiphospholipid syndrome and Sjögren’s syndrome) were not reported in the studies (98, 99). Hence, transparent reporting of the classification criteria used for classification and any underlying endotypes would have facilitated a more accurate interpretation of our results. Second, evidence of publication bias was detected, suggesting an overestimation of prevalence in our meta-analysis due to potential unpublished studies. Third, due to the many different scoring systems used for disease activity and the limited number of studies, we were unable to perform a meta-regression to explore the relationship between rheumatological disease activity and the prevalence of periodontitis. Fourth, smoking and the use of immunosuppressants may be confounding factors that could contribute to the development of periodontitis. However, these confounding factors were not assessed in many of the included studies and should be analyzed in detail for future work. Lastly, most of the included studies were cross-sectional in design, limiting their ability to establish a causal relationship between periodontitis and SLE. Future well-designed longitudinal, case-control or cohort studies are needed to explore this relationship and determine if temporal and causal links exist between these two conditions (100). By addressing these limitations, future researchers can help to advance the understanding between periodontitis and rheumatic diseases by improving the quality of the research in this field.

This meta-analysis and NMA established that SLE patients have a significantly higher likelihood of experiencing periodontitis (1.49-fold higher odds) compared to RA, although no significant difference in the prevalence of periodontitis was found between RA and SLE. Considering that RA is traditionally linked with periodontal disease, the elevated odds of periodontitis in SLE are striking. Irrespective of the highlighted limitations, especially that of variations in periodontitis assessment criteria among the studies, these results underscore the importance of addressing the dental health needs of SLE patients. Future research should explore the extent of awareness regarding the association between SLE and periodontitis within the dental and rheumatology communities. Enhancing awareness among healthcare providers and enhancing educational efforts in both disciplines will be crucial in alleviating the considerable disease burden of periodontitis in SLE. Further clinical and translational research is warranted to advance the understanding of periodontitis and its broad impact on SLE immunopathogenesis and disease activity.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

PT: Writing – original draft, Writing – review & editing, Data curation, Formal analysis, Visualization. AL: Data curation, Formal analysis, Visualization, Writing – original draft, Writing – review & editing. JZ: Formal analysis, Methodology, Writing – original draft, Writing – review & editing. YC: Methodology, Writing – original draft, Writing – review & editing. JF: Conceptualization, Writing – original draft, Writing – review & editing. MM: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. ST: Conceptualization, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing.