Periodontopathic bacteria in rheumatoid arthritis pathogenesis: bridging clinical associations to molecular mechanisms

Abstract

Periodontitis (PD) is a chronic inflammatory disease linked to microbial dysbiosis, while rheumatoid arthritis (RA) is an autoimmune disorder characterized by anti-citrullinated protein antibodies (ACPA). Despite their distinct etiologies, a clinical and serological association between PD and RA has been observed. Oral microorganisms, especially Porphyromonas gingivalis (P. gingivalis), may contribute to RA onset or progression through dissemination to joints or systemic inflammation. This review explores a: the role of oral microbiota and immune responses in RA b; clinical pathogenic pathways from oral pathogens to the joints c; mechanistic studies on the impact of periodontal pathogens on RA; and d. preventive and therapeutic strategies. P. gingivalis and other periodontal pathogens have been detected in synovial tissues and fluids of RA patients. Microbiome analyses show a more diverse oral microbiota with elevated periodontal disease-associated bacteria in RA patients. Studies demonstrate that P. gingivalis can induce citrullination, autoantibody production, and inflammation, exacerbating joint damage. Future research should investigate the impact of periodontal therapy and RA treatments on the oral microbiota, while large-scale clinical trials are needed to validate the causal relationship between periodontal pathogens and RA.

1 Introduction

Rheumatoid arthritis (RA) has attracted widespread attention due to its substantial impact on human health and the considerable socioeconomic burden it imposes. It is commonly associated with progressive disability, premature mortality, and elevated healthcare and societal costs. The global prevalence of RA varies substantially, ranging from 0.25% to 1% (1), and is projected to continue rising through 2040. This trend poses a significant challenge to global public health (2). RA primarily affects individuals over the age of 40. The prevalence is particularly higher in women, who are two to three times more likely to be affected than men (3). RA is a systemic autoimmune inflammatory disease that primarily affects the joints. The pathological hallmark of RA is persistent synovitis, which leads to joint pain, cartilage degradation, joint deformity, and functional impairment. In advanced stages, RA can result in severe disability (4).

1.1 Risk factors for rheumatoid arthritis

The development of RA is influenced by both genetic and environmental risk factors (Figure 1). Genetic predisposition is estimated to account for approximately 60 percent of RA risk (5, 6). First-degree relatives of RA patients have a two- to fivefold higher risk compared to the general population. The genetic susceptibility to RA is strongly associated with specific human leukocyte antigen (HLA) haplotypes, particularly the presence of the shared epitope (SE), a five–amino acid motif encoded by certain HLA-DRB1 alleles (7). Compelling evidence supports HLA-DRB1 as the primary genetic determinant in anti-citrullinated protein antibodies(ACPA)-positive RA (8). Genome-wide association studies (GWAS) have further revealed the contribution of non-HLA genes to RA pathogenesis. The genetic risk of seropositive RA, defined by the presence of ACPA and/or rheumatoid factor, is primarily linked to signaling networks involving interferon alpha/beta and interleukin-12/23. Variants in genes within the JAK-STAT pathway, including STAT4, TYK2, and FLT3, have shown significant associations with disease susceptibility (9). Individuals who are ACPA-positive have a substantially increased risk of progressing to classified RA and are considered to be in an at-risk state (10), which is marked by immune dysregulation. Epigenetic studies have revealed nonspecific regulatory abnormalities in peripheral B cells, as well as in naïve and memory T cells of ACPA-positive individuals. Studies of antigen-specific T cells have identified a higher frequency of CD4⁺ T cells that recognize citrullinated epitopes, especially citrullinated cartilage intermediate layer protein I (cit-CILP), in at-risk individuals. These T cells tend to exhibit pro-inflammatory phenotypes, such as T helper cell (Th) 1, Th17, and stem-like memory characteristics. Additionally, antibody–antigen microarray analysis has detected increased levels of autoantibodies against citrullinated clusterin, fibrinogen, and histone H4 in both at-risk individuals and patients with early RA, with the highest levels found in the latter (10). These findings suggest that widespread early epigenetic alterations may disrupt immune tolerance and lead to the activation of cit-CILP–specific T cells, which in turn support B cell responses and drive the production of autoantibodies against a broader array of citrullinated antigens. This multifaceted immune imbalance promotes the progression from asymptomatic autoimmunity to clinically evident arthritis.

Figure 1

An increasing number of environmental factors have been identified as contributing to the risk of developing RA. Among them, cigarette smoking is currently recognized as the most strongly associated environmental risk factor for seropositive RA, with a clear dose-dependent effect (11). Compared to non-smokers, RA patients who carry SE alleles and smoke exhibit elevated ACPA production by peripheral B cells (12). Further studies indicate that smoking and HLA-SE contribute at distinct stages of RA development. Smoking promotes the generation of ACPA and the onset of symptoms, while HLA-SE primarily facilitates the emergence of clinical manifestations and progression to classified RA (13). The role of the microbiome in RA has also garnered growing interest, and the involvement of oral and gut microbial communities is now well recognized. Studies suggest that mucosal exposure and/or dysbiosis in patients with early RA (diagnosed within one year) or long-standing active disease may play a causal role in the at-risk phase of RA progression (14). Periodontal dysbiosis may induce local inflammation, disrupt mucosal barriers, and allow microbial components to translocate into the bloodstream. Certain bacterial elements may also mimic host autoantigens at the molecular level, potentially triggering joint-specific immune responses (15). Overweight and obesity, defined as a body mass index (BMI) of ≥25 kg/m² and ≥30 kg/m², respectively, have also been linked to increased RA risk (16). Studies have shown that individuals with a BMI ≥25 kg/m² and ≥30 kg/m² experience a 15% and 21–31% greater risk of developing RA, respectively (17). This association may be mediated by the pro-inflammatory activity of white adipose tissue and its immunomodulatory effects (18). Nevertheless, the role of obesity in RA onset remains controversial. Other potential environmental risk factors, such as dietary habits and estrogen levels, have been proposed but require further investigation to confirm their relevance (1). Overall, most known environmental contributors to RA point toward the involvement of chronic mucosal inflammation in disease initiation, although additional research is required to clarify the underlying mechanisms (1).

1.2 The pivotal role of citrullination in RA pathogenesis

The pathogenesis of RA is complex. Immune dysregulation may begin years before the appearance of joint symptoms, a period commonly referred to as the preclinical phase of RA (19). The formation and recognition of citrullinated self-antigens span the entire course of the disease, from the subclinical phase to the clinical manifestation (20). This process is primarily attributed to the loss of immune tolerance, resulting in aberrant immune responses against citrullinated self-antigens (21). Citrullination is a key post-translational modification in which arginine residues in specific self-antigens, such as immunoglobulin G (IgG), type II collagen, and vimentin, are converted into citrulline by peptidyl arginine deiminases (PADs) (22). Among the five calcium-dependent PAD isoenzymes in humans (23), PAD2 and PAD4 are most strongly associated with RA. These enzymes are highly expressed in synovial tissue, synovial fluid, and infiltrating mononuclear cells, with expression levels positively correlated with the severity of inflammation (24, 25). Citrullinated proteins have also been abundantly detected in synovial fluid, where they serve as key targets for local immune responses (26–28). Citrullination exposes cryptic epitopes that are normally hidden from immune surveillance, leading to their misrecognition as non-self antigens. This is achieved by altering protease cleavage sites and destabilizing protein structures, which unmasks peptides derived from native sequences (29). In the presence of susceptibility alleles such as HLA-DR1 and HLA-DR4, the positively charged P4 pocket of the SE binding groove selectively binds citrullinated peptides through electrostatic complementarity. These complexes are misrecognized as foreign, triggering downstream immune cascades (30). Citrullinated antigens are taken up by antigen-presenting cells, which initiate dendritic cell-mediated responses and activate both T and B cells in a process known as costimulation. B cells undergo somatic hypermutation and class-switch recombination, eventually differentiating into plasma cells that produce specific autoantibodies against citrullinated epitopes, known as ACPAs (31). ACPAs can be detected in the bloodstream approximately four to five years before the clinical onset of arthritis. As genetic and environmental risk factors interact, ACPA levels increase, the range of recognized protein epitopes expands, and circulating pro-inflammatory proteins rise (20). These changes collectively contribute to the breakdown of immune tolerance and the eventual transition to clinically evident arthritis, whether classified or undifferentiated (29).

Increasing evidence supports the mucosal origin hypothesis in the pathogenesis of RA, suggesting that autoimmune processes may begin at extra-articular mucosal sites—such as the lungs, oral cavity, and gut—where local immunological changes lead to both local and systemic autoantibody production (14). Among these sites, the oral mucosa, particularly in the setting of PD, has garnered significant attention. A meta-analysis demonstrated that individuals with PD lasting more than five years are significantly more likely to develop RA, with a 69% higher risk than healthy controls (32). Citrullination may initiate autoimmune responses at periodontal sites before the clinical onset of RA (33, 34). PAD2, PAD4, and ACPAs have been detected in inflamed gingival tissues and gingival crevicular fluid in individuals with PD (35). ACPAs targeting citrullinated peptides are among the most extensively studied autoantibodies in RA. Their targets include intracellular proteins such as α-enolase and vimentin, as well as extracellular citrullinated proteins such as fibrinogen, type II collagen, and fibronectin (36, 37). These antigen–antibody complexes accumulate in synovial fluid and contribute to RA pathogenesis (38). Porphyromonas gingivalis (P. gingivalis), a key periodontal pathogen, produces peptidyl arginine deiminase (PPAD), an enzyme that citrullinates arginine residues in host periodontal proteins and its own bacterial proteins. Arginine-specific gingipains (Rgps), another major virulence factor of P. gingivalis, cleaves fibrinogen and α-enolase to generate C-terminal arginine-containing peptides, which serve as preferred substrates for PPAD (39, 40). Co-incubation of these proteins with PPAD and RgpB has confirmed the formation of novel citrullinated peptides, including 37 derived from fibrinogen and 11 from α-enolase (41).Rheumatoid factors (RFs), another class of autoantibodies in RA, target the Fc region of host IgG (42). Rgps cleave lysine and arginine residues within the CH2 and CH3 domains of IgG, producing fragments that enhance Rheumatoid factor (RF) binding. Moreover, P. gingivalis generates short-chain fatty acids that attract neutrophils to periodontal tissues (43), where they activate and release reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals. These ROS enhance the reactivity of IgG, facilitating RF-mediated immune complex formation (44). The resulting immune complexes involving ACPAs and RFs accumulate in synovial fluid, where they drive persistent synovitis and joint destruction—the pathological hallmarks of RA (38, 42). Other oral pathogens that may contribute to citrullination include Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) (45) and Prevotella intermedia (P. intermedia) (46), which will be further discussed in subsequent sections.

1.3 Epidemiological association RA– periodontal disease

Periodontal disease affects the gums, supporting connective tissues, and alveolar bone, ranking sixth in disease burden among chronic non-communicable diseases. Between 2011 and 2020, its prevalence reached nearly 62% among adults who had received dental treatment (47). In 2021, over 1 billion people worldwide suffered from severe periodontitis, accounting for approximately 11% of the adult population (48). It is broadly classified into gingivitis and PD. Gingivitis is characterized by inflammation limited to the gingival epithelium and adjacent soft connective tissues, whereas periodontitis is a chronic, non-communicable, and multifactorial inflammatory condition primarily initiated by bacterial infection, leading to inflammation of the tooth-supporting structures (49). This process results in the loss of connective tissue attachment and alveolar bone destruction, with an overall population prevalence estimated at 45 to 50 percent. The pathogenesis of periodontitis involves the invasion of periodontal tissues by pathogenic bacteria and their products within the dental biofilm, which stimulate the production of pro-inflammatory mediators. Recurrent disruption of the oral mucosal barrier facilitates the translocation of oral pathogens and their virulence factors into the bloodstream (50). This leads to elevated systemic levels of inflammatory cytokines and a sustained immune-inflammatory response, which may serve as a persistent driver of systemic immune activation.

A growing body of clinical and epidemiological evidence supports a bidirectional relationship between RA and PD (51). The prevalence of PD among individuals with RA is at least twice as high as that observed in healthy populations (52). A study by Eriksson et al. reported that approximately 75 percent of RA patients exhibited moderate to severe periodontitis, while the remaining patients had either no periodontitis or only mild forms (53). A meta-analysis further revealed that individuals with RA display significantly worse periodontal conditions, characterized by greater clinical attachment loss (CAL), higher rates of tooth loss, elevated plaque index scores, and increased probing depth (54). These differences appear to be independent of age, sex, ethnicity, and smoking status (55). Notably, RA patients with severe periodontitis tend to exhibit higher levels of disease activity, highlighting a potential link between periodontal burden and RA progression (56).

2 Oral microorganisms in RA

The oral microbiota is a highly diverse and structured microbial community comprising over 700 bacterial species, including more than 250 recognized pathogens, which can influence host pathophysiology on a systemic level (57). Factors such as aging, poor oral hygiene, systemic comorbidities, and the use of medications can disrupt the composition of the oral microbiota, contributing to the onset of oral diseases (58). Over the past two decades, a growing number of clinical studies have examined the oral microbial characteristics of individuals at high risk of developing RA and of patients already diagnosed with the condition (summary provided in Table 1), revealing a potential link between oral microbial dysbiosis and RA pathogenesis.

2.1 Oral microbiota

Individuals at high risk of RA are characterized by seropositivity for autoantibodies and inflammatory arthralgia in the absence of clinically evident synovitis (59–64). Oral microbiota perturbations have been observed during this “preclinical” phase of RA. Studies have demonstrated a reduction in salivary microbial diversity among these high-risk individuals, particularly a decrease in Defluviitaleaceae_UCG-011 and Neisseria oralis, along with an increase in Prevotella_6 (60). Dysbiosis of the subgingival microbiota has also been detected in anti-cyclic citrullinated peptide (CCP)⁺ individuals without arthritis, who show higher prevalence of both periodontitis and gingivitis (62, 64). Furthermore, the oral microbiota composition in at-risk individuals closely resembles that of early RA patients, with no significant differences observed in the microbial profiles of saliva and tongue coating. Compared to healthy controls, these groups exhibit increased abundance of Veillonella in both saliva and tongue coating, and Prevotella in saliva (59). This similarity suggests that specific shifts in the oral microbiota may constitute early pathogenic events in RA development. Additionally, studies have identified enrichment of Porphyromonadaceae family bacteria and Saccharimonas species in subgingival plaque samples from at-risk individuals prior to RA diagnosis (63). These microbial signatures may hold predictive potential but require further confirmation in prospective investigations.

To investigate the oral microbiota across different stages of RA, patients are commonly categorized into early-stage and chronic RA, with healthy individuals serving as controls (61–66). Early RA is typically defined as meeting the 2010 ACR/EULAR classification criteria, with disease duration under 6 months (63), less than one year since diagnosis (61, 65), initiation of disease-modifying antirheumatic drugs (DMARDs) therapy within 3 months (62, 64), or symptom onset within two years (66). Compared to healthy individuals, early RA patients tend to experience more severe periodontitis, including greater loss of periodontal attachment and alveolar bone. Subgingival Tannerella forsythia and supragingival Streptococcus anginosus are markedly elevated—by sixfold and threefold, respectively—indicating their potential as characteristic pathogens in early RA (66). The composition of the oral microbiota in RA patients shifts in accordance with the severity of coexisting periodontitis. In individuals with no or mild periodontitis, Prevotella oris and Porphyromonas species are more abundant, whereas in moderate to severe cases, the dominant species include Desulfobulbus sp., Prevotella sp., NA sp., Bulleidia sp., and Capnocytophaga sp., along with higher levels of Tannerella forsythia (53). This indicates that the hypoxic and inflamed periodontal microenvironment remains a critical determinant of subgingival microbial composition in the context of RA. Distinct oral microbial signatures have also been identified based on RA disease activity. Staphylococcus and Porphyromonas are associated with higher disease activity, while Treponema sp. and Absconditabacteriales are more frequently found in patients during remission (67). A seemingly paradoxical yet significant observation is that patients with active RA sometimes exhibit better periodontal health and a more “eubiotic” subgingival microbiota compared to those in remission (68). This strongly suggests that anti-rheumatic treatments may substantially alter the oral microbial landscape and inflammatory status, necessitating careful consideration of therapy as a major confounding factor when interpreting microbiota–disease activity relationships. Oral microbiota may also correlate with the presence and titers of RA-specific autoantibodies. Marked differences in subgingival microbial communities have been observed between RF-high and RF-negative/low patients, with enrichment of Fusobacteria, Saccharibacteria, and Spirochaetes, as well as the families Saccharimonas, Porphyromonadaceae, and Spirochaetaceae, associated with elevated RF levels (63). Similarly, ACPA positivity has been linked to more severe PD (53). Certain taxa, such as Prevotella_9, show a positive correlation with both ACPA and RF levels (67), whereas reductions in Porphyromonas and Aggregatibacter have been associated with higher ACPA titers, independent of RF status, HLA-DRB1 SE alleles, or methotrexate usage (61). This may reflect a unique host–microbe interaction in which ACPA targets citrullinated bacterial membrane antigens, potentially facilitating the clearance of specific pathogens both locally and systemically. Notably, no significant microbial differences have been found between superficial and deep gingival sites in RA patients (69). Moreover, subgingival microbiota profiles in RA patients resemble those of individuals with osteoarthritis (OA), and microbial diversity indices do not correlate with RA disease activity, suggesting that microbial dysbiosis in the subgingival niche is not exclusive to RA (70). Overall, RA patients exhibit higher total bacterial loads and a more diverse oral microbiota, with increased prevalence of proinflammatory and citrulline-producing organisms (71), while the abundance of health-associated commensals is concurrently reduced (67, 72, 73).

2.2 Periodontal pathogen distribution in oral niches and clinical correlates in RA patients

Although numerous studies have highlighted the alterations in oral microbiota associated with different stages of RA, disease activity levels, and autoantibody profiles, it is important to consider the complexity of the oral environment. The oral cavity consists of distinct ecological niches that support heterogeneous microbial communities. Microbial composition differs significantly between sites such as dental plaque, the dorsal tongue, and keratinized gingiva (79). Within this complex microenvironment, P. gingivalis has become a central focus of mechanistic research due to its unique ability to generate citrullinated proteins and its strong epidemiological association with RA, as discussed in Section 1.3. As a Gram-negative anaerobe, P. gingivalis is commonly found in individuals with poor oral hygiene and has also been implicated in several systemic diseases. Meta-analyses have demonstrated that individuals exposed to P. gingivalis have a significantly increased risk of developing RA (80). In ACPA⁺ individuals at high risk of RA, P. gingivalis shows increased abundance in subgingival plaque (62, 64), but reduced levels in oral mucosal surfaces and saliva (60, 61). A large cross-sectional study involving 600 participants found that elevated P. gingivalis DNA levels in saliva were associated with increased serum ACPA titers (81), suggesting the potential for systemic dissemination. Furthermore, in participants with concurrently elevated salivary P. gingivalis DNA and C-reactive protein (CRP), ACPA reactivity against citrullinated α-enolase and vimentin was commonly observed (82). Interestingly, other studies have reported no significant difference in the prevalence of P. gingivalis in subgingival plaque between RA patients and healthy controls (83–85). Additionally, P. gingivalis abundance has shown no consistent association with RA disease activity, ACPA, or RF levels (68, 70, 81, 86), but instead correlates more strongly with PD severity. These findings suggest that PD, rather than P. gingivalis per se, may be the primary factor modulating RA outcomes. Nonetheless, this does not negate the potential involvement of P. gingivalis in RA. In tongue biofilm samples, the proportion of P. gingivalis has been positively correlated with RA disease activity, with higher detection rates in non-remission patients compared to those in remission (83). Although findings vary depending on the sample type, existing evidence supports the participation of P. gingivalis in the pathogenesis of RA. Beyond P. gingivalis, other periodontal pathogens have also been implicated in RA. A. actinomycetemcomitans is more frequently detected in the gingival crevicular fluid of RA patients (87), and its subgingival presence is positively correlated with DAS28, RF, anti-CCP, and ACPA levels (88). In addition, Staphylococcus aureus has been found at higher prevalence in the oral cavities of RA patients compared to controls (89, 90), indicating that multiple oral microbes may contribute to RA-related immune dysregulation.

Substantial evidence indicates that individuals at high risk for RA and RA patients often show characteristic oral microbiome dysbiosis, including reduced microbial diversity and altered abundance of various bacterial taxa. These changes have been linked to autoantibody presence, especially ACPA, as well as disease stage and activity. However, most studies are cross-sectional, limiting conclusions about causality and temporal sequence. Small sample sizes (n < 100), limited geographic scope (mainly Europe and East Asia), and inconsistent sampling sites further constrain generalizability. Although some studies control for confounders like smoking, age, sex, and medication use, fully eliminating these factors is difficult, particularly given the frequent co-occurrence of periodontitis and RA. Thus, observed microbial changes may partly reflect confounding rather than RA-specific patterns. Identifying reliable microbial biomarkers for RA diagnosis or prediction remains challenging. Future research should adopt large-scale, standardized, prospective designs and evaluate microbiome-targeted interventions for RA prevention and treatment. The next section discusses the role of periodontal pathogens in RA pathogenesis.

3 Pathogenic translocation of oral microbiota to synovial compartments

Oral pathogens possess the capacity to translocate from their primary infection sites to distant local tissues, including the joints. Several clinical studies in patients with RA (Table 2) have identified nucleic acids from periodontal pathogens within synovial fluid and synovial tissues, lending support to the hypothesis that oral bacteria may reach the joint environment and participate in the initiation and progression of arthritis. In a pioneering study, Moen et al. reported a greater diversity and higher concentration of oral bacterial DNA in synovial fluid compared to serum samples from patients with active RA. Notably, multiple periodontal pathogens such as Tannerella forsythensis, P. intermedia, Streptococcus intermedius, P. gingivalis, A. actinomycetemcomitans, and Fusobacterium nucleatum were detected (91), preliminarily confirming that oral bacteria can disseminate into the joint cavity. Subsequent studies have concentrated on specific pathogenic species. Reichert et al. demonstrated that the detection rate of P. gingivalis DNA was significantly higher in both the synovial fluid and oral plaque of RA patients compared to non-RA controls (92), suggesting preferential enrichment of this pathogen within the RA-affected joint environment. Further investigations revealed that P. gingivalis DNA was present not only in synovial fluid but also in synovial tissue, with a significantly higher positivity rate in RA patients (33.3%) than in those with undifferentiated polyarthritis (5.9%) (93). Moreover, the positivity rate in synovial tissue was particularly elevated in patients carrying the HLA-DRB1*04 allele, implying a potential interaction between bacterial localization and genetic susceptibility (93). However, it is important to note that the detection rates of P. gingivalis in subgingival plaque, peripheral blood, and synovial fluid did not significantly differ between patients with RA and those with undifferentiated arthritis (93). Furthermore, the presence of P. gingivalis was not significantly correlated with disease activity, disability levels, or autoantibody status in RA patients. In patients with refractory RA complicated by periodontitis, P. intermedia and P. gingivalis DNA were frequently detected in subgingival plaque and synovial fluid, with detection rates of 73.6% and 42.1%, respectively (94). These findings further support the hypothesis that specific periodontal bacteria may colonize the joint space, particularly in patients with both systemic and oral inflammatory conditions. Further insights into the joint microbiome have been gained from a study conducted in China, which found abundant bacterial nucleic acids in both synovial fluid and synovial tissue samples from RA patients. Among periodontal species, Porphyromonas was consistently detected in all samples, while Veillonella dispar, Haemophilus parainfluenzae, Prevotella copri, and Treponema amylovorum were more prevalent in synovial fluid. In contrast, genera such as Agrobacterium, Comamonas, Kocuria, Meiothermus, and Rhodoplanes were more abundant in synovial tissue (95), revealing the complex microbial composition within the RA joint microenvironment. Oral streptococci are dominant commensals in the human oral and pharyngeal cavities, and their bacterial fragments have also been identified in the joint spaces of RA patients (96). Animal models further corroborate the dissemination of periodontal pathogens. P. gingivalis, Treponema denticola, and Tannerella forsythia are recognized as periodontal pathogens that typically emerge in the mature stages of biofilm development. This microbial consortium, known as the red complex, constitutes a keystone polybacterial community within the subgingival biofilm of progressive periodontitis sites (97). Among members of the red complex, only P. gingivalis was found to disseminate hematogenously to synovial joints. Fluorescence in situ hybridization confirmed its presence in the perinuclear region of ankle joint cells in mice (98). Additionally, streptococcal cell walls extracted from the oral cavity of RA patients have been shown to induce arthritis in murine models. Local gingival inflammation and barrier dysfunction may facilitate the translocation of pro-inflammatory streptococcal components into the synovium, especially given the limited degradation capacity for such pathogen-associated molecular patterns (99).

These studies have established a chain of evidence for the translocation of oral bacteria to the joints, with particular emphasis on the colonization of P. gingivalis in synovial tissues, its intracellular localization potential, and its association with genetic susceptibility. These findings provide strong clues for its direct involvement in local joint pathology. However, the specific routes through which oral bacteria reach the joints, the extent of their contribution to arthritis pathogenesis, and the active components involved, such as intact bacteria, DNA, or metabolic products, remain to be fully elucidated.

4 Effects of periodontopathogen on experimental arthritis

Although many oral bacteria have been linked to RA, P. gingivalis is the most extensively studied species in terms of its impact on arthritis progression in animal models. As the predominant pathogen in subgingival polymicrobial communities associated with PD, P. gingivalis has been the focus of numerous experimental investigations in this field. Various arthritis models incorporating P. gingivalis infection have been employed to simulate its differential effects on RA. In these models, variations in immunization protocols, bacterial dosages, and routes of administration can markedly influence experimental outcomes. Moreover, the timing of arthritis induction relative to periodontal infection introduces additional complexity to experimental design, making reproducibility and interpretation particularly challenging. Twenty-three studies have examined the effect of P. gingivalis infection on the progression of RA using animal models (Table 3). Seventeen studies reported that P. gingivalis exacerbated arthritis, while four studies investigated the role of P. gingivalis combined with other oral pathogens, with three showing synergistic effects and one showing no significant effect on pristane-induced arthritis (98, 100, 101). Three reported synergistic effects, while one found no significant effect on pristane-induced arthritis (102). One study showed that oral inoculation with P. gingivalis led to the onset of seropositive arthritis, systemic inflammation, and bone erosion over an 8-month observation period (103). Additional study suggested that P. gingivalis failed to worsen arthritis but altered synovial proteome characteristics, suggesting that oral pathogens may contribute to the formation of particular disease subtypes (104). These studies had highly variable designs, using different P. gingivalis strains, models, and time points.

Polymicrobial oral infections have been shown to accelerate experimental arthritis, leading to earlier disease onset and increased severity characterized by enhanced inflammatory cell infiltration and pannus formation. In addition to the well-established role of the red complex, a major pathogenic group in periodontitis (98), the combined infection with P. gingivalis, Fusobacterium nucleatum, and A. actinomycetemcomitans similarly promotes the onset and progression of RA (100). Interestingly, while this bacterial consortium exacerbates arthritis, it results in comparatively less alveolar bone loss in mice than individual pathogens, suggesting a complex interplay between local and systemic immune responses (100). Repeated oral inoculation with P. gingivalis and Prevotella nigrescens promotes RA through Th17-mediated immune responses, and their effect is directly correlated with the severity of joint bone erosion (101). However, not all oral bacteria aggravate experimental arthritis. For instance, periodontitis induced by A. actinomycetemcomitans does not affect the course of antigen-induced arthritis (AIA) in mice, whereas arthritis aggravates alveolar bone loss caused by this bacterium, primarily due to enhanced systemic inflammation and lymphocyte polarization (120). Notably, both anti-TNF-α and antimicrobial therapies can alleviate periodontitis in this context (120).

5 Systemic humoral immune responses to periodontopathogens in RA patients

5.1 Circulating antibodies against P. gingivalis and related bacterial components

Recent studies suggest that humoral immune responses targeting oral bacteria may play a role in the pathogenesis of RA (121). Infection with P. gingivalis elicits a host immune response characterized by the generation of specific antibodies, primarily targeting its bacterial components and major virulence factors, including arginine-specific gingipains (RgpA and RgpB) and PPAD (122). Multiple serological studies have consistently reported that individuals with RA exhibit significantly elevated levels of P. gingivalis-specific antibodies compared to healthy controls or first-degree relatives (123–126). The seroprevalence of these antibodies is also comparable between patients with RA (48.9%) and those with PD (52.7%) (83). Moreover, antibody titers have been shown to correlate with the severity of PD (127).

Antibodies targeting P. gingivalis are closely associated with key biomarkers of RA (Table 4). Among these, the association between serum P. gingivalis antibody titers and ACPAs has been one of the most robust and consistently observed findings across multiple studies (124, 128–132). Mikuls et al. reported that elevated P. gingivalis antibody titers were positively correlated with specific ACPA subtypes, particularly anti-CCP IgM and IgG2 (124). Similarly, another study observed that patients with subgingival P. gingivalis colonization and elevated antibody titers exhibited increased expression of selective ACPAs, including antibodies to citrullinated filaggrin (85). Additionally, P. gingivalis antibody titers have been shown to correlate with RF levels in patients with RA, particularly among those with moderate-to-high disease activity (126). Notably, individuals with RF-IgA levels exceeding 75 IU/mL exhibited a five-fold increase in P. gingivalis antibody titers (133). However, some studies did not observe a direct association between P. gingivalis antibody levels and RA disease activity (123, 126, 127), suggesting that these antibodies may play a more specific role in autoimmune mechanisms rather than contributing directly to systemic inflammation.

Serum antibodies against P. gingivalis demonstrate potential in the diagnosis of RA, as well as in predicting disease progression and treatment outcomes (Table 4). Double positivity for anti-RgpA and anti-PPAD antibodies in peripheral blood significantly enhances the diagnostic accuracy for RA, with a specificity of 93.7% and a positive predictive value of 82.5% (134). Two independent studies have implicated P. gingivalis in accelerating the severity and progression of joint damage in RA. In patients experiencing rapid radiographic progression (RRP), the IgA/IgG ratio of anti-P. gingivalis lipopolysaccharide (LPS) antibodies was closely correlated with disease activity parameters, including DAS28-ESR, RF, erythrocyte sedimentation rate (ESR), and CRP levels (135). Similarly, a large early RA cohort study found that non-smoking patients with elevated P. gingivalis antibody titers had a higher rate of bone erosion (47.5%) (136). Beyond diagnosis and progression, P. gingivalis antibodies may serve as prognostic indicators of suboptimal therapeutic response. Early RA patients who are seropositive for these antibodies tend to exhibit higher disease activity, impaired joint function, and elevated levels of anti-CCP, RF, and systemic inflammation. Even after 12 months of standard treatment, this subgroup continues to display a trend toward increased disease activity (130). Convergent evidence from a separate study involving 82 treatment-naïve RA patients revealed that those with higher P. gingivalis antibody titers showed a less favorable response to therapy after three months (129).

Although existing evidence suggests a role for P. gingivalis antibodies in RA, growing evidence indicates that these antibodies are more strongly associated with PD. This suggests that the observed link to RA may reflect the broader pathophysiological state of PD rather than the effect of a specific pathogen.

5.2 Circulating antibodies against other periodontal pathogens and related bacterial components

Beyond P. gingivalis, circulating antibodies targeting other periodontal pathogens and their virulence factors have also been implicated in the pathogenesis and clinical manifestations of RA, expanding our understanding of how humoral immune responses to periodontal infections may contribute to RA development.

Serological studies have identified a significant association between elevated anti-A. actinomycetemcomitans IgG titers and RA (126). Notably, all individuals infected with A. actinomycetemcomitans were found to be anti-CCP⁺ (144). The influence of HLA-DRB1 SE alleles on autoantibody positivity appears to be restricted to RA patients exposed to A. actinomycetemcomitans (145). Leukotoxin A (LtxA), a key virulence factor secreted by A. actinomycetemcomitans, has recently been identified as a potential risk factor for the progression from arthralgia to RA (146). Anti-LtxA antibodies, including IgM, IgG, and IgA isotypes, can be detected across different stages of RA development, with significantly elevated IgM levels observed in both early and established RA patients (146). These antibodies are more prevalent among ACPA⁺ arthralgia patients and are associated with an increased likelihood of progression to RA (147). LtxA is thought to mimic membranolytic mechanisms involved in sustaining self-antigen citrullination in RA joints, inducing neutrophil morphological alterations and promoting neutrophil extracellular trap (NET) formation, which facilitates the release of highly citrullinated proteins in the oral cavity (145). Additionally, the N-terminal region of the DnaJ protein from A. actinomycetemcomitans elicits a specific immune response in RA patients, offering further insights into the disease’s etiology (148).

P. intermedia is a key periodontal pathogen implicated in chronic oral infection. Musculoskeletal ultrasound examinations have revealed that more than half of RA patients in clinical remission exhibit persistent synovitis. Notably, IgG titers against P. intermedia are significantly higher in patients with active RA and in those with ultrasound-detected synovitis (149). These findings suggest that P. intermedia may contribute to the chronic inflammatory state observed in RA. Through its enzymatic capacity to induce protein citrullination, P. intermedia may play a role in the generation of specific ACPA subtypes during the preclinical phase of RA. Prior to diagnosis, anti-P. intermedia antibodies are positively correlated with anti-CCP2, ACPA targeting vimentin, histones, and α-enolase, as well as with RF isotypes including IgA, IgG, and IgM (46). Further research has shown that P. intermedia-specific antibodies in gingival crevicular fluid are closely associated with ACPAs against citrullinated cytokeratin 13, a novel antigenic target with heightened antibody responses in RA patients that appears to lack cross-reactivity with antibodies directed against P. gingivalis gingipains (150). Interestingly, a large cross-sectional study (n = 33,994) found that elevated IgG responses to P. intermedia and Capnocytophaga ochracea were inversely associated with RF seropositivity (151). These findings imply that humoral immune responses to different periodontal pathogens may differentially influence RA-associated serological markers.

Circulating antibodies targeting other periodontal bacterial components, as well as the presence of these bacteria in the oral cavity, have also been linked to RA serological markers, although current evidence remains limited. Haemophilus species have been found to be depleted in both dental and salivary samples from RA patients and are negatively correlated with anti-CCP antibody levels (76). Subgingival colonization by Aminipila butyrica and Peptococcus simiae has been proposed to contribute to the generation of ACPAs (74). Additionally, Lactobacillus salivarius has been associated with elevated RA disease activity (74), further suggesting a potential role of specific oral microbiota in modulating systemic inflammatory states.

6 Molecular mimicry and immune cross-reactivity as core mechanisms of periodontopathogen-induced autoimmunity

6.1 Induction of citrullination and breaking immune tolerance

One of the central pathogenic mechanisms of RA is the breakdown of immune tolerance to citrullinated proteins, which involves increased production of citrullinated antigens and enhanced autoimmune responses against these antigens, particularly ACPA. Among various periodontal pathogens, P. gingivalis has drawn considerable attention due to its unique ability to induce citrullination. In animal models, oral administration of P. gingivalis has been shown to significantly elevate serum ACPA levels, accompanied by the detection of abundant P. gingivalis components and citrullinated proteins in the ankle joints (109). Upregulation of citrullinated protein expression has also been observed in multiple organs (108, 114). Moreover, a marked increase in the proportion of Tfh-gcB cell subsets responsible for autoantibody generation has been reported in lymphoid tissues (106). The contribution of P. gingivalis PPAD to citrullination has been demonstrated using gene manipulation approaches. Notably, wild-type P. gingivalis, but not PAD-deficient strains, induced the development of ACPA (108, 111) and production of citrullinated proteins (108, 112, 113), underscoring the mechanistic role of PPAD in linking P. gingivalis infection to RA pathogenesis. However, opposing evidence suggests that PPAD may not serve as the initial cross-reactive target for ACPA induction, as its absence does not prevent P. gingivalis-induced intestinal barrier impairment or exacerbation of arthritis in certain models (115).

A key mechanism by which PPAD induces host immune responses is enzymatic mimicry. This hypothesis, first proposed in 2009, suggests that P. gingivalis infection and PPAD-mediated citrullination of human antigens can trigger the ACPA response (39). Subsequent studies in RA patients have provided supporting evidence. It has been observed that peripheral plasmablasts in RA patients can produce ACPA, and approximately 63% of these antibodies cross-react with P. gingivalis outer membrane antigens and/or citrullinated enolase (152). Notably, in addition to C-terminal citrullination, P. gingivalis PAD exhibits prominent endocitrullination, targeting internal arginine residues (152). A 2020 study cloned and purified the PPAD enzyme (RACH2007-PPAD) from P. gingivalis strain CH2007 isolated from an RA patient and found that it could citrullinate internal arginine residues of major RA autoantigens such as fibrinogen and vimentin. Moreover, anti-RACH2007-PPAD antibody levels correlated with ACPA titers (153). More recently, a 2023 study proposed a possible mechanism by which persistent P. gingivalis exposure disrupts immune tolerance in RA. Repeated episodes of oral bacteremia in RA patients may result in widespread citrullination of oral bacteria, with subsequent translocation of citrullinated microbial antigens into circulation due to mucosal barrier breaches. This process activates proinflammatory monocyte subsets and inflamed synovial tissue, and further stimulates ACPA-producing B cells, thereby promoting affinity maturation and epitope spreading toward citrullinated human proteins (154).

Subsequent research has indicated that P. gingivalis primarily serves as an exogenous source of citrullinated antigens rather than modulating host-derived citrullination processes. Experimental evidence shows that when P. gingivalis is co-cultured with human peripheral blood mononuclear cells and macrophages, PPAD activity is detected exclusively in mononuclear cells exposed to the bacteria, leading to increased extracellular citrullination. In contrast, the expression of endogenous PAD enzymes and intracellular citrullination within monocytes and macrophages remains unaffected by P. gingivalis exposure (155).

6.2 Immune evasion

P. gingivalis employs various mechanisms to evade the host’s innate immune defense. P. gingivalis evades the immune response through PPAD-mediated citrullination by: 1) decreasing levels of neutrophil-derived proteins associated with phagocytosis and the antimicrobial activity of histone H2; 2) citrullinating histone H3, which facilitates P. gingivalis in evading NETs; 3) citrullinating the lysozyme-derived cationic antimicrobial peptide LP9, thereby limiting its antimicrobial activity (156). However, this immune evasion has been primarily observed in the oral cavity, and further confirmation in the context of RA is needed. Additionally, P. gingivalis facilitates immune evasion through A-type lipopolysaccharide (A-LPS), which assists in the localization of PPAD to Outer membrane vesicles (OMVs). OMVs are secreted by P. gingivalis as spherical bilayer structures made up of outer membrane proteins, phospholipids, DNA, lipopolysaccharides and segments of the periplasm (157). These vesicles package and transport bacterial virulence factors, including PPAD, to various host tissues. A-LPS modification not only localizes PPAD to OMVs, but also protects PPAD from proteolytic degradation, thus facilitating its “protective secretion” (158). Although PPAD is not essential for bacterial biofilm formation, or for the attachment and penetration of gingival epithelial cells by P. gingivalis, it functions as a powerful regulator of the immune response by enhancing the expression of genes related to cytokines (159).

6.3 Modulation of host immune responses

Exposure to P. gingivalis in gingival tissue exerts systemic effects by activating the host immune response. It may accelerate arthritis progression in CIA mice by mobilizing dendritic cells, macrophages, and neutrophils to the joints (116). Oral infection with P. gingivalis in CIA mice not only increases arthritis scores but also elevates serum RF levels (63). Chronic oral colonization with P. gingivalis prior to arthritis induction enhances immune activation that favors Th17 cell responses (107, 110, 114). Studies using IL-17RA knockout mice have confirmed that the exacerbating effect of P. gingivalis on arthritis is dependent on the Th17/IL-17 signaling pathway (117). Interestingly, P. gingivalis can also compromise the intestinal barrier and alter gut microbiota, thereby contributing to systemic inflammation and further aggravating arthritis (105, 108). These effects are partially mediated by increased serum IL-17 levels and a higher proportion of Th17 cells in mesenteric lymph nodes (105). In addition, downregulation of IL-10–producing regulatory B cells has been proposed as a key mechanism by which P. gingivalis promotes RA, since other immunosuppressive cells such as Tregs and myeloid-derived suppressor cells (MDSCs) are upregulated rather than suppressed (107). It is noteworthy that experimental arthritis does not affect the degree of P. gingivalis-induced alveolar bone loss (117).

6.4 Effects on promotes bone destruction and cartilage damage

Osteoclast overactivation and differentiation are the primary mechanisms underlying articular bone erosion in RA. P. gingivalis is a key contributor to bone loss associated with inflammation. Toll-like receptor (TLR) signaling modulates both inflammation and bone metabolism, whereas the receptor activators of nuclear factor kappa-B(NF-κB) ligand (RANKL) and its receptor, RANK, serves as a crucial regulator of osteoclast activation and bone remodeling processes. In isolated cultures of mouse parietal bone, P. gingivalis-LPS, via TLR2, promotes the formation of differentiated, mature osteoclasts, leading to bone loss. This process is primarily dependent on elevated RANKL levels (160). Subsequent studies revealed novel crosstalk between TLR and RANKL signaling cascades in the process of osteoclastogenesis. P. gingivalis modulates differently RANKL-induced nuclear factor of activated T-cells 1 (NFATc1) and cellular proto-oncogene Fos (c-Fos) expression, contingent upon the differentiation stage of osteoclast precursors. It inhibits RANKL-driven osteoclastogenesis at initial stages but promotes osteoclast maturation at later phases. TLR2/MyD88 is a central regulator of osteoclast differentiation by P. gingivalis, while RANKL reduces cytokine production triggered by P. gingivalis by down-regulating TLR/NF-κB and up-regulating NFATc1 (161). Mycorrhizal hairs, a major virulence factor of P. gingivalis, also contribute to osteoclast activation. The long-type FimA and short-type Mfa1 filaments are proteinaceous structures originating from P. gingivalis (162). The study found that both Mfa1 and FimA hyphae promote the differentiation and activation of osteoclasts. Significantly, the effect of Mfa1 on osteoclast differentiation was intense than that of FimA, and Mfa1 promoted osteoclast differentiation and activation in osteoclast precursor cells stimulated by RANKL (163).

Infection of macrophages by bacteria triggers the release of pro-inflammatory cytokines, with TNF-α stimulating osteoclasts that differentiate bone marrow macrophages both directly in vitro and indirectly via osteoblasts. A study in an environment exposed to P. gingivalis highlights the critical role of TLR2 signaling in osteoclastogenesis. P. gingivalis promotes the increased expression of TLR2 on macrophage surfaces, which in turn increases TNF-α production and enables a functional response of these macrophages to reinfection. The macrophage reaction to P. gingivalis stimulation depends on TNF-α and is independent of RANKL, IL-6, and IL-1β (164). Conversely, an alternative investigation proposed that P. gingivalis directly promotes RANKL-triggered osteoclastogenesis in RAW264 subclonal mouse macrophages, with TNF-α not involved in this process (165).

Chondrocyte apoptosis can lead to cartilage damage, resulting in tissue degeneration and joint deformity. A study found that infection with P. gingivalis significantly increased both early and late apoptosis of human primary chondrocytes (166). This finding was corroborated by Pischon et al., who showed that P. gingivalis can localize within cells (167).

In conclusion, numerous in vitro experiments and animal studies have highlighted the potential of P. gingivalis to elicit changes associated with RA. In animal studies, P. gingivalis is often introduced into the oral cavity to observe changes in distal joints, thereby mimicking the clinical situation. Moreover, the experimental design, in which the control group is typically sham or bacteria-free, should be reconsidered to better assess the specific role of P. gingivalis compared to other periodontal pathogens.

7 Preventive aspects from the microbiological point of view

The essence of establishing proof-of-concept hinges on tackling the underlying causative factor with treatments like nonsurgical periodontal treatment (NSPT), which involves providing oral hygiene guidance and mechanically removing microbes from tooth surfaces both above and below the gingival margin. Currently, there is no consensus on the common management strategies for periodontitis and rheumatoid arthritis. Studies have found that NSPT relieves inflammation for 6 weeks to 6 months and reduces DAS28, VAS, SJC, TJC and improves clinical periodontal parameters (168, 169). The meta-analysis showed that, beyond enhancing the management of disease activity in RA, NSPT alleviated the systemic biomarker serum CRP among individuals with RA. It also exhibited a tendency of decreased ESR, morning stiffness, RF, TNF-α, and IL-6 (170). Therefore, promoting and developing NSPT for RA patients should be prioritized. However, due to issues such as selection bias and frequent changes in RA medication, there remains a pressing need for well-designed studies to further investigate this topic. At present, it remains challenging to definitively assess the effect of periodontal treatment on RA. Nonetheless, the promotion and development of NSPT for RA patients should not be overlooked.

Another approach targets the virulence factors of microorganisms. FimA, an important bacterial protein of P. gingivalis, demonstrated the ability to minimize alveolar bone loss and arthritic bone destruction when preincubated with FimA antibody. It also lowered the adhesion and aggregation of bacteria on gingival and synovial fibroblasts derived from humans (116). A distinct amino acid sequence within the catalytic domain of RgpA exhibits homology to the sequence of type II collagen. Pre-immunization rats with the purified recombinant structural region of RgpA similarly reduced joint inflammation and bone erosion (119). Targeting key virulence factors of P. gingivalis through preimmunization or small molecule inhibitors have the potential to diminish the likelihood of pathogens spreading to distal tissues and decrease their ability to trigger or exacerbate pathological changes in RA.

Recent studies have shown that DMARDs can improve clinical parameters of PD while treating RA. To eliminate the potential confounding influence of patients adopting proper oral hygiene habits, the investigators selected a 4-week follow-up period. Following 4 weeks of treatment with methotrexate (MTX), hydroxychloroquine (HCQ), and sulfasalazine (SSZ), patients diagnosed with RA and comorbid periodontitis exhibited improvements in CAL and probing depths when compared to periodontally healthy subjects. Moreover, MTX alone reduced probing depth after 3 months in contrast to the combination of MTX with SSZ and HCQ. Other drugs, including the JAK-inhibitor baricitinib, tocilizumab, rituximab, and anti-TNF-α monoclonal antibodies, also provide similar remission in PD (171). Paradoxically, some studies have questioned the treatment effectiveness of DMARDs in PD. Treatment with synthetic DMARDs, alone or in combination with another synthetic or biologic DMARD, for 6 months did not significantly improve periodontal parameters, nor did it affect the presence of P. gingivalis (172). In contrast, no improvement in the periodontal inflammatory surface area or in anti-P. gingivalis antibody levels was observed after 2 months of treatment with MTX or 3–6 months of treatment with anti-TNF-α antibody (173). The heterogeneity of periodontal parameters, variations in monitoring period duration, and the small quantity of randomized controlled trials with diverse DMARDs make it difficult to identify the most effective DMARD for treating PD. This requires further investigation.

Plant-derived products have been proposed as potential modulators of both microbiota and host responses. Curcumin, the primary curcuminoid in turmeric, is an effective antimicrobial, antioxidant, and anti-inflammatory agent against P. gingivalis infections and biofilm formation. It suppresses the pro-inflammatory response of Th17 cells and enhances the immunoregulatory functions of Tregs, yielding a dual therapeutic effect (174). Clinically, topical curcumin has been shown to reduce microbial load in patients with chronic PD (175). Curcumin can inhibit P. gingivalis biofilm formation by more than 80%, even at very low concentrations (20 μg/mL) (176).

8 Conclusion and outlook

An increasing body of preclinical animal studies and epidemiological research supports a close association between RA and the oral microbiome. This review explores the role of oral pathogens in the initiation and progression of RA, and highlights the presence and potential effects of various pathogenic species in the oral microbiota of RA patients. Most clinical studies have found that dysbiosis of the oral microbiome is already evident during the preclinical phase of RA. Pathogenic bacteria and their virulence factors may enter systemic circulation, elicit immune responses, and be detectable through the identification of bacterial DNA in peripheral samples. The review also analyzes key virulence factors of oral microbes, their pathogenic mechanisms, and their impact on host immune responses. Notably, P. gingivalis infection appears to increase the risk of developing RA and may reduce the therapeutic efficacy of DMARDs. However, most clinical studies are cross-sectional in nature and are subject to heterogeneity and confounding factors, making it difficult to establish definitive causal relationships. Identifying reliable microbial biomarkers for RA diagnosis or prediction remains a major challenge. In contrast, animal studies have provided stronger evidence that P. gingivalis and its major virulence factors accelerate the progression of experimental arthritis. These pathogenic effects are primarily mediated through four mechanisms (1): protein citrullination, (2) immune evasion, (3) modulation of host immune responses, and (4) promotion of bone destruction. It is important to note that current studies predominantly focus on the role of a single bacterial species in RA pathogenesis. Given that periodontitis is a polymicrobial and chronic inflammatory condition, future research should also investigate how microbial consortia contribute to RA development.

The unique pathogenicity of P. gingivalis remains a subject of ongoing debate. Although experimental animal models have demonstrated RA-related alterations following P. gingivalis exposure, the complexity of human disease makes the available evidence inconsistent, and the observed associations do not establish causality. Since RA primarily affects the joints, human studies, due to ethical and humanitarian considerations, are largely limited to analyses of the oral cavity and peripheral blood. As a result, there are limited opportunities to directly investigate changes at the primary site of disease. Although several studies have detected periodontal pathogens in synovial fluid and tissue, the specific pathogenic features, migration pathways from the oral cavity to the joints, and key molecular mediators involved in this process remain to be fully elucidated.

In conclusion, the roles of PD, P. gingivalis, and other periodontal pathogens in the pathogenesis of RA remain incompletely understood. The underlying mechanisms by which non-surgical periodontal therapy improves RA outcomes also require further clarification. Well-designed clinical trials with large sample sizes and extended follow-up periods are needed to provide more robust evidence. In the future, rigorous, standardized, and large-scale prospective studies, along with in-depth mechanistic investigations, are essential to clarify the causal relationship between oral pathogens and RA. Moreover, exploring interventions targeting the oral microbiome may offer valuable insights for RA prevention and management, potentially contributing to personalized therapeutic strategies.

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