Rheumatoid arthritis (RA) and periodontitis are two prevalent chronic inflammatory conditions with profound systemic and local consequences. RA, a systemic autoimmune disease, predominantly affects synovial joints, leading to progressive joint destruction and systemic comorbidities, including cardiovascular disease and osteoporosis. Periodontitis, on the other hand, is a destructive inflammatory disease of periodontal tissues characterized by bone loss and potential tooth loss if left untreated (1). While they affect different anatomical regions, pathophysiological mechanisms underlying both diseases show considerable overlap, particularly in the context of immune-mediated inflammation.

Recent systematic reviews and large population cohorts confirm a bidirectional association between periodontitis and RA, with periodontitis linked to a higher risk of developing RA and patients with RA exhibiting a greater periodontal burden (2-4). However, current evidence still supports an association rather than a definitive causal association (5). The present review summarizes the interconnectedness of oral health conditions, examining inflammatory mechanisms, the role of oral pathogens and clinical implications for the management of these conditions.

RA and periodontitis, although distinct in their anatomical manifestations, share a rich and evolving medical history marked by significant advancements in understanding their pathogenesis and clinical management. RA has been a subject of medical interest since the 19th century, with Alfred B. Garrod formally distinguishing it from other forms of arthritis in 1859(6). Early conceptions of RA were grounded in the notion of chronic synovial inflammation; however, the discovery of rheumatoid factor (RF) in the early 20th century and the subsequent identification of autoantibodies, such as the anti-perinuclear factor in the 1960s, later recognized as a precursor to the modern anti-citrullinated protein antibody (ACPA) tests, marked a pivotal shift toward recognizing RA as an autoimmune condition. These immunologic insights lay the groundwork for the development of biological and targeted therapies, most notably tumor necrosis factor-α (TNF-α) inhibitors, which markedly alter disease outcomes by reducing inflammation, attenuating joint destruction and improving the quality of life of patients. Despite these advancements, RA continues to be a progressive systemic disorder with multifaceted manifestations beyond joint involvement (7).

In parallel, periodontitis has been recognized as a significant oral health concern for the millennia, with archeological evidence of periodontal destruction found in ancient human remains. However, it was not until the 20th century that its microbial etiology was firmly established. The identification of specific periodontal pathogens, such as Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola, revolutionized the understanding of periodontitis as a biofilm-mediated disease (8). This paradigm shift was further reinforced in the 1970s with the emergence of the microbial biofilm concept, which emphasized the structured and cooperative nature of bacterial communities in dental plaque. In addition to microbial research, increasing attention has been paid to the host immune response, particularly the role of inflammatory cytokines in mediating periodontal tissue breakdown (9). Together, these discoveries have shaped the modern view of periodontitis as a chronic inflammatory disease driven by complex interactions between dysbiotic microbial communities and a dysregulated host immune response.

The historical development of knowledge surrounding RA and periodontitis highlights a shared trajectory wherein advances in immunology and microbiology have informed both diagnostic and therapeutic approaches. This convergence has sparked growing interest in their potential bidirectional association, particularly in the context of systemic inflammation and immune modulation (10).

RA and periodontitis share common epidemiological features in that both conditions are prevalent worldwide and exhibit sex-based differences. RA affects ~0.5-1% of the global population, with women being more frequently affected than men. Onset typically occurs between the ages of 30 and 50 years. Global epidemiological studies suggest that periodontitis affects >50% of adults, with estimates ranging from 45-55% for any form of disease. Notably, ~10-15% of adults are affected by severe periodontitis, while the remainder exhibit mild-to-moderate disease. The prevalence varies substantially depending on population, socioeconomic status, and risk factors (11).

Numerous studies have highlighted the connection between RA and periodontitis, with several population-based studies revealing a greater prevalence of periodontitis in patients with RA than in healthy controls (12). The meta-analysis by de Pablo et al demonstrated that patients with RA are at a 2-fold greater risk of developing moderate-to-severe periodontitis. Additionally, patients with periodontitis show a greater prevalence of RA, particularly when the levels of serological markers, such as anti-cyclic citrullinated peptide antibodies are elevated. Current evidence supports an association, but does not confirm causality (13).

One particularly notable finding was derived from the study of Porphyromonas gingivalis, a key periodontal pathogen. This bacterium is capable of generating citrullinated peptides, which are major targets of autoantibodies in RA, suggesting a microbial trigger for the autoimmune response observed in RA (14).

RA and periodontitis are both chronic inflammatory diseases characterized by dysregulated immune responses and progressive tissue destruction, albeit occurring in different anatomical sites. RA primarily affects the synovial joints and is classified as an autoimmune disease. It arises from a complex interplay of genetic predispositions, environmental exposures and immune dysregulation (15). A key genetic factor linked to RA susceptibility is the presence of specific HLA-DRB1 alleles, particularly those encoding the ‘shared epitope’, a conserved amino acid sequence associated with an increased risk. Environmental triggers, such as cigarette smoking and exposure to certain microbes, can initiate an aberrant immune response in genetically susceptible individuals, leading to chronic synovial inflammation (2,15).

Immunologically, RA is characterized by the infiltration of immune cells, including CD4⁺ T-cells, B-cells, macrophages and neutrophils into the synovial membrane. These cells release pro-inflammatory cytokines, such as TNF-α, interleukin (IL)-1β, IL-6 and IL-17, which sustain the inflammatory environment and contribute to synovial hyperplasia and pannus formation (16). The receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) axis is critically involved in bone remodeling in RA; an imbalance favoring RANKL promotes osteoclastogenesis and bone resorption, leading to characteristic joint destruction (15).

Similarly, periodontitis is driven by a chronic immune-inflammatory response initiated by the accumulation of pathogenic subgingival bacteria, such as Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola. These organisms form structured biofilms on tooth surfaces and subvert the host immune response, leading to a persistent inflammatory state. Immune cell infiltration in gingival tissues involves neutrophils, macrophages, dendritic cells, and T helper 17 (Th17) cells, with IL-17 playing a pivotal role in sustaining inflammation. IL-17 enhances neutrophil chemotaxis and stimulates the release of matrix metalloproteinases (MMPs), which degrade extracellular matrix components and contribute to connective tissue breakdown (17).

Moreover, the RANKL/OPG axis is also dysregulated in periodontitis. The increased expression of RANKL by activated T-cells and osteoblasts enhances osteoclast differentiation and activity, resulting in alveolar bone resorption and periodontal attachment loss. The overlapping pathogenic mechanisms, particularly the roles of proinflammatory cytokines, Th17 cells and the RANKL/OPG pathway, highlight the shared molecular pathways between RA and periodontitis, supporting the growing body of evidence linking these two chronic inflammatory diseases (18).

The overlapping immunopathological mechanisms between RA and periodontitis suggest a bidirectional association (Fig. 1). Both diseases are characterized by excessive inflammation mediated by Th17 cells and increased levels of IL-17. This cytokine promotes the activation of osteoclasts via the RANKL/OPG axis, leading to bone resorption in both the joints in RA and the alveolar bone in periodontitis (19).

Another key intersection is the presence of citrullinated proteins. Among periodontal pathogens, Porphyromonas gingivalis produces peptidyl arginine deiminase, which catalyzes the citrullination of host proteins, thereby providing a possible link to ACPA formation. In addition, Aggregatibacter actinomycetemcomitans can induce neutrophil hypercitrullination, representing another microbial mechanism potentially associated with RA. These findings highlight that multiple periodontal pathogens may contribute to autoimmune responses, although a definitive causal role has not yet been established. These citrullinated peptides can initiate an autoimmune response in genetically susceptible individuals, contributing to the development of RA (16,20).

Systemic inflammation is another common feature of both diseases, with elevated levels of pro-inflammatory cytokines, such as TNF-α, IL-6 and C-reactive protein (CRP). These markers not only reflect disease activity, but may also contribute to the pathogenesis of both RA and periodontitis (1).

Several observational studies have confirmed the association between RA and periodontitis. The Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, for example, revealed that individuals with severe periodontitis are at an increased risk of developing RA (21). Other studies have shown that patients with RA with periodontitis exhibit increased levels of systemic inflammation and worse disease outcomes (5,7).

Clinical intervention studies have also demonstrated the benefits of periodontal therapy in the management of RA. For example, Kaushal et al (22) reported that non-surgical periodontal treatment improved the disease activity score in 28 joints (DAS-28) in patients with RA, suggesting that managing periodontal health can have a positive impact on systemic inflammation in patients with RA.

Animal models have also been instrumental in elucidating the bidirectional association between RA and periodontitis. In a previous study, in a mouse model of collagen-induced arthritis, it was shown that when combined with Porphyromonas gingivalis infection, animals developed more severe joint damage (23). Similarly, the ligature-induced periodontitis model in rats has been used to determine how periodontal disease exacerbates systemic inflammation and joint pathology (24).

Double-hit models, in which both RA and periodontitis are induced simultaneously, provide further evidence for the synergistic association between these two diseases. These models reveal elevated levels of IL-17, RANKL and MMPs, mimicking the clinical scenario observed in human patients (25,26).

There are two primary theories that explain the connection between RA and periodontitis, as follows:

The clinical manifestations of RA and periodontitis involve inflammation and progressive tissue destruction, with overlapping inflammatory pathways that complicate diagnosis and management when both conditions are present.

RA typically presents with symmetrical polyarthritis, affecting both large and small joints, often beginning in the hands and feet. Symptoms include joint pain, stiffness, swelling and warmth of the affected joints (15,20). Morning stiffness that persists for at least 1 h tends to improve with movement. Over time, joint damage may cause deformities, such as ulnar deviation and swan-neck deformities. Systemic symptoms include fatigue, low-grade fever, weight loss and anemia. Extra-articular manifestations, such as rheumatoid nodules, cardiovascular complications, such as atherosclerosis, pulmonary fibrosis and severe rheumatoid vasculitis can also occur, affecting small blood vessels and causing skin lesions and ulcers (1,29).

Periodontitis, an inflammatory disease affecting the supporting structures of the teeth, is characterized by gingival inflammation, pocket formation, alveolar bone loss and tooth mobility. Clinical signs include bleeding gums, swelling and redness, which worsen with brushing or probing. As the disease progresses, deep periodontal pockets form, leading to tooth mobility and visible bone loss on radiographs. Gingival recession exposes tooth roots, causing sensitivity and aesthetic concerns. Severe periodontitis may result in abscesses, swelling, pain and pus formation. Halitosis often accompanies the disease due to bacterial activity in the pockets (30,31).

The bidirectional association between RA and periodontitis complicates clinical management. Patients with RA are often more susceptible to developing periodontal disease due to factors, such as immunosuppressive therapy, reduced manual dexterity and medication side-effects such as xerostomia. In turn, periodontitis in patients with RA can exacerbate systemic inflammation, worsen joint symptoms, and create a vicious cycle that accelerates joint damage and decreases treatment effectiveness. Chronic periodontal inflammation can significantly affect RA disease activity, rendering both conditions more difficult to manage (32).

The diagnosis of both RA and periodontitis involves a combination of clinical evaluation, laboratory testing and imaging studies. For patients with overlapping RA and periodontitis, early and accurate diagnosis is crucial for implementing effective treatment strategies.

Given the potential for increased disease severity when both RA and periodontitis co-occur, screening for periodontal disease in patients with RA and vice versa is strongly recommended. Routine oral assessments for patients with RA can aid in the early detection and management of periodontal disease, which may, in turn, aid in controlling the disease activity of RA. Conversely, screening patients with RA for periodontal involvement can improve the management of both conditions through a coordinated care approach (29,31).

The management of RA and periodontitis requires a comprehensive, interdisciplinary approach that addresses both local and systemic factors. Treatment for both conditions aims to control inflammation, prevent further damage and improve the overall quality of life of affected individuals.