Periodontitis Patients Likely To Suffer From Rheumatoid Arthritis Treatment
In recent years, research has increasingly confirmed a robust epidemiological link between periodontitis and rheumatoid arthritis (RA), with studies since 2017 reinforcing this connection. However, questions remain regarding the reciprocal effects of treating either condition and the underlying biological mechanisms. This review examines recent evidence addressing these unresolved issues, including the clinical impact of periodontal therapy on RA and potential mechanistic links identified in human and preclinical studies.
THE STUDY BACKGROUND
The link between periodontitis and rheumatoid arthritis (RA) has been extensively studied in recent decades, with epidemiological and mechanistic investigations aiming to elucidate their relationship [1]. Initial assessments of epidemiological data yielded inconsistencies, leading to uncertainties regarding the strength of the association [2]. However, subsequent research, including a comprehensive review in 2017, has solidified the evidence, elevating the epidemiological association from “minimal” to “substantial” [3].
Despite this clarity, questions persist regarding the reciprocal effects of treating periodontitis or RA and the underlying biological mechanisms linking the two conditions. This review aims to address these unresolved issues by examining recent evidence published since 2017, mainly focusing on the clinical impact of periodontal therapy on RA and potential mechanistic links identified in both human and preclinical studies.
THE STUDY METHOD
The methodology involves reviewing evidence published since 2017 to address unresolved questions about the relationship between periodontitis and rheumatoid arthritis (RA). Specifically, the focus is on assessing the clinical impact of periodontal therapy on RA and investigating potential mechanistic links through human and preclinical studies.
DISCUSSION AND RELEVANT FINDINGS
Clinical effect of Periodontal therapy on RA
The discussion focuses on the outcomes of randomized clinical trials (RCTs) investigating the effect of periodontal therapy on rheumatoid arthritis (RA), highlighting methodological variations among studies, such as follow-up periods ranging from 6 weeks to 24 months and varying patient populations and interventions. A recent systematic review with meta-analysis of nine RCTs concluded that non-surgical periodontal treatment could improve various RA parameters, including Disease Activity Score relating to 28 joints assessed (DAS28), tender joint counts (TJCs), swollen joint counts (SJCs), visual analog scale (VAS), and serum C-reactive protein (CRP). However, the review also noted limitations in the quality of evidence due to selection bias and the dynamic nature of RA medication, emphasizing the urgent need for well-designed studies in this area [4].
Despite the clarity provided by RCTs, non-randomized clinical studies, though excluded from meta-analyses, support the beneficial effect of periodontal therapy on RA parameters [4]. Additionally, concerns arise about whether RA affects the efficacy of periodontal treatment, with a systematic review indicating no significant impact [5]. Furthermore, some studies investigate whether the severity of periodontitis influences the response to RA medications, suggesting an association between periodontitis severity and poorer clinical response to specific RA treatments [6].
These findings underscore the complexity of addressing the relationship between periodontitis and RA and highlight the need for further research to optimize treatment strategies for patients with both conditions.
Clinical effect of RA therapy on periodontitis
The discussion explores the clinical effect of rheumatoid arthritis (RA) therapy on periodontitis, focusing on the potential impact of biologic disease-modifying anti-rheumatic drugs (bDMARDs) on periodontal health. While RA treatment has evolved with bDMARDs targeting specific steps of the inflammatory process, their influence on periodontitis remains uncertain [7].
Studies evaluating the effect of RA drugs on periodontal and inflammatory parameters of patients with periodontitis show limited impact. However, caution is advised due to methodological limitations and reliance on surrogate measures of inflammation [7]. Challenges in assessing the oral effects of bDMARDs include limited reporting, changes in medication indications over time, and the emergence of new drugs such as Janus kinase (JAK) inhibitors [7]. Despite these complexities, the established epidemiological relationship between RA and periodontitis underscores the importance of investigating the impact of periodontal therapy on RA outcomes.
Groundbreaking studies have begun to shed light on the mechanism underlying this link, particularly regarding host-pathogen interactions at mucosal surfaces and their role in precipitating joint inflammation [8]. Human studies investigating citrullination, anti-citrullinated antibodies, the microbiota, and inflammation as potential mediators of the periodontitis-RA link are summarized, alongside animal studies evaluating associated features of both conditions [8].
Potential Mechanisms Linking Periodontitis and Rheumatoid Arthritis
The potential mechanisms linking periodontitis and rheumatoid arthritis (RA) have been the subject of intensive research. One proposed mechanism involves periodontitis-mediated citrullination and carbamylation, which may contribute to developing anti-citrullinated autoimmunity, a hallmark of RA. Citrullinated proteins, detected in both gingival tissues and synovium, suggest a possible extra-articular initiation of RA at mucosal surfaces [9]. Notably, citrullinated proteins were found in gingival biopsies and were associated with increased expression of peptidyl arginine deiminase (PAD) enzymes, suggesting a role for periodontal tissues as a source of antigens recognized by the immune system in RA [9].
Furthermore, studies investigating anti-citrullinated antibodies (ACPA) in periodontitis patients yielded variable results. Some studies suggested an association between periodontitis and ACPA positivity in systemically healthy individuals [10], while others found no evidence of such an association in patients with RA. However, studies on first-degree relatives of RA patients showed a higher prevalence of periodontitis in ACPA-positive individuals, suggesting a potential link between periodontitis and ACPA production.
The oral bacterial microbiota may also play a role in RA pathogenesis, with dysbiosis associated with RA even in periodontally healthy individuals [11]. Specific oral pathogens like Porphyromonas gingivalis and Aggregibacter actinomycetemcomitans are hypothesized to drive citrullination locally within periodontal tissues and induce ACPA production [9]. Additionally, Fusobacterium nucleatum was shown to exacerbate arthritis via outer membrane vesicles translocating to the joint, suggesting a possible contribution of periodontal pathogens to RA pathogenesis [12].
Inflammation is another potential link between periodontitis and RA. Experimental periodontitis induced epigenetic changes in hematopoietic stem and progenitor cells, exacerbating responses to experimental arthritis [13]. Studies also found elevated levels of inflammatory markers in the saliva and gingival fluid of RA patients, suggesting a bidirectional association between oral inflammation and RA severity.
Overall, while evidence suggests a complex interplay between periodontitis and RA, further research is needed to elucidate the molecular mechanisms and therapeutic targets underlying this relationship. Longitudinal studies are crucial to determine whether citrullination or carbamylation in periodontal tissues precedes RA development.
Animal studies of the relationship between Periodontitis and RA
Animal models are crucial in understanding disease pathogenesis, identifying treatment targets, and testing novel therapies. However, studying the relationship between two diseases, such as periodontitis and rheumatoid arthritis (RA), in animal models presents numerous challenges due to the variability in models, experimental protocols, and outcome measures. Nonetheless, animal studies provide essential proof of concept and preclinical data. For example, infection of DBA1/J mice with wild-type P. gingivalis has been shown to induce the development of anti-citrullinated protein antibodies (ACPAs), implicating peptidyl arginine deiminase (PPAD) in ACPA generation [14].
In a recent review of 26 animal studies combining periodontitis and arthritis models, the studies were highly heterogeneous, using different models and interventions. Of these studies, 21 combined models of periodontitis with arthritis, while the remaining five focused on outcomes relevant to the pathogenesis of the other disease. The results varied, with 19 out of 23 studies reporting that periodontitis exacerbated arthritis, while 8 out of 16 studies showed that arthritis exacerbated periodontitis. However, there were inconsistencies in the findings, reflecting variations in model protocols and other factors [15].
Some studies suggested that disruption of oral homeostasis, as induced by periodontitis, could lead to distant changes in the joint, while others reported no impact. Conversely, arthritis alone was found to alter the oral barrier in some cases, leading to alveolar bone loss, although this was not universally observed. One intriguing finding is the proposal that compromised gut barrier integrity due to arthritis allows oral bacteria to mediate systemic inflammatory effects and exacerbate arthritis [15].
Overall, while there is a consistent pattern of periodontitis exacerbating RA in most animal models, discrepancies exist, likely due to variations in model protocols, animal strains, and environmental factors. Despite these limitations, animal models offer valuable insights into the mechanisms by which periodontitis and RA relate to each other, though translating these findings to humans remains a challenge [15].
European contribution to the field
European researchers have contributed to understanding the connection between periodontitis and rheumatoid arthritis (RA). Collaboration between European universities and institutions globally has facilitated research in this field. Three major European projects from 2010 to 2017 have contributed extensively to this area. One such project, GUMS AND JOINTS, investigated the link between periodontitis and RA, pioneering studies on P. gingivalis PPAD (peptidyl arginine deiminase) and analyzing epidemiological data of both diseases [16].
Another project, RAPID, focused on training highly skilled researchers and advancing discoveries on the relationship between periodontitis and RA. The third project, TRIGGER, explored the impact of periodontal pathogens on various diseases and treatment strategies. These projects generated numerous publications, conferences, and workshops, significantly advancing the understanding of the epidemiology, microbiological, and immunological mechanisms underlying periodontitis and RA. While the details of these projects are not extensively covered in the current narrative review, their contributions have been pivotal in shaping the field [16].
CONCLUSION
This narrative review highlights the intricate relationship between periodontitis and arthritis, underlining their evident epidemiological association. However, comprehending this connection poses substantial challenges due to the multifaceted nature of both conditions.
Concerning the next steps, there is a pressing need to explore innovative methodologies to unravel these complexities and enhance prevention and treatment strategies for improved health outcomes. By addressing the intricate interplay between oral and systemic health, researchers can contribute to fostering a healthier future for individuals and communities alike.
References
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- Hussain SB, Botelho J, Machado V, et al. Is there a bidirectional association between rheumatoid arthritis and periodontitis? A systematic review and meta-analysis. Semin Arthritis Rheum. 2020; 50(3):414-422. (https://doi.org/10.1016/j.semarthrit.2020.01.009)
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- Al-Katma MK, Bissada NF, Bordeaux JM, Sue J, Askari AD. Control of periodontal infection reduces the severity of active rheumatoid arthritis. J Clin Rheumatol. 2007; 13(3):134-137. (https://doi.org/10.1097/RHU.0b013e3180690616)
- Ortiz P, Bissada NF, Palomo L, et al. Periodontal therapy reduces the severity of active rheumatoid arthritis in patients treated with or without tumor necrosis factor inhibitors. J Periodontol. 2009; 80(4):535-540. (https://doi.org/10.1902/jop.2009.080447)
- Pinho MD, Oliveira RD, Novaes AB Jr, Voltarelli JC. Relationship between periodontitis and rheumatoid arthritis and the effect of non-surgical periodontal treatment. Braz Dent J 2009; 20(5):355-364. (https://doi.org/10.1590/S0103-64402009000500001)
- Okada M, Kobayashi T, Ito S, et al. Periodontal treatment decreases levels of antibodies to Porphyromonas gingivalis and Citrulline in patients with rheumatoid arthritis and periodontitis. J Periodontol. 2013; 84(12):e74-e84. (https://doi.org/10.1902/jop.2013.130079)
- Monsarrat P, Fernandez de Grado G, Constantin A, et al. The effect of periodontal treatment on patients with rheumatoid arthritis: the ESPERA randomized controlled trial. Joint Bone Spine. 2019; 86(5):600-609. (https://doi.org/10.1016/j.jbspin.2019.02.006)
- Kaushal S, Singh AK, Lal N, das SK, Mahdi AA. Effect of periodontal therapy on disease activity in rheumatoid arthritis patients with chronic periodontitis. J Oral Biol Craniofac Res. 2019; 9(2):128-132. (https://doi.org/10.1016/j.jobcr.2019.02.002)
- Mariette X, Perrodeau E, Verner C, et al. Role of good oral hygiene on the clinical evolution of rheumatoid arthritis: a randomized study nested in the ESPOIR cohort. Rheumatology. 2020; 59(5):988-996. (https://doi.org/10.1093/rheumatology/kez368)
- Nguyen VB, Nguyen TT, Huynh NC, Nguyen KD, Le TA, Hoang HT. Effects of non-surgical periodontal treatment in rheumatoid arthritis patients: a randomized clinical trial. Dent Med Probl. 2021; 58(1):97-105. (https://doi.org/10.17219/dmp/131266)
- Balci Yuce H, Gokturk O, Aydemir Turkal H, Inanir A, Benli I, Demir O. Assessment of local and systemic 25-hydroxy-vitamin D, RANKL, OPG, and TNF levels in patients with rheumatoid arthritis and periodontitis. J Oral Sci. 2017; 59(3):397-404. (https://doi.org/10.2334/josnusd.16-0677)
- Kurgan S, Önder C, Balcı N, et al. Gingival crevicular fluid tissue/blood vessel-type plasminogen activator and plasminogen activator inhibitor-2 levels in patients with rheumatoid arthritis: effects of non-surgical periodontal therapy. J Periodontal Res. 2017; 52(3):574-581. (https://doi.org/10.1111/jre.12425)
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- Lopez-Oliva I, Malcolm J, Culshaw S. Periodontitis and rheumatoid arthritis—Global efforts to untangle two complex diseases. Periodontol 2000. 2024; 00:1-19. (https://doi.org/10.1111/prd.12530)
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