This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This review examines the bidirectional relationship between periodontitis and systemic health conditions, offering an integrated perspective based on current evidence. It synthesizes epidemiological data, biological mechanisms, and clinical implications to support collaborative care strategies recognizing oral health as a key component of overall wellness. Periodontitis affects 7.4% to 11.2% of adults worldwide, and its prevalence increases with age. Beyond its local effects, including gingival inflammation, periodontal pocket formation, and alveolar bone loss, periodontitis is associated with various systemic conditions. Emerging evidence has established links with obesity, diabetes mellitus, cardiovascular disease, chronic kidney disease, inflammatory bowel disease, rheumatoid arthritis, respiratory diseases, adverse pregnancy outcomes, certain malignancies, neurodegenerative diseases, psychological disorders, and autoimmune conditions. These associations are mediated by 3 primary mechanisms: dysbiotic oral biofilms, chronic low-grade systemic inflammation, and the dissemination of periodontal pathogens throughout the body. The pathophysiology involves elevated levels of pro-inflammatory cytokines (including interleukin 6, tumor necrosis factor alpha, and C-reactive protein), impaired immune function, oxidative stress, and molecular mimicry. Periodontal pathogens, particularly Porphyromonas gingivalis, are crucial in initiating and sustaining systemic inflammatory responses. Treatment of periodontitis has demonstrated measurable improvements in numerous systemic conditions, emphasizing the clinical significance of these interconnections. Periodontitis should be understood as more than just a localized oral disease; it significantly contributes to the overall systemic inflammatory burden, with implications for general health. An integrated, multidisciplinary approach to prevention, early detection, and comprehensive treatment is vital for optimal patient outcomes. Healthcare providers should acknowledge oral health as an essential element of systemic well-being.
Periodontitis is a chronic inflammatory disease known to affect the supportive structures of the teeth [1-3]. In addition to its local impacts, such as gingival inflammation, periodontal pocket formation, and alveolar bone loss, periodontitis is strongly associated with systemic inflammation, which leads to various systemic conditions. These include obesity, diabetes mellitus, cardiovascular disease, pregnancy, chronic kidney disease (CKD), respiratory diseases, rheumatoid arthritis, neurodegenerative diseases, malignancy, stress, depression, and autoimmunity [1-7].
The global prevalence of periodontitis underscores its status as a public health issue. Overall, 7.4% [2] to 11.2% [3] of the adult population exhibit severe periodontitis, with a higher prevalence among older generations. The rising prevalence of this condition in tandem with increasing life expectancy, as well as reductions in root caries-related tooth loss, make periodontitis a primary concern given its adverse economic, social, and health system impacts [2]. In 2015, severe periodontitis accounted for an estimated 3.5 million disability-adjusted life years, exceeding the burden of untreated dental caries [8]. Nevertheless, its indirect consequences, such as reduced chewing efficiency, aesthetic compromise, and diminished quality of life, remain underemphasized [8].
The biological mechanisms underpinning these systemic links are multifactorial, including dysbiotic oral biofilms, chronic low-grade inflammation, and the dissemination of periodontal pathogens and their bioproducts throughout the body [1]. These mechanisms trigger an immune reaction that causes additional local tissue damage while mediating systemic inflammatory states, thereby altering the pathophysiology of diseases beyond the oral cavity [6].
However, findings regarding periodontitis and systemic conditions have sometimes been misinterpreted due to a lack of uniformity in study design, inconsistent disease definitions, and small sample sizes [1-8]. With improved definitions of periodontal diseases and global research guidelines, these issues are now being addressed, paving the way for more robust and reproducible studies [4,5,7].
Objectives
The purpose of this review is to provide an integrative perspective, based on contemporary evidence, on the relationship between periodontitis and systemic diseases. Grounded in epidemiologic data, biological plausibility, and clinical implications, the review underscores the ongoing need for collaborative care strategies that recognize oral health as an integral component of general health and wellness.
Ethics statement
As this study is a literature review, it did not require institutional review board approval or individual consent.
Periodontitis and obesity
Obesity is known to be strongly associated with periodontitis [9-13]. Individuals with a body mass index of 30 kg/m2 or greater face a significantly elevated risk of periodontal disease [9,11,14-16]. Many studies have found that obesity contributes to periodontitis through systemic inflammation, altered immune function, and dysbiosis of the oral microbiota [9,10,12,13,17-19]. Studies report that central obesity, particularly when defined using the waist-to-hip ratio, significantly increases the likelihood of developing periodontitis [10-12,18]. Various meta-analyses have demonstrated a linear dose-response correlation of adiposity with the risk and severity of periodontal tissue damage [10,18,20,21]. Prospective studies have revealed that individuals with overweight and obesity experience more rapid progression of periodontitis compared to their normal-weight counterparts [14,16,20].
Obesity drives chronic low-grade systemic inflammation, characterized by elevated levels of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP) [11]. These cytokines exacerbate the destruction of periodontal tissues by disturbing the balance between bone resorption and regeneration [22-24]. Dysbiotic changes in the oral microbiome, such as an increase in gram-negative anaerobic bacteria, create an ideal environment for the development of periodontal disease [17,19]. Other factors, such as adipokines, also link obesity to periodontitis [20,23,25]. For example, increased leptin levels mediate inflammation, while low adiponectin levels impair tissue repair and regeneration [26,27]. Insulin resistance associated with obesity further compromises immune cell function, reducing the capacity of the immune system to defend against bacterial infections of the periodontal tissues [25].
Clinical guidelines
A comprehensive, multidisciplinary approach is necessary to manage periodontal disease in patients with obesity. Effective periodontal treatment, such as scaling and root planing, helps reduce microbial load and inflammation [28]; however, adjunctive anti-inflammatory medications may also be required. Dentists should emphasize the importance of weight management and lifestyle changes—particularly regarding diet and exercise—in decreasing systemic inflammation. Active collaboration with primary physicians and nutritionists is essential for addressing comorbidities. Regular follow-up appointments should ideally occur every 3 to 4 months to evaluate periodontal disease progression and the effectiveness of treatment strategies [29]. Patient education should focus on fostering intrinsic motivation to maintain good oral health and on understanding the interactive relationship between obesity and periodontal health [28,29].
Periodontitis and diabetes mellitus
Diabetes mellitus and periodontitis have a well-established reciprocal association. Periodontitis is termed the sixth complication of diabetes, and patients with diabetes are about 3 times more likely to develop severe periodontitis as their nondiabetic counterparts [28,30-33]. Hyperglycemia exacerbates periodontal disease by promoting oxidative stress and the formation of advanced glycation end products [34-37]. Conversely, periodontitis worsens glycemic control by increasing the systemic inflammatory load. Longitudinal research indicates that patients with poorly managed diabetes experience more severe periodontal tissue loss and recover more slowly after therapy compared to those without diabetes.
Diabetes accelerates the deterioration of periodontal tissue through several mechanisms [34]. Oxidative stress induced by chronic hyperglycemia results in an overabundance of advanced glycation end products, which attach to receptors on various cells [35]. This interaction triggers the release of pro-inflammatory cytokines, including TNF-α and IL-6, thereby exacerbating both local and systemic inflammation [38]. Furthermore, reduced neutrophil function in patients with diabetes impairs pathogen removal, while elevated CRP levels contribute to delayed wound healing [39,40]. Pathogens such as Porphyromonas gingivalis worsen systemic insulin resistance by triggering inflammatory cytokine cascades [41].
Clinical guidelines
Effective management of periodontal disease in patients with diabetes requires cooperation between dentists and endocrinologists. Individuals with poorly controlled diabetes should undergo periodontal evaluation every 3 months. Non-surgical therapy, including scaling and root planing, improves glycemic control, with reductions in hemoglobin A1c levels of up to 0.4% [28]. During invasive procedures for patients with uncontrolled diabetes, the dentist should monitor blood glucose levels and administer prophylactic antibiotics. A focused educational program can inform patients about the role of oral health in glycemic control. Individualized oral hygiene measures, including antiseptic mouthwashes and interdental cleaning, should be encouraged for all patients. Nutritional counseling and smoking cessation programs also contribute to improved treatment outcomes [42].
Periodontitis and cardiovascular disease
Epidemiological evidence supports a robust association between periodontitis and cardiovascular disease [43-45]. Severe periodontitis increases the risk of major adverse cardiovascular events, such as myocardial infarction or stroke, by a factor of 1.4 [44]. The primary mechanisms linking these conditions include chronic inflammation, endothelial dysfunction, and microbial dissemination [46,47]. Periodontal pathogens such as P. gingivalis have been detected in atherosclerotic plaques, demonstrating the systemic impact of periodontitis [48]. Longitudinal studies indicate that periodontitis accelerates the progression of cardiovascular disease by elevating levels of certain systemic inflammatory markers, such as CRP [49].
Periodontal inflammation provokes a systemic acute-phase response, increasing levels of CRP, IL-6, and TNF-α [49-52]. These inflammatory mediators can act on the endothelium, causing dysfunction and promoting atherogenesis. Lipopolysaccharides from periodontal pathogens, particularly P. gingivalis, circulate into the bloodstream, triggering macrophage foam cell formation and rapid plaque development [53-55]. Periodontal infections also promote platelet aggregation, thereby increasing the risk of thrombosis. Dysbiotic changes in the oral microbiota further induce systemic inflammation, creating a feedback loop that aggravates both periodontal and cardiovascular conditions [56].
Clinical guidelines
The management of patients with cardiovascular disease complicated by periodontal disease may require additional medications and follow-up visits with a cardiologist. The dentist should assess the risk of bleeding for patients on antiplatelet or anticoagulant therapy before performing invasive procedures [57,58]. Non-surgical periodontal therapy, in conjunction with adjunctive anti-inflammatory medication to reduce systemic inflammation, is a promising approach [59]. Regular dental check-ups, typically every 3 to 4 months, are recommended to monitor oral health and mitigate systemic risk factors, avoiding delayed diagnosis of any issues. Patients should be informed of the potential cardiovascular benefits of maintaining good periodontal health. Preventive lifestyle changes, such as smoking cessation and dietary modifications, are crucial for improving treatment outcomes [60].
Periodontitis and chronic kidney disease
Periodontitis and CKD share a bidirectional relationship. Patients with CKD are predisposed to eburnation due to immune dysfunction; as such, they may experience persistent periodontal inflammation that, in turn, accelerates CKD progression [61-63]. Observational studies have also shown that patients with advanced periodontal disease are at an increased risk of developing further renal impairment [62,64]. Furthermore, periodontal therapy has been linked to improvements in renal parameters, such as serum creatinine and estimated glomerular filtration rate [65].
Chronic systemic inflammation driven by periodontal pathogens, such as P. gingivalis, may contribute to the onset of CKD [66]. Elevated concentrations of pro-inflammatory cytokines—including IL-6, TNF-α, and CRP—further amplify endothelial dysfunction and oxidative stress in renal tissues [67,68]. Bacterial pathogens and their endotoxins can enter the bloodstream, creating a pro-inflammatory state that provokes renal damage. Furthermore, uremia in CKD impairs immune responses, exacerbating the adverse effects on both periodontal and kidney health [69].
Clinical guidelines
Managing periodontal disease in patients with CKD necessitates close collaboration with nephrologists. Periodontal examinations are recommended every 3 months to control microbial load and, consequently, systemic inflammation. Non-surgical periodontal therapies, such as scaling and root planing, have been shown to be effective in reducing systemic inflammatory markers among those with CKD [70-72]. Dentists should avoid prescribing medications that may compromise renal function and must carefully manage bleeding tendencies in patients taking anticoagulants [65,70]. Patient education should emphasize proper oral hygiene and the interrelationship between periodontal and kidney health. Nutritional counseling for these patients may also include recommendations to reduce sodium and phosphate intake.
Periodontitis and inflammatory bowel disease
Epidemiological evidence suggests a strong association between inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, and periodontitis [73]. Patients with IBD exhibit a significantly increased frequency and severity of periodontitis, characterized by greater clinical attachment loss and deeper periodontal pockets [74,75]. Both conditions share common inflammatory pathways, with elevated levels of pro-inflammatory cytokines—namely IL-6, IL-1β, and TNF-α—contributing significantly to tissue destruction at both systemic and local levels [76,77]. Microbiota dysbiosis also plays a major role; periodontitis is marked by an overgrowth of pathogenic bacteria, such as P. gingivalis and Fusobacterium nucleatum, which may translocate to the gut and exacerbate IBD symptoms [78]. In addition, shared genetic predispositions, including polymorphisms in IL23R and NOD2, support a common immunological basis for these conditions [79].
Clinical guidelines
Given this bidirectional interaction, the dental regimen for patients with IBD should include routine periodontal examinations, oral hygiene instruction, and non-invasive periodontal therapy to reduce bacterial load [73,80]. During active IBD flares, extreme caution is advised when scheduling dental treatments. Non-steroidal anti-inflammatory drugs, which may aggravate gut inflammation, should be avoided. Due to the immunosuppressive state, prophylactic antibiotics may be considered [81-83]. Close collaboration between dentists and gastroenterologists is essential to enhance periodontal health and, when possible, reduce systemic inflammation to improve IBD management [84].
Periodontitis and rheumatoid arthritis
Periodontitis and rheumatoid arthritis share common inflammatory pathways and genetic predispositions, which underpin the relationship between these conditions. Studies have shown that individuals with rheumatoid arthritis are nearly twice as likely to develop periodontitis compared to the general population [85]. This is a reciprocal association, as periodontitis exacerbates systemic inflammation in rheumatoid arthritis, potentially worsening joint symptoms [86,87]. Moreover, observational studies have demonstrated that untreated periodontitis is associated with higher disease activity scores in patients with rheumatoid arthritis, highlighting the impact of local and systemic oral inflammation [86].
The pathogenic link between periodontitis and rheumatoid arthritis primarily involves immune dysregulation driven by P. gingivalis, a major periodontal pathogen. This organism produces peptidylarginine deiminase, an enzyme that catalyzes the citrullination of proteins—a hallmark of the pathogenesis of rheumatoid arthritis [88,89]. The citrullination process results in the generation of anti-citrullinated protein antibodies, which promote joint inflammation [90]. Elevated levels of inflammatory cytokines, such as TNF-α, IL-6, and IL-17, are common to both periodontitis and rheumatoid arthritis, contributing to systemic and local tissue destruction [91,92]. Additionally, dysbiosis of the oral microbiome perpetuates inflammatory cycles, creating a vicious feedback loop that increases the severity of both diseases [93].
Clinical guidelines
Effective management of periodontitis in patients with rheumatoid arthritis requires a multidisciplinary approach. Collaboration between periodontal and rheumatology teams is essential to concurrently address systemic and oral inflammation. Follow-up periodontal examinations should be performed every 3 months. Evidence indicates that non-surgical periodontal therapy, including scaling and root planing, reduces systemic inflammatory markers and improves rheumatoid arthritis symptoms. In severe cases, adjunctive therapies—such as anti-inflammatory or antibiotic treatments—may be considered [94,95]. Patients should receive oral hygiene instructions, including proper techniques for brushing, flossing, the use of interdental brushes, and chlorhexidine rinses. Given that smoking is a known aggravating factor for both rheumatoid arthritis and periodontitis, smoking cessation should be strongly encouraged [96]. Nutritional counseling aimed at avoiding inflammatory food triggers may further improve overall health outcomes for these patients.
Periodontitis and respiratory diseases
Evidence suggests that periodontitis may play a role in the evolution and exacerbation of respiratory diseases such as pneumonia, chronic obstructive pulmonary disease (COPD), and asthma [97]. Strong evidence indicates that aspiration of oral contents into the respiratory tract can initiate or worsen respiratory tract infections [98,99]. Severe periodontitis is associated with an increased prevalence of pneumonia, particularly among hospitalized and ventilated patients. Studies have also reported a higher tendency for the development of COPD in individuals with periodontitis, with inflammatory markers and microbial load serving as significant mediators [98,100].
The translocation of oral pathogens, including bacteria such as P. gingivalis and F. nucleatum, into the respiratory tract is a key factor in the pathogenesis of periodontitis-related respiratory diseases [101,102]. These pathogens stimulate local and systemic inflammation, triggering the release of pro-inflammatory cytokines such as IL-1β and TNF-α and thereby aggravating airway inflammation and tissue damage. The dysbiosis observed in the oral cavity and respiratory tract is driven by the uncomplicated colonization of these bacteria. Toxins associated with the periodontium serve as markers of systemic inflammation, weakening the respiratory system’s immune defense against pathogens and increasing the risk of infection [101,102].
Clinical guidelines
Managing periodontal health in patients with respiratory diseases requires a preventive approach. Regular dental checkups, professional cleanings, and improved oral hygiene practices are essential to minimize the risk of aspiration-related infections. The use of antimicrobial mouthwashes and effective plaque control techniques can significantly reduce the bacterial load in the oral cavity [103]. Collaboration with pulmonologists is recommended for patients with severe respiratory conditions, particularly those who are immunocompromised or on ventilatory support [103]. Patient education should emphasize the importance of maintaining oral health, including smoking cessation, to improve respiratory outcomes and overall quality of life [104].
Periodontitis and adverse pregnancy outcomes
Periodontitis has been shown to be significantly correlated with adverse pregnancy outcomes, including preterm birth, low birth weight, and preeclampsia [105,106]. In pregnant women with untreated periodontal disease, the risk of such outcomes is about 1.5 times greater than in those without periodontal disease [107]. Periodontal infection is thought to alter fetal intrauterine development through systemic inflammation and the dissemination of microflora from periodontal pockets. Meta-analyses have confirmed the correlation between maternal periodontal disease and preterm birth, particularly among women with severe periodontitis [107]. In addition, elevated levels of inflammatory biomarkers such as IL-6 and CRP in mothers with periodontitis are linked to impaired placental function [108].
The underlying pathophysiology involves both local and systemic inflammatory mechanisms. Oral pathogens, such as F. nucleatum, can migrate from the periodontal tissues to the placenta, triggering an immune response that ultimately destabilizes placental integrity [109]. Elevated levels of cytokines, including IL-1β, TNF-α, and prostaglandins, can provoke uterine contractions, leading to preterm birth [110]. Chronic periodontal inflammation potentiates oxidative stress and endothelial dysfunction, jeopardizing fetal nutritional supply and growth [111,112]. Dysbiosis of the maternal oral microbiota further increases systemic inflammation, initiating a cascade of adverse pregnancy events [113].
Clinical guidelines
Managing periodontal disease in pregnant women requires adherence to specific strategies, as improper management may lead to systemic inflammation. Non-surgical periodontal therapies such as scaling and root planing can be safely performed during the second trimester [114,115]. Regular oral examinations, along the use of antimicrobial mouthwashes and other oral hygiene methods, are consistently recommended for high-risk pregnancies [115-117]. Pregnant women should be informed of the maternal and fetal complications associated with untreated periodontal disease. Obstetricians should collaborate closely for high-risk pregnancies to ensure coordinated healthcare. Moreover, prenatal care may be optimized by incorporating targeted nutritional guidance and smoking cessation support, promoting both maternal and fetal health.
Periodontitis and malignancy
Periodontitis has been implicated as a precipitating factor for various malignancies, especially oral, pancreatic, and colorectal cancers [118-120]. Chronic inflammation, induced by persistent infection and immune dysregulation, is the primary factor linking periodontitis to tumor development and progression [121]. Certain pathogens, such as F. nucleatum, have been shown to play a role in the etiology of colorectal cancer, modulating the tumor microenvironment and stimulating metastasis [122,123].
The connection between periodontitis and malignancy occurs through both direct and indirect mechanisms. The sustained inflammation in periodontal tissues leads to the systemic release of pro-inflammatory cytokines, such as IL-6 and TNF-α, which, in turn, promote angiogenesis and enable immune evasion during tumor growth [124,125]. Oncogenic signaling pathways are activated when oral pathogens, including F. nucleatum, adhere to epithelial cells, thereby encouraging cell proliferation and survival [123]. Furthermore, dysbiosis of the oral microbiome fosters additional systemic inflammation that supports carcinogenesis. Increased oxidative stress associated with chronic gingival infections also contributes to DNA damage, potentially heightening the risk of malignant transformation [126,127].
Clinical guidelines
For patients with cancer or at risk of cancer, intervention aimed at chemoprevention should incorporate maintenance of periodontal health [128]. Periodontal examinations and cleanings should be performed regularly to reduce systemic inflammation and microbial load [129]. Collaboration with oncologists is necessary to develop an effective dental care protocol, especially for patients undergoing chemotherapy and radiation therapy, whose side effects impact oral health [119]. Specifically, dentists should educate patients on the benefits of maintaining proper oral hygiene—such as regular brushing—and the use of topical measures, including fluoride applications and antimicrobial rinses [130,131]. Nutritional counseling may also help bolster immune support and manage systemic inflammation.
Periodontitis and neurodegenerative diseases
The mechanisms linking periodontitis with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, include both systemic inflammation and direct microbial invasion [132-135]. Periodontal pathogens, particularly P. gingivalis, produce virulent factors—specifically, gingipains—that compromise the integrity of the blood-brain barrier, allowing bacteria and inflammatory mediators to enter the central nervous system [136]. This process triggers microglial activation and the release of pro-inflammatory cytokines, such as TNF-α and IL-1β, which further contribute to neuronal damage [137,138]. Additionally, P. gingivalis has been shown to induce the deposition of amyloid-β plaques and the phosphorylation of tau proteins, both hallmarks of Alzheimer’s disease [139]. Systemic inflammation caused by chronic periodontitis may further augment oxidative stress and neuroinflammation, thereby accelerating neurodegeneration [140].
Clinical guidelines
For patients at risk of developing neurodegenerative diseases, as well as those already diagnosed, an ongoing, preventive approach to managing periodontitis is recommended. Regular dental appointments and periodic cleanings should be instituted to minimize the microbial burden and reduce systemic inflammation [141]. Caregivers should be involved to help ensure adherence to proper oral health practices, such as brushing with fluoride toothpaste and using an antimicrobial mouthwash. Collaboration with neurologists is recommended to monitor the interplay between oral and cognitive health. Dentists should educate patients on the importance of maintaining oral health for overall neurological function. For individuals in the advanced stages of neurodegenerative disease, care plans should be personalized to account for physical and cognitive limitations [142].
Periodontitis, stress, and depression
Stress and depression are strongly correlated with periodontitis through both behavioral and physiological mechanisms. Studies indicate that individuals experiencing chronic stress or depression may require more extensive periodontal treatment, with odds ratios reaching approximately 1.5 compared to those without these conditions [143-145]. Lifestyle factors common among stressed or depressed individuals, such as poor oral hygiene, smoking, and unfavorable dietary practices, can exacerbate the progression of periodontal disease [144,146]. Additionally, depression heightens systemic inflammation, contributing to periodontal tissue breakdown [147]. Stress-related hormones, particularly cortisol, interfere with the immune response by suppressing the activity of immune cells that target periodontal pathogens, which can lead to increased bacterial proliferation and inflammation in periodontal tissues [148]. In conjunction with depression, stress elevates the release of pro-inflammatory cytokines such as IL-6 and TNF-α, further worsening tissue destruction and bone resorption [148].
Clinical guidelines
Managing periodontal disease in patients experiencing stress or depression requires a holistic approach that addresses both psychological and oral health [149,150]. Dentists should collaborate with mental health professionals to provide integrated care. Regular periodontal evaluations and cleanings are recommended to control bacterial load and reduce inflammation. To improve overall health outcomes, stress relief options such as mindfulness, counseling, or cognitive-behavioral therapy should be suggested. Dentists should educate patients about the importance of maintaining good oral hygiene and the bidirectional relationship of stress and depression with periodontal health. In addition, treatments may include the use of antimicrobial mouthwashes and anti-inflammatory medications to help control inflammation. Furthermore, smoking cessation and nutritional counseling to support immune function should be key components of the treatment regimen [151,152].
Periodontitis and autoimmunity
Autoimmune diseases such as systemic lupus erythematosus, diabetes mellitus type 1, and rheumatoid arthritis share inflammatory pathways and dysregulated immune responses with periodontitis. In these conditions, periodontal attachment loss is often particularly severe. Meta-analyses have revealed that systemic lupus erythematosus significantly increases the risk of periodontitis compared to the general population [153,154]. These conditions are characterized by elevated inflammatory markers, such as CRP, which link systemic inflammation with the progression of oral disease. However, apart from studies on rheumatoid arthritis, there is a marked deficiency of well-designed studies investigating the correlation between periodontitis and other autoimmune diseases, largely due to methodological weaknesses—particularly the inconsistent use of clinical indices. Thus, the conclusions that can be drawn at this time are limited and should be interpreted with discretion [155-158]. P. gingivalis-induced molecular mimicry and immune dysregulation exacerbate the autoimmune response by elevating IL-17 levels, which in turn causes further destruction of periodontal tissues [159]. In the production of autoantibodies, a process known as citrullination, P. gingivalis has been shown to contribute to several autoimmune diseases, especially rheumatoid arthritis. Dysbiosis of the oral microbiome enhances systemic immune activation and further impairs tissue repair mechanisms. Moreover, periodontal pathogens stimulate dendritic cell maturation and the release of pro-inflammatory cytokines, thereby intensifying autoimmune activity and tissue destruction [160].
Clinical guidelines
Patients with autoimmune diseases require multidisciplinary care to effectively manage both systemic and periodontal inflammation. Coordination between dental professionals and rheumatologists can facilitate favorable treatment outcomes. Periodontal debridement should ideally be performed at least every 3 months, depending on the severity of the condition, to reduce bacterial load and inflammation. In addition, anti-inflammatory and immunomodulatory therapies tailored to the patient’s systemic condition may positively impact periodontal outcomes [161]. Dentists must carefully evaluate and consider the potential oral side effects of systemic treatments, such as dry mouth caused by immunosuppressive therapies; in such cases, adjunctive therapies like topical fluorides and artificial saliva support may be necessary [161-163]. For patients receiving biologic or high-dose immunosuppressive therapies, medical clearance may be required prior to dental treatment [162].
Conclusion
Periodontitis is a chronic inflammatory condition with significant implications for systemic health. It is more than simply a localized oral disease, as evidenced by its established associations with systemic conditions such as diabetes, cardiovascular disease, adverse pregnancy outcomes, respiratory disorders, autoimmune diseases, and neurodegenerative diseases. These links are mediated by dysbiotic biofilms, systemic inflammation, and the dissemination of bacterial components and inflammatory mediators into the circulation—mechanisms implicated in the pathogenesis of numerous systemic diseases.
Despite extensive research on periodontitis, historical impediments such as varying definitions of the disease, differences in study design, and small sample sizes have limited the comparability of findings. However, recent advances in classification systems and evidence-based research guidelines have substantially improved the quality and interpretability of periodontal studies, enabling researchers to better understand the systemic implications.
This review underlines the need for an integrated approach to the management of periodontitis. Collaborative care across dental and medical disciplines can address the systemic effects of periodontitis and oral diseases, improving both oral and general health outcomes. Given the rising prevalence of periodontitis due to aging populations, increased life expectancy, and lifestyle issues, such an effort is especially timely.
In addressing periodontitis and systemic disease, priority should be given to prevention, early detection, and comprehensive treatment within an integrated model of care. Interdisciplinary networks should be established and strengthened to emphasize evidence-based interventions for individuals with periodontitis and those at risk, ultimately enhancing intervention options. By considering oral health as an integral component of systemic well-being, healthcare providers can be better positioned to improve quality of life and mitigate the overall impact of this widespread disease.
No potential conflict of interest relevant to this article was reported.
Funding
None.
Data availability
Not applicable.
Acknowledgments
None.
Supplementary materials
None.
References
1. Tonetti MS, Jepsen S, Jin L, Otomo-Corgel J. Impact of the global burden of periodontal diseases on health, nutrition and wellbeing of mankind: a call for global action. J Clin Periodontol 2017;44:456-462. https://doi.org/10.1111/jcpe.12732
2. Kassebaum NJ, Smith AGC, Bernabe E, Fleming TD, Reynolds AE, Vos T, Murray CJ, Marcenes W; GBD 2015 Oral Health Collaborators. Global, regional, and national prevalence, incidence, and disability-adjusted life years for oral conditions for 195 countries, 1990-2015: a systematic analysis for the global burden of diseases, injuries, and risk factors. J Dent Res 2017;96:380-387. https://doi.org/10.1177/0022034517693566
3. Kassebaum NJ, Bernabe E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression. J Dent Res 2014;93:1045-1053. https://doi.org/10.1177/0022034514552491
4. Eke PI, Page RC, Wei L, Thornton-Evans G, Genco RJ. Update of the case definitions for population-based surveillance of periodontitis. J Periodontol 2012;83:1449-1454. https://doi.org/10.1902/jop.2012.110664
5. Caton JG, Armitage G, Berglundh T, Chapple IL, Jepsen S, Kornman KS, Mealey BL, Papapanou PN, Sanz M, Tonetti MS. A new classification scheme for periodontal and peri-implant diseases and conditions: introduction and key changes from the 1999 classification. J Clin Periodontol 2018;45 Suppl 20:S1-S8. https://doi.org/10.1111/jcpe.12935
7. Li X, Kolltveit KM, Tronstad L, Olsen I. Systemic diseases caused by oral infection. Clin Microbiol Rev 2000;13:547-558. https://doi.org/10.1128/CMR.13.4.547
8. Listl S, Galloway J, Mossey PA, Marcenes W. Global economic impact of dental diseases. J Dent Res 2015;94:1355-1361. https://doi.org/10.1177/0022034515602879
11. Martinez-Herrera M, Silvestre-Rangil J, Silvestre FJ. Association between obesity and periodontal disease: a systematic review of epidemiological studies and controlled clinical trials. Med Oral Patol Oral Cir Bucal 2017;22:e708-e715. https://doi.org/10.4317/medoral.21786
12. Keller A, Rohde JF, Raymond K, Heitmann BL. Association between periodontal disease and overweight and obesity: a systematic review. J Periodontol 2015;86:766-776. https://doi.org/10.1902/jop.2015.140589
14. Morita I, Okamoto Y, Yoshii S, Nakagaki H, Mizuno K, Sheiham A, Sabbah W. Five-year incidence of periodontal disease is related to body mass index. J Dent Res 2011;90:199-202. https://doi.org/10.1177/0022034510382548
15. Manovijay B, Swaminathan M, Rajaseker S, John William Felix. A, Srinivasan S, Kavitha J. Relationship between body mass index, waist hip ratio and chronic periodontitis: a case control study. Bhavnagar Univ J Dent 2013;3:1-7.
16. Suvan J, Petrie A, Moles DR, Nibali L, Patel K, Darbar U, Donos N, Tonetti M, D’Aiuto F. Body mass index as a predictive factor of periodontal therapy outcomes. J Dent Res 2014;93:49-54. https://doi.org/10.1177/0022034513511084
17. Maciel SS, Feres M, Goncalves TE, Zimmermann GS, da Silva HD, Figueiredo LC, Duarte PM. Does obesity influence the subgingival microbiota composition in periodontal health and disease? J Clin Periodontol 2016;43:1003-1012. https://doi.org/10.1111/jcpe.12634
20. Munoz-Torres FJ, Jimenez MC, Rivas-Tumanyan S, Joshipura KJ. Associations between measures of central adiposity and periodontitis among older adults. Community Dent Oral Epidemiol 2014;42:170-177. https://doi.org/10.1111/cdoe.12069
21. D’Aiuto F, Sabbah W, Netuveli G, Donos N, Hingorani AD, Deanfield J, Tsakos G. Association of the metabolic syndrome with severe periodontitis in a large U.S. population-based survey. J Clin Endocrinol Metab 2008;93:3989-3994. https://doi.org/10.1210/jc.2007-2522
22. Genco RJ, Grossi SG, Ho A, Nishimura F, Murayama Y. A proposed model linking inflammation to obesity, diabetes, and periodontal infections. J Periodontol 2005;76 Suppl 11S:2075-2084. https://doi.org/10.1902/jop.2005.76.11-S.2075
23. Schmidt FM, Weschenfelder J, Sander C, Minkwitz J, Thormann J, Chittka T, Mergl R, Kirkby KC, Faßhauer M, Stumvoll M, Holdt LM, Teupser D, Hegerl U, Himmerich H. Inflammatory cytokines in general and central obesity and modulating effects of physical activity. PLoS One 2015;10:e0121971. https://doi.org/10.1371/journal.pone.0121971
24. Hasturk H, Kantarci A. Activation and resolution of periodontal inflammation and its systemic impact. Periodontol 2000 2015;69:255-273. https://doi.org/10.1111/prd.12105
26. Shimada Y, Komatsu Y, Ikezawa-Suzuki I, Tai H, Sugita N, Yoshie H. The effect of periodontal treatment on serum leptin, interleukin-6, and C-reactive protein. J Periodontol 2010;81:1118-1123. https://doi.org/10.1902/jop.2010.090741
27. Zimmermann GS, Bastos MF, Dias Goncalves TE, Chambrone L, Duarte PM. Local and circulating levels of adipocytokines in obese and normal weight individuals with chronic periodontitis. J Periodontol 2013;84:624-633. https://doi.org/10.1902/jop.2012.120254
28. Sanz M, Ceriello A, Buysschaert M, Chapple I, Demmer RT, Graziani F, Herrera D, Jepsen S, Lione L, Madianos P, Mathur M, Montanya E, Shapira L, Tonetti M, Vegh D. Scientific evidence on the links between periodontal diseases and diabetes: consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology. J Clin Periodontol 2018;45:138-149. https://doi.org/10.1111/jcpe.12808
29. Nasseh K, Vujicic M, Glick M. The relationship between periodontal interventions and healthcare costs and utilization: evidence from an integrated dental, medical, and pharmacy commercial claims database. Health Econ 2017;26:519-527. https://doi.org/10.1002/hec.3316
33. Morita T, Yamazaki Y, Mita A, Takada K, Seto M, Nishinoue N, Sasaki Y, Motohashi M, Maeno M. A cohort study on the association between periodontal disease and the development of metabolic syndrome. J Periodontol 2010;81:512-519. https://doi.org/10.1902/jop.2010.090594
34. Chang PC, Chien LY, Yeo JF, Wang YP, Chung MC, Chong LY, Kuo MY, Chen CH, Chiang HC, Ng BN, Lee QQ, Phay YK, Ng JR, Erk KY. Progression of periodontal destruction and the roles of advanced glycation end products in experimental diabetes. J Periodontol 2013;84:379-388. https://doi.org/10.1902/jop.2012.120076
35. Daffu G, del Pozo CH, O’Shea KM, Ananthakrishnan R, Ramasamy R, Schmidt AM. Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond. Int J Mol Sci 2013;14:19891-19910. https://doi.org/10.3390/ijms141019891
36. Luevano-Contreras C, Chapman-Novakofski K. Dietary advanced glycation end products and aging. Nutrients 2010;2:1247-1265. https://doi.org/10.3390/nu2121247
37. Zizzi A, Tirabassi G, Aspriello SD, Piemontese M, Rubini C, Lucarini G. Gingival advanced glycation end-products in diabetes mellitus-associated chronic periodontitis: an immunohistochemical study. J Periodontal Res 2013;48:293-301. https://doi.org/10.1111/jre.12007
40. Polak D, Shapira L. An update on the evidence for pathogenic mechanisms that may link periodontitis and diabetes. J Clin Periodontol 2018;45:150-166. https://doi.org/10.1111/jcpe.12803
41. Demmer RT, Jacobs DR Jr, Singh R, Zuk A, Rosenbaum M, Papapanou PN, Desvarieux M. Periodontal bacteria and prediabetes prevalence in ORIGINS: the oral infections, glucose intolerance, and insulin resistance study. J Dent Res 2015;94(9 Suppl):201S-211S. https://doi.org/10.1177/0022034515590369
42. Albert DA, Ward A, Allweiss P, Graves DT, Knowler WC, Kunzel C, Leibel RL, Novak KF, Oates TW, Papapanou PN, Schmidt AM, Taylor GW, Lamster IB, Lalla E. Diabetes and oral disease: implications for health professionals. Ann N Y Acad Sci 2012;1255:1-15. https://doi.org/10.1111/j.1749-6632.2011.06460.x
43. Mattila KJ, Nieminen MS, Valtonen VV, Rasi VP, Kesaniemi YA, Syrjala SL, Jungell PS, Isoluoma M, Hietaniemi K, Jokinen MJ. Association between dental health and acute myocardial infarction. BMJ 1989;298:779-781. https://doi.org/10.1136/bmj.298.6676.779
44. Tonetti MS, Van Dyke TE; working group 1 of the joint EFP/AAP workshop. Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Periodontol 2013;84(4 Suppl):S24-S29. https://doi.org/10.1902/jop.2013.1340019
45. Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A, Libby P, Offenbacher S, Ridker PM, Van Dyke TE, Roberts WC; American Journal of Cardiology; Journal of Periodontology. The American Journal of Cardiology and Journal of Periodontology editors’ consensus: periodontitis and atherosclerotic cardiovascular disease. J Periodontol 2009;80:1021-1032. https://doi.org/10.1902/jop.2009.097001
46. Leira Y, Seoane J, Blanco M, Rodríguez-Yáñez M, Takkouche B, Blanco J, Castillo J. Association between periodontitis and ischemic stroke: a systematic review and meta-analysis. Eur J Epidemiol 2017;32:43-53. https://doi.org/10.1007/s10654-016-0170-6
47. Mehta LS, Beckie TM, DeVon HA, Grines CL, Krumholz HM, Johnson MN, Lindley KJ, Vaccarino V, Wang TY, Watson KE, Wenger NK; American Heart Association Cardiovascular Disease in Women and Special Populations Committee of the Council on Clinical Cardiology, Council on Epidemiology and Prevention, Council on Cardiovascular and Stroke Nursing, and Council on Quality of Care and Outcomes Research. Acute myocardial infarction in women: a scientific statement from the American Heart Association. Circulation 2016;133:916-947. https://doi.org/10.1161/CIR.0000000000000351
50. Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB, Wensley F, Higgins JP, Lennon L, Eiriksdottir G, Rumley A, Whincup PH, Lowe GD, Gudnason V. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med 2008;5:e78. https://doi.org/10.1371/journal.pmed.0050078
51. van Holten TC, Waanders LF, de Groot PG, Vissers J, Hoefer IE, Pasterkamp G, Prins MW, Roest M. Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses. PLoS One 2013;8:e62080. https://doi.org/10.1371/journal.pone.0062080
52. Wu T, Trevisan M, Genco RJ, Falkner KL, Dorn JP, Sempos CT. Examination of the relation between periodontal health status and cardiovascular risk factors: serum total and high density lipoprotein cholesterol, C-reactive protein, and plasma fibrinogen. Am J Epidemiol 2000;151:273-282. https://doi.org/10.1093/oxfordjournals.aje.a010203
53. Li L, Messas E, Batista EL Jr, Levine RA, Amar S. Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model. Circulation 2002;105:861-867. https://doi.org/10.1161/hc0702.104178
55. Roth GA, Ankersmit HJ, Brown VB, Papapanou PN, Schmidt AM, Lalla E. Porphyromonas gingivalis infection and cell death in human aortic endothelial cells. FEMS Microbiol Lett 2007;272:106-113. https://doi.org/10.1111/j.1574-6968.2007.00736.x
56. Lowe GD. The relationship between infection, inflammation, and cardiovascular disease: an overview. Ann Periodontol 2001;6:1-8. https://doi.org/10.1902/annals.2001.6.1.1
57. Li C, Lv Z, Shi Z, Zhu Y, Wu Y, Li L, Iheozor-Ejiofor Z. Periodontal therapy for the management of cardiovascular disease in patients with chronic periodontitis. Cochrane Database Syst Rev 2017;11:CD009197. https://doi.org/10.1002/14651858.CD009197.pub3
58. Graziani F, Cei S, Tonetti M, Paolantonio M, Serio R, Sammartino G, Gabriele M, D’Aiuto F. Systemic inflammation following non-surgical and surgical periodontal therapy. J Clin Periodontol 2010;37:848-854. https://doi.org/10.1111/j.1600-051X.2010.01585.x
59. Bizzarro S, van der Velden U, Teeuw WJ, Gerdes VE, Loos BG. Effect of periodontal therapy with systemic antimicrobials on parameters of metabolic syndrome: a randomized clinical trial. J Clin Periodontol 2017;44:833-841. https://doi.org/10.1111/jcpe.12763
61. Deschamps-Lenhardt S, Martin-Cabezas R, Hannedouche T, Huck O. Association between periodontitis and chronic kidney disease: systematic review and meta-analysis. Oral Dis 2019;25:385-402. https://doi.org/10.1111/odi.12834
62. Zhang J, Jiang H, Sun M, Chen J. Association between periodontal disease and mortality in people with CKD: a meta-analysis of cohort studies. BMC Nephrol 2017;18:269. https://doi.org/10.1186/s12882-017-0680-9
63. Sharma P, Dietrich T, Ferro CJ, Cockwell P, Chapple IL. Association between periodontitis and mortality in stages 3-5 chronic kidney disease: NHANES III and linked mortality study. J Clin Periodontol 2016;43:104-113. https://doi.org/10.1111/jcpe.12502
65. Graziani F, Cei S, La Ferla F, Vano M, Gabriele M, Tonetti M. Effects of non-surgical periodontal therapy on the glomerular filtration rate of the kidney: an exploratory trial. J Clin Periodontol 2010;37:638-643. https://doi.org/10.1111/j.1600-051X.2010.01578.x
67. Fisher MA, Taylor GW, Papapanou PN, Rahman M, Debanne SM. Clinical and serologic markers of periodontal infection and chronic kidney disease. J Periodontol 2008;79:1670-1678. https://doi.org/10.1902/jop.2008.070569
68. Ioannidou E, Swede H, Dongari-Bagtzoglou A. Periodontitis predicts elevated C-reactive protein levels in chronic kidney disease. J Dent Res 2011;90:1411-1415. https://doi.org/10.1177/0022034511423394
69. Slinin Y, Ishani A, Rector T, Fitzgerald P, MacDonald R, Tacklind J, Rutks I, Wilt TJ. Management of hyperglycemia, dyslipidemia, and albuminuria in patients with diabetes and CKD: a systematic review for a KDOQI clinical practice guideline. Am J Kidney Dis 2012;60:747-769. https://doi.org/10.1053/j.ajkd.2012.07.017
71. Wehmeyer MM, Kshirsagar AV, Barros SP, Beck JD, Moss KL, Preisser JS, Offenbacher S. A randomized controlled trial of intensive periodontal therapy on metabolic and inflammatory markers in patients with ESRD: results of an exploratory study. Am J Kidney Dis 2013;61:450-458. https://doi.org/10.1053/j.ajkd.2012.10.021
72. da Silva JC, Muniz FW, Oballe HJ, Andrades M, Rosing CK, Cavagni J. The effect of periodontal therapy on oxidative stress biomarkers: a systematic review. J Clin Periodontol 2018;45:1222-1237. https://doi.org/10.1111/jcpe.12993
73. Papageorgiou SN, Hagner M, Nogueira AV, Franke A, Jager A, Deschner J. Inflammatory bowel disease and oral health: systematic review and a meta-analysis. J Clin Periodontol 2017;44:382-393. https://doi.org/10.1111/jcpe.12698
76. Brito F, de Barros FC, Zaltman C, Carvalho AT, Carneiro AJ, Fischer RG, Gustafsson A, Figueredo CM. Prevalence of periodontitis and DMFT index in patients with Crohn’s disease and ulcerative colitis. J Clin Periodontol 2008;35:555-560. https://doi.org/10.1111/j.1600-051X.2008.01231.x
77. Van Dyke TE, Dowell VR Jr, Offenbacher S, Snyder W, Hersh T. Potential role of microorganisms isolated from periodontal lesions in the pathogenesis of inflammatory bowel disease. Infect Immun 1986;53:671-677. https://doi.org/10.1128/iai.53.3.671-677.1986
78. Al-Qutub MN, Braham PH, Karimi-Naser LM, Liu X, Genco CA, Darveau RP. Hemin-dependent modulation of the lipid A structure of Porphyromonas gingivalis lipopolysaccharide. Infect Immun 2006;74:4474-4485. https://doi.org/10.1128/IAI.01924-05
79. Elphick DA, Mahida YR. Paneth cells: their role in innate immunity and inflammatory disease. Gut 2005;54:1802-1809. https://doi.org/10.1136/gut.2005.068601
80. Chapple IL, Bouchard P, Cagetti MG, Campus G, Carra MC, Cocco F, Nibali L, Hujoel P, Laine ML, Lingstrom P, Manton DJ, Montero E, Pitts N, Range H, Schlueter N, Teughels W, Twetman S, Van Loveren C, Van der Weijden F, Vieira AR, Schulte AG. Interaction of lifestyle, behaviour or systemic diseases with dental caries and periodontal diseases: consensus report of group 2 of the joint EFP/ORCA workshop on the boundaries between caries and periodontal diseases. J Clin Periodontol 2017;44 Suppl 18:S39-S51. https://doi.org/10.1111/jcpe.12685
83. Muhvic-Urek M, Tomac-Stojmenovic M, Mijandrusic-Sincic B. Oral pathology in inflammatory bowel disease. World J Gastroenterol 2016;22:5655-5667. https://doi.org/10.3748/wjg.v22.i25.5655
84. Kim MS, Hwang SS, Park EJ, Bae JW. Strict vegetarian diet improves the risk factors associated with metabolic diseases by modulating gut microbiota and reducing intestinal inflammation. Environ Microbiol Rep 2013;5:765-775. https://doi.org/10.1111/1758-2229.12079
85. Demmer RT, Molitor JA, Jacobs DR Jr, Michalowicz BS. Periodontal disease, tooth loss and incident rheumatoid arthritis: results from the First National Health and Nutrition Examination Survey and its epidemiological follow-up study. J Clin Periodontol 2011;38:998-1006. https://doi.org/10.1111/j.1600-051X.2011.01776.x
87. Arkema EV, Karlson EW, Costenbader KH. A prospective study of periodontal disease and risk of rheumatoid arthritis. J Rheumatol 2010;37:1800-1804. https://doi.org/10.3899/jrheum.091398
89. Darveau RP, Hajishengallis G, Curtis MA. Porphyromonas gingivalis as a potential community activist for disease. J Dent Res 2012;91:816-820. https://doi.org/10.1177/0022034512453589
90. Nesse W, Westra J, van der Wal JE, Abbas F, Nicholas AP, Vissink A, Brouwer E. The periodontium of periodontitis patients contains citrullinated proteins which may play a role in ACPA (anti-citrullinated protein antibody) formation. J Clin Periodontol 2012;39:599-607. https://doi.org/10.1111/j.1600-051X.2012.01885.x
92. Assuma R, Oates T, Cochran D, Amar S, Graves DT. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J Immunol 1998;160:403-409.
94. Yamazaki K, Honda T, Oda T, Ueki-Maruyama K, Nakajima T, Yoshie H, Seymour GJ. Effect of periodontal treatment on the C-reactive protein and proinflammatory cytokine levels in Japanese periodontitis patients. J Periodontal Res 2005;40:53-58. https://doi.org/10.1111/j.1600-0765.2004.00772.x
95. Duarte PM, da Rocha M, Sampaio E, Mestnik MJ, Feres M, Figueiredo LC, Bastos MF, Faveri M. Serum levels of cytokines in subjects with generalized chronic and aggressive periodontitis before and after non-surgical periodontal therapy: a pilot study. J Periodontol 2010;81:1056-1063. https://doi.org/10.1902/jop.2010.090732
98. Zeng XT, Tu ML, Liu DY, Zheng D, Zhang J, Leng W. Periodontal disease and risk of chronic obstructive pulmonary disease: a meta-analysis of observational studies. PLoS One 2012;7:e46508. https://doi.org/10.1371/journal.pone.0046508
99. Kowalski M, Kowalska E, Split M, Split W, Wierzbicka-Ferszt A, Pawlicki L, Kowalski J. Assessment of periodontal state in patients with chronic obstructive pulmonary disease: part II. Pol Merkur Lekarski 2005;19:537-541.
100. Shi Q, Zhang B, Xing H, Yang S, Xu J, Liu H. Patients with chronic obstructive pulmonary disease suffer from worse periodontal health-evidence from a meta-analysis. Front Physiol 2018;9:33. https://doi.org/10.3389/fphys.2018.00033
101. Takahashi T, Muro S, Tanabe N, Terada K, Kiyokawa H, Sato S, Hoshino Y, Ogawa E, Uno K, Naruishi K, Takashiba S, Mishima M. Relationship between periodontitis-related antibody and frequent exacerbations in chronic obstructive pulmonary disease. PLoS One 2012;7:e40570. https://doi.org/10.1371/journal.pone.0040570
102. Wilson R, Sethi S, Anzueto A, Miravitlles M. Antibiotics for treatment and prevention of exacerbations of chronic obstructive pulmonary disease. J Infect 2013;67:497-515. https://doi.org/10.1016/j.jinf.2013.08.010
104. Kucukcoskun M, Baser U, Oztekin G, Kiyan E, Yalcin F. Initial periodontal treatment for prevention of chronic obstructive pulmonary disease exacerbations. J Periodontol 2013;84:863-870. https://doi.org/10.1902/jop.2012.120399
105. Ide M, Papapanou PN. Epidemiology of association between maternal periodontal disease and adverse pregnancy outcomes: systematic review. J Clin Periodontol 2013;40 Suppl 14:S181-S194. https://doi.org/10.1111/jcpe.12063
106. Sgolastra F, Petrucci A, Severino M, Gatto R, Monaco A. Relationship between periodontitis and pre-eclampsia: a meta-analysis. PLoS One 2013;8:e71387. https://doi.org/10.1371/journal.pone.0071387
108. Jarjoura K, Devine PC, Perez-Delboy A, Herrera-Abreu M, D’Alton M, Papapanou PN. Markers of periodontal infection and preterm birth. Am J Obstet Gynecol 2005;192:513-519. https://doi.org/10.1016/j.ajog.2004.07.018
109. Blanc V, O’Valle F, Pozo E, Puertas A, Leon R, Mesa F. Oral bacteria in placental tissues: increased molecular detection in pregnant periodontitis patients. Oral Dis 2015;21:905-912. https://doi.org/10.1111/odi.12364
111. Chaparro A, Sanz A, Quintero A, Inostroza C, Ramirez V, Carrion F, Figueroa F, Serra R, Illanes SE. Increased inflammatory biomarkers in early pregnancy is associated with the development of pre-eclampsia in patients with periodontitis: a case control study. J Periodontal Res 2013;48:302-307. https://doi.org/10.1111/jre.12008
112. Kumar A, Begum N, Prasad S, Lamba AK, Verma M, Agarwal S, Sharma S. Role of cytokines in development of pre-eclampsia associated with periodontal disease: cohort study. J Clin Periodontol 2014;41:357-365. https://doi.org/10.1111/jcpe.12226
114. Sadatmansouri S, Sedighpoor N, Aghaloo M. Effects of periodontal treatment phase I on birth term and birth weight. J Indian Soc Pedod Prev Dent 2006;24:23-26. https://doi.org/10.4103/0970-4388.22831
116. Lopez NJ, Smith PC, Gutierrez J. Periodontal therapy may reduce the risk of preterm low birth weight in women with periodontal disease: a randomized controlled trial. J Periodontol 2002;73:911-924. https://doi.org/10.1902/jop.2002.73.8.911
117. Lopez NJ, Da Silva I, Ipinza J, Gutierrez J. Periodontal therapy reduces the rate of preterm low birth weight in women with pregnancy-associated gingivitis. J Periodontol 2005;76 Suppl 11S:2144-2153. https://doi.org/10.1902/jop.2005.76.11-S.2144
118. Aida J, Kondo K, Yamamoto T, Hirai H, Nakade M, Osaka K, Sheiham A, Tsakos G, Watt RG. Oral health and cancer, cardiovascular, and respiratory mortality of Japanese. J Dent Res 2011;90:1129-1135. https://doi.org/10.1177/0022034511414423
119. Hwang IM, Sun LM, Lin CL, Lee CF, Kao CH. Periodontal disease with treatment reduces subsequent cancer risks. QJM 2014;107:805-812. https://doi.org/10.1093/qjmed/hcu078
120. Chung SD, Tsai MC, Huang CC, Kao LT, Chen CH. A population-based study on the associations between chronic periodontitis and the risk of cancer. Int J Clin Oncol 2016;21:219-223. https://doi.org/10.1007/s10147-015-0884-6
121. Chen H, Nie S, Zhu Y, Lu M. Teeth loss, teeth brushing and esophageal carcinoma: a systematic review and meta-analysis. Sci Rep 2015;5:15203. https://doi.org/10.1038/srep15203
122. Ren HG, Luu HN, Cai H, Xiang YB, Steinwandel M, Gao YT, Hargreaves M, Zheng W, Blot WJ, Long JR, Shu XO. Oral health and risk of colorectal cancer: results from three cohort studies and a meta-analysis. Ann Oncol 2016;27:1329-1336. https://doi.org/10.1093/annonc/mdw172
124. Panezai J, Ghaffar A, Altamash M, Sundqvist KG, Engstrom PE, Larsson A. Correlation of serum cytokines, chemokines, growth factors and enzymes with periodontal disease parameters. PLoS One 2017;12:e0188945. https://doi.org/10.1371/journal.pone.0188945
125. Lopez-Galindo MP, Bagan JV, Jimenez-Soriano Y, Alpiste F, Camps C. Clinical evaluation of dental and periodontal status in a group of oncological patients before chemotherapy. Med Oral Patol Oral Cir Bucal 2006;11:E17-E21.
128. Lee YL, Hu HY, Yang NP, Chou P, Chu D. Dental prophylaxis decreases the risk of esophageal cancer in males; a nationwide population-based study in Taiwan. PLoS One 2014;9:e109444. https://doi.org/10.1371/journal.pone.0109444
129. Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, Qian Y, Kryczek I, Sun D, Nagarsheth N, Chen Y, Chen H, Hong J, Zou W, Fang JY. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 2017;170:548-563. https://doi.org/10.1016/j.cell.2017.07.008
130. Huang J, Roosaar A, Axell T, Ye W. A prospective cohort study on poor oral hygiene and pancreatic cancer risk. Int J Cancer 2016;138:340-347. https://doi.org/10.1002/ijc.29710
131. Abnet CC, Kamangar F, Islami F, Nasrollahzadeh D, Brennan P, Aghcheli K, Merat S, Pourshams A, Marjani HA, Ebadati A, Sotoudeh M, Boffetta P, Malekzadeh R, Dawsey SM. Tooth loss and lack of regular oral hygiene are associated with higher risk of esophageal squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 2008;17:3062-3068. https://doi.org/10.1158/1055-9965.EPI-08-0558
132. Shoemark DK, Allen SJ. The microbiome and disease: reviewing the links between the oral microbiome, aging, and Alzheimer’s disease. J Alzheimers Dis 2015;43:725-738. https://doi.org/10.3233/JAD-141170
133. Teixeira FB, Saito MT, Matheus FC, Prediger RD, Yamada ES, Maia CS, Lima RR. Periodontitis and Alzheimer’s disease: a possible comorbidity between oral chronic inflammatory condition and neuroinflammation. Front Aging Neurosci 2017;9:327. https://doi.org/10.3389/fnagi.2017.00327
136. Rae Yoo J, Taek Heo S, Kim M, Lee CS, Kim YR. Porphyromonas gingivalis causing brain abscess in patient with recurrent periodontitis. Anaerobe 2016;39:165-167. https://doi.org/10.1016/j.anaerobe.2016.04.009
138. Kamer AR, Craig RG, Pirraglia E, Dasanayake AP, Norman RG, Boylan RJ, Nehorayoff A, Glodzik L, Brys M, de Leon MJ. TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer’s disease patients and normal subjects. J Neuroimmunol 2009;216:92-97. https://doi.org/10.1016/j.jneuroim.2009.08.013
139. Carter CJ, France J, Crean S, Singhrao SK. The Porphyromonas gingivalis/host interactome shows enrichment in GWASdb genes related to Alzheimer’s disease, diabetes and cardiovascular diseases. Front Aging Neurosci 2017;9:408. https://doi.org/10.3389/fnagi.2017.00408
140. Sochocka M, Sobczynski M, Sender-Janeczek A, Zwolinska K, Blachowicz O, Tomczyk T, Zietek M, Leszek J. Association between periodontal health status and cognitive abilities: the role of cytokine profile and systemic inflammation. Curr Alzheimer Res 2017;14:978-990. https://doi.org/10.2174/1567205014666170316163340
141. Chen CK, Huang JY, Wu YT, Chang YC. Dental scaling decreases the risk of Parkinson’s disease: a nationwide population-based nested case-control study. Int J Environ Res Public Health 2018;15:1587. https://doi.org/10.3390/ijerph15081587
142. Pradeep AR, Singh SP, Martande SS, Raju AP, Rustagi T, Suke DK, Naik SB. Clinical evaluation of the periodontal health condition and oral health awareness in Parkinson’s disease patients. Gerodontology 2015;32:100-106. https://doi.org/10.1111/ger.12055
143. Zheng DX, Kang XN, Wang YX, Huang YN, Pang CF, Chen YX, Kuang ZL, Peng Y. Periodontal disease and emotional disorders: a meta-analysis. J Clin Periodontol 2021;48:180-204. https://doi.org/10.1111/jcpe.13395
144. Peruzzo DC, Benatti BB, Ambrosano GM, Nogueira-Filho GR, Sallum EA, Casati MZ, Nociti FH Jr. A systematic review of stress and psychological factors as possible risk factors for periodontal disease. J Periodontol 2007;78:1491-1504. https://doi.org/10.1902/jop.2007.060371
145. Araújo MM, Martins CC, Costa LC, Cota LO, Faria RL, Cunha FA, Costa FO. Association between depression and periodontitis: a systematic review and meta-analysis. J Clin Periodontol 2016;43:216-228. https://doi.org/10.1111/jcpe.12510
146. Amaral Cda S, Vettore MV, Leão A. The relationship of alcohol dependence and alcohol consumption with periodontitis: a systematic review. J Dent 2009;37:643-651. https://doi.org/10.1016/j.jdent.2009.04.011
147. Decker A, Askar H, Tattan M, Taichman R, Wang HL. The assessment of stress, depression, and inflammation as a collective risk factor for periodontal diseases: a systematic review. Clin Oral Investig 2020;24:1-12. https://doi.org/10.1007/s00784-019-03089-3
148. Mengel R, Bacher M, Flores-De-Jacoby L. Interactions between stress, interleukin-1beta, interleukin-6 and cortisol in periodontally diseased patients. J Clin Periodontol 2002;29:1012-1022. https://doi.org/10.1034/j.1600-051x.2002.291106.x
149. Bakri I, Douglas CW, Rawlinson A. The effects of stress on periodontal treatment: a longitudinal investigation using clinical and biological markers. J Clin Periodontol 2013;40:955-961. https://doi.org/10.1111/jcpe.12142
151. Palmer RM, Wilson RF, Hasan AS, Scott DA. Mechanisms of action of environmental factors: tobacco smoking. J Clin Periodontol 2005;32 Suppl 6:180-195. https://doi.org/10.1111/j.1600-051X.2005.00786.x
153. Zhong HJ, Xie HX, Luo XM, Zhang EH. Association between periodontitis and systemic lupus erythematosus: a meta-analysis. Lupus 2020;29:1189-1197. https://doi.org/10.1177/0961203320938447
154. Rutter-Locher Z, Smith TO, Giles I, Sofat N. Association between systemic lupus erythematosus and periodontitis: a systematic review and meta-analysis. Front Immunol 2017;8:1295. https://doi.org/10.3389/fimmu.2017.01295
155. Maarse F, Jager DH, Alterch S, Korfage A, Forouzanfar T, Vissink A, Brand HS. Sjogren’s syndrome is not a risk factor for periodontal disease: a systematic review. Clin Exp Rheumatol 2019;37 Suppl 118:225-233.
156. Zhang X, Gu H, Xie S, Su Y. Periodontitis in patients with psoriasis: a systematic review and meta-analysis. Oral Dis 2022;28:33-43. https://doi.org/10.1111/odi.13617
157. Ratz T, Dean LE, Atzeni F, Reeks C, Macfarlane GJ, Macfarlane TV. A possible link between ankylosing spondylitis and periodontitis: a systematic review and meta-analysis. Rheumatology (Oxford) 2015;54:500-510. https://doi.org/10.1093/rheumatology/keu356
158. Sheu JJ, Lin HC. Association between multiple sclerosis and chronic periodontitis: a population-based pilot study. Eur J Neurol 2013;20:1053-1059. https://doi.org/10.1111/ene.12103
159. Cheng WC, van Asten SD, Burns LA, Evans HG, Walter GJ, Hashim A, Hughes FJ, Taams LS. Periodontitis-associated pathogens P. gingivalis and A. actinomycetemcomitans activate human CD14(+) monocytes leading to enhanced Th17/IL-17 responses. Eur J Immunol 2016;46:2211-2221. https://doi.org/10.1002/eji.201545871
161. De-Gennaro LA, Lopes JD, Mariano M. Autoantibodies directed to extracellular matrix components in patients with different clinical forms of periodontitis. J Periodontol 2006;77:2025-2030. https://doi.org/10.1902/jop.2006.060104
162. Sims TJ, Lernmark A, Smith T, Page RC, Persson GR. Treatment outcome for IDDM patients in relation to glutamic acid decarboxylase autoantibodies and serum IgG to periodontal pathogens. J Clin Periodontol 2001;28:550-557. https://doi.org/10.1034/j.1600-051x.2001.028006550.x
163. Zhu XW, Wang Y, Wei YH, Zhao PP, Wang XB, Rong JJ, Zhong WY, Zhang XW, Wang L, Zheng HF. Comprehensive assessment of the association between FCGRs polymorphisms and the risk of systemic lupus erythematosus: evidence from a meta-analysis. Sci Rep 2016;6:31617. https://doi.org/10.1038/srep31617
