The Oral Health Systemic Health Connection: What’s the Evidence? THOMAS M. PAUMIER DDS

Oral Health Systemic Health Connection

 Are there systemic medical conditions which cause or lead to the progression of or periapical pathology?

 Does periodontal disease or periapical pathology cause or lead to the progression or worsening of systemic medical conditions?

Introduction Question 1 Question 2

 Metastatic spread of infection from the mouth as a result of transient bacteremia

 Metastatic injury from the effects of circulating oral bacterial toxins

 Metastatic inflammation caused by immune response induced by oral bacteria

 Bacteremia ….. Infective /PJI

 Ulcers ……. Heliobacter pylori

Introduction Question 1 Question 2 Current Research

 Nearly one third of all recent periodontal research

 57 different systemic disease conditions

 Bi-directional relationship

 Observational studies vs. Randomized Controlled Trials

 Association vs Causality

 Surrogate evidence vs. Direct evidence

 Methodology

Introduction Question 1 Question 2 Challenges to Conducting Quality Research

 How to define periodontal disease  Attachment loss, pocket depths, bone loss, BOP, mobility  Tooth loss, edentulism (surrogate markers)  Clinical exam, chart review, patient self report  Length of time since diagnosed with periodontal disease  Treatment protocols ….. Root planing, surgery,  Response to treatments …… maintenance, relapse, refractory cases  Length of time following treatment and disease improvement  Confounders

Introduction Question 1 Question 2 Challenges to Conducting Quality Research

COMMON RISK FACTORS FOR PERIODONTAL DISEASE AND SYSTEMIC DISEASES (confounders)

 Smoking

 Diabetes

 Obesity

 Metabolic Syndrome

 Age

 Others …… Low Ca++, Vit D, Alcohol Consumption, Osteoporosis, Stress

Introduction Question 1 Question 2 Observational Studies

 Researchers simply watch what happens to a series of people in one group  CONTROL GROUP …… like group of people who have not had intervention or treatment being studied  CASE CONTROL ….. Compares two groups: those with the disease or condition (case) vs a very similar group without the disease or condition  COHORT ……people are exposed to a factor of interest (smoking, diet, occupation) and followed over a time period sufficient to allow any effects of that exposure to occur and be measured  LONGITUDINAL ….. Data are collected from a number of people over a long period of time ….. Prospective/retrospective

Introduction Question 1 Question 2 Randomized Controlled Trial (RCT)

 Participants are assigned by chance to separate groups that compare different treatments

 Participants or Researchers cannot choose group

 Must be a control group …… placebo or no intervention

 Ethical Considerations of withholding treatment

 Gold standard

 Strongest evidence about a particular intervention would come from a RCT with a low risk of bias and large sample sizes

Introduction Question 1 Question 2 Research Terminology

 Odds Ratio (OR): measure of association between exposure and outcome  Hazard Ratio (HR): (1) odds of survival no different between the two groups  Relative Risk (RR): (>1): risk of developing the disease is higher than other group  95% Confidence Interval: range of values that you can be 95% certain contains the true mean …… narrow vs. wide  Meta analysis: combines the results of multiple studies in an effort to improve estimates of the size of the effect (power) or resolve uncertainty when reports disagree  P value used to determine whether there is an association between a risk factor and an outcome or whether an intervention produces better results than control …… statistical significance. P value <.05 considered statistically significant

 OR of 2.5 95% CI (1.8-3.3)

Introduction Question 1 Question 2 EVIDENCE PYRAMID Evidence Based Dentistry

 BARRIERS TO INTEGRATION INTO CLINICAL PRACTICE  Must be able to understand and evaluate the literature  Know where to look for credible information  Resistance to change long held clinical dogmas  Reliance on own clinical experience or that of peers  Time to read journals and attend CE courses Evidence Based Dentistry (EBD)

CHALLENGES AND LIMITATIONS Flossing Controversy Jumping out of an airplane Toilet Paper

The absence of evidence does not mean there is evidence of absence Evidence Based Science During a Pandemic

 Clinical decisions based on case reports and observational studies

 No time for adequate peer review

 Everyone will be wrong about something

 Ability to acknowledge shortcomings rather than saying definitively “the science says” ……. “the best available science to date with the following limitations”

 Mask use in public setting controversy

N = 1 Evaluation of Journal Articles

Peer reviewed Journals  JADA  Journal of Evidence Based Dental Practice  Specialty Journals  JAMA  NEJM  Circulation (JAHA) Evaluation of Journal Articles JADA April 2019

 SPIN ….Risk of Colon cancer18% higher if eat processed meat (relative risk RR). Risk of colon cancer is 4.5%. Means absolute risk only increases 0.8% from 4.5% to 5.3%.

 MISINTERPRETATION … authors conclusions are not supported by the study outcomes.

 INAPPROPRIATE METHODOLOGY … hypothesizing after results are known. Wrong study design, inappropriate statistical tests, inappropriate data analysis Don’t Believe Everything You Read

CROSS SECTIONAL ANALYSIS Abstract or Full Text?

 JADA January 2020

 Evaluated 75 Abstracts of RCTs from 9 peer reviewed journals with statistically non significant primary outcomes in 2015

 31% revealed existence of SPIN in conclusions

 Claimed clinical significance, or clinical equivalence or emphasized statistically significant secondary outcomes Quality Research Bradford Hill Criteria

 Statistical strength of association  Consistency  Specificity  Temporal relationship (cause precedes consequence)  Biologic gradient or dose-response relationship  Biologic plausibility  Coherence  Experimental reversibility  Analogy …… other precedents

Introduction Question 1 Question 2 Association vs Causality

 Causality requires evidence that the factor precedes the disease  Causality requires evidence of knowledge of the mechanism of action of the risk factor on the disease  Causality requires evidence that modification of the risk factor will prevent or moderate the disease

Introduction Question 1 Question 2 Controversy

 JADA 2018

 Dr. Harold Slavkin

 IF IT CAUSES EVERYTHING, THEN IT CAUSES NOTHING

Introduction Question 1 Question 2 Direct Crown Anterior Direct Crown Anterior Direct Crown Anterior My crown is loose ….. Direct Bonded Bridge

PERIAPICAL SYSTEMIC DISEASE PATHOLOGY ASSOCIATION Association Between Apical Periodontitis and Systemic Diseases

 Systematic Review 2016 American Association of

: There is moderate evidence to show an association between endodontic pathosis and CVD: NO cause/effect established

 Diabetes: Current evidence is inconclusive and insufficient to suggest an association

 Chronic Liver Disease no good studies

 Blood Disorders/Hemophilia to show

 Bone Mineral Density any association

Introduction Question 1 Question 2 Apical Periodontitis and Diabetes

JADA June 2021

6M patients/7749 dx with AP matched with 7749 controls

T2D was independently associated with significantly greater prevalence of AP (OR 2.05)

The use of metformin or statins was independently associated with lower prevalence of AP (OR 0.82/0.7)

HbA1c > 8 was significantly associated with greater prevalence of AP (OR 2.46)

Bioburden and inflammatory mediators shared by both diseases … controlling T2D maintains health by immunomodulatory effect? Or do those with better disease management also have better oral hygiene and diet? Endodontic Lesions and CVD Journal of Endodontics Sept 2018

 Systematic Review of Longitudinal Cohort Studies only-- as the temporal association implying causality can be proposed.  Studies had high risk of bias and high heterogeneity  Level of evidence is low  No confidence in results and cannot make conclusion from meta-analysis  Recommend better well controlled studies PERIODONTAL SYSTEMIC DISEASE DISEASE ASSOCIATION Periodontal Disease

 Chronic bacterial infections caused by subgingival dental BIOFILM  Virulent organisms cause tissue destruction or trigger destructive immunopathologic host response  Over 50% of adult population with nearly 20% having severe disease  Affects the systemic immune response  Common pathogens: Gram - anaerobes:  Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forysythia, Prevotella intermedia, Treponema denticola, Fusobacterium nucleatum  PMN (neutrophil) dysfunction  CHRONIC INFLAMMATION

Introduction Question 1 Question 2

Biologic Plausability

Inflammation

 Inflammatory cytokines: - C-reactive protein (CRP) - interleukin-1, interleukin-6 (IL-1, IL-6) - tumor necrosis factor alpha(TNF) - prostaglandin E  Bacteremia and hematogenous spread  Associated with many chronic systemic diseases

Introduction Question 1 Question 2 Biofilm

 Complex aggregation of microorganisms within a sticky extracellular matrix

 Adheres to moist mucosal and tooth surfaces and foreign surfaces including dental prostheses, catheters, prosthetic valves and joints

 Protect embedded slow growing microorganisms from physical dislodgement as well as , , antimicrobials, and antibiotics

 Associated with Periodontal Disease, Dental Caries, Infective Endocarditis, Coronary Artery Plaques, PJI, VAP and HAP, AV Shunts for Dialysis, UTI and many other infections

 Biofilms enable bacterial resistance

Introduction Question 1 Question 2 Are there systemic medical conditions which cause or lead to the progression of periodontal disease or periapical pathology? Systemic Medical Conditions as Risk Factors for Periodontal Disease

 DIABETES  METABOLIC SYNDROME  OBESITY

Introduction Question 1 Question 2 Systemic Medical Conditions as Risk Factors for Periodontal Disease

DIABETES  BIDIRECTIONAL RELATIONSHIP

 Estimated 415 million people worldwide/2015 …… projected 642M/2024  More than 10% of adults in 25 states had diabetes/2015  Glycemic control and duration of disease, is associated with accelerated attachment loss and progression of periodontal disease

Introduction Question 1 Question 2 Systemic Medical Conditions as Risk Factors for Periodontal Disease

DIABETES – continued

 Diabetics have hyperactive inflammatory response leading to more periodontal tissue destruction

 Diabetics have increased receptors for advanced glycation end products which result in increased levels of inflammatory cytokines

 Diabetics have reduced healing ….. Fibroblast death, microangiopathy

Introduction Question 1 Question 2 Systemic Medical Conditions as Risk Factors for Periodontal Disease

METABOLIC SYNDROME

 Cluster of Disorders (obesity, hypertension, hyperglycemia, low HDL, elevated triglycerides)  Obesity plus 2 of 4 other factors  5x greater risk of developing Type 2 diabetes  Predicts worsening periodontal disease in men  38-71% more likely to have periodontal disease  Patients with MetS have increased oxidative stress leading to increased inflammation impairing host defenses exacerbating PD  Oxidative stress and medications taken due to MetS lead to decreased salivary flow

Introduction Question 1 Question 2 Metabolic Syndrome (MetS)

JADA December 2019

 Patients with MetS had fewer teeth and increasing likelihood of lacking functional dentition  MetS associated positively with tooth loss  Very low level of evidence  Better conducted studies necessary to establish a causal relationship Metabolic Syndrome (MetS) Oct 2020 FASEB Journal Japan

 Studied patients with MetS and found a positive correlation of those with high titers to P. gingivalis and increased insulin resistance

 Infection with P. gingivalis causes skeletal muscle metabolic dysfunction, the precursor to MetS, by altering the composition of the gut microbiome

 Mice fed high fat diet with P. gingivalis developed increased insulin resistance and lower glucose uptake in skeletal mm compared mice that did not receive P. gingivalis

 Possible mechanism underlying the relationship between periodontal disease and development of MetS ….. Increased risk of DIABETES & CVD Systemic Medical Conditions as Risk Factors for Periodontal Disease

OBESITY

 Association exists, but no causation

 Adipose tissue releases cytokines (TNF, IL-6) and hormones which contribute to periodontal tissue destruction

 Obesity related inflammation can deregulate the body’s immune system

 Elevated CRP ….. INFLAMMATION

Introduction Question 1 Question 2 Obesity

 British Dental Journal August 2019

 Interventional studies to measure effect of obesity on outcomes of non surgical periodontal treatment suggest a positive association but heterogeneous results

 Where there were better outcomes in non surgical treatment they were not clinically relevant Systemic Medical Conditions as Risk Factors for Periodontal Disease

 European Federation of Periodontology and American Association of Periodontology Workshop on Periodontitis and Systemic Disease (2013)

 “Reported associations do NOT imply causality and the establishment of causality would require new studies that fulfill the Bradford Hill or equivalent criteria”

Introduction Question 1 Question 2 Does periodontal disease or periapical pathology cause or lead to the progression or worsening of systemic medical conditions?

PERIODONTAL DISEASE SYSTEMIC HEALTH ASSOCIATION Systemic Diseases Associated With Periodontal Disease

 Cardiovascular Disease  Stroke  Diabetes  Respiratory Diseases  Dementia  Cancer  Pregnancy   Chronic Kidney Disease  Systemic Lupus Erythematosus  Liver Disease Periodontal Disease and Risk of Mortality

 JOURNAL OF DENTAL RESEARCH: Periodontitis, Edentulism and Risk of Mortality: A Systematic Review with Meta-analyses, January 2021  57 studies involving 48 cohorts and 5.7M participants  First systematic review on the subject  Chronic inflammation/infection from PD and its most advanced sequelae (edentulism) associated with increased risk of all cause mortality (47% - 2x) including CVD, Stroke, CA, and Pneumonia Periodontitis and Bacteremia Potentially Infecting Donated Blood

 Blood Transfusion: Feb 2, 2021

 Prevalence of bacteria was 6.4x higher in blood donated by people with periodontitis than those without.

 Oral bacteria evade routine blood testing that may lead to transfusion-transmitted infections. (TTI)

 Over 100M units transfused yearly and TTI’s are leading cause of post-transfusion mortality and morbidity. Other complications include , pneumonia and meningitis

 LIMITATIONS: cross sectional study, only 60 patients, did not study oral microbiome of patients, did not study whether those donations led to TTI in patients receiving transfusion. COVID-19

Blood Glucose on Admission Predicts COVID-19 Severity in All November 23,2020 Annals of Medicine

 Hyperglycemia at hospital admission – regardless of diabetes status – is a key predictor of COVID-19 related death and severity among non critical patients.

 11,000 patients March-May in Spain

 Those with abnormally high glucose levels (>180mg/dL) were more than twice as likely to die (41.4% vs 15.7%)

 Periodontal disease and blood glucose control? Oral Manifestations of COVID-19

 ACE-2 receptor site …. High prevalence in tongue, salivary glands, buccal mucosa and  GINGIVAL INFLAMMATION …. Elevated cytokines and interleukins  XEROSTOMIA …. Mask use and infection of salivary glands can influence quality and quantity of saliva  ORAL ULCERATIONS …. Virus in endothelial cells cause oxygen deprivation and tissue necrosis  CRACKED TEETH ….. Clenching and bruxism, stress, mask use, sleep deprivation and OSA  LOSS OF TASTE AND SMELL …. Viral disruption of cranial nerves 1,7,9&10 affecting neural transmission, virus in tongue Association Between Periodontitis and Severity of COVID-19 Infection: A Case-Control Study

 J Clin. Periodontology February 1, 2021 (Qatar)

 568 patients hospitalized with COVID. 40 experienced major complications and 528 were discharged without complications.

 258 patients had periodontitis; 33 experienced complications and only 7 of the 310 patients w/o perio had complications.

 After adjustment for confounders and comorbidities periodontitis was significantly associated with COVID complications ….. 3.67 x more likely.

 Risk of death 8.8x higher, ICU admission 3.54x higher, need for ventilation 4.5x higher

 HbA1c, WBC and CRP were significantly higher in COVID-19 patients with PD CAUTION …. Small study, very wide CI’s, perio defined by BW radiographs only Oral lesions in 2 asymptomatic teenage patients

Oral lesions related to COVID-19 Hospital Acquired Pneumonia (HAP) is the #1 nosocomial infection (surpassing C. diff.)

Oral pathogens strongly linked to HAP &VAP

Ventilator Associated Pneumonia (VAP) is the leading cause of death in ICU patients Missing Lateral Incisor Direct Bonded Bridge Direct Bonded Bridge #22-24 Direct Bonded Onlay #21 CARDIOVASCULAR MYOCARDIAL INFARCTION ATHEROSCLEROSIS DISEASE PERIPHERAL ARTERY DISEASE How Does Periodontal Disease Potentially Impact CVD

 COMMON SUSCEPTIBILITY MODEL -genetically determined phenotype which leads to a greater risk of atherosclerosis and infection …… perio does not cause atherosclerosis

 SYSTEMIC INFLAMMATION MODEL -increased circulating cytokines (CRP) damage the vascular endothelium and result in atherosclerosis

 INFECTION MODEL -direct infection of the blood vessels by bacteria in the atherosclerotic plaques. P. gingivalis found in 100% of plaques (Ford et al.)

Introduction Question 1 Question 2 Inflammation and CVD

 In one study of over 400 patients with defined Cardiovascular Disease the highest levels of CRP were seen in those with the most advanced periodontal disease

 Chronic inflammation increases macrophage secretion of specific cytokines (Ccl12) to inhibit reparative myofibroblast activation …. A critical step for scar formation and healing after MI

 Impaired cardiac wound healing, increased risk of mortality, and heart failure for patients with chronic inflammatory disease

Introduction Question 1 Question 2 Inflammation and CVD

 Impairs the function of the endothelium  Promotes atheroma formation in arteries  Compromises the integrity of arterial plaques ….. Leads to thrombotic and embolic events  Nearly half of all cardiovascular events occur in subjects who do not have traditional risk factors (high cholesterol, low HDL) ….. INFLAMMATION?

Introduction Question 1 Question 2 Atherosclerosis/P. gingivalis

 P. gingivalis is the most abundant species detected in coronary and femoral arteries

 Viable P. gingivalis and A. actinomycetemcomitans could be isolated from atherosclerotic plaques

 P. gingivalis cultured from 100% of healthy arterial walls with no atherosclerosis …… representing nearly 80% of all bacterial species

 P. gingivalis resides in diseased atherosclerotic tissue, aneurysmal walls of blood vessels, and has induced atherosclerosis in pigs following bacteremia regardless of cholesterol levels

Introduction Question 1 Question 2 Atherosclerosis/P. gingivalis

 P.gingivalis possesses unique properties to invade arterial walls and survive intracellularly and escape the immune system

 Unknown whether colonization occurs prior to atherosclerosis disease onset OR whether diseased tissues form before colonization and enable subsequent colonization

 May be associated with the initiation and/or exacerbation of Atherosclerosis with or without any role in causation

Introduction Question 1 Question 2 Cardiovascular Disease (CVD) Myocardial Infarction

 MI incidence correlates with the number of pockets >4mm, BOP sites and severity of tooth loss, even after adjustment of known CVD risk factors  P. gingivalis antibodies elevated in MI patients  POLAND STUDY: looked at periodontal disease by different measures: Community Perio Index, Clinical Attachment Loss, BOP and pocket depth  Patients with BOP> 50% had 4x higher odds of past MI  Patients with severe perio had 3x higher odds of past MI  Patients with CAL>6 had 1.28 higher odds of past MI  CONCLUSION: An association was found between chronic periodontal disease and past MI

Introduction Question 1 Question 2 Cardiovascular Disease (CVD) Myocardial Infarction

 Shuai study 2017: meta analysis of 22 studies (129,630 participants) --Patients with PD have increased risk of MI (OR 2.02 95% CI 1.59-2.57)  Teeuw et al., pooled 25 studies on the treatment of periodontitis and demonstrated intervention of PD improved atherosclerotic lipid profiles but direct evidence of reduction of risk of cardiovascular events is lacking  Ohki et al, showed 3 species of periodontal bacteria present in thrombi of patients with acute MI  Periodontal pathogens may play a role in plaque inflammation and instability ….. P. gingivalis induces platelet aggregation  Holmund study 2017: 5297 patients with PD treated in same clinic followed for 17 yrs: Those who did not respond as well to perio treatment had a higher risk of a future CVD than those who responded to perio treatment

Introduction Question 1 Question 2 Cardiovascular Disease (CVD) Myocardial Infarction

 Ryden et al., 2016: Periodontal Disease and first MI risk  Risk for MI was significantly increased among subjects with periodontitis -- OR 1.49 (95% CI 1.21-1.83)  After adjustment for confounders of diabetes, smoking, education, and marital status still a positive association -- OR 1.28 (95% CI 1.03-1.60)  Largest study to date with very strong design and case/control matches, use of bone loss as objective measure of periodontitis  Weakness ….. Observational study  CONCLUSION: PERIODONTITIS COULD BE LOOKED ON AS A RISK FACTOR OF FIRST-TIME MI INDEPENDENT OF OTHER RISK FACTORS

Introduction Question 1 Question 2 Cardiovascular Disease (CVD)

 COCHRANE STUDY (2017): Insufficient evidence to support or refute that periodontal therapy can prevent the recurrence of CVD in patients with chronic periodontal disease

 NO evidence on primary prevention of CVD was found

 Periodontal treatment DOES have a significant effect on surrogate markers: --decreases CRP and systemic inflammatory markers --improvement in endothelial function

Introduction Question 1 Question 2 Cardiovascular Disease (CVD)

AHA SCIENTIFIC STATEMENT: (2012)

 Observational Studies support an association between PD and atherosclerotic vascular disease independent of known confounders

 Do NOT support a causative relationship

 Periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction

 NO evidence they prevent atherosclerotic vascular disease or modify its outcomes

Introduction Question 1 Question 2 Cardiovascular Disease (CVD)

BALE & DONEEN METHOD (Brad Bale, MD, Amy Doneen DNP)  INFLAMMATION  Amount of lipid in arterial plaque predicts risk of heart attack and stroke  Soft “young” plaque more dangerous than calcified “old” plaque  Need ultrasound to detect  IT IS MANDATORY TO INCORPORATE ORAL HEALTH INTO ANY CV PREVENTION PROGRAM. THE BDM COULD NOT GUARANTEE ARTERIAL WELLNESS WITHOUT EXCELLENT ORAL HEALTH CARE PROVIDERS BEING INVOLVED. SNUFFING ARTERIAL INFLAMMATION IS THE KEYSTONE OF THE BDM AND THAT REQUIRES EXCELLENT ORAL HEALTH

Introduction Question 1 Question 2 Bale/Doneen Method Inside Dentistry/December 2019 Hypertension 2020 Study and Review Hypertension

 European Society of Cardiology: Cardiovascular Research Jan 2020

 Meta-analysis of 46 studies

 Meta-analysis of 3 cohort studies found NO association with periodontitis

 Meta-analysis of 15 cross-sectional studies found people with periodontitis have a 22% higher odds of having hypertension  OBSERVATIONAL STUDIES …. CrossMISLEADING sectional weakest design …. Cohort studies longitudinal …… better evidence TITLE  RCT’s did not show convincingly that periodontal therapy had a beneficial effect on hypertension Atrial Fibrillation & Heart Failure

 INFLAMMATION associated with AF/CHF  2019 Korean Study  161,000 patients followed over 10 years  Those who brushed 3x/day had 10% and 12% lower risk of AF and CHF  Those who had more than 22 missing teeth 31% higher risk of CHF  CONCLUSION: Frequent tooth brushing and professional dental cleaning may reduce the risk of atrial fibrillation and heart failure STROKE Stroke

2018 Sen ARIC Study (U. of S. Carolina)

PERIODONTAL HEALTH HAZARD RATIO

 A ….. Healthy  A ….. 1.0

 B ….. Mild perio  B ….. 1.86 95% CI (1.16-2.97)

 C ….. High BOP score  C ….. 2.06 95% CI (1.21-3.51)

 D ….. Tooth loss  D ….. 2.03 95% CI (1.26-3.26)

 E ….. Posterior perio disease  E ….. 2.22 95% CI (1.41-3.50)

 F …… Severe tooth loss  F ….. 2.08 95% CI (1.29-3.35)

 G ….. Severe perio disease  G ….. 2.20 95% CI (1.27-3.81)

Introduction Question 1 Question 2 Stroke (Sen study)

 High gingival inflammation in the absence of severe perio disease and the highly inflamed severe perio disease are at higher risk than those with mild, moderate, or posterior disease patterns.

 Emphasizes the importance of inflammation rather than just the level of attachment as being the determinant of risk.

 Compared with a reference group of episodic dental care users, regular dental care users had a lower risk for ischemic stroke HR .77 95% CI (.63-.94)

Introduction Question 1 Question 2 Stroke (Sen study)

 Risk for Cardioembolic stroke 2.6x higher

 Risk of Thrombotic stroke 2.2x higher

 Risk of Lacunar stokes not strongly associated after adjusting for risk factors such as age, hypertension, diabetes, and socioeconomic status

 PERIODONTAL DISEASE IS AN INDEPENDENT RISK FACTOR F0R ISCHEMIC STROKE

Introduction Question 1 Question 2 Stroke

 Population based study in Taiwan found cleanings or periodontal treatment could reduce the incidence of ischemic stroke  Similar data lacking in the U.S.  RCT’s have established periodontal treatment improves systemic inflammation, lipid profile, hypertension and endothelial dysfunction …. All surrogate markers.

Introduction Question 1 Question 2 Stroke

JAHA May 2019

 75 patients treated for ischemic stroke

 59 had a strain of Streptococci commonly found in mouth

 May contribute to thrombotic events and progression of cerebrovascular diseases

 “The significance of the finding is open to question ….. Finding evidence of bacteria in blood clots doesn’t mean they have a role in the disease process” Dr. Peter Lockhart

Introduction Question 1 Question 2 Stroke

 Periodontitis as a Risk Factor for Stroke: A Systematic Review and Meta-Analysis (November 2019)

 7 case control studies, 3 cohort studies

 Suggest an increased risk of stroke in patients with periodontal disease

 Strong association between both diseases …. 2x increased risk

 Evaluate results with caution ….. Need well planned prospective studies for more reliable conclusions

 Oral care for stroke patients important as many may have dysphagia and at increased risk for aspiration and pneumonia Periodontal Disease, Atrial Fibrillation and Stroke

 American Heart Journal: Sen, January 2021

 Systemic inflammation is linked to higher risks of AF

 Independent association between severe PD and AF

 Suggests that AF mediates the association between PD and stroke

 Those with regular dental care vs episodic care had a lower risk for AF (22%)

DIABETES Diabetes

 26.9M patients of all ages diagnosed with diabetes (8.2% of US population)

 34.2M patients of all ages diagnosed and undiagnosed (10.5%) Diabetes

 Patients with periodontitis exhibit a higher chance of developing BIDIRECTIONAL prediabetes and diabetes RELATIONSHIP  Patients with T2D have an increased risk of developing periodontitis

 Infections reduce the uptake of glucose into cells  Endotoxins and inflammatory mediators reduce the efficiency of insulin

 Diabetics have hyper inflammatory response …. More tissue destruction  Microangiopathy and poor healing

Introduction Question 1 Question 2 Diabetes

 There is strong evidence for an association between periodontitis and glycemic status in people who are not diabetic  Periodontitis was significantly associated with poorer glycemic control in Type 2 diabetics  There is insufficient data to support an association between periodontitis and poorer glycemic control in Type 1 diabetics

Introduction Question 1 Question 2 Diabetes/Complications

 Retinopathy significantly associated with periodontitis after adjusting for confounders (OR 1.2-2.8)

 People with periodontitis and either T1D or T2D have significantly MICROVASCULAR more renal complications COMPLICATIONS

 Significant association of neuropathic foot ulcerations in patients with severe periodontitis

 Cardiovascular complications have been significantly associated with T2D and periodontitis

Introduction Question 1 Question 2 Diabetes/Complications

 DIABETES CARE DECEMBER 2019

 Cost effectiveness analysis of expanding periodontal treatment for patients with T2 diabetes

 Tooth loss reduced by 34%

 Kidney complications reduced by 20.5% MICROVASCULAR

 Neuropathy reduced by 17.7% COMPLICATIONS

 Retinopathy reduced by 19.2%

 Net lifetime savings average $5,900 Diabetes

COCHRANE STUDY 2015

 Low quality evidence that SRP does improve glycemic control in diabetics with a mean reduction of HbA1c of .29% at 3-4 months

 Insufficient evidence that the reduction is maintained after 4 months

 Ongoing periodontal treatment is necessary to maintain benefit after 6 months

Introduction Question 1 Question 2 Diabetes

J EVIDENCE BASED DENTAL PRACTICE 2016

 Many limitations on the quality of the RCT studies included in systematic review meta-analysis

 A reduction of .29% in HbA1c at 3 months based on low quality studies may not be a suitable consideration when clinical decisions are to be made

 The question of whether periodontal treatment improves glycemic control in patients with diabetes remains to be answered

Introduction Question 1 Question 2 Diabetes/2018 RCT (Spain study)

 90 pts./2 groups ….Treatment: OHI/SRP ….. Control: supragingival scaling only

 Significant reduction in HbA1c (0.51%) and fasting blood glucose seen in patients treated by SRP at 3 and 6 months follow up

 Metabolic control unchanged in the non treatment group

 Those studies that did not show metabolic control improvement with SRP had participants with significantly higher BMI

 Clinical significance of reduced HbA1c …… 1% reduction associated with a 21% reduction in deaths related to diabetes, 14% reduction in MI and a 37% reduction in microvascular complications

Introduction Question 1 Question 2 Diabetes/2018 RCT (D’Aiuto)

 12 mo study/ 264 pts. Type 2 diabetes and moderate to severe perio

 Treatment: root planing and surgery followed by scaling and root planing every 3mo for one year. Control: supragingival cleaning only

 HbA1c was 8.1% for both groups at baseline. Treatment group HbA1c 7.8% at 12 mo Control group HbA1c 8.3% at 12 mo

 HbA1c 0.6% reduction in treatment group. Also improved periodontal disease, vascular and kidney function and quality of life measures

Introduction Question 1 Question 2 Diabetes 2018 Madianos Systematic Review

 Reduction of HbA1c with SRP at 3-4 mo was reported in all reviews

 At 6mo HbA1c reduction was less

 Successful periodontal treatment which results in the reduction of inflammation improves metabolic control .. in accordance with earlier data

 HbA1c reductions range from .27 - .48% …… Avg reduction of .40%

 2013 AAP/EFP review HbA1c reduction avg .36%

 Similar to adding a second medication to a pharmacologic regimen

Introduction Question 1 Question 2 RESPIRATORY COPD DISEASES PNEUMONIA COPD/Pneumonia

MECHANISMS OF ACTION:  Aspiration of oral pathogens  PD associated enzymes alter oral mucosal surfaces to enable colonization by respiratory pathogens  Cytokines originating from periodontal tissues may promote inflammation of the lower airway following aspiration of respiratory pathogens and reduce immune response Introduction Question 1 Question 2 COPD

 Common risk factors: smoking, socioeconomic status, age, obesity

 Shared ; dysfunctional neutrophil behavior, sustained neutrophilic inflammation, connective tissue loss

 Meta-analysis of 14 observational studies: OR 2.08 for having COPD in patients with periodontitis

 Leuckfeld study: presence of periodontitis (>4mm bone loss) was 44% in the COPD group vs 7% in the non COPD group …… adjusted for age, pack years smoked, BMI, and corticosteroid use ….. Only 180 patients

Introduction Question 1 Question 2 Pneumonia

 July 2020 Nature/Scientific Reports: ASSOCIATION BETWEEN ORAL HEALTH AND INCIDENCE OF PNEUMONIA: A POPULATION-BASED COHORT STUDY FROM KOREA (Son, M. et al.)

 The risk of pneumonia increased significantly in groups with a higher number of dental caries and missing teeth (27%) and decreased significantly in frequent tooth brushing and professional dental cleaning groups (15%) Pneumonia

THE TONGUE (Asakawara July 2018 mSphere)  Frail elderly (especially long term care patients) have more dysphagia  Elderly adults with poorer oral health (and edentulous patients) swallow a more dysbiotic microbiota formed on the tongue  Dominant source of microbiota in aspirated saliva is dorsum of tongue  Prevotella histicola, Veillonella atypica, Strep salivarus, Strep parasanguinis Candida  Found 2 groups of predominant commensals associated with increased risk of mortality due to pneumonia in frail elderly patients  More predominant in elderly with fewer teeth, higher plaque index, and more caries

Introduction Question 1 Question 2 Pneumonia

 THE TONGUE  2017 Hong Study. 1 yr longitudinal study of 60 dependent elderly. 17 developed pneumonia  Significant Risk Factors: calculus index and colonization of the tongue with P. aeruginosa and H. influenza  90% of patients harbored these respiratory pathogens on the tongue rather than in the plaque

 CONCLUSION: Mechanical removal of tongue biofilm and calculus to eradicate specific bacterial species may be needed to reduce pneumonia development from oral sources. Tongue Sweeper Ventilator Associated Pneumonia (VAP)

 Second most common hospital acquired infection

 Leading cause of death in critically ill patients in the ICU

 Associated with gastric aspiration …. Enteric and Respiratory pathogens

 Oropharyngeal pathogens cultured ….. Elderly nursing home and hospitalized patients oral plaque colonize with respiratory and enteric pathogens COCHRANE REVIEW

 High quality evidence that chlorhexidine reduces risk of VAP from 24% to 18%

 For every 17 pts treated with CHx 1VAP prevented

 Limited evidence of the effects of toothbrushing on the risk of developing VAP

Introduction Question 1 Question 2 Ventilator Associated Pneumonia (VAP)

 September 2020 Study funded by Dentaquest: looked at Medicaid ICU patients from 2016-2018.

 Those who had at least one preventive dental visit within 3 years of being placed on a ventilator were 22% less likely to be diagnosed with VAP Hospital Acquired Pneumonia (HAP)

RISK FACTORS:  Resident oral bacteria, aspiration potential (dysphagia, reduced consciousness) and host factors (age, frailty, comorbidity)  85% of hospitalized patients had respiratory pathogens in dental plaque and buccal mucosa vs 39% of non hospitalized patients  Risk of HAP increases by 9.6x in ICU patients when dental plaque is colonized by respiratory pathogens in the first 5 days following admission  Occurs on all types of patients and in every hospital unit ….. 51% occur in patients under age of 65  All hospitalized patients at risk  MOST COMMON HOSPITAL ACQUIRED INFECTION IN US

Introduction Question 1 Question 2

DEMENTIA Alzheimer’s Disease

 Beta-Amyloid protein deposits  Neurofibrillary tangles  Neuroinflammation RISK FACTORS:  Smoking, depression, hypertension, diabetes, obesity, age, stroke, traumatic brain injury ……. Periodontal disease?  Infectious diseases associated with low grade inflammation may play a substantial role in the pathogenesis of AD  Microbes implicated in etiology: Borrelia, T. denticola, P. gingivalis, E. coli, oral fungi (C. albicans)

Introduction Question 1 Question 2 Alzheimer’s Disease

ROLE OF P. gingivalis  Administration of P. gingivalis LPS in middle aged mice caused learning and memory deficits  Master immune evader and immunosupressor , cytokine release  P. gingivalis LPS contain proteolytic enzymes which contribute to degradation of endothelial cells and loss of blood brain barrier (BBB) integrity  P. gingivalis (and LPS) frequently found in autopsied brains of AD patients but not in normal brain tissue  Inflammatory mediators activate microglia and promote amyloid production as well as enhance BBB permeability

Introduction Question 1 Question 2 Alzheimer’s Disease Alzheimer’s Disease

Dominy et al., Study Jan 2019 Science Advances  P.gingivalis gingipains (virulence factors) promote neuronal damage  P.gingivalis found in CSF and brain tissue … CLAIM CAUSALITY  Developed gingipain inhibitors which block gingipain induced neurodegeneration  Broad spectrum antibiotics do not protect against P. gingivalis induced cell death but gingipain inhibitors do …. Possible treatment to slow disease progression  “I’m fully on board with the idea that this microbe could be a contributing factor. I'm much less convinced that it causes AD” Dr. Robert Moir, Harvard Neurobiologist

Introduction Question 1 Question 2 Alzheimer’s Disease

 Chen Study: 10 year exposure to chronic periodontitis led to a 1.7 fold increase in risk of developing AD  Leira Study: The presence of periodontal disease has a significant association with AD. (OR 1.69 95% CI 1.21-2.35). Severe PD shows stronger association. (OR 2.98 95% CI 1.58-5.62)  A prospective interventional study has shown that effectively treating periodontitis can lead to improvements in cognition  CAUSATION NOT ESTABLISHED  Periodontitis a risk factor and may contribute to progression  Patients with AD lose ability to maintain proper oral hygiene increasing periodontal disease, inflammation and poor nutrition

Introduction Question 1 Question 2 Alzheimer’s Disease

 J of Alzheimer’s Disease Feb 2020, (Beydoun, M. et al.)

 Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer’s Disease Dementia in a Large National Survey

 26 year follow up of patients

 Authors conclude: “ This study provides evidence for an association between periodontal pathogens and AD. Effectiveness of periodontal pathogen treatment on reducing sequelae of neurodegeneration should be tested in randomized controlled trials.” Convexi-T band …dead soft

CANCER Cancer

 24% higher risk of first primary cancer in participants with severe periodontal disease

 28% higher risk in patients who reported being edentulous

 Positive associations observed for lung CA, oral CA, colorectal CA, esophageal CA, and pancreatic CA

 Biologic plausibility …… animal models demonstrate periodontal pathogens increase tumor burden in the colon and oral cavity

Introduction Question 1 Question 2 Cancer

 Among male never smokers periodontal disease was associated with a 33% increase in risk of smoking related cancers  A 2.5 fold increase in risk in men who had advanced periodontitis  Smoking related cancers include: lung, bladder, oropharyngeal, esophageal, kidney, stomach and liver

Introduction Question 1 Question 2 Lung Cancer

 5 studies all adjusting for smoking demonstrated a positive risk related to severe periodontal disease

 Among NEVER SMOKERS …… 4x greater risk with severe perio (18cases)

 Positive association observed for women with higher intensity of smoking and periodontal disease compared to those with higher smoking dose and no periodontal disease

 AN INTERACTION BETWEEN SMOKING AND PERIODONTAL DISEASE MAY EXIST

Introduction Question 1 Question 2 Oral and Oropharyngeal Cancer

 Account for 3% of all cancers (53,000/yr) and 1.6% of cancer deaths  ORAL CANCER …… risk factors: alcohol and tobacco ….PD?  Squamous Cell CA account for 90% of all head and neck CA  2 studies measuring bone loss reported strong associations with bone loss and risk of oral CA  Also a positive relationship between number of teeth lost and oral CA  Strong association observed for periodontitis and oropharyngeal and esophageal cancers in never smokers  Esophageal CA ….. Higher risk associated with P. gingivalis (ESCC) and Tannerella forsythia (EAC)

Introduction Question 1 Question 2 Esophageal and Gastric CA

 BMJ July 2020 Study by Harvard researchers (Chun-Han, L et al.)

 Followed nearly 150,000 patients for 22-28 years

 Found a history of periodontal disease was associated with a 43% and 52% increased risk of esophageal and gastric cancer, respectively

 PD and poor oral hygiene promote the formation of nitrosamines known to cause gastric CA, and T. forsythia and P. gingivalis associated with esophageal CA

 “these data supports the importance of the oral microbiome in these cancers ….. and may serve as readily accessible, non-invasive biomarkers and help identify individuals at high risk for these cancers” Oral Cancer

 October 2020 Study PLOS PATHOGENS, (Kamarajan)

 P. gingivalis, T. denticola, and F. nucleatum promote oral cancer via specific host cell interactions and enhanced oral squamous cell carcinoma (OSCC) cell migration, invasion , tumorsphere formation and tumorogenesis in vivo

 Oral commensal bacteria did not affect OSCC cell migration

 Nisin, a bacteriocin, and commonly used food preservative reduced oral cancer tumorogenesis ….. May have a therapeutic potential to inhibit periodontal-pathogen enhanced oral carcinogenesis Oropharyngeal Cancer

 75% of OPC are HPV related …… 18,000 cases/year … 80% men  80% of population will have HPV infections in their lifetime ….. 99% clear with no symptoms  HPV 16 and HPV 18 cause 85-90% …. Fastest growth rate  Primarily located in the tonsils, tonsillar crypt and pillars, and base of tongue  White, non smoking males age 35-55 most at risk  SYMPTOMS: difficulty/pain swallowing, sore throat, hoarse voice, painless lump in neck, unilateral earache persisting for several days, constant coughing  www.oralcancerfoundation.org

Introduction Question 1 Question 2 HPV Vaccine

 Vaccine developed for HPV associated cervical CA but oropharynx is the most common site for HPV associated CA

 Recommended for girls and boys at age 11-12

 Most effective prior to sexual activity

 2 doses 6-12 months apart

 Vaccine age 9-26 recommended if not given earlier (approved up to age 45)

 3 doses after age 15 …… 1-2 months/6-12 months

 Gardasil/Gardasil 9 …. Approved by FDA for head and neck cancers 2020 (Cervarix discontinued) Pancreatic Cancer

 2012 Michaud Study: 5 cohort studies showed consistent results of a 50% increase in risk for patients with periodontal disease Positive association between P. gingivalis and A. actinomycetemcomitans  2013 European Prospective Cohort study showed a 2 fold increase in risk with elevated levels of antibody to P. gingivalis (405 cases vs 416 matched controls. 500,000 total)  2016 Prospective Study of 361 pts who developed pancreatic CA matched against 371 patients w/o CA over 10 yrs Took mouthrinse samples at baseline. Those with P. gingivalis had 59% greater risk of developing pancreatic cancer. Those with A. a. had 50% greater risk. Oral bacteria as risk factor along with older age, male, smoking, African American race and family history of disease  2019 Study: African American Women who self reported hx of PD were 77% more likely to develop pancreatic cancer (only 78 cases of 60,000 women followed 2007-16)

Introduction Question 1 Question 2 Colorectal Cancer

 80% increase in risk for edentulous patients  50% increase in risk for patients with severe periodontitis  Strong associations among never smokers with edentulism and severe periodontitis

 Tooth loss not associated with increased risk  No association with periodontal disease

 HETEROGENEITY OF RESULTS FROM DIFFERENT STUDIES Introduction Question 1 Question 2 Colorectal Cancer

A diagnosis of periodontal disease in the past was associated with a modest increase in the subsequent risk (17%) of serrated polyps and conventional adenomas (11%) and more tooth loss (>4) was associated with a higher risk (20%) of serrated polyps.

Compared with healthy individuals, patients diagnosed with colorectal cancer had higher transmission rates of bacteria from the oral cavity to the gut.

Fusobacterium, Prevotella, Parvimonas Colorectal Cancer

Fusobacterium nucleatum association

 Shown to accelerate the progression of colorectal cancer

 Confers the growing tumor with protection against immune cells

 Frequently found in stool samples

 Most likely a “passenger” that multiplies in the more favorable conditions caused by the malignant tumor

 NOT likely a causative factor

Introduction Question 1 Question 2 Colorectal Cancer

Fusobacterium nucleatum association (Columbia U. study)

 One third are associated

 Annexin A1 protein stimulates cancer growth

 F. nucleatum increases production of Annexin A1 attracting more bacteria

 Presence of Annexin A1/F. nucleatum worsens prognosis regardless of cancer grade and stage, age, or sex

Introduction Question 1 Question 2 Cancer Take Home Message

 While relative risk for CA may not be very large, the associations observed are significant due to high prevalence of periodontal disease  Many common risk factors  Link between systemic inflammation and CA well established  Need better standardization of definition and measurement of periodontal disease  P. gingivalis and other bacterial assays as predictors of CA risk/disease  CA prevention ….. Possible focus on highest risk patients (smokers with severe perio) for screening (Lung CA)  Colon CA/F. nucleatum …….. HPV/Oropharyngeal CA  Health Insurance coverage for oral health care for high risk patients?

Introduction Question 1 Question 2 RHEUMATOID ARTHRITIS Rheumatoid Arthritis

 Affects 0.5-1% of population …… women 2-3x more than men  Bidirectional?  Both PD and RA are immunoinflammatory diseases …. Both destroy bone  Common inflammatory markers …. IL-1, IL-6, CRP, TNF, MMP, Pentraxin 3  Alteration in the protein Arginine implicated as a major cause or RA  As the structure of the protein changes due to citrullination the host recognizes them as foreign and produces auto-antibodies  P. gingivalis can cause citrullination of host proteins  RA often accompanied by antibodies to P. gingivalis

Introduction Question 1 Question 2 Rheumatoid Arthritis/Periodontal Treatment

 Periodontal treatment in patients with moderate to severe periodontitis and RA reduced severity of RA as measured by disease activity score (DAS-28)

 Reduction in number of tender and swollen joints

 Reduction in serum TNF and ESR

 Those patients taking anti-TNF therapy showed improvement in periodontal health

 Untreated periodontal disease may be an aggravating factor in those who don’t respond to RA treatments

Introduction Question 1 Question 2 Is There a Bidirectional Association Between RA and Periodontitis?

Seminars in Arthritis and Rheumatism January 2020  Systematic Review and meta-analysis of 6 case-control studies  NO substantial effect of RA on pocket depth or clinical attachment loss  However, Periodontal Disease was associated with substantially worse RA disease activity  Not Bidirectional

Introduction Question 1 Question 2 November 17 2020 Arthritis &Rheumatology

 Periodontal bacteria may increase heart disease risk in RA patients

 Exposure to Aggregatibacter actinomycetumcomitans (Aa) and the protein toxin it secretes was strongly associated with atherosclerosis in the coronary and carotid arteries of RA patients

 “These findings may suggest that assessing immunity against Aa may predict CVD in RA patients and that Aa-exposed patients may be appropriate for heightened CVD screening and primary prevention … and suggests a role for treatment/prevention of periodontal disease in the prevention of CVD in RA.” Dr. Jon Giles Columbia U.

 Cross-sectional study PRETERM BIRTH PREGNANCY LOW BIRTH WEIGHT Pregnancy/Preterm Birth/Low Birth Weight

 Normal gestation 40 weeks ….. Preterm<37 weeks / Low birth weight<2500g (5.5lb)  12-13% in U.S.

 Oral bacteria can be found in amniotic fluid and placenta  Risk Factors: age<17 or >35, socioeconomic, alcohol, African American race, low prenatal care, smoking, GU infection, multiple pregnancies, systemic diseases of the mother (hypertension, gestational diabetes)  Associations first reported by Offenbacher in 1996

 COCHRANE STUDY: --No clear difference in preterm birth <37 weeks between perio treatment and no treatment --Low quality evidence that perio treatment may reduce low birth weight

Introduction Question 1 Question 2 Pregnancy

IMPORTANCE OF ORAL HEALTH BEFORE AND DURING PREGNANCY  Baby born without bacteria in mouth  Mother and caregivers transfer oral bacteria to baby  Increased risk of caries for child  Dental care is safe and effective during pregnancy  Age 1 dental visit

Introduction Question 1 Question 2 Other Oral Health Systemic Health Issues

 Sleep Apnea  Nutrition  Social Chronic Systemic Disease: Cost Savings with Dental Treatment

 Total medical costs were considerably lower for individuals who received periodontal treatment or cleanings even when considering the cost of the dental care

 Savings realized irrespective of medical compliance but greater ($1849) for non-medically compliant than medically compliant ($264)

 Those receiving no dental care or only extractions, root canals or restorative care and no cleanings or perio treatment had the highest health care costs Medicare Cost Savings with Periodontal Treatment Benefit

 Avalere Health Study 2016  FOR PATIENTS WITH DIABETES, HEART DISEASE AND STROKE  Produce an estimated savings of $63.5B from 2016-2025  Includes new cost of $7.2B for periodontal treatment  $70.7B reduction in Medicare spending largely related to fewer hospitalizations and ED visits 3 Most Important Contributors to Oral Health/Systemic Health Connection

 INFLAMMATION

 INFLAMMATION

 INFLAMMATION ……. (& BIOFILM) Clinical Applications

 Culture oral microbiome and risk analysis for caries and periodontal disease …… customized recall, fluoride, sealants etc.

 Should patients with specific systemic diseases have insurance coverage for dental care through medical insurance …. Diabetic, stroke and cardiovascular risk?

 Culture oral microbiome as risk factors for certain medical conditions …… P. gingivalis (RA, Alzheimers, Atherosclerosis), Fusobacterium nucleatum ….. Colon CA

 Hospitalized patients and ICU patients get standard oral care to prevent pneumonia … post stroke rehab What do we do with this information?

 Educate patients on the value of good oral health and where it may impact systemic health

 Use to motivate patients to improve oral health and see dentist more regularly

 Educate and other health care providers ….. Outcomes based reimbursement models (especially pneumonia, diabetes, atherosclerosis)

- Dentist referral / Dentist – Physician referral

 Dentist as primary care health provider

 Expanded scope of practice

 Collaborative education model

 CHRONIC INFLAMMATION

 Good oral health provides better quality of life regardless of impact on systemic health! Thanks for your attention! Questions?? [email protected] REFERENCES References/CVD

 Periodontitis Increases the Risk of a First Myocardial Infarction: A Report From the PAROKRANK Study. Ryden L, et al, Circulation. 2016 Feb 9;133(6):576-83  Periodontal Disease and Atherosclerotic Vascular Disease: Does the Evidence Support an Independent Association?: A Scientific Statement From the American Heart Association. Lockhart P, et al., Circulation 2012; 125(20):2520-44.  Results From the Periodontitis and Vascular Events (PAVE) Study: A pilot Multicentered, Randomized, Controlled Trial to Study the Effects of Periodontal Therapy in a Secondary Prevention Model of Cardiovascular Disease. Offenbacher S, et al., J Periodontol. 2009 February:80(2):190-201  Periodontal Therapy for the Management of Cardiovascular Disease in Patients with Chroniic Periodontitis (Review). Cochrane Database of Systematic Reviews. Li C., et al., 2017, Issue 11.  Bacterial Signatures in Thrombus Aspirates of Patients With Myocardial Infarction. Pessi T, et al., Circulation. 2013;127:1219-1228 References/CVD

 Poor Response to Periodontal Treatment May Predict Future Cardiovascular Disease. Holmund A, et al., J Dental Research 2017, Vol 96 (7) 768-773  Evidence Summary: the Relationship Between Oral and Cardiovascular Disease. Dietrich, T et al., Bristish Dental Journal 2017 March: 222: 381-385  Treatment of Periodontitis Improves the Atherosclerotic Profile: A Systematic Review and Meta-Analysis. Teeuw WJ, et al., J Clinical Periodontol 2014:41: 70-79.  The Association Between Periodontal Disease and the Risk of Myocardial Infarction: A Pooled Analysis of Observational Studies. Shuai X, et al., BMC Cardiovascular Disorders 2017 17:50  Porphyromonas gingivalis is the Most Abundant Species Detected in Coronary and Femoral Arteries. Mougeot J, et al., J Oral Microbiology, 2017 Vol 9(1)1-9.  Improved oral hygiene care is associated with decreased risk of occurrence for atrial fibrillation and heart failure: A nationwide population-based cohort study. Chang Y., et al., European Journal of Preventive Cardiology. October 2019 References/Stroke

 Periodontal Disease, Regular Dental Care Use, and Incident Ischemic Stroke. Sen, et al., Stroke, February 2018 (49) 355-362.  Periodontal Disease and Stroke: A Meta-analysis of Cohort Studies. Lafon A. European Journal of 2014,(21) 1156-1161.  Gingival Inflammation Associates with Stroke – A Role for Oral Health Personnel in Prevention: A Database Study. Soder B, et al., PLOS ONE September 2015, 1- 7.  Oral Bacterial Signatures in Cerebral Thrombi of Patients With Acute Ischemic Stroke Treated With Thrombectomy. Patrakka O. et al.,J Am Heart Assoc. May 2019;8:e012330. DOI: 10.1161.  Periodontitis as a Risk Factor for Stroke: A Systematic Review and Meta- Analysis. Fagundes, NCF, et al., Vascular Health and Risk Management. Nov 2019:15 519-532. References/Diabetes

 Treatment of Periodontal Disease for Glycaemic Control in People with Diabetes Mellitus. Simpson TC, et al., Cochrane Database Syst Rev. 2015 Nov 6: (11)  The Effect of Nonsurgical Periodontal Therapy on HbA1c levels in Persons With Type 2 Diabetes and Chronic Periodontitis. Engebretson S, et al., JAMA, 2013. 310, 2523-2532.  Weak Evidence Hinders the Understanding of the Benefits of Periodontal Therapy on Glycemic Control in Patients With Diabetes and Periodontitis. Medina CR, et al., J Evid Base Dent Pract 2016: (236-238)  A Systematic Review and Meta-analysis of Epidemiologic Observational Evidence on the Effect of Periodontal Disease on Diabetes: An Update of the Review of the EFP-AAP Workshop. Graziani F, et al., J Clin Periodontol. 2018 Feb Vol 45 (2)167-87. References/Diabetes

 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. Sanz M, et al., J Clin Periodontol. 2018:45:138-149.  An Update of the Evidence on the Potential Impact of Periodontal Therapy on Diabetes Outcomes. Madianos P, Koromantzos P, J Clin Periodontol. 2018:45:188-195.  Periodontitis and Systemic Diseases: A Record of Discussion of Working Group 4 of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. Linden G, Herzberg M, J Clin Periodontol. 2013:40 S20-23.  Benefits of Non-surgical Periodontal Treatment in Patients With Type 2 Diabetes Mellitus and Chronic Periodontitis: A Randomized Controlled Trial. Mauri-Obradors E, et al., J Clin Periodontol. 2018:00:1-9.  Intensive Periodontal Treatment Shows Potential for Reducing Glycosylated Hemoglobin Among People with Diabetes: D’Aiuto F, et al., Lancet Diabetes Endocrinol. 2018;6(12):954-965 References/Cancer

 Periodontal Disease Assessed Using Clinical Dental Measurements and Cancer Risk in ARIC Study. Michaud D, et al., J Natl Cancer Inst. 2018 110(8) 1-12.  Systemic Meta-analysis on Association of Human Papilloma Virus and Oral Cancer. Chaitanya NC, J Can Res Ther 2016 Vol 12 issue 2, 969-74.  Periodontal Disease, Tooth Loss, and Cancer Risk. Michaud DS et al., Epidemiol Rev. 2017;39:49-58.  Oral Microbiome Composition Reflects Prospective Risk for Esophageal Cancers. Peters B, et al., Cancer Research. Dec 2017, 77 (23) 6778-87.  Periodontal Disease, Edentulism, and Pancreatic Cancer: A Meta-analysis. Maisonneuve P, et al., Annals of Oncology. 2017 28:985-995  Oral Health in Relation to Pancreatic Risk in African American Women. Gerlovan H., et al., Cancer Epidemiol Biomarkers Prev. Apr 3 2019 28(4)675-9 References/Cancer

 Periodontal Disease and Risk of all Cancers Among Male Never Smokers: An Updated Analysis of the Health Professionals Follow Up Study. Michaud D, et al., Annals of Oncology. 2016 Vol 27 No 5, 941-46.  Oral Health and Risk of Colorectal Cancer: Results from 3 Cohort Studies and a Meta-analysis. Ren HG, et al., Annals of Oncology. 2016, 27, 1329-36.

 Fusobacterium and Colorectal Cancer: Causal Factor or Passenger? Results From a Large Colorectal Cancer Screening Study. Amitay EL, et al., Carcinogenesis. 2017 Vol. 38, No 8, 781- 788.  Tumor Targeting by Fusobacterium nucleatum: A Pilot Study and Future Perspectives. Abed J, et al., Frontiers in Cellular and Infection Microbiology. June 2017, Vol. 7, Article 295  F. nucleatum Promotes Colorectal Cancer by Inducing Wnt/Beta-catenin Modulator Annexin A1. Rubinstein, M. et al., EMBO reports. (2019) e47638.

 Plasma Antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Michaud DS., et al., Gut Dec 2013,62(12)1764-70 References/Rheumatoid Arthritis

 Hand to Mouth: A systematic Review and Meta-analysis of the Association Between Rheumatoid Arthritis and Periodontitis. Fuggle N, eta al., Frontiers in . March 2016 Vol 7, Article 80.

 Influence of Periodontal Treatment on Rheumatoid Arthritis: A Systematic Review and Meta-analysis. Calderaro D, et al., Rev Bras Rheumatol 2017, 57(3)238-44.

 Association of Periodontal Disease and Tooth Loss With Rhematoid Arthritis in the US Population. dePablo P, et al., J Rhematol. 2008 Jan35(1)70-76.

 Periodontal Therapy Reduces the Severity of Active Rhematoid Arthritis in Patients Treated with or Without Tumor Necrosis Factor Inhibitors. Ortiz P, Bissada NF, et al., Jperiodontol. 2009 April: 80(4)535-40.

 Serum Antibody Levels Against Porphyromonas gingivalis in Patients with and without Rheumatoid Arthritis-a Systematic Review and Meta-analysis. Bender P, et al., Clin Oral Investig. 2017 Jan;21(1)33-42. References/Pregnancy

 Treating Periodontal Disease for Preventing Adverse Birth Outcomes in Pregnant Women (Review). Iheosor-Ejiofor Z, et al., Cochrane Database of Systematic Reviews 2017, Issue 6.

 No Association Between Periodontitis and Preterm Low Birth Weight: A Case-Control Study. Fogacci MF, et al., Arch Gynecol Obstet. Oct 11, 2017.

 Treatment of Periodontal Disease and the Risk of Preterm Birth. Michalowicz BS, et al., New England Journal of Medicine. 2006, Nov: 355:1885-94. References/COPD, Pneumonia

 Oral Hygiene Care for Critically Ill Patients to Prevent Ventilator-Associated Pneumonia (Review). Hua F, et al., Cochrane Database of Systematic Reviews 2016, Issue 10.  Is Periodontitis a Comorbidity of COPD or can Associations be Expalined by Shared Risk Factors/Behaviors? Hobbins S, et al., International Journal of COPD. 2017:12; 1339-49.  Severe Chronic Obstructive Pulmonary Disease: Association with Marginal Bone Loss in Periodontitis. Leuckfeld I, et al., Respiratory Medicine. 2008:102, 488-494.  Role of Oral Bacteria in Respiratory Infection. Scannapieco F, J Periodontol. July 1999: Vol 70, No 7, 793-802 References/COPD, Pneumonia

 Nursing Home-Associated Pneumonia, Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia: The Contribution of Dental Biofilms and Periodontal Inflammation. Raghavendran K, et al., Periodontal 2000. 2007: 44:164-177  Oral Biofilms, Periodontitiis, and Pulmonary Infections. Paju S, Scannapieco F, Oral Disease. 2007 November;13(6):508-512.  Periodontal Disease and Risk of Chronic Obstructive Pulmonary Disease: A Meta-Analysis of Observational Studies. Zeng X, et al., Plos One. October 2012. Vol 7, Issue 10.  The Association Between Oral Health Status and Respiratory Pathogen Colonization with Pneumonia Risk in Institutionalized Adults. Hong, CHL, et al., Int J Dent Hygiene. 2018;16:e96-e102. References/Alzheimer’s Disease

 Periodontitis, Microbiomes and their Role in Alzheimer’s Disease. Frontiers in Aging Neuroscience. Pritchard AB, et al., October 2017, Vol 9, Article 336.  Periodontitis Induced by Bacterial Infection Exacerbates Features of Alzheimer’s Disease in Transgenic Mice. Ishida N. et al., npj Aging and Mechanisms of Disease (2017)3:15.  Association Between Chronic Periodontitis and the Risk of Alzheimer’s Disease: A Retrospective, Population-based, Matched-Cohort Study. Chen CK, et al., Alzheimer’s Research and Therapy. (2017) 9:56.  Is Periodontal Disease Associated with Alzheimer’s Disease? A Systematic Review with Meta-Analysis. Leira Y, et al., Neuroepidemiology 2017;48:21-31.  P. gingivalis in Alzheimers disease brains: Evidence for disease causation and treatment withj small-molecule inhibitors. Dominy, S. et al., January 2019, Sci Adv References/Alzheimer’s Disease

 Can Better Management of Periodontal Disease Delay the Onset and Progression of Alzheimer’s Disease? Harding A, et al., J of Alzheimer’s Disease 58 (2017) 337-348.

 Periodontitis and Alzheimer’s Disease: A Possible Comorbidity Between Oral Chronic Inflammatory Condition and Neuroinflammation. Teixeira F, et al., Frontiers in Aging Neuroscience. October 2017, Vol 9, Article 327 References/Chronic Kidney Disease

 Connection Between Periodontal Disease and Chronic Kidney Disease: A Literature Review. Sapata DM, et al., Dental Press Implantol. 2014, Jan-Mar; 8(1) 81-85.

 Dental Health and Mortality in People with End-Stage Kidney Disease Treated with Hemodialysis: A Multinational Cohort Study. Palmer SC, et al., Am J Kidney Dis., 2015;66(4):666-67

 Periodontitis and Early Mortality Among Adults Treated with Hemodialysis: A Multinational Propensity-Matched Cohort Study. Ruospo M, et al., BMC Nephrology. (2017)18:166

 Association Between Periodontal Disease and Mortality in People with CKD: A Meta-Analysis of Cohort Studies. Zhang J, et al., BMC Nephrology (2017)18:269 References/Systemic Lupus Erythematosus

 Association Between Systemic Lupus Erythematosus and Periodontitis; A Systematic Review and Meta-Analysis. Rutter-Locher Z, et al., Frontiers in Immunology. October 2017, Vol 8, Article 1295

 Association Between a History of Periodontitis and the Risk of Systemic Lupus Erythematosus in Taiwan: A Nationwide Population-based, Case- Control Study. Wu Y, et al., Plos One. October 23, 2017

 Antibodies to periodontogenic bacteria are associated with higher disease activity in lupus patients. Bagavant H., et al., Clinical and Experimental Rheumatology 2019;37: 106-111. References/Liver Disease

 Periodontal Disease and Liver : A Systematic Review. Gronkhaer L, Sage Open Medicine. July 2015.

 Interaction Between Periodontitis and Liver Diseases (Review). Pengyu H, et al., Biomedical Reports. 2016; 5:267-276.

 The Linking Mechanisms Between Liver and Periodontal Diseases. Elhassan AT, Peeran SW, EC Dental Science. 4.2 (2016): 758-66.