Inflammation and Periodonta l Dis eas esA paradigm shift in periodontology and what it means for patient care

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Outline of Presentation All about inflammation: the paradigm shift in

periodontology Inflammation, periodontal disease and cardiovascular

disease Inflammation, periodontal disease and other disease

states Risk factors for periodontal disease Treatment of periodontal inflammation Five Things to Remember Future Directions and Questions

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Media Coverage Re ce n t Ne w s Cove ra g eThe Bos ton Globe

November 2, 2009 )Audience: 713,083)

WebMDJanuary 12, 2010 (Audience: 10,845,896)

Eating WellJanuary 1, 2010 (Audience: 530,309)

Men’s HealthJanuary 1, 2010 (Audience: 7,438,572)

Medica l News TodayFebruary 20, 2010 (Audience: 1,800,000)

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Periodontal Disease: A Quick Overview

Periodontal disease is a chronic inflammatory disease that destroys the bone and gum tissues that support the teeth.

The American Academy of Periodontology (AAP) estimates that 3 out of 4 Americans are affected by periodontal disease, ranging from mild gingivitis to more severe periodontitis.

If left untreated, mild cases of gingivitis can lead to periodontitis.

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Periodontal Disease However, the periodontal disease of

yesterday is not the periodontal disease of today.

Yesterday: researchers believed that gum loss in periodontal disease was caused by the bacteria in plaque.

Today: researchers have determined that the gum loss in periodontal disease is caused by the inflammatory response to the bacteria in plaque.

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J Periodontol 2008;79:1560-1568.

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What is Inflammation? Inflammation is the body’s first response to an injury. The first phase (acute inflammation) includes redness, swelling, heat,

and altered function. It is self-perpetuating. There are several biological markers of inflammation in your blood,

including C-reactive protein (CRP). CRP is a protein found in the blood which can rise in response to

inflammation. Acute inflammation often causes elevated C-reactive protein. Elevated CRP is a risk factor for several chronic inflammatory diseases.

Inflammation appears to be a common link between several common diseases of aging. These diseases include heart disease, arthritis, and periodontitis.

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Examples of Inflammation

Sunburn

Infection

A cut on the skin

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Inflammation’s Objective

Inflammation tries to contain the injury to the local site.

The body’s reaction is immediate (called the innate response).

Its ultimate purpose is to protect the body from further damage.

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Inflammation is Damaging when Uncontrolled

Though inflammation can be helpful under certain conditions, uncontrolled inflammation, also called chronic inflammation, is harmful and causes tissue loss.

Chronic inflammation occurs when there is a sustained infection, like periodontitis.

Chronic inflammation involves more inflammatory mediators than the immediate innate response.

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Chronic Inflammation

Chronic inflammation can negatively affect all organs and tissues of the body.

Chronic diseases of aging are connected through common chronic inflammatory mechanisms.

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Periodontal Paradigm Shift:

Because of this new focus on inflammation, there has been a

shift in the way periodontists view periodontal disease and its

relationship to other disease states.

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Periodontitis is a Chronic Inflammatory Disease of Aging

Periodontitis involves a microbial challenge to the gums which stimulates an inflammatory response

Genetic and acquired risk factors lead to immuno-inflammatory response

A prolonged immuno-inflammatory response leads to destruction of connective and bone tissues, which leads to the possible loss of teeth.

Chronic inflammatory diseases, such as periodontitis, arise over decades.

Periodontal disease is a significant contributor to the total inflammatory burden on your body and can adversely affect your systemic health.

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“Inflammation and Periodontal Diseases: A Reappraisal”

In January 2008 a workshop sponsored by the AAP brought together more than 80 leading experts: Periodontists, cardiologists, diabetologists, geneticists,

gerontologists, inflammation researchers

This was an opportunity to engage in collaborative thinking and brainstorming across many different fields- using inflammation as a common finding.

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Workshop, cont. The workshop was developed to expand and advance our

understanding of inflammation and the role it plays in diseases of aging.

The experts from the diverse fields addressed topics of inflammation: What is inflammation? What specific mechanisms constitute inflammation? What factors regulate inflammation? Why do individuals have different expression levels of inflammation? Is the inflammation in one disease common to the inflammation in

other diseases?

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Workshop, cont.

The experts engaged in discussion of the future of inflammation therapies and how they may change the future of periodontics.

Proceedings from the Workshop were published in a supplement to the Journal of Periodontology in August 2008.

(Available for free at: http://www.joponline.org/toc/jop/79/8s)

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Workshop, cont. What we learned:

Periodontal disease is a bacterially-induced chronic inflammatory disease that does not resolve by itself.

The inflammatory response is extremely complex . Environmental and genetic factors affect expression of

inflammation in individuals . The initiation and resolution of inflammation are well

controlled processes. Diabetes, CVD, and stroke all share common inflammatory

processes similar to periodontal inflammation. Resolution of any inflammation in the body is helpful for

overall health.

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The Workshop helped highlight the relationship between

various disease states, and suggested that inflammation may be the basis for these

relationships.

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Perio-Cardio Link:The relationship between periodontal disease and cardiovascular disease (CVD)

Cardiovascular Disease: A Quick Overview

Cardiovascular disease generally refers to conditions that involve narrowed or blocked blood vessels that can lead to a heart attack, chest pain (angina), or stroke.

The American Heart Association reports that cardiovascular disease is the leading killer of men and women in the United States.

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Inflammation and CVD Inflammation contributes to heart attacks as much as

or more than cholesterol.*

Atherosclerosis always begins with injury to the endothelium of blood vessels. Periodontal pathogens have been found in

atherosclerotic lesions.

*Ridker PM, et al. N Engl J Med. 2005 Jan 6;352(1):20-8.

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Periodontal Disease and CVD

Data derived from meta-analysis: Five prospective cohort studies Five cross sectional studies Five case control studies

Subjects with periodontitis had a 1.14 - 1.59 fold greater risk for developing CVD compared to those without periodontitis. Adjustments made for risk factors: smoking, diabetes, alcohol intake, obesity

and blood pressure

Bahekar AA, Singh S, et al. Am Heart J 154:830-837, 2007

meta-analysis combines the results of several studies that address a set of related research hypothesesAbility to control for between-study variation

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C-Reactive Protein (CRP) CRP is a protein found in the blood that reflects the

amount of inflammation in your body. Periodontitis and other sources of inflammation elevate

CRP levels. Elevated CRP is a direct risk factor for CVD.

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AJC-JOP Consensus Paper

The American Journal of Cardiology contacted the AAP after reading the August 2008 Journal of Periodontology supplement from the Workshop on Inflammation.

A consensus paper was developed in collaboration with the American Academy of Periodontology and top cardiologists.

The paper was published simultaneously in the Journal of Periodontology and the American Journal of Cardiology in June 2009.

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AJC-JOP Consensus Paper, cont.

The consensus paper is a summary of research that shows a connection between periodontal disease and CVD.

It explains the underlying biologic and inflammatory mechanisms that may be the basis for the connection.

Clinical recommendations for treating patients with cardiovascular disease and periodontal disease are also included.

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CVD-PD Clinical Recommendations Examples of the clinical recommendations:

Dentists are asked to consider their patients’ heart health and risk for CVD. Assess risk factors for CVD such as smoking and family

history of CVD Physicians are asked to consider their patients’

periodontal health and risk for periodontal disease. Assess symptoms such as tooth loss or bleeding and

swollen gum tissue All health professionals are asked to educate patients

on chronic inflammatory diseases and how they are related.

Health professionals are also asked to work together to ensure patients are in best health.

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The Relationship of Periodontal Disease to Other Inflammatory Diseases

Inflammation appears to be the basis for the association between oral and systemic disease.

One chronic inflammatory disease potentially influences the expression of other diseases: Tissue destruction is caused by prolonged inflammation. Moderate/severe periodontitis increases systemic inflammation. Systemic inflammation is associated with most chronic diseases of

aging. For example, periodontal disease influences diabetes and diabetes

influences periodontal disease.

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The Relationship of Periodontal Disease to other Chronic Inflammatory Diseases of Aging

Cardiovascular diseaseArthritisDiabetesAlzheimer’s DiseaseCancers

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Arthritis Arthritis (Rheumatoid arthritis

and osteoarthritis) is an inflammation of the joints.

Patients with arthritis have a higher incidence of periodontal disease compared to healthy controls.*

Source: National Institutes of Health

Periodontal treatment decreases arthritis parameters:** Patients’ number of swollen and tender joints decreased following

periodontal treatment. Patients’ assessment of pain also decreased following periodontal

treatment.

*Pischon N, et al. J Periodontol. 2008 Jun;79(6):979-86. **Ortiz P, et al. J Periodontol. 2009 Apr;80(4):535-40.

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Diabetes Worldwide incidence is expected to increase with increased

prevalence of obesity. Major public health burden because of serious microvascular

sequelae. nephropathy retinopathy neuropathy cardiovascular disease periodontitis

Total annual costs exceed $132 billion in US alone

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Risk Factors for Diabetes Genetics Diet Sedentary lifestyle Perinatal environment Age Obesity Chronic Inflammation Type I and Type II Diabetes

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Diabetes Type I Diabetes Adolescents and young adults Autoimmune destruction of pancreatic islet cells that produce

insulin Increased CRP in patients with long termed type I diabetes

Type II Diabetes Occurs mainly in adults but prevalence among young people

increasing due increase in childhood obesity Characterized by increased cellular non responsiveness to

insulin (insulin resistance) Pancreatic beta cells do not secrete sufficient insulin

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Diabetes Hyperglycemia inhibits the resolution of inflammation.

High CRP and IL-6 promotes insulin resistance.

Patients with diabetes are threetimes more likely to have periodontaldisease.

Controlling periodontal disease helpscontrol blood sugar levels.

Insulin

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Obesity Patients with a higher body mass index (BMI) tend to have

higher levels of CRP.

Calorie reduction leads to decreased gingival bleeding and rate of periodontal disease progression.*

*Branch-Mays GL, et al. J Periodontol. 2008Jul;79(7):1184-91.

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Alzheimer’s Disease Progressive intellectual failure and a major cause of dementia

Pathologic hallmarks: amyloid plaques and neurofibrillary tangles which are distributed in the

frontal neocortex and limbic system

Alzheimer’s Dz is an innate inflammatory response in an attempt to remove the amyloid deposits from the brain

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Alzheimer’s Disease Antibodies and immune cells cross the blood brain barrier.

Exposure to chronic periodontaldisease quadruples an individual'srisk of developing Alzheimer'sdisease.*

*Watts A, et al. Neuropsychiatr Dis Treat. 2008 Oct;4(5):865-76.

© 2000 - 2009 American Health Assistance Foundation

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Cancers Pancreatic cancer

Men with a history of gum disease are 54% more likely to develop pancreatic cancer than men with healthy gums.*

Head and neck cancers Chronic periodontitis is independently associated with the

incidence of head and neck cancers.** Smoking increases this association.

*Michaud DS, et al. Lancet Oncol. 2008 Jun;9(6):550-8. Epub 2008 May 5.

**Tezal M, et al. Cancer Epidemiol Biomarkers Prev. 2009 Sep;18(9):2406-12.

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Other Inflammatory Diseases Asthma and other chronic respiratory diseases

Osteoporosis

Kidney disease

Metabolic syndrome

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Risk Factors for Periodontal Disease

Genetic risk factors Can be minimized with proper diet, exercise, and oral hygiene.

Biological risk factors Other systemic diseases of inflammation may increase the risk of

periodontal disease. Predisposition to inflammatory conditions such as obesity,

diabetes, or CVD

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Risk Factors for Periodontal Disease, cont.

Behavioral risk factors Poor oral hygiene Smoking (specifically, nicotine intake)

Smokers have higher levels of CRP. Stress Sleep deprivation Poor diet

Biologic Risk Factors

Behavioral Risk FactorsGenetic Risk Factors

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Treatment of Periodontitis Reduction of tissue inflammation

Reducing one type of inflammation may reduce another: Patients with periodontitis and rheumatoid arthritis who received

periodontal treatment: Reduced inflammation in periodontal tissues. Reduced severity of RA symptoms.*

* Ortiz P, et al. J Periodontol. 2009 Apr;80(4):535-40.

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The good news is that inflammation levels can be reduced.

When chronic inflammation is controlled, the associated chronic inflammatory diseases may be controlled.

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How to Reduce Inflammation: What does this mean for patients?

Reduce direct sources of inflammation: Visceral fat

Exercise Reduce calories

Chronic infections Periodontists can help reduce inflammation in the oral cavity.

Have your teeth professionally examined and cleaned regularly.

Stop smoking. Activate inflammation resolution systems:

Add Omega-3 fatty acids to your diet. Take a daily low-dose aspirin.

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Inflammation: 5 things to remember

1. There has been a paradigm shift in the field of periodontology.

Periodontal disease today is defined by the inflammatory response to the biologic components of plaque.

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Inflammation: 5 things to remember

2. The relationship between periodontal disease and other chronic inflammatory diseases of aging is better understood.

These diseases include cardiovascular disease, respiratory diseases, diabetes and arthritis.

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Inflammation: 5 things to remember

3. Treatment of chronic oral inflammation should be done by trained dental professionals.

Co-management with periodontal specialists to help in evaluating, diagnosing, and treating periodontal inflammation and disease.

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Inflammation: 5 things to remember

4. Reducing inflammation in the body can reduce the occurrence and severity of chronic inflammatory diseases.

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Inflammation: 5 things to remember

5. Dentists and physicians need to work together to ensure the best health of their patients.

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Conclusions: Future Directions

A paradigm shift is occurring in both medicine and dentistry in our understanding of preventing many of today’s systemic diseases.

The incidence and amount of inflammation that patients experience may be critical to the onset and progression of certain systemic diseases.

Prospective treatment studies are needed that define whether or not periodontal treatment makes a substantial difference in the expression of certain diseases.

As we wait for such studies, we should educate our patients about what is known and to help them manage their own health by assisting in the reduction of inflammation.

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Future Directions

Significant clinical limitation in diagnosing and monitoring periodontal inflammation gingival inflammation and bleeding periodontal pocket depth gingival attachment level

Classical approaches to controlling periodontal inflammation rely on attempts to suppress bacteria that incite inflammatory response Mechanical (SC/RP, flap surgery) Chemical (antimicrobials, antibiotics)

Emerging and future approaches need to rely more on Modifying the inflammatory response itself

Limiting the activities of pro-inflammatory pathways, effector cells and mediators

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Pathogenesis of Periodontal Disease

HealthPink, Healthy Tis s ue , No Clin ica l S igns of Dis eas e

Good Oral HygieneLow Sus ceptib ility

No Sys temic Ris k Factors

Na tura l Enzyme Inhib itors Tis s ue Des truc tive Enzymes

Balance of Tissue Destructionin the Periodontium

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Pathogenesis of Periodontal DiseaseDis eas e Poor Ora l Hygiene

High Sus cep tib ilitySys temic Ris k Fac tors

• Smoking• Genetics• Diabetes

Natura l Enzyme Inh ib ito rs

Overproduc tion

Tis s ue Des truc tive Enzymes

Imbalance of Tissue Destruction

in the Periodontium

Pathogenesis of Periodontal DiseaseDis eas e

Chronic Overproduction

(Bone Los s , Deeper Pocke ts Are Grea tly Affec ted)

Tis s ue Des truc tive Enzymes

Natura l Enzyme Inh ib ito rs

Smokers

Studies show smokers have a les s favorable response to traditiona l modes of periodonta l

therapy

Imbalance of Tissue Destruction

in the Periodontium

Pathogenesis of Periodontal Disease

Dis eas eSmoking increas es leve ls o f Pro-in flammatory media tors ;

inc reas e re leas e o f des truc tive co llagenas e

Tis s ue Des truc tive Enzymes

SRP + Perios ta t

Smokers

Hea lth

Natura l Enzyme Inh ib ito rs

Pe rios ta t® decreas es leve ls o f Pro-in flammatory media tors ;

dec reas e o f co llagenas eAdding Perios ta t tips the ba lance towards pe riodonta l hea lth

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The Future of Periodontal Diagnosis

Traditional diagnostic (i.e. PD, AL, BOP, etc.) measures are informative to evaluate disease severity.

We need diagnostic determinants of disease activity.

Extensive research has been ongoing in this area since the 1990’s Presence of biomarkers of measured with the gingival crevicular

fluid (GCF) Presence of biomarkers present within saliva

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Gingival Crevicular Fluid

Most appropriate analytical fluid of choice because it was specific to the periodontal tissues

The three most promising biomarkers for predicting future disease activity Beta-glucuronidase Alkaline phosphatase Cathepsin B

Many diagnostic kits emerged based, many of which demonstrated high levels of sensitivity and specificity demonstrating disease activity at site level.

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Gingival Crevicular Fluid

Problems Too time consuming to perform Site specific - the choice of site was problematic

168 potential sites within the mouth to examine Too costly for routine use Results did not translate to changes in therapeutic

intervention

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Saliva

Medium of choice in the 21st Century.

Contains microbial and host response mediators.

Simple to collect using non-invasive techniques.

Provides whole mouth summary analysis.

Already used as a diagnostic fluid for: Determining hormone levels Drug detection Presence of HIV or Hep C virus

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Saliva

Problems Assays need to be highly sensitive. Biochemistry varies with its origin (whole saliva or specific

gland secretions) Not possible to fully quantify markers within saliva using

chairside technologies. Qualitative analysis may be all that can be achieved

Saliva contains mucins and cell debris making it challenging to work with.

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Saliva

Identify the biomarkers for periodontitis - aid in diagnosis and therapeutic monitoring of disease activity.

Difficult due to the complex nature op periodontal disease - no single etiology with multiple risk factors.

Periodontal researchers do not fully understand the pathogenesis of periodontitis.

However, identification of biomarkers the characterize periodontal tissue destruction will be attainable

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Question?

Can salivary testing for inflammatory biomarkers be a way for medical profession to screen patients for periodontal disease and the dental profession to screen patients for cardiovascular disease, diabetes and systemic diseases?

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