mouth matters - learning stream...

12/31/2014

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Mouth Matters

Oral Manifestations

of

Systemic Diseases

Denis P. Lynch, DDS, PhD

[email protected]

Outline

Xerostomia

Sjogren’s syndrome

Mucocutaneous diseases

Mucous membrane pemphigoid

Pemphigus vulgaris

Diabetes mellitus

Perio – systemic health connection

Pregnancy

Cardiovascular disease

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Synopsis

Major clinical signs and symptoms

Diagnostic criteria and tests

Currently accepted therapeutic modalities

References

References

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Xerostomia

Saliva . . .

. . . lacks the drama of blood,

the sincerity of sweat and

the emotional appeal of tears.

Mandel (1990)

Etiology

Sjögren's syndrome

Iatrogenic

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Clinical Features

Subjective ≠ objective

Thick / ropey or foamy saliva

Mucosal "tackiness“

Fissured, atrophic tongue

Dysgeusia and dysphagia

Increased incidence of candidiasis

Increased Class V and root caries

Sjögren's Syndrome

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Etiology

Autoimmune disorder

Genetic predisposition

(?) Relationship to EBV

Epidemiology

0.5% of USA population

Middle-aged adults

Women > men (9:1)

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Clinical Features

Primary Sjögren's syndrome

Xerostomia

Xerophthalmia

Secondary Sjögren's syndrome

Xerostomia

Xerophthalmia

Other disorder, e.g., RA, LE

Clinical Features

Salivary gland enlargement

Firm, diffuse, asymptomatic

Abnormal sialography

Reduced lacrimation

Mucoid discharge

“Gritty" sensation

Corneal abrasion

Differential Diagnosis

Mumps

Salivary gland neoplasm

Drug-induced xerostomia

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Diagnosis

Minor salivary gland biopsy

Schirmer test

Serology

Slit lamp examination

MSG Biopsy

Schirmer test

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Slit Lamp Examination

Slit Lamp Examination

Treatment

Water

Artificial saliva / moisturizers

Salivary stimulants

Topical fluoride

Caries management

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Side Effects

Sweating

Lacrimation

Urinary frequency

Salivary Stimulants

OTC sialogogues

Sugarless candy

Sugarless gum

Dental Caries

Aggressive therapy

Scrupulous oral hygiene

Dietary alterations

Chlorhexidine mouth rinses

Topical fluoride

Salivary stimulation

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Prognosis

Good

Increased lymphoma risk (40x)

Mucous Membrane Pemphigoid

Also Known As . . .

benign mucous membrane pemphigoid

(but it’s not a neoplasm)

cicatricial pemphigoid

(but oral lesions rarely scar)

ocular pemphigus

(no relationship to pemphigus)

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Etiology and Epidemiology

Auto-immune phenomenon

Attack basement membrane proteins

BP-180; epiligrin (laminin-5); other

Middle-age

Females >> males

Clinical Features (Skin)

Skin lesions uncommon

Face, neck and upper trunk

Scalp

Scarring

Atrophy

Alopecia

Clinical Features (Mucosa)

Mucosal lesions common

Oral

Ocular (symblepharon)

Genital

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Clinical Features (Ocular)

Clinical Features (Genital)

Clinical Features (Oral)

Pain

Gingival erythema

Intact blisters rare

Scarring uncommon

Variable Nikolsky’s sign

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Periodontal disease

Pemphigus vulgaris

Lichen planus

Erythema multiforme

Primary herpetic gingivostomatitis

Diagnosis

Routine biopsy

Sub-basilar cleft

No acantholysis

No Tzanck cells

Direct immunofluorescence

IgG and C3 at the BMZ

Indirect immunofluorescence not useful

Treatment

Corticosteroids

Antimetabolites / immunosuppressants

Dapsone

Cyclophosphamide (Cytoxan®)

Azathioprine (Imuran®)

Calcineurin inhibitors (Tacrolimus®)

Tetracycline and niacinamide (B3)

Thalidomide (Thalomid®)

Ophthalmology consult

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Thalidomide

Prognosis

Good

Exacerbations and remissions

No mortality

Pemphigus Vulgaris

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Etiology and Epidemiology

Auto-immune phenomenon

Attack desmosome-tonofilament complex

Multiple clinical forms

Vulgaris is the most severe

Middle age

No gender differences

More common in Ashkenazic Jews

Clinical Features (Skin)

Fragile blisters

Wide-spread distribution

Rupture with minimal manipulation

Shallow ulcers

Clinical Features (Oral)

Oral lesions precede skin disease (65%)

Blisters and ulcers

Stomatodynia

Fetor oris

Positive Nikolsky’s sign

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Cicatricial pemphigoid


Bullous lichen planus

Erythema multiforme

Dermatitis herpetiformis

Diagnosis

Routine biopsy Supra-basilar cleft

Acantholysis

Tzanck cells

Direct immunofluorescence Interepithelial IgG and C3

Indirect immunofluorescence Titers parallel clinical disease


Cicatricial pemphigoid


Bullous lichen planus

Erythema multiforme

Dermatitis herpetiformis

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Diagnosis

Routine biopsy Supra-basilar cleft

Acantholysis

Tzanck cells

Direct immunofluorescence Interepithelial IgG and C3

Indirect immunofluorescence Titers parallel clinical disease

Treatment

Corticosteroids

Antimetabolites / immunosuppressants

Azathioprine (Imuran®)

Cyclophosphamide (Cytoxan®)

Mycophenolate mofetil (CellCept®)

Cyclosporine (Sandimmune®)

Methotrexate (Trexall®)

Niacinamide (B3) with tetracycline

Plasmapheresis

Prognosis

Fair

High morbidity

<5% mortality

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Diabetes Mellitus

Classification

Type 1 Immune-mediated

NOT called IDDM or JODM

Type 2 Insulin deficient or resistant

NOT called NIDDM or AODM

Characteristics of Diabetes

Characteristic Type 1 (IDDM) Type 2 (NIDDM)

Frequency 5% 85-90%

Pathogenesis Beta cell autoimmunity Insulin resistance

Clinical Abrupt onset Gradual onset

Age <20 years >40 yearsWeight Normal ObeseEndogenous insulin Low or absent VariableIslet cell antibodies Present AbsentKetoacidosis Common Uncommon

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Symptoms of Diabetes

Type 1 (IDDM) Type 2 (NIDDM)

Polydipsia ParesthesiasPolyuria NocturiaPolyphagia Visual changesWeight loss Weight loss or gainVisual changes Loss of sensation

Nocturia Postural hypotensionXerostomiaHeadacheIrritability

Epidemiology

12 – 14 million in US have diabetes mellitus

Only 50% of affected individuals are diagnosed

Type 2 diabetes constitutes 85 to 90% of cases

Insulin Preparations

Type Onset (hr) Duration (hr)

Fast-acting insulinLispro 15 min <5Regular insulin 30-60 minSemilente insulin 1-2 12-16

Intermediate-acting insulin

NPH insulin 1-2 18-28Lente insulin 1-3 18-28

Long-acting insulinUltralente insulin 4-8 20-36

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Oral PreparationsAgent Generic Name Brand Name

SulfonylureasFirst generation Chlorpropamide Diabinese

Tolbutamide OrinaseTolazimide TolinaseAcetohexamide Dymelor

Second generation Glyburide Diabeta, MicronaseGlipizide GlucotrolGlimepiride Amaryl

Biguanides Metformin GlucophageThiazolidinediones Rosiglitazone Avandia

Pioglitazone Actos

Alpha-glucosidase inhibitors Acarbose PrecoseInsulin inhibitors Repaglinide Prandin

Nateglinide Starlix

Diabetic Glycemia

Glycohemoglobin Level (HbA1c) Clinical Interpretation

4-6% Normal6-7.5% Good diabetes control7.6-8.9% Moderate diabetes control>9% Poor diabetes control

Periodontal Disease as a Risk Factor for Diabetes

Considerable evidence suggests that diabetes and periodontitis have a direct relationship

Uncontrolled or poorly controlled diabetes is associated with an increased susceptibility to periodontitis

The presence of periodontal disease may aggravate glycemic control

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Compared to Non-Diabetic individuals:

Diabetics are 3 times more likely to develop periodontal disease

Type 2 DM subjects are 2.8 times more likely to have clinical attachment loss

Type 2 DM subjects are more likely to have 3.4 times radiographic bone loss

Considered the 6th complication of diabetes

Measurement of Diabetic Glycemia – Then

Fasting blood glucose

2-hour post-prandial blood glucose

Glucola

Measurement of Diabetic Glycemia – Now

HbA1c Level

4-6%

6-7.5%

7.6-8.9%

>9%

Interpretation

Normal

Good control

Moderate control

Poor control

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Glycemic Control

Periodontal disease makes it more difficult for diabetics to control their blood sugar.

Severe periodontal disease can increase blood sugar contributing to diabetic hyperglycemia.

Poor control places person at increased risk for diabetic complications.

Diabetes as a Risk Factor for Periodontal Disease

Reduced PMN function

Chemotaxis

Adherence

Phagocytosis


Collagen metabolism & advanced glycation endproducts (AGE)

Synthesis, maturation and homeostasis of collagen affected by glucose levels

Proteins & collagen undergo glycosylation

process to form AGE, which play a central role in diabetic complications (eye disease, vascular disease, etc.)

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Infections

Diabetics are more susceptible to the development of infections than those without diabetes

Wound Healing

Unknown mechanisms

Cumulative effects of altered cellular activity, susceptibility to infection and collagen metabolism further contribute to the defective wound healing

Oral Manifestations

Gingivitis

Periodontitis

Periodontal abscess

Candidiasis

Mucormycosis

Peripheral neuropathy

Xerostomia

Dental caries

Gingivitis

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Periodontitis

Periodontal Abscess

Pseudomembranous Candidiasis

Infants and debilitated adults

White, non-adherent plaques

Erythematous base

Stomatopyrosis

stomatodynia

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Erythematous candidiasis

Most common form

Diffuse erythema

Variable symptoms

“denture sore mouth”

Limited to denture bearing mucosa

Frequently painless

Diagnosis

Smear

Culture

Latex agglutination

Therapeutic

Treatment

Topical antifungals

Systemic antifungals

Topical antimicrobials

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Topical Antifungals

Nystatin (Mycostatin®) Oral suspension

Pastilles

Vaginal suppositories

Cremes and ointments

Clotrimazole (Mycelex®) Troche

Cremes and ointments

Systemic Antifungals

Ketoconazole (Nizoral®)

Fluconazole (Diflucan®)

Topical antimicrobials

Gentian violet

Chlorhexidine

Peridex

Periogard

GUM (alcohol-free)

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Mucormycosis

Peripheral Neuropathy

Rule out candidiasis first

Periodontal Disease –Systemic Health Connection

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Periodontal Disease andPregnancy

Periodontal Disease and Pregnancy

No consistent relationship between periodontal disease, periodontal disease treatment and preterm birth rate or low birth weight

Polyzos NP, et al. BMJ 2010 Dec 29;341:c7017 (systematic review and meta-analysis of 11 RCTs; n=6558) – NO

George A, et al. Int J Evid Based Health 2011 Jun;9(2):122-47 (systematic review and meta-analysis of 10 RCTs; n=5645) – MAYBE

Chambrone L. et al. J Clin Periodontol 2011 Oct:38(10):902-14 (systematic review and meta-analysis of 13 RCTs) – NO

Kim AJ, et al. J Periodontol 2012 Dec;83(12):1508-19 (systematic review and

meta-analysis of 13 RCTs) – HIGH RISK ONLY

Bulut G, et al. Acta Odontol Scand 2014 May 22:1-8 (n=100) – NO

BUT

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Han YW, et al.Obstet Gynecol 2010;115:442-5

35 YO Asian female

39 5/7 weeks

H/O bleeding gums through pregnancy

Recent URTI with mild fever

Noted loss of fetal movement at 5 AM

No fetal heart beat at presentation

Stillborn female delivered weighing 3,300 gm


Foul smelling amniotic fluid

Evidence for ascending infection ruled out by vaginal/rectal swabs, but

Gram (-) bacilli in amnion & subchorion


Gingival crevicular sampling demonstrated a genetic match between F. nucleatum from mother’s subgingival flora and the fetal pathogen

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Periodontal Disease andCardiovascular Disease

References

Friedewald VE, et al. Am J Cardiol. 2009 Jul 1;104(1):59-68

Tonetti MS, et al. J Periodontol 2013 Apr;84 (4 Suppl):S24-9

Schenkein HA and Loos BG. J ClinPeriodontol. 2013 Apr;40 Suppl 14:S51-69

Epidemiology(Developed Nations)

Gingivitis – 50%

Moderate periodontitis – 30%

Severe periodontitis – 5-10%

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Risk Factors

Smoking (6-7X more bone loss)

Diabetes (2.5X more common)

Poor oral hygiene

Genetics / family history

Lack of regular dental care

Obesity

Alcohol

Stress

Medications / hormones

Confounding Factors

Smoking

Genetics /

Family History

Obesity

Stress

Theory

Pro-inflammatory cytokines (TNF-a, eicosanoids, matrix metalloproteins, etc.) released in response to the presence of Gram (-) periodontal pathogens, causing CIPD

Gram (-) bacteria enter systemic circulation in CIPD

Bacteremia and cytokines induce liver to produce acute phase proteins (C-RP) and IL-6 and release into the bloodstream

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Theory

Shared risk factors for CIPD and CAD, e.g., diabetes mellitus, cigarette smoking, hypertension, elevated triglycerides, hyperlipidemia, etc., resulting in increased C-RP, IL-6, et al.

Gram (-) periodontal pathogens found in CAD atheromas.

Floss or Die?

SKEPTICS

Focal infection theory revisited

Confounding is problematic

Associations are weak

ADVOCATES

Strong biological plausibility

Modest associations seen after statistical correction for confounders

Serious public health issue

Focal Infection Theory (Billings – 1912)

“Foci” of sepsis was thought to be responsible for the inflammatory diseases of arthritis, peptic ulcers, and appendicitis.

Microorganisms or their products

spread from distant chronically

infected sites (such as the mouth)

to target organs.

Therapeutic edentulation was commonplace.

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Bradford Hill Criteria for Causality

Strength of Association – The stronger the association the more likely the causal connection

Consistency – Relationship is observed repeatedly i.e. different study designs or across populations

Specificity – A factor influences a specific outcome or population

Temporality – Exposure A occurs before outcome B is seen (Tough to see in slowly developing diseases)

Biological Gradient – As exposure increases so does the outcome, i.e., dose response is seen

Bradford Hill Criteria for Causality

Plausibility – The association makes sense according to our substantive knowledge

Coherence – The association doesn’t contradict our substantive knowledge

Experiment – Causation more likely if evidence is based on randomized experiments

Analogy – For analogous exposures and outcomes an effect has already been shown. i.e. bacterial vaginosis & preterm birth

Arguments Against Causality

Smoking and other factors can’t be adequately adjusted for

Spurious associations

Edentulation doesn’t improve morbidity over 10 years

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Problems with Interpretation

Positive outcomes are easy to interpret

Negative outcomes are tough to interpret

Wide confidence intervals

Inconclusive causal inference due to inappropriate timing, ineffective intervention, etc.

ABSENCE OF PROOF IS NOT PROOF OF ABSENCE

Hierarchical Levels of Evidence

STRONGEST

WEAKEST

CASE CONTROL

PROSPECTIVE COHORT

INTERVENTIONAL

TRIAL

RCT

META-ANALYSIS

SYSTEMATIC REVIEW OF RCTs

EPIDEMIOLOGICAL CROSS SECTIONAL STUDIES

Case series, case report, animal & lab studies

Dental Health and Myocardial Infarction

2 case control studies

MI patients < 50

MI patients < 65

Community Controls

Random recruitment

Comparing dental health

Dental index

Perio + caries + PA radiolucency

Dental Index > in MI patients vs controls, both studies

“Statistically Adjusted” for smoking, HDL, HTN, etc.

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Wound Significance

In moderate to advanced periodontitis the surface wound area of the periodontium exposed to a Gm (-) anaerobic biofilm estimated to be between 8 – 20 cm2

Acute phase reactants

Case-controlled studies show higher C-RP levels in periodontitis compared to healthy subjects

Confirmed by systematic reviews with meta-analysis

Consistent “dose-response” relationship

More periodontitis –> more C-RP

Plasma IL-6 also higher in periodontitis patients compared to controls

Intervention Studies

Treatment of severe periodontitis

Improves endothelial cell dysfunction as measured in the brachial artery using flow mediated dilation.

Reduces serum C-RP, Ox-LDL, IL-6

CIPD and Atherosclerosis

Modest association

Additional large scale epidemiologic and intervention studies are necessary to validate the observations and determine causality

No evidence to date that periodontal therapy will decrease CVD morbidity

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CIPD and Atherosclerosis

Significant association between total periodontal pathogen burden and CAD

Significant association between the number of A. actinomycetemcomitans in periodontal pockets and CAD

Macrophages can accumulate cholesterol-rich lipids such as oxidized low-density lipoprotein and convert to large foam cells on interaction with periodontal pathogens

Biological Plausibility

Dental treatment can lead to bacteremia (1935)

Bacteremias from oral sources occur frequently (1980s)

Periodontal pathogens identified in 67% of human atheroma samples (2000)

Viable, invasive periodontal pathogens are isolatable from atheromas (2005)

Tissue tropism for periodontal pathogens & coronary arteries (2007)

Bacteremia from tooth brushing is 200X greater than for extraction (2008)

Periodontal Pathogens

Alive and well in carotid plaque

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CIPD and C-reactive Protein

Treatment studies

Beneficial reduction in C-RP

Not statistically significant

Greater reduction with more aggressive periodontal therapy

Summary

Significant association of MI / CVA with poor dental health in majority of cross-sectional & longitudinal studies

All but one case-control study show modest, yet significant association

2 meta analyses indicate CIPD is an independent risk factor for CAD

2 meta analyses indicate more study is needed

Joint Recommendations for Patients with CIPD

LEVEL OF CONFIDENCE

1. Very confident

2. Confident

3. Marginally confident

4. Not confident

TYPE OF EVIDENCE

A. RCTs

B. Single RCT or retrospective case control studies

C. Cohort studies

D. Expert opinion

U. No appropriate evidence

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Patient Information

Patients with moderate-severe CIPD should be told they may be at increased risk for CAD – 2C

Patients with moderate to severe CIPD and one known major CAD risk factor should consider medical evaluation – 3D

Patients with CIPD and more than one known major CAD risk factor should be referred for medical evaluation – 2D

Medical-Dental Evaluations

Medical evaluation of patients with CIPD should include assessment of CAD risk – 2D

Medical evaluation of patients with CIPD should include an annual physical examination, including BP measurement – 2D

Medical evaluation of patients with CIPD should include blood lipid profile and blood glucose measurement. C-RP should be considered – 2D

Risk Factor Treatment –Abnormal Lipids

Patients with periodontitis and more than one abnormal lipid or elevated C-RP should have lifestyle changes recommended – 1C

Patients with periodontitis whose target LDL levels are not reached with lifestyle changes should be treated pharmacologically – 2D

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Risk Factor Treatment –Cigarette Smoking

All patients with CIPD who smoke should discontinue tobacco use – 1C

Risk Factor Treatment --Hypertension

All patients with CIPD & HTN should be treated to target BP levels – 1C

All patients with CIPD and HTN should undertake lifestyle changes – 1A

All patients with CIPD and HTN not controlled by lifestyle changes should be treated p’cologically – 2D

Patients with CIPD and HTN treated with calcium channel blockers should be monitored for gingival hyperplasia – 1D

Risk Factor Treatment –Metabolic Syndrome

Metabolic syndrome

Elevated body weight

Elevated trigycerides

Decreased high-density lipoproteins

Elevated blood pressure

Elevated fasting blood glucose

Patients with CIPD and metabolic syndrome should be treated for all CAD risk factors, beginning with weight reduction – 1D

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Special Considerations

Except in patients taking calcium channel blockers to treat HTN, treatment of CIPD in patients with CAD is no different than treatment of CIPD in patients without CAD

Joint Recommendations for Patients with CAD w/ or w/o CIPD

For patients with CAD and previously diagnosed CIPD, periodontists and physicians should collaborate – 1D

For patients with CAD and no previous dx of CIPD

Periodontal evaluation should be considered in patients with gingival disease, tooth loss or elevated C-RP – 2D

Periodontal evaluation should include clinical and radiographic assessment. If CIPD is diagnosed, treatment should focus on plaque control and reduction of

inflammation – 2D

For patients with CAD and newly-diagnosed CIPD, periodontists and physicians should collaborate – 1D

I believe, based on the data, to date, . . .

… there is a relationship between CIPD and systemic health.

… the relationship between

CIPD and specific conditions varies from marginal to significant.

… the strength of association between CIPD and specific conditions will solidify over time.

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