Mouth Matters. Denis P. Lynch, DDS, PhD. Oral Manifestations of Systemic Diseases. Outline. 12/31/2014.

Transcription

1 Mouth Matters Oral Manifestations of Systemic Diseases Denis P. Lynch, DDS, PhD Outline Xerostomia Sjogren s syndrome Mucocutaneous diseases Mucous membrane pemphigoid Pemphigus vulgaris Diabetes mellitus Perio systemic health connection Pregnancy Cardiovascular disease 1

2 Synopsis Major clinical signs and symptoms Diagnostic criteria and tests Currently accepted therapeutic modalities References References 2

3 Xerostomia Saliva lacks the drama of blood, the sincerity of sweat and the emotional appeal of tears. Mandel (1990) Etiology Sjögren's syndrome Iatrogenic 3

4 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 4

5 Etiology Autoimmune disorder Genetic predisposition (?) Relationship to EBV Epidemiology 0.5% of USA population Middle-aged adults Women > men (9:1) 5

6 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 6

7 Diagnosis Minor salivary gland biopsy Schirmer test Serology Slit lamp examination MSG Biopsy Schirmer test 7

8 Slit Lamp Examination Slit Lamp Examination Treatment Water Artificial saliva / moisturizers Salivary stimulants Topical fluoride Caries management 8

9 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 9

10 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) 10

11 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 11

12 Clinical Features (Ocular) Clinical Features (Genital) Clinical Features (Oral) Pain Gingival erythema Intact blisters rare Scarring uncommon Variable Nikolsky s sign 12

13 Differential Diagnosis 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 13

14 Thalidomide Prognosis Good Exacerbations and remissions No mortality Pemphigus Vulgaris 14

15 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 15

16 Differential Diagnosis Cicatricial pemphigoid Primary herpetic gingivostomatitis 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 Differential Diagnosis Cicatricial pemphigoid Primary herpetic gingivostomatitis Bullous lichen planus Erythema multiforme Dermatitis herpetiformis 16

17 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 17

18 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 years Weight Normal Obese Endogenous insulin Low or absent Variable Islet cell antibodies Present Absent Ketoacidosis Common Uncommon 18

19 Symptoms of Diabetes Type 1 (IDDM) Polydipsia Polyuria Polyphagia Weight loss Visual changes Nocturia Xerostomia Headache Irritability Type 2 (NIDDM) Paresthesias Nocturia Visual changes Weight loss or gain Loss of sensation Postural hypotension Epidemiology 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 insulin Lispro 15 min <5 Regular insulin min Semilente insulin Intermediate-acting insulin NPH insulin Lente insulin Long-acting insulin Ultralente insulin

20 Oral Preparations Agent Generic Name Brand Name Sulfonylureas First generation Chlorpropamide Diabinese Tolbutamide Orinase Tolazimide Tolinase Acetohexamide Dymelor Second generation Glyburide Diabeta, Micronase Glipizide Glucotrol Glimepiride Amaryl Biguanides Metformin Glucophage Thiazolidinediones Rosiglitazone Avandia Pioglitazone Actos Alpha-glucosidase inhibitors Acarbose Precose Insulin inhibitors Repaglinide Prandin Nateglinide Starlix Diabetic Glycemia Glycohemoglobin Level (HbA1c) Clinical Interpretation 4-6% Normal 6-7.5% Good diabetes control % 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 20

21 Periodontal Disease as a Risk Factor for Diabetes 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% % >9% Interpretation Normal Good control Moderate control Poor control 21

22 Periodontal Disease as a Risk Factor for Diabetes 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 Diabetes as a Risk Factor for Periodontal Disease 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.) 22

23 Diabetes as a Risk Factor for Periodontal Disease 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 23

24 Periodontitis Periodontal Abscess Pseudomembranous Candidiasis Infants and debilitated adults White, non-adherent plaques Erythematous base Stomatopyrosis stomatodynia 24

25 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 25

26 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) 26

27 Mucormycosis Peripheral Neuropathy Rule out candidiasis first Periodontal Disease Systemic Health Connection 27

28 Periodontal Disease and Pregnancy 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 metaanalysis of 11 RCTs; n=6558) NO George A, et al. Int J Evid Based Health 2011 Jun;9(2): (systematic review and meta-analysis of 10 RCTs; n=5645) MAYBE Chambrone L. et al. J Clin Periodontol 2011 Oct:38(10): (systematic review and meta-analysis of 13 RCTs) NO Kim AJ, et al. J Periodontol 2012 Dec;83(12): (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 28

29 Han YW, et al. Obstet Gynecol 2010;115: 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 Han YW, et al. Obstet Gynecol 2010;115:442-5 Foul smelling amniotic fluid Evidence for ascending infection ruled out by vaginal/rectal swabs, but Gram (-) bacilli in amnion & subchorion Han YW, et al. Obstet Gynecol 2010;115:442-5 Gingival crevicular sampling demonstrated a genetic match between F. nucleatum from mother s subgingival flora and the fetal pathogen 29

30 Periodontal Disease and Cardiovascular Disease References Friedewald VE, et al. Am J Cardiol 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 Clin Periodontol Apr;40 Suppl 14:S51-69 Epidemiology (Developed Nations) Gingivitis 50% Moderate periodontitis 30% Severe periodontitis 5-10% 30

31 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 31

32 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. 32

33 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 33

34 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 META-ANALYSIS RCT SYSTEMATIC REVIEW OF RCTs INTERVENTIONAL TRIAL PROSPECTIVE COHORT CASE CONTROL WEAKEST 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. 34

35 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 cm 2 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 35

36 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 36

37 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 crosssectional & 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 TYPE OF EVIDENCE 1. Very confident 2. Confident 3. Marginally confident 4. Not confident A. RCTs B. Single RCT or retrospective case control studies C. Cohort studies D. Expert opinion U. No appropriate evidence 37

38 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 38

39 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 39

40 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. 40