Bacteria ¡nöuce thedisease process

AntigensLipopolysaccharides

Host response:monocytes/macrophages, etc

Cylokines(IL-1,TNF-o

Recruiied cells:fibroblasts. endothelial and

epithelial cells, etc

PGE, Matrix metallcproleinases

Bonerésorption

Loss ofconnective tissue

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Changing Periodontal Paradigms:Therapeutic Innplications

Gary Greenstein, DDS, MS*Ira Lamster, DDS. MMSc**

Many paradigms concerning the epidemiology, pathogeoesis, and systemic

impact oí penodontai diseases have been modified. For example, bacterial

hioñims are essential to induce penodontitis, but their mere presence is not suffi-

cient to mitiate disease. Jt is also now recognized that the host response to these

b/ofiims causes most of the destruction of the periodontal tissues. Code terminants

that influence the clinical severity of the disease process (ficiude enw'ranmentai,

genetic, and acquired factors. In general, the prevalence of advanced periodonti-

tfs and the incidence of disease progression are tower thar) previously believed.

However, pen'odontitis remains the rnost common chronic illness, in addition, the

finding that acquired systemic diseases may predispose individuals to periodonti-

tis, and conversely that periodontitis may be a risk factor for certain systemic dis-

eases, fias expanded the scope of periodon tics. These changed paradigms and

their consequences with regard to selecting therapies are discussed in this review

article. (Int J Periodontics Restorative Dent 2000;20:337-357.)

'Clinical Professor, Department of Period ontology. University ofMedicine and Dentistry New Jersey, Newark. New Jersey.

'Assistant Dean, Columbia School of Dentistry, New York, New York.

Reprint requests: Dr Gary Greenstein, 900 West Main Street, Freehold,New Jersey 07728.

Periodontal diseases are the result ofinfectionsoftheperiodontJum.^Theyshould be considered infectionsbecause there is a bacterial etiologyand a subsequent immune response.A microbial challenge often results ina subclinical infection because thehost response prevents the bacterialchallenge from reaching the thresh-old necessary to cause symptoms.^However, when subgingival bacteriaoverwhelm the host response, tissuedestruction occurs; this is termedpedodonta! disease. During the lastdecade, numerous paradigmsregarding periodontal diseases havebeen modified, including preva-lence, incidence of disease progres-sion, etiology, pathogenic mecha-nisms, predisposing factors, andimpact on the systemic health of thepatient. This article addresses thesemodified concepts and explorestheir therapeutic implications.

Prevalence of gingivitisand adult periodontitis

Epidemiologie surveys have found

that gingivitis without accompanying

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338

^ ^ ^ ^ ™ InriHpnrp of diipasp pmqrpisinn in patiptitc with pprinrlnntitis' ^

Study

Grbjc et al^°Deas et al- 'Persson and Page^^Halazonetisetal^^Jeffcoatand Reddy^"

No. ofpatients

7521255530

No. ofsites

11,4662,094

200

24,720

—

Evaluationperiod ¡mo)

69

245-12

6

Disease activitythreshold (mm)

2.52.02.01.750.4

% of patientsdeteriorating

in > 1 site

41.390.040.042.077.0

% of sitesdeteriorating

0.996.1

10.75.0

29.0

periodontitis affects 50% of adultsover 18 years old and involves anaverage of 6 or more teeth per pa-tient.^ Furthermore, most inflamedsites do not progress to periodonti-tis,''"' This was documented in stud-ies that longitudinally monitoredpatients with gingivitis'* and in inves-tigations that assessed the preva-lence of attachment loss in untreatedpopulations,^'* and it was supportedby animal studies.' However, Löe^concluded that gingivitis is oftenassociated with and precedes peri-odontitis. Therefore, elimination ofinflammation remains a critical ob-jective of periodontal treatment be-cause the absence of inflammation isa negative predictor of future clinicalattachment loss,'''"

The prevalence of moderateperiodontitis in the adult populationis approximately 30%,^ and severeperiodontitis afflicts approximately10% of the population. " - I s Unfor-tunately, these data underestimatethe occurrence of periodontitis forthe following reasons: epidemiologic

studies often record measurementsat the line angles of the teeth, butthe mid-proximal areas tend to dis-play deeper probing depths'^ '" ;and the use of survey teeth routinelymisrepresents the prevalence of dis-eased sites.'^" In addition, the stan-dard used to define periodontitisdramatically impacts on the data.For example, when Brown et aP^ sel-ected a 5-mm loss of clinical attach-ment at one or more sites as athreshold to characterize periodon-titis, 12% o f the study populationhad advanced periodontal disease.However, if a 3-mm standard wasemployed (equivalent to 25% ofthelength of a maxillary molar root),then 42% ofthe subjects had peri-odontitis; depending on the estab-lished threshold used to define peri-odontitis. the data change. Despitethe impression that the prevalence ofadvanced periodontit is has de-creased during the past several de-cades, it still affects over 30 millionAmericans and remains the mostcommon chronic disease.

Incidence of diseaseprogression

The incidence of disease progres-sion will also be influenced by thestandard that is selected to definedisease progression. The data pre-sented in Table 1 suggest that asmall number of sites in a limitednumber of individuals manifests dis-ease progression during a definedperiod."'^°"^'' The following resultscan be deduced from the data; 0)less than 50% of individuals withperiodontitis manifested diseaseactivity within 1 year; 0 around 5%to 10% of diseased sites demon-strated deterioration within 1 to 2years; and (3) approximately 20% ofthe patients accounted for 60% of allsites that progressed.

The finding that a small numberof individuals provides the majority ofsites demonstrating disease pro-gression supports the concept thatall individuals are not equally sus-ceptible to periodontitis. Support forthis conclusion is provided by the

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study of Loe et al,* which monitoreduntreated patients in Sri Lanka duringa 15-year period. This study assesseda homogeneous population that didnot practice oral hygiene and hadno dental care, thereby providing anunusual opportunity to monitor thenatural history of periodontal dis-ease. They noted that 9% of the indi-viduals developed severe periodon-titis, 81% displayed moderate boneloss, and 11% had gingivitis. Thesedata underscorethe need to identifysusceptible individuals and provideappropriate therapy.

• • • • •• g ñ g j f l Models of disease progression

Model

Continuous modeP'Episodic burst theory^*-"Synchronous bursttheory^^

Epidemiologie model^*

Brownian motion orstochastic model^^

Random walking modeP'

Fracturai modeP

Mechanism

Slow, steady, progressive disease processIrregular periods of exacerbation and remissionPeriods of exacerbation and remission during adefined period

Consistent with continuous disease aging processthat depends only on the duration of the process

Random periodsof sharp bursts and/or remission canoccur, but underlying disease activity remains constant

When observed at regular intervals, modei is similar toBrownian motion model

Multifactorial model,simulates disease advancing withage in bursts and remissions

Patterns of disease progression

Several models of disease progres-sion have been proposed to explaintemporal patterns of tissue destruc-tion fiable 2 ) . ^ " " Historically, it wasbelieved that periodontitis resultedin a slow, continuous, and progres-sive deterioration of the periodon-tium.^^ However, this did not ac-count for patterns of destnjction thatdeveloped quickly, or for observedperiods of remission. Subsequentclinical studies suggested that dis-ease progression occurs as episodicbursts of activity with periods of re-mission.^*'^' Other models of dis-ease progression listed in Table 2suggest that episodes of diseaseprogression may be superimposedon linear changes.^^^°

Several authors question the sta-tistical procedures used to supportthe episodic burst theory becausedisease progression at sites wastreated as independent events andnot related to the fact that sites

ithin a patient share a common^ " ^ Studies that employed

large thresholds to identify diseaseprogression may have spuriouslysupported the burst theory. For in-stance, in one study when both 0,4-mm and 2.4-mm standards for dis-ease progression were used, thenumber of sites deteriorating dur-ing a ó-month period was 29% and2%, respectively.^^ Different thresh-olds not only resulted in altering thenumber of deteriorating sites, but itwas dear that rejection of small alter-ations was misleading with respectto identifying patterns of clinical at-tachment loss. In that investigation,use of the 0.4-mm threshold resultedin linear disease progression at 76%of the deteriorating sites, and only12% of sites were characterized as

experiencing bursts of disease pro-gression,^* Similarly, others note thata linear pattern is the most commonmodel of tissue breakdown,-^'' Oneexplanation isthat discrete episodesof disease progression occur, butthese microbursts cannot be de-tected by clinicians. Therefore, overtime, the cumulative result appearsas a linear change. On the otherhand, it is possible that large incre-ments of attachment loss can hap-pen before destruction is containedby the host response. The variousmodels described in Table 2 explaina variety of clinical and radiographiefindings. Nevertheless, several pat-terns of disease progression mayoccur at different sites within thesame mouth or at the same site atdifferent periods. Patterns of disease

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340

Moderate

S ¡ntermediusP microsF nucleatumE corrodensEubacteñum sp

Very strong

A actinomycetemcomitansP gingivalisB fors y thus

Strong

P intermediaC rectusE nodatumTreponema sp

Fig 1 Ranking of suspected bacterial pathogens.'-

progression will be affected by a vari-ety of risk factors, the virulence of theinfecting bacteria, and the suscepti-bility of the patient. At present, itappears that no single model of dis-ease progression should be ac-cepted as dogma. Therefore, to pre-clude any patterns of diseaseprogression from occurring, the mainconcern of clinicians should be elim-ination of inflammation and controlof identifiable risk factors.

Etiology: Bacterialpathogens associatedwith periodontitis

Diversity of bacteria

More than 500 bacterial specieshave been identified in the oral cav-ity of humans.^^ Approximately 150to 200 different species can befound in any individual's mouth,^^and each periodontal pocket cancontain 30 to 100 different types of

microflora.' It has been estimatedthat healthy sites (probing depths <3 mm) harbor 10^ microorganisms,whereas deep pockets (> 6 mm) maybe inhabited by > 10^ bacteria.^^

Criteria used to identify putativepathogens associated with peri-odontal diseases include their highnumbers in progressive lesions, thefact that their elimination or sup-pression is associated with a return tohealth, host response (antibody pro-duction), virulence factors, and dis-ease progression in animal studies.^^Of the 500 species detected in theoral cavity, relatively few are corre-lated with periodontal diseases.Three bacteria are very strongly asso-ciated with per iodont i t is; Por-phyromonas gingivalis, Bacteroidesforsythus, and Actinobacillus actino-mycetemcomitans.^^ Other organ-isms listed in Fig 1 are considered tobe strongly or moderately associ-ated with periodontal diseases.'However, the mere presence of bac-teria cannot be used to predict future

disease progression in untreated ortreated patients.^'^^ Furthermore,even among sites diagnosed as dis-eased, the microbiota cannot beused to forecast which areas willundergo clinical attachment or alve-olar bone loss. ^-'' Bacteria are nec-essary to develop periodontal dis-eases, but their presence alone isnot sufficient to predict disease ini-tiation or progression. For diseaseprogression to occur, certain criteriamust be satisfied; (1) susceptiblehost; 0 pathogens present; C3) viru-lent pathogens exceed a tolerablethreshold for the host; (4) absence ofbeneficial species; and (5) conduciveenvironment.-^''

Types of infectior^s

Most of the bacteria listed in Fig 1can inhabitecologic niches adjacentto teeth without causing disease.This is because of resistance of thetooth-soft tissue interface, rapidly

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341

responsive inflammatory cascade,and specificity of the immune re-sponse. When there is a disruption ofthe host-parasite equilibrium, a poly-microbial infection overwhelms thehost defenses and the disease pro-cess is considered an opportunisticinfection.'^'* The term opportunisticinfection denotes that indigenousbacteria (normal residents) induceinfection in a systemically or locallyimpaired host. This is different froma true infection that is caused by ex-ogenous bacteria (not normal inhab-itants of the oral cavity)."" Anothertype of infection, referred to as asuperinfection, can occur after anti-biotic therapy alters the microbiota,predisposing the patient to an over-growth of potentially harmful oppor-tunistic pathogens.'^ These infec-tions can involve indigenous orexogenous microorganisms (eg, en-teric rods, pseudomonads). As manyas 15% of refractory periodontitispatients manifest severe infectionswith one or more superinfecting or-ganisms."^ It is difficult to treat theseinfections with only mechanical treat-ment; adjunctive systemic drug ther-apy is usually necessary to managesuperinfections and other true infec-tions.'"

Biofilms

Dental plaque is composed of bac-terial aggregates that are adherentto one another and to surfaces or in-terfaces."^ These bacteria form bio-films, which are écologie communi-ties that manifest the followingcharacteristics: they provide bacteria

with a variety of microenvironments(different pH, Eh, etc), exhibit meta-bolic cooperativity, share a primitivecirculatory system, and develop anexopolysaccharide matrix for mutualprotection.''^-''^ This organizationcan prevent drugs from penetratinginto the biofilm, and it has been esti-mated that concentrations that areeffective against plani<tonic bacte-ria (single bacteria) may need to beincreased by 500 times to be effec-tive against biofi lms."' ' Thus,mechanical disruption of plaquedeposits prior to local or systemicdrug delivery is needed to facilitateoptimal results.

Plaque regeneration (doublingtime) occurs rapidly when plaque ini-tially develops, but the regenerationtime dramatically slows in maturebiofilms.''' The growth of selectedmicrocolonies occurs within the bio-film and is referred to as bacterialblooms."^ However, factors that in-fluence the growth of specific bac-teria are unclear. Thus, maintenancevisits for patients previously treatedfor advanced periodontitis shouldbe modulated based on clinicalmanifestations of disease, past his-tory of disease progression, and oralhygiene performance. In general,supportive periodontal therapyevery 3 months has been successfulat maintaining clinical health and in-hibiting the kinetics of bacterial re-population.^°

Supragingival and subgingivalbiofilms have similar structural char-acteristics, but they differ in bacterialcomposition."^ Subgingival bacterialdeposits harbor more gram-nega-tive anaerobes and motile forms. It is

recognized today that supragingivalplaque control can affect subgingivalbacterial proliferation in periodon-tal crevices that are less than 5mm.^'-^^ Therefore, optimal plaquecontrol is advantageous because itimpedes supragingival plaque fromproviding nutrients and bacterialseeding of the subgingival area.

Subgingivally, a wall of neutro-phils separates the biofilm from theadjacent junctional epithelium andprovides a protective line that is crit-ical for maintaining the host-para-site equilibrium.^^ This defensivemechanism is facilitated by severalmolecular components that areresponsible for the release of neutro-phils from the vasculature (eg, E-selectin, intracellular adhesion mol-ecule [ICAM])."* However, certainbacteria, eg, P gingivalis, have theability to interfere with the release ofE-selectin, thereby impeding anacute inflammatory response.^"Thismay explain why Pg/ngii/afe alone orin combination with other bacteria isoften associated with periodontitis.

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^ ^ ^ ^ ^ 1 Relative risk for disease progression*'

Bacteria

Pgingivalis

Disease threshold(No. of bacteria)

10*A acrinomycetemcomitans 10^

5 intermedius10^

10^

Relativerisk

2.24.13.24.32.43.0

"Attachment loss >2 mm in 2-mo period

Bacteria! invasion of tissues

Some microbes found within bio-films can invade periodontal tissues.For instance, P gingivalis and A actin-omycetemcomitans have beenfound within epithelial cells,^^'^* butthe relationship between bacterialinvasion of tissue and disease pro-gression is unclear.'" It has not beendetermined whether tissue invasionis directly related to disease recur-rence. Nevertheless, infections asso-ciated with A actmomyceiem-comitans are difficult to managenonsurgically or surgically, and itoften is necessary to administer sys-temic antibiotics to suppress this

Bacterial thresholds

When the microbial flora associatedwith health and gingivitis are com-pared, gingivitis patients demon-strate an increased microbial load(10^ to 10* organisms per site) andan elevated percentage of gram-negative bacteria (15% to 50%).'"'The bacterial load is approximately10^ to 10^ microorganisms per sitewhen periodontitis is present, con-sisting mostly of gram-negative, an-aerobic bacteria.''^ As previously in-dicated, bacteria cannot be usedto predict which sites will undergodisease progression; however,for some pathogens bacterial loadthresholds reflect an increased

relative risk that sites will manifestdisease progression.' Therefore, itis prudent to reduce pathogeniclevels to below the thresholds listedin Table 3.

Endogenous vs exogenousbacteria

Most bacteria found within the oralcavity are considered endogenous;however, it is unresolved as towhether P gingivalis and A actir^o-mycetemcom/tans are endogenousor exogenous.^' Several lines of evi-dence suggest that P gingivaiis andA act/nomycetemcomitans are ex-ogenous: they may induce an anti-body response, they are often asso-ciated with disease, and they are notcommonly found in periodontallyhealthy individuals at levels that ex-ceed 10^ organisms per sample.*° Incontrast, factors indicating that theyare endogenous include: a relativelylarge percentage of the population,including periodontally healthy in-dividuals, may harbor these bacteriaat very low levels (less than 10^ persample), and there are numerousclonal types of these bacteria.^^

Cionality

Clonality denotes that within a spe-cies there are subspecies that aregenetically different, eg, there are atleast 32 clonal types of P gingivaíié^and 10 types of A actinomycetem-comitans.^^ Usually multiple clonaltypes are indicative of endogenousbacter ia.^ ' The occurrence of

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multiple clonal types provides anexplanation as to why certain indi-viduals colonized with the samespecies of bacteria may or may notmanifest signs of disease. Forinstance, a microbiologie test maydetect elevated levels of A actino-mycetemcomitans in a healthy pa-tient. This may be because of detec-tion of a nonvirulent cicnal type.This creates a dilemma because rou-tine microbiologie assessments donot differentiate between clones ofa bacterial species, nor do theyassess pathogenicity. Thus, cliniciansmust rely on clinical and radi-ographie manifestations of diseaseto signal that therapy is needed.Furthermore, since most potentialpathogens are considered endoge-nous and thus elimination is not fea-sible, therapy needs to be directedat suppression to facilitate man-agement ofthe bacterial challengeby the host response,^' In contrast,if an organism can be labeled asexogenous, then treatment shouldbe aimed at its eradication.'''' Toensure that alleged pathogens havebeen reduced below levels that aredetectable by culturing (10^ bacte-ria), it may be worthwhile in certainindividuals to culture after therapyas opposed to prior to treatment.

bacteria may reside in different fam-ily members, thereby providingstrong evidence that bacterial trans-mission occurred. At present, thedata indicate that microorganismscan be transferred betweenspouses*^'*'' and from parents tochildren.^^'^^ However, the inci-dence of transmission varies, and itshould not be assumed that trans-fer of bacteria will result in diseaseinitiation. Furthermore, transfer ofbacteria should not be interpretedto mean that periodontitis is conta-gious for the following reasons:bacteria are not easily transmittedbetween spouses or from parents tochildren, many healthy individualsharbor potential pathogens, andtransfer of bacteria does not nec-essarily result in disease,^' There-fore, community efforts to eradi-cate specific types of bacteria arenot needed. On the other hand, itwould be prudent to Increase clin-ical monitoring and possibly micro-biologic testing of individuals ex-posed to a close family memberwith advanced periodontitis, espe-cially if there is an extended familyhistory of increased susceptibilityto periodontitis.

Transmission of bacteria

DNA fingerprinting techniques (ie,reduction endonuclease analysis)have been used to assess routes oftransmission of putative periodon-tal pathogens.^' Investigators con-firm that the same clonal types of

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i toraJmed by systemic factois, eg, puberty, menstrual cycle, pregnancy

by medications-Gingivitis mooified by malnutrition•Non piaque-induceö gingival lesions, eg, viral, fungal, genetic, mucocutaneous, allergic

•Ctironic periodontitis (formerly called adult periodontitis)Seventy: mild {< 3 mm CAL), moderate (3-4 mm CAL), severe (> 5 mm CAL): char-acterized by the extent of CAL (clinical attachment less]

Amount of destruction consistent with local factorsAssociated with variable microbial patternsSlow to moderate disease progression, but may have periods of rapid progressionCan occur at any age, and there oan be localized or generalized forms

•Aggressive periodontitis, localized and generalized (formerly called early-onset peri-odonfitis, which inoludes juvenile, prepubertal, and rapid-progress penodontitis)

Rapid attachment loss and bone desiruotiorAmount of microbial deposits inoonsistent with severity of tissue destructionFamilial aggregationFrequently associated with A actinomycelemcomilans infectionsLocalized affects molars and incisorsGeneralized affeots molars, incisors, and at least 3 other teeth

•Periodontitis as a manifesfalion of systemic diseases, eg, hématologie or geneticdisorders

•Necrotizing periodontal diseasesNeorotizing ulcerative gingivitisNecrotizing ulcerative periodontitis

•Periodontal abcesses•Periodontitis associated with endodontic lesions•Developmental or acquired deformities, eg, mucogingival deformities, occlusal trauma

Fig 2 New classification of periodontaldiseases ¡for a complete listing, seeAr mi tsge").

Pathogenesis ofperiodontal disease

The term periodontitis denotes afamily of diseases that has similarhistopathologic features, pathwaysof destruction, and healing mecha-nisms. However, disease entitieslisted in Fig 2 differ with regard totheir etiology, natural history, pro-gression, and response to therapy,* 'It is now recognized that the diseaseprocess may be modified by geneticfactors, environmental factors (eg,smoking), and acquired factors (eg.

stress, systemic diseases),*^ Thecomplex interplay among the micro-bial challenge, the intrinsic host re-sponse, and disease modifiers deter-mines the clinical manifestations andseverity of periodontal disease. Dis-ease modifiers can affect host re-sponse, tissue homeostasis, tissuerepair, age of onset, patterns of de-struction, rate of disease progres-sion, response to therapy, severity ofdisease, and frequency of diseaserecurrence,*'

The fol lowing sequence ofevents characterizes the initiation

and progressiThe initial phase of disease occurswhen a bacterial challenge over-whelms the neutrophils, B, and Tlymphocytes. Then the bacteria, inparticular the gram-negative spe-cies, release cell wall componentsin vesicles that contain lipopolysac-charides, etc. When these vesiclesenterthetissues, they induce a hostresponse in which initially mono-cytes/macrophages release cyto-kines (proinflammatory mediators)such as interleukin (IL)-1 and tumornecrosisfactor(TNF]-a(Fig3],These

DI Periodontics & Restorative Dentistry

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Fig 3 Model for path ogenesis of peri-odontal diseases.

Bacteria induce thedisease process

AntigensLipopolysaccharides

Host response'monocyles/macrophages, etc

•

Cylokines(IL-i,TNF-o)

Recmiled cells:fibroblasts, endothelial and

epilhelial cells, etc

PGEj

Bonerésorption

•

Matrix metalloproteinases

Loss ofconnective tissue

mediators recruit other cells (eg,fibroblasts, junctional epithelium,endothelium) to produce prosta-glandin E (PGE^), which are re-sponsible for bone destruction andmatrix metalloproteinases that des-troy connective tissue. IL-ó, IL-1ß,and TNF-a also participate in alveo-lar bone loss, but to a lesser extentthanPGE^.*'

Gingivitis is the initial lesion inthe development of periodontitis-^However, differentiating betweengingivitis and periodontitis may bedifficult when assessing clinical

parameters (eg, clinical attachmentlevel). Nevertheless, a biochemicalshift may signal the transition fromgingivitis to periodontitis. Gingivitisis characterized by increased leuko-triene B levels derived from de-granulating neutrophils in the gin-gival crevicularfluid.^^'*' In contrast,periodontitis lesions manifest in-creased levels of PGEj, IL-1, andTNF-a, which reflect activation ofmacrophages and lymphocytes.^-^These findings may lead to thedevelopment of chairside tests todetect these mediators and provide

biochemical differentiation amongaspects of the disease process.

In general, feedback mecha-nisms regulate the inflammatoryresponse, thereby modulating theresponse to bacteria, tissue turn-over, and facilitating repair An exu-berant release of pro inflammatorymediators results in uncoupling ofanabolic and catabolic processes,which causes tissue destruction.Subsequently, the host usuallyrestores the host-parasite equilib-rium, and the perceived burst of dis-ease progression is replaced with a

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phase of remission. Interestingly,there appears to be a radius of influ-ence induced by the pathogenicbiof i lm.* ' Several investigatorshypothesize that breakdown occurswhen the biofilm plaque front iswithin 2.5 mm of the connective tis-sue attachment""^ It was suggestedthat if the bacterial challenge is notcontrolled by host defenses, the tis-sues recede away from the noxiousstimulus, which is perceived by clin-icians as development of pocketingor bursts of disease progression.This pattern can then be repeatedwhen the biofilm again encroacheson the junctional epithelium andconnective tissue. Thus, even dis-eased sites that are not progressingshould be treated to break this chainof events. This concept is supportedby evidence that deeper probingsites harbor more bacteria, are moreoften associated with inflammation,and are more prone to additionalclinical attachment loss in treatedand untreated patients.'''

Suppression of the bacterialchallenge remains the sine qua nonof treatment. Nevertheless, recog-nition that the host response topathogens is mainly responsible fortissue destruction has provided animpetus to explore the potential ofhost response modification as anadjunct to conventional periodontaltherapy. Preliminary data suggestthat inhibition of matrix metallopro-teinases by administration of tetra-cycline analogues or inhibition ofprostanoids with nonsteroidal anti-inflammatory drugs (NSAID, eg, flur-biprofen) may be helpful in the man-agement of certain patients.''^

Periodonta! destructivesyndromes

Periodontitis reflects a family of peri-odontal diseases that may be epi-sodic, site specific, and induced by avariety of microorganisms.'-'^ Thevarious clinical forms of periodontitismay share common histopathologicmechanisms and manifest commonclinical signs of pathosis.*' However,their etiologic and triggering mech-anisms for disease progression stillneed clarification. For example,investigators demonstrated that thebacteria detected in lesions that werelosing clinical attachment (> 2 mm)and those that were stable were notdifferent.^^'*'^ This finding under-scores that the precise factors thatupset the host-parasite balance arenot defined. Therefore, the termperiodontal destructive syndromesmay appropriately describe differenttypes of periodontitis' ' ; the term syn-drome is used to label a pattern ofclinical signs and symptoms whoseetiologies are not fully understood.

Tooth ¡OSS

The concept that tooth loss after theage of 35 is mainly caused by peri-odontal diseases is no longer valid.Recent studies note that caries, notperiodontitis, is the principal reasonfor extractions in all patients exceptthe very oldest.'^''"

Recurrent vs refractory

periodontitis

Usually periodontal pathogens canonly be suppressed, thereby result-ing in microbial persistence evenafter clinically successful treat-ment. ' '^ ' This provides a partialexplanation as to why recurrent peH-odontitis can occur despite appar-ently successful treatment. However,the term recurrent periodontitis,which applies to sites and patients,should be differentiated from refrac-tory periodontitis, which indicatesthat a patient (not a site) is nonre-sponsive to conventional treatment.Characteristics employed to differ-entiate between these terms arelisted in Table 4.'^ It should be notedthat refractory periodontitis requiresantibiotic therapy in conjunction withconventional treatment."''

Risk factors

The clinical expression of periodon-tal disease is modified by risk factorsthat can be classified as acquired(eg, diabetes), environmental (eg,smoking), an

Diabetes

There are 2 major types of diabetes:

Type 1-insulin dependent and Type2-non insulin dependent. Type 1 ischaracterized by reduction of insulincaused by destruction of pancreaticbeta cells, whereas in Type 2 there isresistance of target tissues to theaction of insulin.^* Investigators have

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^ ^ ^ ^ 9 Characteristics of recurrent and refractory periodontitis^^

Characteristic

Definition

Phase of therapy

Etiology

Immune systemAntibiotic therapy

Recurrent periodontitis

Sites successfully treated but disease returns;may refer to sites or patients

May be because of inadequate therapy duringmaintenance or no maintenance

May be because of reinfection with microbes thatwere suppressed but not eliminated, reinfectionwith eliminated organisms,ornew bacteria

ImmunocompetentNot usually needed

Refractory periodontitis

Sites do not respond to conventional therapy; usuallyrefers to patients but may refer to sites

May be because of inadequate therapy during activetreatment or other factors

May be because of infection with tissue-invasivemicrobes that cannot be eliminated with conven-tional therapy or because of immunoincompetence

May not be immunocompetentUsually needed

indicated that diabetics have a 2 to3 times greater chance of develop-ing periodontitis than nondiabet-1-5 68.76,77 Q ^ | g ^^^^^ hand, pa-tients whose diabetes is medicallymanaged respond normally to ther-apy and are not at increased risk forpen'odontitis.'^

No difference in the subgingivalmicroflora was detected among dia-betics and nondiabetics.™'" How-ever, itwas suggested that diabeticsrespond differently to pathogensbecause of impaired host defenses,thereby making them more suscep-tible to infections.''^'* This has beenattributed to vascular changes, poty-morphonuclear leukocyte dysfunc-tion, and altered immune regula-tion.*^'''' Vascular changes seen indiabetics are caused by prolongedexposure to hyperglycemia. This re-sults in formation of advanced glyca-tion endproducts (nonenzymatic gly-cated proteins and lipids), whichinduce irregularthickness and rigid-ity of blood vessels that impair leuko-cyte diapedesis, oxygen diffusion.

and metabolic waste removal. It alsoresults in an increased secretion ofproinflammatory cytokines [IL-1ß,TNF-ß), impaired neutrophil chemo-taxis, and altered connective tissuemeta bo I i sm.*^'^* These alterationsmay contribute to a predisposition tothe initiation and increased severityof periodontal disease and delayedwound healing among diabetics.The clinical finding of rapid changesin the periodontal status of patientswith diabetes should increase theclinician's suspicion of a change inthe metabolic status of the patient,and a medical consultation may berequired.

Smoking

Tobacco smoking is a major risk fac-torfordeveloping severe periodon-titis.*^ Individuals classified as lightsmokers and heavy smokers have agreaterchance of developing severeperiodontitis (2 and 7 times greater,respectively).^°^' A meta-analysis

performed for the 1996 WorldWorkshop in Periodontics indicatedthat smokers have a 2.8 timesgreater chance of developing peri-odontitis than nonsmokers.^^ To-bacco use is also related to diseaserecurrence and decreased responseto therapy.^^'^"" The underlyingmechanism has not been defined,but it may be related to an increasedbacterial load detected subgingi-vally.^^ This may occur because ofdecreased oxygen tension, whichencourages the growth of peri-odontal pathogens. Systemic alter-ations in the host response amongsmokers include impaired chemo-taxis and phagocytosis by neu-trophils, reduced antibody produc-tion, and increased circulating levelsof TiMF-ö. S'36,s7 Smoking is also as-sociated with delayed healing afternonsurgical^^ and surgical therapy.^'

Smoking appears to be associ-ated with a reduction in tissueinflammation and bleeding on prob-ing because of nicotine-inducedvasoconstriction of blood vessels

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subjacent to the junctional epithe-iium.''^ This can mask severe pock-eting and alveolar bone loss.Clinicians should counsel patientsregarding the negative impact ofsmoking on their periodontal health.Since smokers are high-risk individ-uals for additional disease recur-rence, they should be monitoredmore closely and provided with quar-terly maintenance visits to help themmanage their bacterial challenge.

Psychologic stress

Several studies suggest that stresscan reduce the efficacy of the im-mune response. There is strong his-torical evidence that the develop-ment of acute necrotizing ulceratlvegingivitis is at least in part stress re-lated.*" However, at present thereare no longitudinal psychoneuroim-munologic studies that addressalterations in host defenses to peri-odontal organisms In patients expe-riencing psychoemotional stress.*^A possible mechanism for stress toinfluence pathogenesis could beCO rti costero ids exerting an inhibitoryeffect on Inflammatory cells.'^'^Stress is a potential risk factor forperiodontal disease, but the under-lying mechanisms need to be thor-oughly evaluated.*^

Osteoporosis

Currently, the data that estrogendeficiency, which causes osteoporo-sis, isa risk factor for periodontltis arenot con elusive,' ^ However, evidence

that suggests that this may be trueis beginning to emerge. For exam-ple, women with osteoporosis man-ifest adverse effects on mandibularbone mass''' and crestal boneheight,'^ and they demonstratemore clinical attachment loss thannormal women.*** Furthermore,estrogen-deficient women havemore bleeding on probing and lessalveolar bone density than estrogen-sufficient women.'^"'^ In addition,hormone-replacement therapy re-sults in greater retention of teeth'™and is associated with a reduction inclinical attachment loss."*'

Mechanisms that Induce post-menopausal women with osteo-porosis to lose bone may also pre-dispose individuals to developperiodontitis. This could be attrib-uted to decreased levels of estro-gen, which normally has an ana-bolic effect on osteoblast-l ikecells.'°^ Estrogen also downregu-lates IL-6, which converts mono-cytes into osteoclasts.'"^ Thus, areduction of estrogen results in lessbone deposition and Increasedosteoclastic bone résorpt ion.Additional evidence supporting theconcept that osteoporosis is a riskfactor for periodontitis was pro-vided by Jeffcoat,"*" In a clinicaltrial, scaling and root planing wereadministered to all patients plus bis-phosphonate alendronate, anapproved osteoporosis therapy,was administered to half of the pa-tients.'"" The group receiving theantiosteoporosis drug had reducedloss of bone height and density,thus establishing a link betweenosteoporosis and per iodontal

status. Addi t iona l studies areneeded to determine if hormone-replacement therapy in post-menopausal women should beadvocated both to reduce the signsof osteoporosis and to help in themanagement of periodontitis.

Genetics

Several lines of evidence indicatethat genetically determined suscep-tibility is a critical determinant in theclinical manifestations of periodon-tal diseases: studies addressing fam-ily aggregation, formal genetic stud-ies of different forms of early-onsetperiodontitis, association with cer-tain Mendellian inherited diseases(eg, cyclic neutropenia), twin studies,and the finding that certain geneticpolymorphisms are associated withan abnormal host response."'^•"^*Studies that address the familial ag-gregation of early-onset periodonti-tis support the idea that there isautosomal-dominant inheritance forearly-onset periodontit is. '°^'"^'Other genetically transmitted dis-eases (eg, cyclic neutropenia] resultin decreased numbers and alteredphagocytic function of neutrophils,predisposing individuals to developperiodontitis.'™ Enhanced suscep-tibility may also be because of agenetically determined reducedcapacity to produce gamma G im-munoglobin (lgG)2 during peri-odontal Infections'^^ or alteredmonocyte/macrophage functionthat results in Increased releaseof prolnflammatory mediators,thereby enhancing predisposition to

The International Journal of Periodantics & Restorative Dentistry

349

disease, •"''•"° It has been noted thatthe data found in twin studies sug-gest that heredity can account for50% of the enhanced risk for peri-odontitis,'"

A recent study concluded thatsusceptibility to severe periodontitisis significantly enhanced whengenetic polymorphism of both IL-1aand IL-1ß genes is detected,^^ Thisis based on the supposition thatthese polymorphisms induce anoverproduction of interleukins,thereby inducing greater destructionof periodontal tissues. Anotherinvestigation found that a geneticpolymorphism of the IL-1ß genealone is sufficient to induce increasedrisk for periodontitis,"^ These find-ings need to be examined in longi-tudinal studies before specific ther-apeutic approaches are suggested.There appear to be complex inter-actions between multiple genes andenvironmental factors that interactto induce disease and modify itsexpression. As these genes are dis-covered, it may be possible to inte-grate their identification into a riskprofile that will help identify individ-uals who are susceptible to peri-odontitis and early tooth loss.'^^"^

HIV

Individuals infected with the humanimmunodeficiency virus (HIV) andothers in which the infection has pro-gressed to acquired immunodefi-ciency syndrome (AIDS) may be atgreater risk of developing peri-odontal diseases than individualswho are not HIV séropositive.'^^ A

severe, painful, rapidly progressiveperiodontal lesion referred to asnecrotizing ulcerative periodontitisdevelops in < 5% of HIV-infectedpatients.^ '"' It is more common for anHIV-infected individual with peri-odontitis to manifest indistinguish-able radiographie and clinical signsof periodontitis,*^ and the microflorain these individuals is similar to thatin other periodontitis patients,"^These patients may have elevatedlevels of Candida, but the relation-ship of subgingival fungal infectionsand periodontal disease initiation orprogression is unclear."*

The predisposition of HIV pa-tients to develop periodontitis canbe attributed to alterations of inflam-matory cell and immune cell func-t ions . " ' ' " ' For instance, it was re-ported that the recruitment ofpolymorphonuclear neutrophils(PMN) is Impaired in seropositiveindividuals, and there is a signifi-cantly reduced number of T cells(lymphocytes)."* In addition, séro-positive individuals demonstrate ele-vated levels of IL-1 ß, which suggestsan altered immune response,"''

The clinical symptoms mani-fested by some seropositive patients(eg, lineargingival erythema, necro-tizing ulcerative gingivitis, necrotizingulcerative periodontitis) are differentfrom those usually seen in patientswith adult periodontitis. Thus, it wassuggested that HIV infections shouldnot be considered a modifier of gin-givitis or periodontitis, but ratherthey should be considered a differenttype of periodontal disease.*^ Thisissue is unresolved. Regardless ofwhich position is correct, these

patients should be provided with fre-quent supportive periodontal ther-apy to help reduce their oral bac-terial challenge while they receiveappropriate therapy, ie, proteaseinhibitors, from their physicians.

Systemic effects ofperiodontal diseases

While systemic diseases are a riskfactor for the development of peri-odontitis, emerging data from casehistory and cross-sectional studiesindicate that periodontitis may be arisk factor for systemic diseases,'*However, it should be noted that as-sociations based on these types ofinvestigations are not as powerful asdata from longitudinal or interven-tional studies.^^ Additional studiesare needed before preliminary find-ings are used to develop treatmentrecommendations for patients withcertain systemic diseases. At pre-sent, there should be prudent dis-semination of information and judi-cious therapeutic recommendationsbased on the data linking periodon-tal diseases with systemic maladies.

Card/ovascufar disease

Several studies indicate that there isan increased risk of developing var-ious forms of cardiovascular diseaseamong individuals with periodonti-¡5 113-122-|-f,g strength of this asso-

ciation needs to be characterizedas moderate (Table 5), The biologicbasis for the association be-tween cardiovascular disease and

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350

Risk of developing cardiovascular disease based on periodontal findings

Study Design Association Measured

DeStefano et a l " ' '

Joshipuraetal"^Beck et al '^"Gencoet al '^ '

Cohort

CohortCohortCohort

Plaque Index, oral hygiene index Relative risk 1.2Death caused by CHD Relative risk 1.7Tooth loss in men with periodontal disease and CHD Relative ri5k 1,7Pocket depth, bone levels, and new CHD; fatal CHD and stroke Odds ratio 1.5,1,9,2.8Bone loss and new CHD Odds ratio 2.7

CHD = coronary heart disease.

periodontal infections is presentlyunclear.^^^'^^^ However, severalmechanisms to explain this relation-ship have been proposed. For exam-ple, dissemination of oral bacteriathrough the vasculature or elevatedcirculatory levels of proinflammatorycytokines induced by the periodon-tal infection can cause modificationof the vascular endothelium.^^''^^This can ultimately promote devel-opment of fatty streaks and arthero-sclerotic lesions that may cause coro-nary thrombosis, ischémie heartdisease, or a stroke. Another modelsuggests that myocardial ischemia,which is often preceded by acutethromboembolitic events, may beinduced by several bacterial speciesfound in dental plaque (eg. Strepto-coccus sanguis, P gingivalis).^'"''^^^These organisms are capable of pro-moting the aggregation of platelets(confirmed in a rabbit model), whichmay result in development of emboliand thereby possibly predisposeindiv iduals to th rombogen icevents.'^^ In general, the data sup-port the contention that there isan association between the inci-dence of cardiovascular disease

and periodontitis, but this shouldnot be interpreted to indicate acausal relationship. Addit ionalstudies, in particular interventionstudies, are needed to determineif prevention or treatment of peri-odontitis will decrease the inci-dence of cardiovascular diseases.

Pregnancy compHcatiorjs

Approximately 7,3% of babies bornin the United States are consideredpreterm low-birth weight babies [<2,500 g). Preliminary data in a ham-ster modeP^* and several humanclinical trials suggest that periodon-titis may be associated with adverse

pregnancy outcomes. A re-cent study indicated that among 124women there was a 7 times greaterchance of a low-birthweight baby inindividuals with greater clinicalattachment loss (the mean value inthe2groupswas0.3mm,3.1 mmvs2.8 mm).'^^ However, the authorscautioned that odds ratios fromfuture large longitudinal studies willprobably be lower than the mag-nitude of the odds ratio that was

calculated in this relatively smallcase-control study.'^' Thus, cliniciansshould be cautious when interpret-ing these data.

It is believed that a variety ofbiologically active molecules, Süchas PGEj and TNF-a, are increased inassociation with infections, andthese molecules may foster prema-ture labor. Another case-controlstudy [n = 44) found that gingivalcrevicular fluid levels of PGE^ are 2times higher in mothers of low-birth weight babies.'^' Furthermore,microbial data indicate that bacter-ial pathogens are detected at higherlevels in mothers of pretermlow-birth weight babies than inmothers of normal-birth weightbabies.'^^ This additional bacterialburden may account for the in-creased level of proinflammatorymediators found in mothers givingbirth to low-birth weight babies.Large studies are needed to verifythe link between low-birth weightbabies and periodontal disease. Inaddition, intervention studies areneeded to determine whether peri-odontal therapy can reduce the inci-dence of low-birth weight babies.

The International Journal of Periodontics & Restorative Dentistry

351

Diabetes

Diabetes is a risk factor for peri-odontitis, and preliminary data sug-gest that periodontitis may bea riskfactorfor diabetes. Two studies havenoted that periodontal therapy,including scaling and root planingand antibiotics, improves metaboliccontrol among diabetics.'^*"'^' Thisconcept is supported by the findingthat patients manifest reduced levelsof glycated hemoglobin and a re-duced need for insulin in the treat-ment of their diabetes subsequentto periodontal therapy. These datacan be interpreted to suggest thatphysicians should consider the peri-odontal status of diabetic patientshaving difficulty with glycémie con-trol and that periodontal therapymay be a necessary adjunctive ther-apy in the treatment of certain dia-betic patients.'^^

Periodontal therapies

Periodontal treatment consists ofseveral components: preventive,active care, and supportive peri-odontal therapy. Counseling pa-tients with regard to appropriate oralhygiene to prevent the onset of anyform of periodontal disease is an in-tegral part of therapy and remains acritical determinant for long-termpatient management. Active treat-ment consists of antiinflammatoryand regenerative therapy. Scalingand root planing is an effective treat-ment in the management of patientswith gingivitis and early to moderate

titis.'^^-'-^" Expected results

with regard to pocket reduction andgain of clinical attachment are listedin Table 6. Adjunctive, single epi-sodes of subgingival irrigation donot enhance root planing, whereassupragingival irrigation with an irri-gator does reduce gingivitis amongindividuals who do not practice Opti-mal oral hygiene.'^^ In general, bothlocal and systemically delivered an-tibiotics are reserved for patientswho do not respond to conventionaltreatment.''"''^^''^^ Empirical selec-tion of the applied drugs is commonpractice; however, to avoid admin-istration of ineffective medicaments,bacterial sensitivity testing can beused to guide drug therapy.'^* Sub-sequent to active treatment, sup-portive periodontal therapy usuallyensures that the baaerial challengewill be kept below the level neededto initiate progressive disease. How-ever, no precise interval betweenmaintenance visits suits all patients;therefore, scheduling supportiveperiodontal therapy visits needs tobe titrated on an individual basis.

The need for surgical periodon-tal treatment is dictated by theseverity of the defects being treated,the response to nonsurgical therapy,and the desired clinical outcome {ie,regeneration of lost support).'^^'''^'Surgical techniques employing bonegrafts and guided tissue regenera-tion are frequently used in severelesions.'^^"'"° Table 6 lists meanresults that can be expected afterdifferent types of surgical and non-

During the last decade, numer-

ous studies have examined the

potential application of polypeptide

Volume 20, Number 4, 2000

^ ^ ^ ^ ^ 1 Kpprpspntativp rpsiiltsotflittprent Therapies immr

Procedure

Open-flap debridement^'""*Demineralized freeze-dried bone graft^'''"Guided tÍ5sue regeneration"'"'Scaling and root planing'"

Pockets 4-6 mmPockets > 7 mm

Tetracycline fibers (Actisite, Procter & Gamble) + scaling and root planing''"Pockets 4-6 mmPockets >7 mm

Chlorhexidinechip (Periochip, Astra) + scaling and root planing'''^Doxycycline polymer (Atridox.Block Drug)''*^Subantimicrobial doxycycline (Periostat,CollaGenex)'''^ +scaling and root planing

Pockets 4-Ö mmPockets > 7 mm

Enamel matrix protein (Emdogain,Biora)'''^

Pocketreduction

3.0

2.5

5.2

1.292.16

1.02.1

0.951.3

1.031.683.1

Gain of clinicalattachment

1.52.14.2

0.551.29

1.11.20.650.8

0.951.552.2

Bone

fill1.12.23.2

——

————

——

2.6

'Re5ult5 are representative dala taken from large cljnical trials."•Mean results based on a meta-analysis.

groviith and differentiation factors forthe treatment of periodontitis. Theseare a class of biologic mediators thatregulate cellular events in tissue re-pair [ie, cell proliferation, chemo-taxis). Examples of these factors in-clude platelet-, epidermal-, andcementum-derived growth factors;bone morphogenic proteins (BiVlP 1to 12); etc."'* At present, none ofthese growth factors has receivedUS Food and Drug Administration(FDA) approval.'"'* However, oneproduct that employs enamel matrixproteins has been approved and isprobably the forerunner of manyproducts that will eventually be intro-duced to enhance regenerative ther-apy. " ^

A new therapy for periodontaldiseases that does not rely on con-trolling the bacterial challenge issubantimicrobial dosing with doxy-cycline (20 mg twice a day)."

This drug blocksthe action of certainmatrix metalloproteinases (MMP)that are involved in tissue destruc-tion {MMP-8, MMP-9 from neutro-phils). Preliminary data indicate thatthis treatment provides an adjunctiveaid when used with root planing(Table 6).''''' Thus, alteration of thehost response may prove to be avery effective management tool incertain patients who do not respondwell to conventional and antibiotictherapy.

Conc lus ion

Traditional paradigms concerningperiodontal diseases are in the pro-cess of being modified. Thesechanges are expanding the scope

and implications of periodontal diag-nosis and therapy. It is currently rec-ognized that periodontal diseases

are infections that may have bothlocal and systemic consequences.

Accordingly, elimination of peri-odontal Infections facilitates reten-tion of teeth afflicted with peri-odontitis and may preclude orreduce problems associated withsystemic maladies. To enhance man-agement of periodontal patients, itis important that clinicians considerrisk factors for periodontitis, espe-cially systemic modifiers of the dis-ease process. In this regard, peri-odontal patients may requiremedical consultation.

Ultimately, the goal of peri-odontal therapy is retention of teethin health and comfort. Achievementof this goal can be optimized if ourdiagnostic efforts and therapies arebiologically based, ie, control of in-fection and inflammation, and incor-porate new knowledge concerningchanged periodontal paradigms.

The International Journal of Periodontics &. Restorative Dentistry

353

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Volume 20, Number 4, 2000