paradigm shift in etiopathogenesis periodontitis khushbu

A paradigm shift in the etiopathogenesis of periodontitis

Dr. Khushbu Mishra Guided by:- Dr. Veena A

Patil H.O.D.

Dept. of Periodontia

H.K.E.S’s S.N. Dental College Gulbarga

Contents

Introduction Rise of localist and local cause theory Generalist and the remote cause theory Rise of local cause hypothesis Fall of generalist Role of bacteria Role of susceptible host in periodontal tissue destruction Concepts of pathogenesis of periodontal disease Models of disease progression Conclusion

Introduction

Periodontitis is a family of related diseases that differ in etiology, natural history, disease progression and response to therapy.

But have a common underlying chain of events that are influenced by disease modifiers.

Clinical manifestations observed are a result of complex interplay of these factors.

It is well acknowledged that while etiology of periodontitis is bacterial, pathogenesis is inflammatory.

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The understanding of regulation of inflammation is far from complete.

As the understanding of periodontal inflammation increases, current understanding of the microbiology of periodontitis becomes less clear.

While we think we know that bacteria initiate the disease, role of specific bacteria is still unknown.

Proving the link between cause and effect of chronic disease such as periodontal disease is not an easy task.

Current knowledge of microbiology of periodontitis is based on large cross-sectional and association studies.

Periodontitis is seen as the direct consequence of bacterial invasion and is regarded as an infectious disease.

The foundation of our knowledge of periodontal disease is not the product of a linear chronology of events, but rather than bringing together of theories, discoveries and advances that have occurred in parallel.

Scientist and clinicians have been trying to understand and treat periodontal disease for centuries.

Loculosis Blennorrhea gingiva Periostitis Alveolodental periostitis Rigg’s disease Pyorrhea alveolaris Periodontal disease

years ago periodontists were divided into 2 camps

Localist Generalist

Cyril O. Enwonwu. 1972 – Orbans Periodontics a concept-theory and practice

The localists hypothesize that the primary causes of periodontal disease are intra-oral and thus that intra-oral interventions can, by themselves, prevent and successfully treat periodontal disease.

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The generalists hypothesize that the primary causes of periodontal disease are remote from the oral cavity and that periodontal disease is only amenable to chronic disease management unless the remote causes are pinpointed and intervened upon.

This local-cause paradigm became established before comparative clinical research arose as a means by which to objectively assess supporting evidence.

One could say that a reasonable hypothesis (the plaque hypothesis) evolved into accepted wisdom without going through an intervening process of rigorous clinical and epidemiologic investigation.

The rise of Localist & Local cause theory

Pierre fauchard 1746 referred Periodontal disease as different kind of scurvey which without involving other parts of body attacks gums, alveoli & teeth.

i. Periodontal disease is independent of systemic disease manifestations.

ii. Periodontal disease has local etiology.

iii. Local intraoral interventions can prevent & successfully treat periodontal disease.

iv. Local treatment can provide systemic health benefits

4 axioms of localist theory

First axiom

Periodontal disease is independent of systemic disease manifestation.

Second axiom

Periodontal disease has local etiology. Many authors suggested infection as local cause. Parasite – Gallipe 1888 Amoeba Viruses- Baer PN 1962 Mixed infections BANA +ve org.- Loesche WJ 1990 Red cluster bacteria (Socransky 2000) Treponema pallidium (Riverie GR et al.)

Third axiom

Fact that periodontal disease has local etiology, local intraoral interventions can prevent and successfully treat periodontal disease.

Domino theory of Periodontal causation. Dental accretions gingivitis destructive

periodontal disease. Thus, removing causal factor resolves Periodontal disease. So, the concept evolved- periodontal disease is caused by

Dental plaque.

Fauchard suggested no systemic treatment could lead to cure for local disease.

Rigg’s local cure (Dental calculus removal) was urged to be forwarded by journal publication.

(Meritt AH 1921)

Curability became almost unquestionable over subsequent decades.

4th axiom

Local treatment can provide systemic health benefit.

John Riggs made impressive claims for health giving effects provided by his cure.

G.V. Black supported it.

Generalist and the remote cause theory

W.D. Miller (1853-1907)- first oral microbiologist questioned infection as primary cause of Periodontal disease.

He remained unconvinced that local irritation be at all a requisite to origination of this disease.

There is often an inability to influence remote causes and that as a result after treatment is necessary at intervals from 4-6 months in retarding progress of this disease.

Miller hypothesized, potential remote cause

leads to

impaired resistance of periodontal tissue

suitable culture medium for bacteria

typical signs

suppuration, bleeding & oozing occurs

when periodontal tissues becomes infected.

Bunting RW (1920) hypothesized

that in absence of infection,

remote causes

alveolar atrophy (degeneration of bone)

Atrophic shrinkage

Periodontal disease compared to diabetic foot of leg. Several generalist-

periodontal disease as having a complex multi-factorial and remote primary etiology.

Miller Rachitic disease Maurice precocious senility Burchard (1894) Gout Ptaff tobacco smoking Price (1945), Cleave & Cheraskin nutrition factor

Rise of local-cause hypothesis

So, the key point of debate was whether primary cause is remote or local.

Initially, Fauchard & G.V. Black recognized that for a minority of patient, primary cause was remote.

Clinical approach under this tolerant view

if local treatment results in cure, cause is local

if it fails cause is constitutional However, beginning in late 1960’s--- after arrival of model

of pathogenesis it became virtually sacrilegious to ascribe genesis of inflammatory periodontal disease to factors other than oral plaque.

Role of leukemia in gingival bleeding-------not clearcut.

Role of vitamin C deficiency in periodontal scurvey were reinterpreted as periodontitis of bacterial causation.

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Factors to establish dominance

Periodontics became dental speciality.

* Chappin Harris

* John Riggs Dominance of germ theory. Simplicity versus complexity Clinical effectiveness of local therapies.

The fall of Generalists

It can be said that periodontal textbooks are written by winners--- those holding to local cause paradigm..

Bergstrom– prominent in recognizing smoking Cheraskin– relationship between vitamin C, sucrose and

gingival bleeding. ----- Remained uncited Miller’s work, Koch’s disciple --- viewed through the lens

of localists Remote cause perspectives became largely ignored.

Periodontal disease remains largely regarded as a locally caused disease.

Role of Bacteria

In the 1st part of 20th century, microbiologist used to rely on culture methods.

They believed that certain microorganisms such as amoeba/ streptococci were primary etiologic agents.

However, with each decade, data linking specific bacteria to disease causation proved unreliable.

Thus, by 1930s, it was generally believed that all bacteria on teeth could cause periodontal disease.

Amount of bacteria accumulated ∞ incidence and severity of disease (Non specific plaque hypothesis).

But clinician and investigators observed little disease in some persons with poor oral hygiene over long periods.

Large deposits were not related to subsequent destruction of periodontal tissue.

In 1964, Keyes and Jordan demonstrated

a. Periodontal disease could be transmitted from

hamsters with disease without disease.

b. or, by swabbing oral cavity of unaffected animals with suspensions of A. viscous isolated from hamsters with disease.

c. With demonstration of infectious and transmissible component of periodontal disease in the hamster, the field of periodontology changed substantially.

Research efforts were renewed to determine whether specific bacteria rather than all bacteria residing under gingiva caused Periodontal disease.

Socransky et al. undertook pioneering studies to examine the bacteria in periodontal pocket of children with localized juvenile periodontitis.

Site of advanced bone loss adjacent site of no

and formation of deep pockets periodontal disease.

Advanced bone loss--- anaerobic gram negative bacteria. Healthy site----- gram positive (facultative)

-----Golden age of oral microbiology. 1980s longitudinal trials provided further

evidence that specific bacteria are associated with sites of active disease progression.

1990s research findings indicated that out of 500 different types of bacteria, only few are responsible for disease.

1996 World Workshop in periodontics --- agreed on four bacterial types that had supported their involvement in etiology of periodontal disease.

These included – Aggregatibacter actinomycetemcomitans

P.gingivalis

T. forsythia

T. denticola

Recently, field of oral microbiology has focused on oral Biofilms.

a biofilms confers certain properties to bacteria that are not seen in Planktonic state.

cell-cell communication gene transfer antimicrobial resistance regulation of gene expression etc.

Which explains the importance of recognizing plaque as a biofilm not as bacteria in the planktonic state

Oral microbial plaque communities composed of numerous genetically distinct types of bacteria, that live in close juxtaposition on host surface.

(Kolenbrander PE 2000)

As our concepts of etiology of periodontal disease changed so, is the pathogenesis.

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Concepts of pathogenesis of periodontal disease

The modern era of the pathogenesis, prevention and treatment of periodontal disease began in mid 1960s with experiments demonstrating critical role of bacteria in the initiation of gingivitis and periodontitis.

Clear concept in 1960s-

Bacteria causes periodontitis

1960s model tenent

Microbial challenge

Clinical signs of disease initiation and progression

As this model implicated bacterial plaque deposits as the primary direct factor in development of periodontitis,

resulted in abandonment of former concepts that involved non-bacterial factors such as

Trauma from occlusion

systemic conditions

& diet.

Research and scientific discussions based on simple concept of bacterial causation led to great advances in knowledge during the 1970s.

1970s model tenent

Bacterial plaque

Calculus formation

Periodontal pocket formation

Bone loss

Occlusal trauma

• All bacteria on tooth surface are harmful.• Untreated periodontitis progresses slowly, steadily in a linear fashion overtime.

Role of susceptible host in periodontal tissue destruction

20th century brought exceptional years of discovery. Most of the 1900s– focused on periodontal pockets. Histologic specimen from human autopsy. Numerous and diverse theories ---explain why a healthy

gingival sulcus ‘‘shifted’’ to a deepening periodontal pocket.

A review by Glickman (1964) summarized the state of the knowledge within this area of research.

Around 1970, a major shift in emphasis occurred in how the pathogenesis of periodontal disease was studied.

study of pocket formation per se to a study of cells, enzymes, and mediators that might explain the host response in the progression of periodontitis.

Ivanyi and Lehner (1970)

that peripheral blood lymphocytes isolated from

subjects with periodontitis >> lymphocytes from healthy

subjects. Klein and Raisz--- prostaglandins were potent stimulators

of bone resorption in tissue culture. Goodson (1972)--- prostaglandins were in the periodontal

tissues and were likely important in the alveolar bone destruction of periodontal disease.

Horton et al. (1972)--- human peripheral blood leukocytes from subjects with periodontitis produced a substance, termed osteoclast activating factor, which induced bone resorption.

Clark et al. (1977) discovered that subjects with aggressive periodontitis had a neutrophil chemotactic defect.

In 1976, Page and Schroeder summarized what was known about the pathogenesis of periodontitis with regard to the major histopathologic events that occurred from health to advanced disease.

These investigators used histology and evidence from biochemical studies that linked cell types and immune mediators to help elucidate why certain individuals have periodontal disease.

In most of the models of the late 1980s, specific bacteria initiated the disease process by activating host responses, which were protective and destructive.

As immunologic and molecular techniques improved, the roles of cytokines and inflammatory cell mediators came to the forefront of the periodontal literature.

The actual destruction of connective tissue and bone resulted primarily from activated tissue mechanisms such as MMPs, IL-1 & prostaglandins.

1980s model tenent

Microbial challenge

Host immunoinflammatory

response

Clinical signs of disease

initiation & progress

From 1985-1995

Despite a strong and reproducible association between plaque accumulation and the development of gingivitis, these associations were less clear on a patient-to-patient analysis and were confusing on an individual site analysis within the same patient.

In a classic study in beagle dogs, plaque accumulation was associated with a progression to periodontitis, but two of eight dogs failed to develop periodontitis, despite substantial plaque and calculus accumulations and extensive gingivitis.

(Lindhe J, Hamp SE, Loe H. 1975)

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Longitudinal studies of tea plantation workers in Sri Lanka.

As first reported, a failure to clean teeth regularly resulted in the development of extensive gingivitis and in early and severe periodontitis.

However, further analysis determined that there were three distinct subsets of the population relative to the development of periodontitis in response to bacterial accumulations.

(Loe H et al. 1986)

one group that had poor oral hygiene and gingivitis but developed minimal to no periodontitis.

The extensive research started for risk factors modifying clinical expression of disease.

Smoking as a risk factor

Preber H et al. 1984, 1986

Haber 1993

Bergstrom 2006 Diabetes as risk factors

Bissada et al. 1982

Emrich LJ 1991

Genco 1996

Genetics

 Michalowicz et al., 2000

Dowsett et al., 2001

  Ronderos et al., 2001 Age

Grossi et al., 1994; Grossi et al., 1995 Psychological factors(Hugoson et al., 2002; 

Mawhorter and Lauer, 2001; Pistorius et al.,2002; Wimmer et al., 2002).

Risk factors identifiedInnate

• race• Sex

• Genetics• Congenital

immunodeficiencies• Phagocyte dysfunction

• Down’s syndrome• Papillon-lefevre

syndrome• Ehlers-danlos

syndrome

Acquired & environmental

• Poor oral hygiene• Medications

• Tobacco/smoking• Stress

• Acquired immune defects

• Acquired endocrine disease

• Acquired inflammatory disease

•Nutritional deficiencies

With new knowledge of the various factors contributing to periodontal disease came recognition that clinical phenotype is not simply the microbial challenge translated by a standard host response.

Laboratory and clinical research demonstrated that these risk factors were most likely influencing disease expression by altering host protective and destructive mechanisms.

According to Emrich LJ 1991, risk of developing destructive periodontitis increases threefold in people with diabetes.

Thorstenseon et al. 1996 Alba Loureiro et al. 2007 Lalla et al. 2001 Salvi et al. 1998 Iacopimo 1995

Andersen et al. 2007

Smoking

Eichel and shehrik 1969 Kennya et al. 1977 Haffajee et al. 1997 Soder B 1999

In the absence of disease-modifying risk factors, it seems that the host responds appropriately to the bacterial accumulations by attempting to protect against bacterial invasion.

Evidence began to accumulate that disease modifiers, such as smoking, in the presence of bacterial accumulations on the teeth, shifted the immunoinflammatory responses outside of the normal boundaries of host response and repair processes.

In the presence of modifying factors, such as smoking, an exuberant host response and/or impaired repair mechanisms seem to lead to more destructive periodontitis..

The basic conceptual model of periodontitis was revised in 1997, in great part to acknowledge that various risk factors operated by modifying host responses led to changes in disease expression.

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End of session 1Thank you

Models of disease progression

Continuous model -- Slow, steady, progressive disease

process .

Episodic burst theory(1982,1986)---Irregular periods of

exacerbation and remission

Synchronous burst theory(1984)---Periods of exacerbation

and remission during a defined period.

Epidemiologic model(1988)--- Consistent with continuous disease aging process that depends only on duration of the process.

Brownian motion or stochastic model(1989)---Random periods of sharp bursts and/or remission can occur, but underlying disease activity remains constant.

Random walking model(1989)---When observed at regular intervals, model is similar to Brownian motion model.

Fractural model(1991)---Multifactorial model simulates disease advancing with age in bursts and remission.

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1997 model (Page and kornman)

The primary conceptual change in the 1997 model was that it explicitly acknowledged the role of a number of environmental and acquired risk factors, including genetics, as modifiers of the immunoinflammatory response and in resulting connective tissue and bone metabolism.

Simply put, modifying factors such as exposure to cigarette smoke and/or inherent genetic risk factors may alter the nature of the immunoinflammatory response to shift the balance to more severe periodontal destruction.

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Advances in knowledge of the pathogenesis of periodontitis

1. Microbial periodontal pathogens are found in ecologic complexes, and an ecologic shift can lead to emergence of a specific set of microbial pathogens.

2. A number of studies confirmed that a small group of disease modifiers, including diabetes, genotype, and smoking, contribute strongly to individual patient differences in the susceptibility to periodontitis.

3. Many studies Beck JD 2000,

Offenbacher S 1998,

Taylor GW 2000

described associations between periodontitis and other diseases, such as cardiovascular disease, and potentially explained such associations through bacterial seeding, common inflammatory mechanisms, and/or common modifying factors.

4. There was an extension of knowledge about specific bacterial mechanisms and immunoinflammatory mechanisms in periodontitis.

Advances in knowledge of complex diseases

First, inflammatory mechanisms were recognized as common to many chronic diseases of aging, such as cardiovascular disease.

Second, periodontitis and other chronic diseases are now seen as complex in character. This means that the overall biologic system has a distinct behavior that is more than the sum of its parts.

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Third, although the biology is complex, the integrated behavior of the entire system can be studied using new simulation tools. For example, molecular networks of specific biologic components, eg. the immuno-inflammatory response, can be studied as a functional module.

Combinations of modules can be integrated to study the overall system behavior that translates into clinical outcomes.

4. The fourth is the result of a larger appreciation for the effects of environmental factors. For example, smoking or nutrition may affect gene expression in numerous ways, some of which may persist. Additionally, genetic variations from person to person may create different responses to a specific environmental context.

Elements of a new model of pathogenesis of periodontal disease

The principle of system biology is the use of multiple levels to provide a framework for defining the interactions between the cellular and molecular processes occurring at the lowest levels to the clinical presentation of disease at the uppermost level.

Biologic system model (Kornman 2008)

This model represents that the pathogenesis of periodontitis may be defined by the bacterial components, environmental factors and host-genetic variations associated with disease.

Within this framework, discrete modules of genetic, environmental and other modifying factors are combined together to define molecular to clinical expression patterns that are responsible for health or disease.

Ultimately, the goal will be to define expression patterns in the tissues with respect to each set of environmental and genetic conditions and to understand the corresponding clinical parameters and profiles.

Such information will allow construction of system biology model that includes the state of key parameters at the basic biology level, which is critical in defining the regulatory status of tissue at any point of time.

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Although, even partial information should improve the ability to identify an individual’s susceptibility to disease and a likely response to treatment, complete expression of these networks should be a valuable tool for determining new preventive and therapeutic approaches.

Biologic system model (Offenbacher S Barros SP and Beck JD 2008)

A biologic system approach provides a framework for viewing the contributions and relative importance of all the components that contribute to the clinical presentation of disease.

Thus, in the context of periodontal disease such a system would include a person level, a genetic/epigenetic level, the biologic phenotype and ultimately the clinical phenotype.

The model depicts the different biologic factors that underpin the development of periodontal disease in different individuals and ultimately may be used to classify disease according to the contribution provided to the clinical phenotype at each level.

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Conclusion

Periodontal diseases are highly complex, evidencing variations at multiple levels ranging from molecular to clinical.

New information and technical capabilities are helping improve our understanding of these disease.

An improved idea of pathogenesis of disease may facilitate periodontal disease therapy that is better customized to each patient’s need.

References

. Williams RC. Understanding and managing periodontal diseases: a notable past, a promising future. J Periodontol. 2008; 79:1552-1559.2. Kornman KS. Mapping the pathogenesis of perio - dontitis: a new look. J Periodontol. 2008;79:1560-1568.3. Offenbacher S, Barros SP, Beck JD. Rethinking perio - dontal inflammation. J Periodontol. 2008; 79:1577-1584.4. Lindhe J, Haffajee AD, Socransky SS. Progression of periodontal disease in adult subjects in the absence of periodontal therapy. J Clin Periodontol. 1983; 10:433-442.5. Beck JD. Methods of assessing risk for periodontitis and developing multifactorial models. J Periodontol. 1994; 65(5 Suppl):468-478.6. Page RC, Marting JA. Quantification of periodontal risk and disease severity and extent using the Oral Health Information Suite (OHIS). Periodontal Practice Today. 2007;4:163-180.

7. Keyes PH, Jordan HV. Periodontal lesions in the Syrian hamster. III. Findings related to an infectious and trans - missible component. Arch Oral Biol. 1964;32:377-400.9. Clark RA, Page RC, Wilde G. Defective neutrophil chemotaxis in juvenile periodontitis. Infect Immun. 1977;18:694-700.16. Ximenez-Fyvie LA, Haffajee AD, Socransky SS. Com -parison of the microbiota of supra- and sub gin gival plaque in health and periodontitis. J Clin Periodontol. 2000;27:648-57.20. Armitage GC. Periodontal diagnoses and classifi cation of periodontal diseases. Periodontol 2000. 2004; 34:9-21.21. Offenbacher S, Barros SP, Singer RE, Moss K, Williams RC, Beck JD. Periodontal disease at the biofilm-gingival interface. J Periodontol. 2007;78:1911-1925.

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