Host Modulation: Controlling the Inflammation to Control the Infection.

2. Presentation by –
Dr. MD Abdul Haleem
Host Modulation: Controlling the Inflammation to Control the Infection

3. • Introduction
• Bacteria – weather a sole necessity for the
development of periodontitis
• What is the role of specific bacteria in the
pathogenesis of periodontitis
• An emerging paradigm shift in HMT
• A new model for the pathogenesis of periodontitis
• Combination anti-inflammatory + antibacterial therapies
• Host modulatory therapies
• Conclusion
CONTENTS:

4. INTRODUCTION
• Periodontitis can no longer be considered a simple bacterial
infection that leads to periodontal destruction.*
• Rather, it represents a collection of complex diseases involving
active interactions between the
host inflammatory and immune systems,
subgingival microbiota and
modifying environmental factors.
• It is also recognized that the periodontal microbiota is generally of
a commensal nature and its relationship to the host is usually in a
state of homeostasis.
• However, ‘pathologic’ shifts in the microbiota may occur by the
overgrowth of organisms normally present in low numbers creating
what has been termed a ‘dysbiosis’ of the periodontal subgingival
microbiota.*

5. Not withstanding this microbial shift favoring pathogenic species, the requirement for a
suitable environment and a ‘susceptible’ host is essential in order for periodontitis to
manifest clinically.

6. • Another way to consider the periodontal diseases is that they are
‘eco-genetic diseases’ whereby patients are rendered susceptible by
genetic or environmental factors such as
• Polymorphisms in the gene for interleukin-1
• Cigarette smoking
• Chronic hyper-inflammatory disorders
• Diabetes.
INTRODUCTION

7. • Creating chronic hyper-inflammation to the subgingival bacteria leads
to the development of destructive periodontal disease.
• Thus, periodontitis is considered to be very much a multifactorial
disease in which bacteria are necessary but not solely sufficient for
the disease to develop.*
• Recognizing the essential inflammatory nature of periodontitis opens
up new opportunities for the diagnosis, treatment and long-term
management of this disease.
INTRODUCTION
Socransky SS, Haffajee AD. The bacterial etiology of destructive periodontal disease: current concepts. J
Periodontol 1992: 63 (Suppl 4): 322–331.

8. Bacteria are necessary but not sufficient for
the development of periodontitis
• Indeed, while many periodontitis patients present within
the normal paradigm of increased plaque and calculus
deposits associated with increased levels of periodontal
inflammation and destruction.
• But we also commonly see the converse where patients
present with very minor visual deposits of plaque and
calculus, yet considerable periodontal destruction.
• This apparent paradox of periodontitis (advanced
destruction seen in the presence of very little visible
plaque and calculus) has led some to reconsider the role of
specific bacteria and oral hygiene in the development of
periodontitis.

9. • Indeed, it is now well accepted that plaque accounts for only 20% of
the risk for developing periodontitis.*
• Such observations formed the basis of a model for the pathogenesis
of periodontitis in which not only was the microbial challenge
considered important but also*
• Host response factors
• Genetic risk factors
• Environmental risk factors and
• Acquired risk factors (e.g.-Diabetes)

10. Proposal for the pathogenesis of periodontitis - 1997.*
Clarke NG, Hirsch RS. Personal risk factors for generalized periodontitis. J Clin Periodontol 1995: 22: 136–145.

11. • At the time this concept was presented, it reshaped our thinking and
firmly refocused our thoughts from plaque to a holistic approach in
understanding the clinical presentation of periodontitis.
• However, this model is now almost 20 years old and newer models
have been proposed.
• One such important model suggests that there is a need to
incorporate gene, protein and metabolite data’s.*
Kornman KS. Mapping the pathogenesis of periodontitis: a new look. J Periodontol 2008: 79 (Suppl 8): 1560–
1568.

12. • Although periodontal inflammation is initiated by components of the
subgingival biofilm, it is the production and release of mediators
generated and controlled by the host’s response to the
microorganisms that are primarily, if not entirely, responsible for the
periodontal breakdown.*
• For periodontitis, there is now convincing longitudinal
data that support the concept that inflammation is the
driver for the conversion of gingivitis to periodontitis
through highly regulated processes.*

13. What is the role of specific bacteria in the
pathogenesis of periodontitis?
• Over the decades, a number of hypotheses have been put forward to define the
relationship between subgingival biofilm bacteria and the development of periodontitis.
• The classical gingivitis studies demonstrating the development of gingivitis in the absence
of oral hygiene demonstrated the non-specific nature of this disease whereby gingivitis
was recognized to be a reaction to the accumulation of dental plaque adjacent to the
gingival margin.*
• In the 1970s the Specific Plaque Hypothesis highlighted the importance of a small number
of specific ‘pathogenic’ species that were frequently associated with disease.*
• Later, in the 1980s, the Non-specific Plaque Hypothesis re-emerged and focused more on
the overall mass of microbiota rather than the composition of the plaque.*

14. • Recognizing that microbiology alone did not clearly distinguish
between patients with similar clinical features, so it became clear that
the level of variability was the patient, not the disease.*
• Subsequently the focus changed again and began to move toward the
host response with the proposal of the Ecological Plaque Hypothesis
in which ‘periodontal pathogens’ appear as a result of the disease
rather than cause it.*
Socransky SS, Haffajee AD. Periodontal microbial ecology. Periodontol 2000 2005: 38: 135–187.
Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL Jr. Microbial complexes in subgingival plaque. J Clin Periodontol 1998:
25: 134–144.
Marsh PD. Are dental diseases examples of ecological catastrophes? Microbiology 2003: 149: 279–294.

15. • Most recently, focus has returned to the central role of bacteria to the
development of periodontitis with the Keystone Pathogen Hypothesis
• Polymicrobial Synergy & Dysbiosis model
• Specific microbes modulate the host response to impair immune
surveillance and tip the balance from bacterial homeostasis to
bacterial dysbiosis.*
• However, the temporal relationship supporting this has not been
demonstrated and it is equally as likely that inflammation initiates the
dysbiosis.

16. • Although periodontitis is a bacterial disease, it is not an infectious disease
in the classical sense.*
• Indeed, it is becoming clear that periodontitis arises from an inappropriate
inflammatory reaction to the normal microbiota subsequently exacerbated
by the overgrowth of some disease associated bacterial species.
• This concept is further supported by earlier work in humans and in animal
models.

17. • In a longitudinal study of bacteria associated with the development of
periodontitis in humans, it was noted that periodontal pathogens emerged
in the subgingival microbiota after disease progression and pocket
formation.*
• Furthermore, in a rabbit periodontitis model, it has been demonstrated
that the pharmacological control of inflammation results in spontaneous
elimination of periodontal pathogens from the periodontal microbiota,
thus reversing dysbiosis.*
Tanner AC, Kent R Jr, Kanasi E, Lu SC, Paster BJ, Sonis ST, Murray LA, Van Dyke TE. Clinical characteristics and microbiota of
progressing slight chronic periodontitis in adults. J Clin Periodontol 2007: 34: 917–930
Hasturk H, Kantarci A, Goguet-Surmenian E, Blackwood A, Andry C, Serhan CN, Van Dyke TE. Resolvin E1 regulates inflammation
at the cellular and tissue level and restores tissue homeostasis in vivo. J Immunol 2007: 179: 7021– 7029.

18. An emerging paradigm shift
• Of the above concepts, it can be argued that the Ecological Plaque
Hypothesis holds considerable credibility.
• When assessing the earliest tissue responses to the subgingival
biofilm, it is noted that the inflammatory reaction of gingivitis always
precedes the overgrowth of periodontal pathogens.
• Furthermore, there is no good evidence to indicate that bacterial
invasion of the periodontal tissues is an early event in the
pathogenesis of periodontitis.

19. An emerging paradigm shift
• Indeed, it seems very likely that the inflammatory responses occurring in
the gingival tissues at the time of first response to the subgingival biofilm
can lead to significant alterations in the microenvironment of the biofilm
that selects for proliferation of specific bacteria.*
• While apparently out of line with current dogma, such concepts are not
new with many authors proposing that the changing pocket environment
appears to select bacteria rather than the bacteria being responsible for the
changing pocket and that it is indeed the host response and not the
microbes that determine the eventual outcome of host–parasite
interactions.*
Marsh PD. Microbial ecology of dental plaque and its significance in health and disease. Adv Dent Res 1994: 8: 263–271.
Clarke NG, Hirsch RS. Personal risk factors for generalized periodontitis. J Clin Periodontol 1995: 22: 136–145.
Mombelli A, McNabb H, Lang NP. Black-pigmenting gramnegative bacteria in periodontal disease. I. Topographic distribution in
the human dentition. J Periodontal Res 1991: 26: 301–307.

20. • Furthermore, it has been demonstrated that the microbiota
associated with periodontitis are ‘inflammophilic’ and that
periodontal pathogens cannot persist without the presence of
inflammation.*
• Importantly, it has been demonstrated that controlling periodontal
inflammation restores normal biofilm homeostasis.*
• Further, resultant shifts associated with the development of
periodontitis are due to specific pathogens such as Porphyromonas
gingivalis that thrive in the inflammatory environment and contribute
to, if not drive, dysbiosis.*

21. A new model for the pathogenesis of
periodontitis
• Accepting that it is the host inflammatory response that largely drives
the pathological process, new concepts for the pathogenesis and
treatment of periodontitis have been proposed.*
• In these models, the development of gingivitis is a mandatory
initiating condition for the subsequent development of periodontitis.
Bartold PM, Van Dyke TE. Periodontitis: a host-mediated disruption of microbial homeostasis. Unlearning learned concepts.
Periodontol 2000 2013: 62: 203–217.
Hajishengallis G. The inflammophilic character of the periodontitis- associated microbiota. Mol Oral Microbiol 2014: 29:
248–257.

23. • It is recognized that gingivitis results from a nonspecific inflammatory
reaction in the gingival tissues to supragingival plaque accumulation.
• The resulting gingival inflammation alters the subgingival
environment as a result of increased concentrations of mediators of
inflammation and products of connective tissue breakdown in the
gingival crevicular fluid (e.g. collagen peptides).
• These conditions provide a suitable environment for the overgrowth
of ‘periodontal pathogens’ within the subgingival biofilm.

24. • If the host inflammatory response is sufficient, and there are
favorable genetic and environmental influences, the lesion may be
‘contained’ as gingivitis and does not progress to periodontitis.*
• On the other hand, if the host and inflammatory and immune
responses do not stabilize the lesion, and the individual is genetically
susceptible as well as influenced by unfavorable environmental
factors (e.g. smoking), the condition will progress leading to the
clinical manifestation of periodontitis.
• On the basis of these concepts, novel treatment strategies have been
proposed for the management of periodontitis.
Page RC, Schroeder HE. Pathogenesis of inflammatory periodontal disease. A summary of current work. Lab
Invest 1976: 34: 235–249.

26. • It is proposed that by controlling the inflammatory response
associated with gingivitis (through mechanical debridement and
adjunctive chemotherapy)
The resulting change in the subgingival environment will reduce the
nutrient supply to the subgingival microbiota, particularly the
asaccharolytic ‘periodontal pathogens’ that degrade collagen peptides
to free amino acids that provide their energy source.
• Hence, by controlling, or resolving, the inflammatory response, it is
possible to contain the infection and to create an environment
conducive for reversal of bacterial dysbiosis to a commensal bacteria
compatable with periodontal health.

27. Periodontal inflammation – new opportunities for
treatment – host modulation
• Recognizing the importance of modulating the inflammatory response,
new treatment opportunities arise whereby adjuncts to mechanical
debridement focusing on controlling or resolving inflammation.
• One product already commercially available,
and approved for clinical use by the US Food
and Drug Administration, is Periostat, which is
a low dose of doxycycline.

29. • It has been long known that tetracyclines, in addition to their antibiotic
properties, can modulate the activities of several host derived matrix
metalloproteinases responsible for tissue breakdown in periodontitis
through several non-antimicrobial mechanisms.
• Other agents that showed considerable promise were the non-steroidal
anti-inflammatory drugs that blocked the production of prostaglandin E2.*
Salvi GE, Williams RC, Offenbacher S. Nonsteroidal anti-inflammatory drugs as adjuncts in the management of periodontal
diseases and peri-implantitis. Curr Opin Periodontol 1997: 4: 51–58.

30. • Early non-steroidal anti-inflammatory drugs  block both the
cyclooxygenase COX-1 and COX-2 enzyme  both of which are responsible
for prostaglandin E2 production.*
• COX-1  protects the gastrointestinal tract and affects platelet
homeostasis.
• Chronic use leads to complications including increased bleeding and
gastrointestinal complications.
• Therefore, attention began to focus on inhibiting only COX-2 and sparing
COX-1.
Day RO, Graham GG. Non-steroidal anti-inflammatory drugs (NSAIDs). BMJ 2013: 346: f3195.

31. • However, due to serious unwanted side effects following the use of COX-2
inhibitors, including
• Adverse gastrointestinal events,
• Increased risk of cardiovascular thrombotic events,
• Myocardial infarction and
• stroke
• This line of investigation in periodontics has stalled.*
Bello AE, Holt RJ. Cardiovascular risk with non-steroidal anti-inflammatory drugs: clinical implications. Drug Saf 2014: 37: 897–
902.

32. • Another promising area for investigation with regard to host
modulation is that of anti-cytokine therapy that has been in use in
medicine for the control of many chronic inflammatory conditions.*
• Most of these agents target interleukin-1 and tumor necrosis factor
and are based on either monoclonal antibodies or modified receptor
proteins.
Gokhale SR, Padhye AM. Future prospects of systemic host modulatory agents in periodontal therapy. Br Dent J
2013: 214: 467–471.

33. • One such agent, Etanercept  a tumor necrosis factor-alpha receptor
antagonist has been found in an animal model of periodontitis to
assist in the reduction of inflammation through*
• Reduced neutrophil infiltration
• Reduced nitric oxide levels
• Reduced apoptosis.
• However, one systematic review reported
limited evidence for the use of these agents for
• periodontitis.*
Di Paola R, Mazzon E, Muia C, Crisafulli C, Terrana D, Greco S, Britti D, Santori D, Oteri G, Cordasco G, Cuzzocrea
S. Effects of etanercept, a tumour necrosis factor-alpha antagonist, in an experimental model of periodontitis in
rats. Br J Pharmacol 2007: 150: 286–297.
Han JY, Reynolds MA. Effect of anti-rheumatic agents on periodontal parameters and biomarkers of
inflammation: a systematic review and meta-analysis. J Periodontal Implant Sci 2012: 42: 3–12.

34. • One of the major problems with anticytokine therapy is that a
functional redundancy of cytokines can enable the host to activate
alternative pathways of inflammation if only one specific cytokine is
targeted by a therapeutic agent.
• These agents also have an unacceptable side-effect profile and are
extremely expensive, thus precluding their use as an adjunct to
periodontal therapy at the present time.*
Atzeni F, Sarzi-Puttini P. Anti-cytokine antibodies for rheumatic diseases. Curr Opin Investig Drugs 2009: 10:
1204–1211.

35. • In order to contain the initial periodontal lesion the innate
inflammatory response must be actively resolved.
• Biological resolution of inflammation is driven largely by resolvins,
lipoxins and protectins.
• With the understanding that this is a biologically active process that
restores inflamed tissues to health (not through an inhibition of
inflammation) a new field of research investigating the use of pro-
resolving agents to control inflammation and restore health has
emerged.*
Freire MO, Van Dyke TE. Natural resolution of inflammation. Periodontol 2000 2013: 63: 149–164.

36. • Two areas of considerable interest are the use of diet or specific synthetic
and natural resolvins as adjuncts to periodontal therapy.
• The use of omega-3 polyunsaturated fatty acids
(precursors of resolvins) is of interest due to
their well documented anti-inflammatory
properties.
• A recent systematic review reported good emerging evidence that dietary
supplementation with fish oil might be of some benefit.*
• The benefit is enhanced if combined with aspirin.
Chee B, Park B, Fitzsimmons T, Coates AM, Bartold PM. Omega-3 fatty acids as an adjunct for
periodontal therapy – a review. Clin Oral Investig 2016: 20: 879–894.

37. • Interestingly, several studies have reported that combining aspirin
with fish oils has a positive clinical benefit in the management of
periodontitis.*
• The addition of aspirin to the treatment regime is based on its ability
significantly to increase the production of more stable resolvins.*
• Since most clinical intervention studies to date have been on small
sample sizes, there is a need for larger and more robust clinical trials
to verify these initial findings.
• Dietary supplementation with fish oil could be a cost effective
adjunctive therapy to the management of periodontal disease.*

38. • In animal models, resolvin E1 has been shown to regulate
inflammation at the tissue and cellular level.
• Importantly these studies have demonstrated that by resolving
experimentally induced inflammation and periodontitis, the damaged
bone is able to regenerate in the absence of any adjunctive
antimicrobial or regenerative therapies.*
Hasturk H, Kantarci A, Goguet-Surmenian E, Blackwood A, Andry C, Serhan CN, Van Dyke TE. Resolvin E1 regulates
inflammation at the cellular and tissue level and restores tissue homeostasis in vivo. J Immunol 2007: 179: 7021– 7029.

39. • An important distinction is the difference between anti-inflammation
and proresolution.
• Anti-inflammation inhibits COX or 5-lipoxygenase enzyme activity and
can affect many biological processes other than inflammation.
• On the other hand, proresolution is a receptor mediated event that
drives cellular processes to restore health.
• The difference between these two processes probably accounts for
the presence or absence of unwanted side effects.*
Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.
Nat Rev Immunol 2008: 8: 349–361.

40. Combination anti-inflammatory and
antibacterial therapies
• Combining both anti-inflammatory and antibacterial therapies is
worthy of consideration.
• Surprisingly, very few studies have addressed this concept with
only one report identified investigating the combined systemic
use of an anti-inflammatory and antibacterial agent.*
• From this study, it was concluded that adjunctive use of both
systemic tetracycline and ibuprofen with scaling and root planing
produced statistically significant improvement compared with
scaling and root planning alone.
Ng VW, Bissada NF. Clinical evaluation of systemic doxycycline and ibuprofen administration as an adjunct treatment for
adult periodontitis. J Periodontol 1998: 69: 772–776.

41. • More recently, interest has focused on the use of the macrolide
antibiotic azithromycin in the management of periodontitis.
• Not only does azithromycin possess antibacterial effects, but it also
exerts considerable anti-inflammation properties.*
• This provides an opportunity to combine the
therapeutic effects of one agent that has
both antibiotic and anti-inflammatory
capabilities with significantly greater potency
that the tetracyclines.*
Bartold PM, du Bois AH, Gannon S, Haynes DR, Hirsch RS. Antibacterial and immunomodulatory properties of azithromycin
treatment implications for periodontitis. Inflammopharmacology 2013: 21: 321–338.
Hirsch R, Deng H, Laohachai MN. Azithromycin in periodontal treatment: more than an antibiotic. J Periodontal Res 2012: 47:
137–148

42. • A recent meta-analysis concluded that azithromycin used as an
adjunct to non-surgical therapy significantly improves the efficacy of
non-surgical periodontal therapy on probing depth reduction,
bleeding on probing and gain of attachment, particularly at the
initially deep probing depth sites.*
• Despite these encouraging findings, caution must be exercised in the
use of azithromycin, because of the potential for permanently
changing the composition of the host microbiome at other body sites,
and particularly in patients with a high baseline risk of cardiovascular
disease due to a small risk of increased cardiovascular death.*
Zhang Z, Zheng Y, Bian X. Clinical effect of azithromycin as an adjunct to non-surgical treatment of chronic periodontitis: a meta-
analysis of randomized controlled clinical trials. J Periodontal Res 2015: 51: 275–283.
Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012: 366:
1881–1890.

43. • A variety of different drug classes have been evaluated as host modulation
agents, such as:
• Nonsteroidal Anti-inflammatory Drugs (NSAIDS)
• Bisphosphonates
• Tetracyclines
• Cytokine Antagonists
• Nitric Oxide Synthase Inhibitors
• Enamel Matrix Proteins
• Growth Factors
• Bone Morphogenetic Proteins.
HOST MODULATORY THERAPY

45. SYSTEMICALLY ADMINISTERED AGENTS
Nonsteroidal Anti-inflammatory Drugs

46. • Goodson et al. (1974) demonstrated with in vivo experiments that
prostaglandins were implicated in the bone resorption process.
• A rapid bone resorption could be induced within 7 days after injection of a
PGE1-containing solution under the skin of rat calvaria.
• In addition to prostaglandins, other AA metabolites such as prostacyclin
and LT appeared to be actively involved in bone resorption.
• Prostacyclin (PGI2) is an endothelial cell product capable of preventing
platelet aggregation and platelet adhesion to vessel walls.
• Findings from tissue culture experiments demonstrated that PGI2
stimulated bone resorption*

47. Modulation of AA metabolites with non-steroidal anti-
inflammatory drugs (NSAIDs)
• Over decades, AA metabolites have been established as mediators of tissue
destruction in various inflammatory diseases including rheumatoid arthritis
and periodontal diseases (Offenbacher et al. 1993, O'Dell 2004).
• The majority of NSAIDs are weak organic acids that selectively or non-
selectively inhibit the synthesis of AA metabolites, thereby blocking the
production of prostaglandins, thromboxane and prostacyclin (Fitzgerald &
Patrono 2001).
• Hence NSAIDs can suppress alveolar bone resorption potentially blocking
periodontal disease progression.

48. In vitro experiments
• Vane 1971 first report that aspirin and aspirin-like drugs inhibited the
production of prostaglandins by inhibiting the COX enzyme.
• In another series of experiments, Goldhaber et al. (1973) added
indomethacin, a known inhibitor of COX, to the culture media, observing a
decrease in bone resorption of up to 50%.
• The amount of prostaglandins released from gingival fragments of monkey
into the culture medium could be reduced by at least 90% by indomethacin
(Gomes et al. 1976).

49. Animal experiments
• Nyman et al. (1979) conducted a study to test the efficacy of systemic doses
of indomethacin on the suppression of alveolar bone resorption and gingival
inflammation in a ligature-induced periodontitis model in beagle dogs.
• The results showed that indomethacin delayed the onset and suppressed the
magnitude of the acute inflammatory response and decreased the amount
of alveolar bone resorption.

50. Clinical studies
• In 1984, Williams and colleagues instituted a 3-year double-blind trial of
the effect of flurbiprofen on the progression of radiographic loss of
alveolar bone in human periodontal disease.
• Fifty-four patients with radiographic evidence of advanced alveolar bone
loss were recruited for study.
• During a 6-months pretreatment period, a baseline rate of bone loss in
each patient was determined.
• These patients were then randomly divided into 2 treatment groups that
had a similar mean rate of bone loss in the pretreatment period.

51. Clinical studies
• Thereafter, one group received flurbiprofen (50 mg bid), whereas the
second group received placebo capsules bid.
• All patients in both groups received a prophylaxis every 6 months for a 2
year treatment period.
• The main variable studied by this group was the rate of alveolar bone loss
measured radiographically over time.
• The data indicated that patients treated with 50 mg flurbiprofen bid
had a significant reduction in the rate of alveolar bone loss at 12 and
18 months of administration when compared with those patients on
placebo.

52. • Both groups showed some improvement in the first 12 months with a
slowing on bone loss, which was most likely due to an increase in overall
good health based on study participation.
• In their initial report (Williams et al., 1988, 1989), these investigators noted
that by 24 months of flurbiprofen treatment the rate of bone loss between
the two groups was statistically not significantly different with a loss of
effect of flurbiprofen.
• No explanation was given for the loss of effect of flurbiprofen, although the
authors were able to conclude that flurbiprofen was a potent inhibitor of
bone loss in the human for an 18-months period.

53. TRICLOSAN
• A compound which has received interest as both an antibacterial and anti-
inflammatory agent is triclosan.
• Triclosan (2, 4, 41-trichloro-2-hydroxy-diphenyl ether) also inhibits CO and LO and
thus may interfere with the production of AA metabolites.
• Use of a dentifrice containing sodium fluoride (0.243%) and triclosan (0.3%) with
2.0% PVM/MA copolymer (Polyvinylmethyl Ether/Maleic Acid) reduced the
frequency of deep periodontal pockets and the number of sites exhibiting
attachment and bone loss in patients deemed highly susceptible to periodontitis
(Rosling B et al 1997).
• At this time, the triclosan/copolymer dentifrice is indicated for the reduction of
plaque, calculus, gingivitis, and caries.

54. Modulation of Matrix Metalloproteinases (MMPs)
• MMPs encompass a family of zinc-dependent membrane-bound and secreted
proteolytic enzymes.
• Their main function is to catalyze the breakdown of proteins in the cell plasma
membrane or within the extracellular matrix.*
• The extracellular matrix consists of collagenous and non-collagenous (e.g.
glycoproteins and proteoglycans) proteins.
• In order for the collagenases to have access to the collagen substrate,
proteoglycans and fibronectin must be removed first by the action of specific
MMPs such as stromelysin (MMP-3).

55. Modulation of Matrix Metalloproteinases (MMPs)
• Deregulation of MMPs activity is involved in a variety of pathological
conditions such as rheumatoid arthritis, tumour cell metastasis and
periodontal disease (Yoon et al. 2003).
• Periodontal tissue cells including fibroblasts, keratinocytes, neutrophils,
macrophages and endothelial cells constitute the primary source of MMPs.
• Under healthy periodontal conditions, collagen homeostasis is a tightly
regulated process controlled extracellularly by fibroblast-derived collagenase
(e.g. collagenase-1 or MMP-1).

56. • Inflammatory mediators such as IL-1, TNF-α and PGE2 as well as bacterial
products have been shown to upregulate MMP production in several in vitro
models.*
• For example, IL-1β-induced MMP-3 production was upregulated by PGE2 in
fibroblasts from periodontally diseased tissue.*
• Production of MMP-1 and MMP-3 by gingival fibroblasts was downregulated
by interferon-γ (IFN-γ).*
• Experimental studies indicate that MMPs activation plays an important role
in extracellular matrix degradation during periodontal tissue destruction.*
• Regulation of MMP functions involves activation of endogenous tissue
inhibitors of MMPs (TIMPs) and α-macroglobulins.

57. Sub-antimicrobial-Dose Doxycycline
• Sub-antimicrobial-dose doxycycline (SDD) is a 20-mg dose of doxycycline
(Periostat) that is approved and indicated as an adjunct to SRP in the
treatment of chronic periodontitis.
• It is taken twice daily for 3 months, up to a maximum of 9 months of
continuous dosing.
• The 20-mg dose exerts its therapeutic effect by enzyme, cytokine, and
osteoclast inhibition rather than by any antibiotic effect.
• Research studies have found no detectable antimicrobial effect on the oral
flora or the bacterial flora in other regions of the body and have identified
clinical benefit when used as an adjunct to SRP.

58. • At present, SDD is the only HMT specifically indicated for the treatment of
chronic periodontitis that is approved by the U.S. Food and Drug
Administration (FDA) and accepted by the American Dental Association
(ADA).
• In addition to its antibiotic properties, doxycycline (as well as the other
members of the tetracycline family) has the ability to downregulate matrix
metalloproteinases.
• The rationale for using SDD as an HMT in the treatment of periodontitis is
that doxycycline downregulates the activity of MMPs by a variety of
synergistic mechanisms, including reductions in cytokine levels, and
stimulates osteoblastic activity and new bone formation by upregulating
collagen production.

59. Mech. of doxycycline inhibiting conn. tissue breakdown

60. Candidate Patients
• When deciding whether to use SDD as an adjunct to SRP, first consider the patient's
motivation toward periodontal care, the medical history, and the patient's
willingness to take a systemic drug treatment.
• SDD is contraindicated in any patient with a history of allergy or hypersensitivity to
tetracyclines.
• It should not be given to pregnant or lactating women or children less than 12 years
old because of the potential for discoloration of the developing dentition.
• Doxycycline may reduce the efficacy of oral contraceptives, and therefore alternative
forms of birth control should be discussed, if necessary.
• There is a risk of increased sensitivity to sunlight (manifested as an exaggerated
sunburn) seen with higher doses of doxycycline, although this has not been reported
in the clinical trials using the sub-antimicrobial dose.

61. Combining with Periodontal Surgery or Local Delivery
Systems
• Most clinical research to date has focused on using SDD as an adjunct to
nonsurgical periodontal treatment.
• However, emerging data in which SDD was used as an adjunct to access flap
surgery in 24 patients revealed better probing depth reductions in surgically
treated sites greater than 6 mm compared with surgically treated sites in
patients given placebo (Gapski et al 2004).
• Furthermore, the SDD group demonstrated greater reductions in CTP
(carboxy-terminal peptide, a breakdown product of collagen) than the
placebo group, indicating that collagenolytic activity was reduced in the
patients taking SDD.

62. • SDD treatment can also be combined with the local delivery of antibiotics
into the periodontal pocket through sustained-delivery systems.
• The two treatment approaches target different aspects of the pathogenic
process: local delivery systems deliver antimicrobial concentrations of an
antibacterial agent directly into the site of the pocket, whereas SDD is a
systemic host response modulator.
• Thus, combining these two complementary treatment strategies is another
example of how antibacterial therapy (SRP + local antibiotics) can be
combined with HMT (SDD) to maximize the clinical benefit for patients.

63. Bisphosphonates
• Bisphosphonates represent a class of chemical compounds structurally related to
pyrophosphate, a natural product of human metabolism present in the serum and
urine with calcium-chelating properties.*
• Pyrophosphate regulates mineralization by binding to hydroxyapatite crystals in
vitro but it is not stable in vivo, undergoing rapid hydrolysis of its labile P–O–P
bond as a result of pyrophosphatase activity (Shinozaki & Pritzker 1996).
• The replacement of the linking oxygen atom with a carbon atom (e.g. P–C–P)
results in the formation of a bisphosphonate molecule.
• This compound is chemically stable and completely resistant to enzymatic
hydrolysis via pyrophosphatase and alkaline phosphatase.

64. • Given their affinity to bind to hydroxyapatite crystals and prevent both of their
growth and dissolution and to their ability to increase osteoblast
differentiation and inhibit osteoclast recruitment and activity 
bisphosphonates are widely used in the management of systemic metabolic
bone disorders such as tumour-induced hypercalcaemia, osteoporosis and
Paget's disease (Fleisch 1997).
• More recent evidence has suggested that bisphosphonates also possess anti-
collagenase properties.
• The ability of bisphosphonates to modulate osteoclast activity clearly may be
useful in the treatment of periodontitis.

65. Adverse effects
• Some bisphosphonates have the unwanted effects of inhibiting bone
calcification and inducing changes in white blood cell counts.
• Also, there have been recent reports of avascular necrosis of the jaws
following bisphosphonate therapy, with the resultant risk of bone necrosis
following dental extractions (Carter G et al).
• As with NSAIDs, at present there are no bisphosphonate drugs that are
approved and indicated for treatment of periodontal disease

66. Modulation of Host cell Receptors
• Cytokines are defined as regulatory proteins controlling the survival, growth,
differentiation and functions of cells.
• Cytokines are produced transiently at generally low concentrations, act and are
degraded in a local environment.
• This is documented by the fact that cytokine-producing cells are often physically
located immediately adjacent to the responding cells.
• Moreover, the responding cell destroys the cytokine that it responds to in the
process of receptor-mediated endocytosis.
• Several cytokines bind to elements of the extracellular matrix, thus restricting their
spread beyond the site of action and increasing their bioavailability to the
responding cells.

67. • Cytokines function as a network, are produced by different cell types and
share overlapping features. This phenomenon is called biological redundancy.
• While very few biological responses are mediated by only one cytokine, many
responses can be achieved by several different cytokines.
• Thus, important cellular functions are usually backed up in mechanisms
where one cytokine can compensate for the loss of another.
• Consequently, blocking one inflammatory mediator or cytokine will not assure
that a receptor-mediated response will not be activated by alternate
pathways.
• This would require the development of poly-pharmaceutical approaches
controlling all pathways associated with inflammation and tissue destruction.

68. • Based upon the increased expression of IL-1 and TNF in inflamed gingiva and
high levels in the GCF of periodontitis patients, several studies have suggested
that increased production of these cytokines may play an important role in
periodontal tissue destruction.
• To counteract tissue destruction and maintain homeostasis, cytokine
antagonists such as IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptors
can competitively inhibit receptor-mediated signal transduction (Dinarello
2004, Levine 2004).
• In vivo application of soluble receptors of IL-1 or TNF-α has been demonstrated
to inhibit a number of pathologic processes including arthritis and septic
shock. IL-1ra is currently approved for treating rheumatoid arthritis.

69. • In diabetics, the chronically elevated glucose levels result in an accelerated
formation of advanced glycation end-products (AGEs).
• AGEs represent a heterogeneous class of non-enzymatically glycated
proteins and lipids found in plasma, vessel walls and tissues.
• Endothelial cells and monocytes possess specific receptors for AGEs called
RAGEs located on their cell surfaces (Hudson & Schmidt 2004).
• Studies have shown that the interaction of AGEs with their receptors
(RAGEs) plays an important role in the development of diabetic
complications.

70. • The interaction of macrophages with AGEs has been shown to stimulate
increased secretions of cytokines such as TNF-α and IL-1 (Vlassara et al.
1988).
• In diabetic mice, blockade of RAGEs with soluble receptors (sRAGEs)
suppressed periodontitis-associated bone loss and reduced the levels of IL-6,
TNF-α and MMPs (Lalla et al. 2000).
• In conclusion, blockade of cytokine receptors (IL-1ra, TNF-αR1, TNF-αR2)
soluble cytokines (rhIL-11) and soluble receptor for advanced glycation end-
products (sRAGEs) reduce periodontal attachment and bone loss in animal
experimental periodontitis.

71. Modulation of Nitric oxide Synthase (NOS) Activity
• Nitric oxide (NO) is a short-lived molecule implicated in a wide range of
biological processes ranging from immune homeostasis to cancer (Brennan et
al. 2003). It is synthesized in vivo from the substrate l-arginine by three
isoenzymes called NOSs.
• While low levels of NO are present in tissue homeostasis, NO is produced at
higher concentrations in response to inflammatory stimuli such as bacterial
LPS via inducible forms of NOS (iNOS) (Southan & Szabo 1996).
• NO is a highly reactive free radical reacting with metal and thiol residues
leading to lipid peroxidation, protein and DNA damages and stimulation of
cytokine release (Brennan et al. 2003).

72. • An exaggerated production of NO has been implicated in the
pathophysiology of several inflammatory processes such as arthritis, colitis
and ileitis (Boughton-Smith et al. 1993, Middleton et al. 1993, Miller et al.
1995, Brahn et al. 1998).
• Animal experiments have shown that pharmacological inhibition of iNOS
with mercaptoalkylguanidines was associated with decreased
inflammation, haemorrhagic shock and arthritis scores (Zingarelli et al.
1997, Brahn et al. 1998, Cuzzocrea et al. 1998).
• This may be explained by the fact that this class of drugs (e.g.
mercaptoethylguanidines (MEGs)) is able to (i) inhibit COX (Zingarelli et al.
1997), (ii) scavenge peroxinitrite (i.e. the product of NO and superoxide)
(Szabo et al. 1997) and (iii) block iNOS (Szabo et al. 1996).

73. • The ligature-induced periodontitis model in rats was used in a proof-of-
principle experiment to investigate the role of iNOS and the effects of its
inhibition with MEG (Lohinai et al. 1998).
• Animals treated with intra-peritoneal injection of MEG exhibited significantly
less plasma extravasation and bone loss at ligated sites compared with
vehicle-treated controls.
• These preliminary results demonstrated that ligature-induced periodontitis
increased NO production and MEG administration protected against bone
loss, suggesting that NO and peroxynitrite played an important role in the
pathogenesis of experimental periodontitis.

74. Locally Administered Agents
Nonsteroidal Anti-inflammatory Drugs
• Topical NSAIDs have shown benefit in the treatment of periodontitis. One
study of 55 patients with chronic periodontitis who received topical
ketorolac mouth rinse reported that gingival crevicular fluid levels of PGE2
were reduced by approximately half over 6 months and that bone loss was
halted (Jeffcoat et al 1995).
• In addition, locally administered ketoprofen has been investigated. To date,
topically administered NSAIDs have not been approved as local HMTs for
the management of periodontitis.

75. Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic Proteins
• A number of local host modulation agents have been investigated for potential
use as adjuncts to surgical procedures, not only to improve wound healing but
also to stimulate regeneration of lost bone, periodontal ligament, and cementum,
restoring the complete periodontal attachment apparatus.
• These have included enamel matrix proteins (Emdogain), bone morphogenetic
proteins (BMP-2, BMP-7), growth factors (platelet-derived growth factor, insulin-
like growth factor), and tetracyclines.
• The only local host modulation agent currently
approved by the FDA for adjunctive use during
surgery is Emdogain.

76. EMERGING HOST MODULATORY THERAPIES
• In the future a variety of HMTs will likely be developed as adjunctive treatments for
periodontitis. One of the most promising groups of potential HMTs is the chemically
modified tetracydines (CMTs).
• These nonantibiotic tetracycline analogs are tetracycline molecules that have been
modified to remove all antibiotic properties, but which retain host modulatory,
anticollagenolytic effects.
• The CMTs are also designed to be more potent inhibitors of proinflammatory
mediators and can increase levels of antiinflammatory mediators such as
interleukin-10 (IL-10).
• This would enable the clinician to increase the dose for patients with more risk
factors and who might be more difficult to manage.

77. • CMTs such as CMT-3 and CMT-8 (both of which lack antibiotic activity but
retain anti-MMP activity) have been shown to inhibit osteoclastic bone
resorption and promote bone formation, enhance wound healing, and inhibit
proteinases produced by periodontal pathogens (Greiner D et al 2002).
• CMTs also are being studied for other effects, such as inhibition of tumor cell
invasion and attenuation of intimal thickening after arterial injury.
• CMTs will likely emerge as drugs that have beneficial effects in a variety of
disease states because of their host modulation capabilities.

78. Conclusions
• In conclusion, it is evident that current preventive management approaches
for the management of the periodontal diseases are only partially effective
and have often failed for the most high-risk individuals.
• This may be due to an overemphasis on the role of plaque and specific
bacteria at the expense of considering the host response, genetic and
environmental factors.
• Accordingly, there is a need for the development of adjunctive agents for
the management of periodontitis based on current understanding of the
etiology and pathobiology of the periodontal diseases.

79. Conclusions
• Host modulation therapy is an important emerging treatment strategy for
managing all forms of periodontitis.
• In light of our current understanding of the central role inflammation plays
in the pathogenesis of periodontitis, old concepts focused solely on
controlling the infection to control the inflammation should be reworked to
consider controlling the inflammation to control the infection.

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