HOST MODULATION THERAPY

ERNIE MADURATNA SETIAWATI

http://orcid.org/0000-0003-4119-4414
Pathobiology of periodontal
disease progression
 Periodontal pathogens produce harmful
by-products and enzymes (e.g.
hyaluronidases, collagenases, proteases)

 break down extracellular matrices, such as

collagen
 host cell membranes ---- bacteria tissue
invasion.
Periodontal pathogen

 Porphyromonas gingivalis, A
actinomycetemcomitans

 possess multiple virulence factors, such as

cytoplasmic membranes, peptidoglycans,
outer membrane proteins,
lipopolysaccharide, capsules and cell-
surface fimbriae (P. gingivalis).
 inflammatory processes

 inflammatory molecules, such as matrix

metalloproteinases, other host enzymes,
cytokines and prostaglandins

 are released from leukocytes, fibroblasts or

other tissue-derived cells .
 Multiple inflammatory signals can
modulate the receptor activator of nuclear
factor kappa B (NF-κB) ligand (RANKL),
RANK, or osteoprotegerin

 cytokines modulate osteoclastogenesis by

enhancing osteoclast differentiation,
activation, life span and function
 Reduction of the bacteria and
associated metabolic by-products

 results in a decrease in both

interleukin-1β and tumor necrosis
factor-α
  the majority of periodontal
breakdown (bone loss, attachment
loss) is caused by

 host destructive enzymes like

matrix metalloproteinases (MMPs)
and inflammatory mediators
(prostaglandins, interleukins)
  Based on this view,
 the therapeutic strategies :

antimicrobial therapy and host

modulation
  host modulation therapy

to restore the balance of

proinflammatory or destructive
mediators
host modulatory therapies (HMT)

---
block pathways
responsible for periodontal tissue
breakdown
Antimicrobial therapies both local and
systemic administration
along with mechanical debridement
is one of the mainstay
in periodontal treatment strategies
 Host Modulatory Therapies
(HMT)

 improve therapeutic outcomes

 slow the progression of disease,
 preventive agents
Specific aspects of HMT

a) Regulation of immune and inflammatory

responses.
b) Regulation of excessive production of
matrix metalloproteinase’s
c) Regulation of arachidonic acid
metabolites
d) Regulation of bone metabolism
e) Regulation of ROS
Agents Used in Host
Modulation

 Inhibitor MMP
 anti-inflammatory
 bone-sparing drugs (anti-
resorptive agents such as
bisphosphonates).
 Antioxidant
 The efficacy of host response modulation
therapy (omega-3 plus low-dose aspirin) as
an adjunctive treatment of chronic
periodontitis

 A. M. Elkhouli
 Journal of Periodontal Research
 Volume 46, Issue 2, pages 261–268, April
2011
M. John Novak et al, 2009

 Combining Host Modulation and Topical

Antimicrobial Therapy in the Management
of Moderate to Severe Periodontitis

 clinical benefits than SRP alone in the

treatment of moderate to severe CP.
REGULATION MMP

 MMPs, a family of the zinc-dependent

enzymes that are capable of degrading
extracellular matrix molecules, including
collagen.
 MMPs are secreted by fibroblasts,
keratinocytes, macrophages, Polymorpho
neutrophil (PMNs), and endothelial cells.
Inhibitor MMP

 Periostat,Marimistat,Agouron AG
3340,BMS 275291
 tetracyclines have anti-collagenolytic
activity
 doxycycline was the most potent
tetracycline in the inhibition of
collagenolytic activities
SDD

 MMP-8, Matrix metalloproteinase-13 and

cross-linked ICTP

 decrease after a subantimicrobial dose of

doxycycline therapy

 as an anticollagenase and bone-sparing

agent
ANTI INFLAMMATORY (NSAID)

 inhibit the formation of prostaglandins

 which is produced by neutrophils,

macrophages, fibroblasts, and gingival
epithelial cells
NSAID

 Salicylates (e.g. aspirin)

 Indomethacin
 Propionic acid derivatives (e.g. ibuprofen,
flurbiprofen, naproxen)
Inhibitor COX2

a selective COX-2 inhibitor

(nimesulide)/scaling and root planing therapy
was compared with a non-selective COX
inhibitor (naproxen)/scaling and root planing

No additional increase was observed in

clinical attachment levels and probing depth
reduction
DISADVANTAGES NSAID

 Gastrointestinal problems
 Hemorrhage (decreased platelet
aggregation)
 Renal and hepatic impairment
 Bone loss accelerates when NSAIDs are
stopped abruptly (rebound effect)
ANTI RESORPTIVE AGENT

 inhibit bone resorption by disrupting

osteoclast activity.
 Biphosponate interfere with osteoblast
metabolism and secretion of lysosomal
enzymes
 bisphosphonates also possess
anticollagenase properties.
Disadvantages biphosponate

 Inhibit bone calcification

 Induce changes in white blood cell count
 Avascular necrosis of the jaws
Newer Agents for Host Modulation

 nitric oxide synthase (NOS) inhibitors

 a selective iNOS inhibitor –
mercaptoethylguanidine
 Antioxidant --- vit E, minocycline, nigela
sativa
Recombinant human interleukin-11

 IL-11 was shown to have anti-inflammatory

effects by inhibition of TNF-α and other
proinflammatory cytokines.

 Significant reduction in the rate of clinical

attachment and radiographic bone loss were
observed after an 8-week period of rhIL-11
administration twice a week.
omega-3 fatty acids

 blocking arachidonic acid cascade .

 This would result in the inhibition of

production of not only prostanoids derived
from the COX pathway but also leukotrienes
derived from the lipooxygenase pathway.
 The efficacy of host response modulation
therapy (omega-3 plus low-dose aspirin) as
an adjunctive treatment of chronic
periodontitis

 A. M. Elkhouli
 Journal of Periodontal Research
 Volume 46, Issue 2, pages 261–268, April
2011
result

 successful reduction of gingival

inflammation, reduction of pocket depth and
attachment level gain

 accompanied by a trend for modulation of

the cytokines profile in gingival crevicular
fluid.
Omega -3 and celecoxib

 a synergism of the anti-inflammatory

effects.

 reductions on periodontal tissue levels of

prostaglandins, leukotriene B4 and platelet-
activating factor
Mouse anti-human interleukin-6 receptor
antibody (MRA)

 MRA inhibits IL-6 function by blocking IL-6

binding to the IL-6 receptor,
 This evidence suggests that MRA has anti-
arthritic effects
MAPK pathway

 Signal transduction pathways closely

involved in inflammation include the MAPK
pathway, phosphatidylinositol-3 protein
kinase (PI3) pathway, janus kinase-signal
transducer and activator of transcription
(Jak-STAT) and NF-κB.
Disruption of Cell Signaling
Pathway
 MAPK inhibitors
 Inhibit LPS-induced MMP, cytokine (IL-1b,
TNF-α, IL-6, IL-8), and prostaglandin
expression

 NF-kB family inhibitors

 Inhibit NF-kB–dependent expression (IL-1,
TNF-α, IL-6, IL-8), MMPs, IFN-c, and others
Minocycline 100 nm

 Inhibit NFkB
 Inhibit PARP-1
 Inhibitor apoptosis

 (setiawati, 2008 )
 Thymoquinone prevents RANKL-induced
osteoclastogenesis activation and osteolysis in an
in vivo model of inflammation by suppressing NF-
KB and MAPK Signalling
Dinesh Thummuria,
Manish Kumar Jeengara,
Shweta Shrivastavaa,
Harishankar Nemanib,
Ravindar Naik Ramavatb,
Pradip Chaudharic,
V.G.M. Naidua,

Pharmacological research, Volume 99, September

2015, Pages 63–73
Thymoquinone

has antiosteoclastogenic effect by

inhibiting inflammation induced activation
of MAPKs, NF-KB and ROS generation

by suppressing the gene expression of c-

Fos and NFATc1 in osteoclast precursors.
 CONCLUSION :

the future that more effective therapeutic

approaches will include multiple,
synergistic host modulation therapies
combined with treatments that target the
microbial etiology.
 INITIAL
THERAPY

Antimicrobial approach Host modulatory approach

SRP SDD
RISK REDUCTION

REEVALUATION

UNSTABLE STABLE
BOP -,PD <5mm,
LOCALIZED Gingival inflamation -
ACTIVE THERAPY
SRP,LOCAL AM,HMT
MAINTENANCE/SPT
GENERALIZED HMT 3-4 MONTHS

SURGERY,SRP,HMT
STABLE
Reevaluation 3 month
SPT,HMT
Thymoquinone

has antiosteoclastogenic effect by

inhibiting inflammation induced activation
of MAPKs, NF-KB and ROS generation

by suppressing the gene expression of c-

Fos and NFATc1 in osteoclast precursors.
Gambaran RÖ Panoramik
Tanggal 6-5-13
 3 bulan post op

6 bulan
post op
Prep for Extra-radicular
Perforation Repair
THE USE OF SDD
 GENETICALLY SUSCEPTIBLE
 SEVERE GENERALIZED PERIODONTITIS
 DIABETES
 OSTEOPOROSIS
 GERIATRIC PATIENTS
 SMOKERS
 NOT BE USED GINGIVITIS/PERIODONTAL ABSCES ---
ALERGY,PREGNANT, CHILDREN LESS THAN 12 YEARS
SITOPROTEKSI

MODULASI SEL EPITEL

GINGIVA
Inhibitor COX

 The cyclooxygenase pathway produces

prostaglandins, prostacyclin and
thromboxane, called prostanoids.
 Some prostanoids have pro-inflammatory
properties and have been associated with
destructive processes in inflammatory
diseases.
Tanda awal periodontitis
METODE TOOTH PICK
MANFAAT METODE TOOTH PICK

1. DETEKSI DINI PERIODONTITIS

2. MEMBERSIHKAN PLAK INTERPROKSIMAL
3. MENINGKATKAN KERATINISASI EPITEL
4. MENINGKATKAN RASIO PCNA DAN
PROCOLAGEN TYPE-1 C PEPTIDE
5. MERANGSANG PELEPASAN PRODUK
TOKSIN BAKTERI DAN MEDIATOR
PROINFLAMASI
PRODUK UNGGULAN DEPT PERIODONSIA FKG UNAIR
NSAID

 arachidonic acid liberated from membrane

phospholipids of cells after tissue damage or
stimulus is metabolically transformed

 via cyclooxygenase or lipooxygenase

pathways, in compounds with potent
biological activities .
 RECALL INTERVAL

FIRST YEAR
 ROUTINE THERAPY --- 3 MONTHS
 COMPLICATED CASE ---1-2 MONTHS
Poor oral hygiene, systemic disease,occlusal problems,
complicated prothesis,recurrent dental caries,many teeth
with less than 50% of alv bone support, smoking, positif
family history or genetic test,more than 20% of pockets
bleed on probing
RESTORATIVE PHASE

 THE BIOLOGIC WIDTH --- AROUND THE

TOOTH AND IMPLANTS
CAUSES OF RECURRENCE

 INCOMPLETE CALCULUS REMOVAL

 IN ADEQUATE RESTORATION
 NO PERIODIC CHECKUPS
 PRESENCE OF SYSTEMIC DISEASE
A FAILING CASE

 RECURRING INFLAMMATION,BOP +
 INCREASING DEPTH OF SULCU
 GRADUAL INCREASES IN BONE LOSS
 GRADUAL INCREASES IN TOOTH MOBILITY
 NOT RESPOND TO ADEQUATE TX –
AGGRESSIVE PERIODONTITIS
CLINICAL APPLICATION

 INITIAL VISIT : MEDICAL ,DENTAL

HISTORY,RISK ASSESMENT
PROFILE,RADIOGRAFIC ANALYSIS
 PATIENT MUST BE MADE AWARE OF THE
FACT THAT PERIODONTAL DISEASE IS NOT
CURABLE
 IT CAN BE TRATED AND WELL CONTROLLED
WITH CONSTANT MONITORING