Host Modulation Therapy in Periodontitis

DR. KRITIKA JANGID
MDS- PERIODONTICS

• Defined as
‘the organism from which a parasite obtains its
nutrition’
Or
‘the individuals that harbours these pathogens’

• Refers to the response of the body of a living
organism i.e. animal or plant against invading
or threatening factors.
• Refers to the modulation of the immune
responses to suppress unwanted reactions to
protect an organism against infectious
disease.

Microbial
challenge
Clinical signs of
disease initiation
and progression

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 over time.

• Ivanyi and Lehner (1970)
Peripheral blood lymphocytes isolated from
subjects with periodontitis >> lymphocytes
from healthy subjects.
• 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)
Subjects with aggressive periodontitis had a
neutrophil chemotactic defect.

Microbial
challenge
Host immuno-
inflammatory
response
Clinical signs of
disease
initiation &
progress

• Smoking as a risk factor
Preber H et al. 1984, 1986
Haber 1993
Bergstrom 1983
• Diabetes as risk factors
Bissada et al. 1982
Emrich LJ 1991
Genco, Papapanaeu 1996

• Mechalowicz et al in 1991
Studies on monozygotic and dizygotic twins
reared together and reared apart
Added genetic component linked to
pathogensis

Microbes
Occlusion
Host
immune
factors
Environmental
factors
Genetics

“ There are compelling data from studies in
animals and humans indicating that
pharmacologic agents that modulate host
response may be efficacious in slowing down the
progression of periodontitis”

• Treatment concept that aims to reduce tissue
destruction and stabilize or even regenerate the
periodontium by modifying or down-regulating
destructive aspects of host response and up-
regulating protective or regenerative responses.
(CARRANZA)

Nonsteroidal anti-
inflammatory
drugs (NSAID’s)
Anti- proteinase
blocking of
MMP’S
Bisphosphonates Statins
Anti cytokine
therapy
NO inhibitors
Antagonists to
cell adhesion
molecules
Inhibitors to
RANK/RANKL
interaction
Disruption of cell
signaling
pathways
Agents that
promote
resolution
Matrix
proteins,growth
factors,BMP’s

• COX-1 is expressed
‘constitutively’
• Known as a
"housekeeping"
enzyme. Functions
include
1. gastric cytoprotection
2. vascular homeostasis
3. platelet aggregation
4. and kidney function
• COX-2 is usually
undetectable in most
tissues.
• Inducible during
states of
inflammation
• Upregulated by pro
inflammatory
cytokines, endotoxin.
VANE 1972
NSAID’S BLOCK
COX

Neutrophils
Macrophages
Fibroblasts

Nyman et al 1979 Canine experimental
Periodontitis model
Systemic indomethacin Suppressed alveolar
bone resorption &
Gingival inflammation
Williams et al 1988 Naturally occurring
periodontitis in dogs
Topical flubiprofen
propylene glycol gel
71% suppression in
radiographic bone loss
Williams et al 1991 Naturally occurring
periodontitis in beagles
Peroral flubiprofen Decreased rate of
at 3,6,9 & 12 months
Howell et al 1991 Naturally occurring
Peroral naproxen Decreased rate of
by 61% when compared
to controls
Howell et al 1991 Naturally occurring
Topical piroxicam Decreased gingival &
bleeding indices after 2
& 4 weeks
Li et al 1996 Spontaneous &
experimental
periodontitis in rhesus
monkeys
Topical ketoprofen(1%) Clinical improvement in
gingival inflammation
but no significant
decrease in PGE2 & LTB4
levels
Paquette et al 1997 Experimental
Periodontitis in beagle
dogs
Ketoprofen Decrease in gingival
inflammation & bone
loss at 2 months

Waite et al 1981 Prevalence of
Periodontal status in
subjects taking NSAID’s
NSAID’s Lower gingival
index scores
& periodontal
pockets
Williams et al
1989
44 adult periodontitis
subjects monitored for
3 years
Systemic
flurbiprofen
Lower bone loss
rates at 12 & 18
months
Jeffcoat et al
1988
15 refractory
periodontitis patients
Systemic
flurbiprofen
Decreased bone
loss over 2 months
compared to
placebo
Jeffcoat et al
1991
7 RPP subjects
7 controls
Systemic
naproxen
Decreased bone
loss 3 months
relative to placebo

• GIT upset
• Gastrointestinal
hemorrhage
(decreased platelet
aggregation)
• Renal impairment
• Hepatic impairment
• Rebound
Phenomenon

Nonsteroidal anti-
inflammatory
drugs (NSAID’s)
Blocking of
MMP’S
Anti cytokine
therapy
NO inhibitors
Antagonists to
cell adhesion
molecules
Inhibitors to
RANK/RANKL
interaction
Disruption of cell
signaling
pathways
Agents that
promote
resolution
Matrix
proteins,growth
factors,BMP’s

 Inhibit the synthesis and/or release of these
enzymes
Block the activation of precursor (latent)
forms of these MMPs (pro-MMPs)
Inhibit the activity of mature MMPs
Stimulate the synthesis of endogenous tissue
inhibitors of MMPs; or
Protect the host’s endogenous inhibitors from
proteolytic inactivation

• CONHOH
• Marimastat
• Ilomastat, Batimastat-
1st to be tested in pts.
– Broad spectrum
inhibitors (No selectivity)
– Muscular and skeletal
pain (Toxicity)

• Hydroxamate
• Sulfonamide
• Substituted aryl
• Stearic Hinderance
• Cipemastat- MMP-1, 3, 9
• Excellent oral efficiency in
animal model of
osteoarthritis

• RSH
• Selectivity- MMP that
release TNFα, L-
selectin, IL-1RA, IL6
are not inhibited
Severe Hepatotoxicity

• Pyramidine based
– Selective for MMP-2,
8, 9, 13
• Hydroxypyrone based
– Selective MMP-3
inhibitor
• Phosphorous based
– Selective MMP-8
inhibitor

• Tetracyclines were found to
directly inhibit collagenases
from a wide variety of cells
including PMN’s,
macrophages, osteoblasts,
osteoclasts, chondrocytes,
and malignant melanoma
cells (Golub et al 1987)
MMP 13 is more sensitive to tetracycline inhibition than MMP 8 and MMP 1 is least
sensitive (Golub et al 1995)
MMP 2 (Gelatinase A)&MMP 9 (Gelatinase B) and other types of MMPs are also
inhibited
TC’s do not inhibit serine proteinases (PMN elastase,plasminogen activator) and acid
proteinases (cathepsins B & L)

TETRACYCLINES INHIBIT CONNECTIVE TISSUE
BREAKDOWN: PLEIOTROPIC MECHANISMS(Golub &
Ryan 1998)
• Mediated by extracellular mechanisms
• Mediated by cellular regulation
• Mediated by pro-anabolic effects

Mediated by extracellular
mechanisms
• Direct inhibition of active MMPs
• Inhibition of oxidative activation of pro-
MMPs
• Promotes excessive proteolysis of pro-MMPs
into enzymatically inactive fragments
• Inhibition of MMPs protects α1-proteinase
inhibitor

Mediated by cellular regulation
• Decrease cytokines, iNOS, phospholipase A2,
prostaglandin synthase
• Effects on protein kinase C, calmodulin

Mediated by pro-anabolic effects
• Increase collagen production
• Increase osteoblast activity and bone formation

Golub et al (J Periodont
Res 1985). reported that the
semisynthetic compound
(e.g., doxycycline) was more
effective than the parent
compound tetracycline in
reducing excessive
collagenase activity in the
GCF of chronic periodontitis
patients.

• Not used as monotherapy, Used as an adjunct to SRP
• Taken as 20mg twice daily for 3 months and up to a
maximum of 9 months
• Three month prescription fits well with the typical
maintenance recall of 3 months.

• History of allergy or hypersensitivity
• Pregnant and lactating women
• Children under 12yrs of age
• May reduce the effectiveness of oral
contraceptives

• 20mg twice daily was well tolerated (Caton et al
2000, Preshaw et al 2002)
• Most frequently reported adverse effects were
headache(0.1%), common cold & influenza like
symptoms, rash(0.1%), dyspepsia(0.2%)
• No typical side effects of tetracycline group of
antibiotics were noted

• 4-dedimethylamino
tetracycline
• Tetracyclinonitrile
• 6-deoxy-6-
demethyl-4-de-
dimethylaminotetr
acycline
• 7-chloro-4-de-
dimethylaminotetr
acycline
•Tetracycline
pyrazole
•4-dedimethyl
amino. 4-
hydroxytetracycline
•12-deoxy-4-
dedimethyl amino
tetracycline
•4-dedimethylamino
doxycycline)

• The anti-collagenase activity of CMTs is
specific against the collagenase produced
from neutrophils but not the fibroblasts.
• Does not affect the normal collagen turnover
required to maintain the tissue integrity.
[Golub et al 1991]

• CMT 8 is the most potent inhibitor of
periodontal breakdown
• CMT-8,-1, - 3, - 4, - 7 and doxycycline inhibited
TNF-α, IL-1, IL-6 and MMPs in descending
order.
• The CMT 1 and 3 also inhibit gingipains
produced by P. gingivalis.

• Inhibition of inducible nitric oxide synthase (iNOS)
expression of inducible nitric oxide synthase (iNOS) and
nitric oxide (NO) activity.
• CMT-3 and CMT-8 have shown maximum inhibitory
effect on the iNOS, CMT-1 and-2 had intermediary
effect while CMT-5 was ineffective.[Trachtman et al
1996]
• Inhibition of proinflammatory mediators-IL-1β, IL-6,
IL-8, TNF–α and PGE2 from LPS stimulated host
immune cells by suppressing phosphorylation of the
nuclear factor κ–B cell signalling pathway.
• CMT-1, CMT-3, CMT-6,-7 and - 8 were effective
inhibitors of osteoblastic collagenase in culture. CMT-8
was the most potent[Rifkin et al 1994]

• Bisphosphonates are analogs of
pyrophosphate(P-O-P) in which the
oxygen is replaced by carbon with
various side chains.

• It binds to the hydroxyapatite crystals
of bone and prevents their dissolution
by interfering with osteoclasts function
• Known as bone sparing agents

FIRST
GENERATION
(alkyl side
chains)
• Etidronate
SECOND
GENERATION
(amino terminal
group)
• Alendronate
• Pamidronate
THIRD
GENERATION
(cyclic side chains)
• Risedronate
•The antiresorptive properties of bisphosphonates
change according to their side chains
•Their potency increases from first to third
generation

Activities of Bisphosphonates on
Osteoclast Function
Tissue Level Cellular Level Molecular Level
↓ bone turnover due to
↓ bone resorption
↓ number of new bone
multicellular units
Net positive whole
body bone balance
↓ osteoclast recruitment
↑ osteoclast apoptosis
↓ osteoclast adhesion
↓ depth of resorption site
↓ release of cytokines by
macrophages
↑ osteoblast differentiation
and number
Inhibit mevalonate
pathway
(can result in
perturbated
cell activity and induction
of apoptosis)
↓ post-translational
prenylation
of GTP-binding proteins
Tenenbaum HC et all 2002

•Alendronate treatment of humans with progressive moderate
to severe periodontitis.
• All subjects had SRP at baseline and were then treated with
either 20 mg of
alendronate daily for 6 months or placebo.
•All subjects were monitored for 9 months.
Jeffcoat et al
1996
Alendronate
Placebo

• Probing depth reduction (Rocha et al 2004;
Lane et al 2005)
• Clinical attachment gain (Lane et al 2005,
Rocha et al 2001)
• Alveolar bone gain (Jeffcoat et al 1996, Rocha
et al 2001,2004) and
• Increase in bone mineral density (El-Shinnawi
et al 2003, Rocha et al 2004)

• The long-term use of bisphosphonates has
been related to osteonecrosis of the jaw
(Marx et al 2003)
• Clinically, ONJ is essentially exposed
bone in the maxilla or mandible that does
BRONJ

• NATURAL(FUNGAL)
• Lovastatin
• Pravastatin
• Simvastatin
• SYNTHETIC
• Atorvastatin
• Fluvastatin
• Rosuvastatin

• Evaluation of anti-inflammatory effect of
statins in chronic periodontitis.
• GCF IL-1β levels in generalized chronic
periodontitis patients who are on statin
medication (Group-I) were lower than the
generalized chronic periodontitis patients
without statin medication (Group-II).- statin
users indicate that statins have anti-
inflammatory effect on periodontal disease.
Snophia Suresh et al J Ind Pharmacol 2013

• Clinical efficacy of subgingivally delivered 1.2-
mg simvastatin in the treatment of individuals
with Class II furcation defects: a randomized
controlled clinical trial.
• Locally delivered SMV provides a comfortable and
flexible method to improve clinical parameters
and also to enhance bone formation.
AR Pradeep et al J Periodontol 2012

Efficacy of subgingivally delivered simvastatin
in the treatment of patients with type 2
diabetes and chronic periodontitis: a
randomized double-masked controlled
clinical trial.
Greater decrease in mSBI and PD and more
CAL gain with significant IBD fill at sites treated
with SRP plus locally delivered SMV in patients
with type 2 diabetes and CP.
Pradeep AR et al J Periodontol 2013

• Risk of diabetes
• Cognitive loss
• Neuropathy
• Pancreatic and hepatic
dysfunction
• Sexual dysfunction.

Neutralization of cytokinesNormal interaction
Inflammatory
signals
Suppression of
inflammatory
cytokines
Anti-
inflammatory
cytokine
Inflammatory
cytokine
Receptor blockade
Activation of
anti-inflammatory pathways
Cytokine
receptor
Soluble
receptor
Monoclonal
antibody
Monoclonal
antibody
Receptor
antagonist
No signal
No signal

Monoclonal A/b to
TNFα
Soluble form of
TNF receptor

ANTICYTOKINE THERAPY &
PERIODONTITIS
• Anti-cytokine agents have shown to
significantly reduce loss of clinical
attachment, loss of alveolar bone &
slowing down the progression of
experimental periodontal disease in
animal studies
Assuma et al 1998, Graves et al 1998, Delima et al
2001, Oates et al 2002, Zhang et al 2004

• The effect of IL-6 receptor inhibition has been analysed in patients
with periodontitis and a significant decrease in the gingival index,
bleeding on probing, probing depth was noted.
Kobayashi 2014
• Subcutaneous injection rhIL-11in experimental periodontitis in dogs
showed significant reduction in the rate of clinical attachment and
radiographic bone loss after an 8-week period.
Martuscelli et al 2000

• Infliximab
– Allergic reactions like swelling
of the lips
– Difficulty in breathing
– Lowered blood pressure.
• Etanercept
– Infections
– Hypersensitivity
• Anakinra
– Infections
– Immunogenicity
– Malignancies
– Decrease in the total white
blood cell and platelet count

MERCAPTO ETHYL
GUANIDINE
• Blocks iNOS
• Inhibits COX
• Scavenges
peroxynitrate
Lohinai et al 1998 - found a reduction of alveolar
bone loss
and gingival inflammation after the use of a
selective

• Effect of quercetin (a flavonoid found in
apples, onions, tea, and red wine) on the
production of NO by murine macrophages
activated with LPS from P. intermedia
• Quercetin significantly inhibits iNOS-
derived NO production in murine
macrophages activated by P. intermedia
LPS.
Cho YJ et al 2013

Nonsteroidal anti-
inflammatory
drugs (NSAID’s)
Anti- proteinase
blocking of
MMP’S
Anti cytokine
therapy
NO inhibitors
Antagonists to
cell adhesion
molecules
Inhibitors to
RANK/RANKL
interaction
Disruption of cell
signaling
pathways
Agents that
promote
resolution
Matrix proteins,
Growth factors,
BMP’s

• ICAM- 1 & E- selectin expressed on
endothelial cell is responsible for PMN rolling
& extravasation
• ICAM – 1 & E – selectin inhibitors –
Tepoxalin, Sodium Cromoglycate, BMS-
190394 have shown promise in inflammatory
models (Hoshino et al 1997, Wilson et al
1998)
• AWAIT TESTING IN PERIODONTAL

• Dinosumab
– Infections
of urinary and respiratory
tracts
– Cataracts
– Constipation
– Rashes
– Joint pain
– Eczema

• Within periodontal resident cell types - tissue
macrophages and other periodontal cells, MAPKs are
activated chiefly by LPS, IL-1 & TNF-α.
• Activation of p38 induces synthesis of pro-inflammatory
cytokines, such as TNF-α, IL-1,IL--6 &IL-8

p-38 inhibitors
• p-38 inhibitors are known cytokine suppressive anti-
inflammatory drugs (CSAIDs)
• BIRB-796 and SCIOS-469 are in phase III for the
treatment of psoriasis and rheumatoid arthritis,
respectively.
• Studies of VX-702, a newer p38 inhibitor which does not
pass through the blood-brain barrier, are currently
underway

Compound SD 282
LPS induced periodontal disease, inflammatory cytokine
expression, osteoclastogenesis, and alveolar bone loss
were reduced in rats model
Rogers JE et al J Periodontol 2007

The NF-κB pathway
LPS, IL-1,TNF,MMP’S,COX-2,iNOS present in large quantities in
periodontal diseased tissues, can also activate NF-κB.

• In vitro studies have established that both P. gingivalis and
other periopathogenic bacteria can activate NF-κB in
periodontal tissues (Sugita N et al. Inflammation 1998).
• Activation of NF-ĸb(p50/p65) is significant in periodontally
diseased tissues(Ambili R, Nandakumar et al JP 2005)

NF-κB Inhibitors
• Proteasome inhibitors block NF-κB activation
• Bortezomib (Velcade®) was tested in multiple myeloma
with highly promising results (Richardson P 2003).
• BMS-345541 - decreased both synovial inflammation and
joint destruction in an arthritis model (McIntyre et al 2003).

• Signals the initiation of resolution of
inflammation (Serhan 1994; 1988)
• LXA4 is shown to effectively inhibit P.
gingivalis induced aggregation and ROS
production in whole blood
Borgeson et al 2011

• Generated from DHA
• Functions
– stop PMN infiltration
– reduce cytokine expression and
– Improved wound healing in mouse models.

• Hasturk H, et al 2006
– On application of ResolvinE1 in rabbit model for treating
periodontitis, histologically revealed no inflammatory
changes, osteoclast formation or bone loss and temporal
shift in the microflora in oral biofilm were also observed
• El-Sharkawy H,:
– SRP followed by 900mg of EPA/DHA with 81mg
aspirin daily for 6 months for treating
periodontitis- improved signs

• Macrophage mediated resolution of inflammation
• Potent up regulation of efferocytosis

• Enamel matrix proteins(EMDOGAIN)
• Bone morphogenetic proteins(INFUSE)
• Growth factors(GEM 21S)

Host Modulation Therapy in Periodontitis

Host Modulation Therapy in Periodontitis

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