Dr SAnandan Dean amp Professor of Dermatology SRMC amp RI Porur Chennai 600 116 OBJECTIVES Introduction Pathogenesis Heat shock protein in OLP Types of OLP Treatment modalities ID: 578788
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Slide1
ORAL LICHEN PLANUS
Dr.
S.Anandan
,
Dean & Professor of Dermatology
SRMC & RI,
Porur
, Chennai – 600 116Slide2
OBJECTIVES
Introduction PathogenesisHeat shock protein in OLP.Types of OLP
Treatment modalities
Algorithmic approach Slide3
OLP
Chronic inflammatory disease of the oral mucosa 1-2% of the population is affected
50%
of patients with LP have oral lesions
Isolated oral LP seen in
15-35%
of casesSlide4
PATHOGENESIS
Expression of keratinocyte
self-antigen
Migration of CD8 lymphocytes into the epidermis
Activation of CD 8 cells through MHC 1 or CD4 cells by IL
2,12
IFN
γ
Apoptosis of basal keratinocte by TNFα, Fas-FasL, Granzyme B.Slide5
PATHOGENESIS
Upregulation of vascular adhesion molecule (lymphocyte homing)Matrix
metalloproteinases
(increase BM disruption)
RANTES(Regulated on Activation, Normal T cell Expressed and Secreted)
Mast cell
degranulation
– TNF-
α, chymase, tryptaseSlide6
6Slide7
OLP
Associated factorsInfections (eg.HCV)Drugs (NSAIDS,
sulfonylureas
, beta blockers, ACE inhibitors, etc.)
Contact allergens (dental amalgams)
Mechanical trauma Slide8
Role of HSP 90 in the pathogenesis and treatment of OLP
: A Molecular Research Work
8Slide9
CLINICAL SIGNIFICANCE
9Slide10
HEAT SHOCK PROTEINS
10
David Whitley, Heat Shock Proteins: A Review Of The Molecular Chaperones, Journal Of Vascular Surgery Volume 29, Number 4
http://www.britannica.comSlide11
HEAT SHOCK PROTEIN 90
11
David Whitley, Heat Shock Proteins: A Review Of The Molecular Chaperones, Journal Of Vascular Surgery Volume 29, Number 4Slide12
WHY THIS STUDY??
12Slide13
WHY HSP 90??
There has not been any studies done till date in India identifying the role of HSP 90 Oral Lichen planus
Based on the literature search, Identifying the Role of HSP 90 in Oral Lichen Planus shall help us in
providing us a prognostic tool as well pave way for further research in the field of targeted therapy.
13Slide14
METHODOLOGY
14Slide15
ROLE OF HSP
90 IN PATHOGENESIS OF OLP
1. Is
HSP
90
the gene causing keratinocyte autoantigenicity?
2. Over
Expression of the gene a role in carcinogenesis?15Slide16
RESULTS
Observations
Total
Mean
Variance
Standard deviation
P value
Group I (8)
7.0
0.8750
0.4107
0.6409
0.000
Group II (23)
43.00
1.86
0.2095
0.4577
16Slide17
NORMAL ORAL MUCOSA
Normal Tissue: (10x View: HE)
Score 1, Mild Intensity
(40x View: IHC)
ORAL LICHEN PLANUS
Section Showing Parakeratotic Epithelium With Basal Cell Degeneration With Intense Chronic Inflammatory Infiltrate (10x View:
H & E)
Section Shows
Score 2, Mild Intensity (10x View:
IHC
), (40x View: IHC)Slide18
18/23 cases(78.3%) had a score 2 and 19/23 cases (82.6%)with mild intensity.
Heat shock proteins expressed by oral keratinocytes may be auto antigenic in Oral lichen planus. Susceptibility to
Oral lichen planus may result from dysregulated heat shock protein gene expression
by stressed oral keratinocytes or from an inability to suppress an
immune response following self-Heat shock protein recognition.
Over expression of Heat shock protein
90
in Oral lichen Planus has been associated to the persistence or chronicity of the disease, or they could have simply reflected cellular injury.
The findings were substantiated with the study done by Bramanti T.E. et al (1995), Yin Cao Shen Li Jia et al (2006) and Ponlatham et al (2009), Yin Cao Shen Li Jia et al (2006) .
18Slide19
Positivity of staining was seen in the infiltrating lymphocytes in the lamina propria and few cells entering the epithelium due to basal cell degeneration
This finding is supported by the pathogenesis, cytotoxic CD8+ cells are responsible for the trigger mechanism. This finding also was concurrent with the results of the study done by
Ponlatham
et al
(2009),
Bramanti
T.E et al
(1995)
19Slide20
CONCLUSION
The results of the study support the role of Heat shock protein
90
in oral tumorigenesis and malignant
transformation.
Indeed
these finding pave the way for using
Heat
shock protein 90 as a marker protein for risk assessment in malignant transformation of oral lichen planus20Slide21
Types of oral LP
Reticular Erosive Atrophic
Plaque
BullousSlide22
Point of Interest
Skin Lichen Planus
Oral Lichen Planus
Clinical Aspects
Shiny,
Violaceous
Flat-topped polygonal papules
1. Bilateral white
lesion forming a lacework Beginning of the lesion
50%- Skin lesions without OLP
40%
- OLP followed by Skin lesions
25%
- Only OLP
Wickham’s strie
Positive
Positive
Main Symptoms
Itching
Burning
sensation and pain
22
Tony Burns, Steephen Breathnach, Rook’s Textbook of dermatology, 8
th
edition, Volume 2, Wiley-Blackwell, Chapter 41, Page 41.1-41.15Slide23Slide24
OLPSlide25
OBJECTIVES OF TREATMENT
Identify interventions to treat OLPTo identify appropriate medications for management of different types of OLPSupport treatment measures with limited evidence.Slide26
Treatment options
CorticosteroidsRetinoids
Calcineurin
inhibitors
Immunosuppresive
agents
Immunomodulators
Antibiotics
PhototherapySurgerySlide27
Pharmacotherapy of OLP
Cochrane database systematic review – 2012RCT’s minimalHeterogenecity in trials
Design methods inappropriate
Different outcome variablesSlide28
Corticosteroids
TCS - First line therapy of OLPModulate inflammation and immune responseStabilizes the
lysosomes
Reduces lymphocyte activity Slide29
Corticosteroids
Midpotency
– Triamcinolone acetonide
0.1%
High potent –
Fluocinonide
acetonide
0.1%,
disodium
betamethasone phosphate
Superpotent – Clobetasol
propionate
In orabase- contains pectin, gelatin and
carboxymethyl
cellulose
Orabase substituted with adhesive paste used for dentures
Steroid mouth washes,
betamethasone
/
dexamethasoneSlide30
Systemic
Most useful in acute erosive oral LP or multisite disease
Pts unresponsive to
topicals
Upto
2
mg/kg/day of
prednisolone
can be given as a short courseMonitor for adverse effects
But studies show topical corticosteroids to be equally or more effective than systemic corticosteroids or the combination of the two.Slide31
Intralesional CTS
Used for localized resistant plaqueHydrocortisone, triamcinolone
acetonide
and
methylprednisolone
have been tried in various studies
Localized side effects like pain and mucosal atrophy. Slide32
Complications of TCS
Secondary
candidiasis
– Rx with topical
antifungals
(azoles)
Adrenal insufficiency (super potent)
Potential
tachyphylaxsisSlide33
Antifungals
Candida albicans in
37%
of oral LP lesions
Exacerbates the symptoms
Candida produce a carcinogen N-
nitrosobenzylmethylamine
Antifungal therapy can change erosive form to reticular form
Topical azoles can be used
Oral antifungals can be usedSlide34
Calcineurin inhibitors
Calcineurin inhibitorsCyclosporine
Tacrolimus
Pimecrolimus
Slide35
Tacrolimus
Inhibits T-cell activation at 10-100 times lower conc. than
CsA
Penetrates skin better than topical
cyclosporin
Tacrolimus 0.1% ointment +
ora
base
Significant improvement in refractory steroid unresponsive erosive oral LP
Side effect- local irritation Flare up after stopping therapy
Oral gel formulation available in IndiaSlide36
TIMS
1% Pimecrolimus
is also effective with low systemic side effects Slide37
Cyclosporin MOA
Inhibits the production of NFAT 1 transcription factor by calcineurin
Suppresses the cytokine production
It was found to be effective, applied as topical or mouth rinse in many studies but not all
Disadvantages – bad taste, transient burning sensation and high cost.
Swish and spit/swallow Slide38
Cyclosporin
was found to be as effective as triamcinolone acetonide in orabase
An alternative in the initial control of oral LP
Not a first line drug due to
high cost
serious side effects (hypertension,
nephrotoxicity
, etc.) availability of alternativesSlide39
Oral Cyclosporin
2.5 mg/kg body weight for 6 to 8 weeks (Acute erosive mucosal LP)Crisis buster
Watch for side effectsSlide40
Retinoids
Topical and systemic drugs usedTopicalIsotretinoin gel
0.1%
and
Tretinoin
oint
Produce significant improvement
Histological, decreased keratinizationTransient burning/irritation Slide41
Treatment of OLP
Topical fenretinideEffective with minimal side effects
Not readily available
Topical
tazarotene
Hyperkeratotic
oral LPSlide42
Systemic retinoids
IsotretinoinAcitretin
Due to side effect profile and low remission rates, used only as adjuvant therapy. Slide43
Steroid sparing agents
AzathioprineReported , effective in erosive and generalized oral LP
Used in severe recalcitrant disease, as steroid sparing agent
As effective as systemic steroids
Need to monitor for bone marrow suppression
Mycophenolatemofetil
-
1 to 1.5
gms per daySlide44
Treatment of OLP
AntimalarialsHydroychloroquine sulfate and
chloroquine
phosphate effective
But implicated in
lichenoid
reaction
Mesalazine
(5-aminosalicylic acid)Used in the Rx of IBDTopical mesalazine used as an adjuvantSlide45
Treatment of OLP
DapsoneIn erosive or bullous
LP, in resistant cases
Levamisole
Used as an
immunomodulator
Combined with low dose oral steroids in severe erosive LP
Can occasionally induce
lichenoid lesionsSlide46
Treatment of OLP
Low molecular weight heparinLow doses inhibits T lymphocyte heparinase
activity needed for T cell migration
suggested that the
immunomodulatory
molecules in heparin are probably sulfated disaccharides that act by inhibiting the production of the key
proinflammatory
cytokine
TNFαSlide47
Treatment of OLP
Interferon Topical human fibroblast interferon (Hu
IFN β) and interferon α
Effective in the erosive forms
Systemic IFN α
(3-10
million U thrice weekly)
In treatment of oral LP, esp. in HCV infected patientsSlide48
Biologicals
Efalizumab
Recombinant humanized monoclonal antibody
Monoclonal
Ab
to CD11a
inhibits T cell activation & trafficking in the skin Slide49
NON-PHARMCOTHERAPY
P-UVAEarlier oral 8-MOP was used as the photosensitizer
Now, topical
0.01%
trioxsalen
can be used to reduce the side effects
Useful for severe form of erosive oral LP resistant to conventional therapy
Carcinogenic potential of PUVA needs further study
Narrow band UVB studied in a few casesSlide50
LASER &PDT
CO2 laser
Multicentric
lesion and difficult areas of
oralLP
Recurrences have been reported
Excimer
308
nm laserEffective in the erosive OLP
Even in difficult to control lesions
Photodynamic therapy
With
methylene
blue
Case reports show
50%
improvement in lesionsSlide51
Oral LP and SCC
Incidence of
squamous
cell carcinoma in oral LP lesion ranges from
0.4% to 2%
Highest rates seen with
erythematous
and erosive lesions
Pathogenesis
Pro inflammatory cytokine rich environment
N-nitrosobenzylmethylamine carcinogen from Candida albicans
HCVSlide52
Surgery
Surgical excision Isolated non healing plaques and erosive lesionsSuspected malignant transformation
Free soft tissue graftsSlide53
Lifestyle modifications
Avoid smoking alcoholAvoid acidic/spicy food substances
To maintain good oral hygieneSlide54
Oral LP
Improve/control oral hygiene. Avoid precipitating factors, drugs, food chemicals, etc.
Erosive or symptomatic
Asymptomatic
Follow up every 6 months
No treatment
Smear for candida
Positive for Candida
Negative for Candida
Topical steroids
Topical steroids +
antifungals
Unsatisfactory response
Satisfactory response
Systemic steroid
Alternatives-
tacrolimus
,
retinoids
, PUVA,
ILS, steroid sparing drugs, DAPSONE, Non-pharmacotherapy
Maintenance with topical steroids
Unsatisfactory response Slide55
MY SUGGESTION
Algorithmic approach
Step 1: TCS/
Tacrolimus
in
orabase
Step 2: Continue Step 1 + Burst of Oral Corticosteroids
Step 3: Continue Step 1 + Cyclosporin
short course
Step 4: Continue Step 1 + MMF/Retinoids/Dapsone/ Non-PharmacotherapySlide56
THANK YOU