Download Oral Lichen Planus

ORAL LICHEN PLANUS
Dr. S.Anandan,
Dean & Professor of Dermatology
SRMC & RI, Porur, Chennai – 600 116
OBJECTIVES
 Introduction
 Pathogenesis
 Heat shock protein in OLP.
 Types of OLP
 Treatment modalities
 Algorithmic approach
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 cases
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.
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,
tryptase
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OLP
Associated factors
 Infections (eg.HCV)
 Drugs (NSAIDS, sulfonylureas, beta blockers, ACE
inhibitors, etc.)
 Contact allergens (dental amalgams)
 Mechanical trauma
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CLINICAL SIGNIFICANCE
Potentially
Malignant
Disorder
0.5%
05-2%
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HEAT SHOCK PROTEINS
David Whitley, Heat Shock Proteins: A Review Of The Molecular Chaperones, Journal Of Vascular Surgery Volume 29, Number 4
http://www.britannica.com
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HEAT SHOCK PROTEIN 90
Environmental
Insults
Increase in HSP
production
Protein folding and
Guarding Chaperones
Protein Misfolding +
Increased exp
Increased Exp: To
maintain tumor
homeostasis in the
hostile environment
Pharmacological
modulation of these
chaperones: Targeted
therapy in cancer
= Tumor Expansion
David Whitley, Heat Shock Proteins: A Review Of The Molecular Chaperones, Journal Of Vascular Surgery Volume 29, Number 4
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WHY THIS STUDY??
Quality
of life
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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.
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METHODOLOGY
Ethics IECNI/11/OCT/25/64
Immunohistochemistry
Real Time PCR
Grading and clinical
correlation
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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?
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RESULTS
Observations
Total
Mean
Variance
Standard
deviation
Group I (8)
7.0
0.8750
0.4107
0.6409
P value
0.000
Group II (23)
43.00
1.86
0.2095
0.4577
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NORMAL ORAL MUCOSA
Normal Tissue: (10x View:
HE)
Section Showing Parakeratotic
Epithelium With Basal Cell
Degeneration With Intense
Chronic Inflammatory Infiltrate
(10x View: H & E)
Score 1, Mild Intensity
(40x View: IHC)
ORAL LICHEN PLANUS
Section Shows
Score 2, Mild Intensity (10x View: IHC), (40x View: IHC)
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
Yin Cao Shen Li Jia et al (2006) and Ponlatham et al (2009), Yin Cao
Shen Li Jia et al (2006) .
(1995),
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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)
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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
planus
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Types of oral LP
 Reticular
 Erosive
 Atrophic
 Plaque
 Bullous
Skin Lichen
Planus
Oral Lichen
Planus
Clinical Aspects
1. Shiny, Violaceous
2. Flat-topped polygonal
papules
1. Bilateral white lesion
forming a lacework
Beginning of the lesion
1. 50%- Skin lesions
without OLP
1. 40% - OLP followed
by Skin lesions
2. 25%- Only OLP
Wickham’s strie
Positive
Positive
Main Symptoms
Itching
Burning sensation and pain
Point of Interest
Tony Burns, Steephen Breathnach, Rook’s Textbook of dermatology, 8th edition, Volume 2, Wiley-Blackwell, Chapter 41, Page 41.1-41.15
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OLP
OBJECTIVES OF TREATMENT
 Identify interventions to treat OLP
 To identify appropriate medications for
management of different types of OLP
 Support treatment measures with limited
evidence.
Treatment options
 Corticosteroids
 Retinoids
 Calcineurin inhibitors
 Immunosuppresive agents
 Immunomodulators
 Antibiotics
 Phototherapy
 Surgery
Pharmacotherapy of OLP
 Cochrane database systematic review – 2012
 RCT’s minimal
 Heterogenecity in trials
 Design methods inappropriate
 Different outcome variables
Corticosteroids
 TCS - First line therapy of OLP
 Modulate inflammation and immune
response
 Stabilizes the lysosomes
 Reduces lymphocyte activity
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 /
dexamethasone
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 course
 Monitor for adverse effects
 But studies show topical corticosteroids to be
equally or more effective than systemic
corticosteroids or the combination of the two.
Intralesional CTS
 Used for localized resistant plaque
 Hydrocortisone, triamcinolone acetonide and
methylprednisolone have been tried in various
studies
 Localized side effects like pain and mucosal
atrophy.
Complications of TCS
o Secondary candidiasis – Rx with topical
antifungals(azoles)
o Adrenal insufficiency (super potent)
o Potential tachyphylaxsis
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 used
Calcineurin inhibitors
 Calcineurin inhibitors
 Cyclosporine
 Tacrolimus
 Pimecrolimus
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 India
TIMS
 1% Pimecrolimus is also effective with low systemic
side effects
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
 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 alternatives
Oral Cyclosporin
 2.5 mg/kg body weight for 6 to 8 weeks (Acute
erosive mucosal LP)
 Crisis buster
 Watch for side effects
Retinoids
 Topical and systemic drugs used
 Topical
 Isotretinoin gel 0.1% and Tretinoin oint
 Produce significant improvement
 Histological, decreased keratinization
 Transient burning/irritation
Treatment of OLP
 Topical fenretinide
 Effective with minimal side effects
 Not readily available
 Topical tazarotene
 Hyperkeratotic oral LP
Systemic retinoids
 Isotretinoin
 Acitretin
 Due to side effect profile and low remission rates,
used only as adjuvant therapy.
Steroid sparing agents
 Azathioprine
 Reported , 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 day
Treatment of OLP
 Antimalarials
 Hydroychloroquine sulfate and chloroquine
phosphate effective
 But implicated in lichenoid reaction
 Mesalazine (5-aminosalicylic acid)
 Used in the Rx of IBD
 Topical mesalazine used as an adjuvant
Treatment of OLP
 Dapsone
 In 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 lesions
Treatment of OLP
 Low molecular weight heparin
 Low 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
TNFα
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
patients
Biologicals
 Efalizumab
 Recombinant humanized monoclonal antibody
 Monoclonal Ab to CD11a
 inhibits T cell activation & trafficking in the
skin
NON-PHARMCOTHERAPY
 P-UVA
 Earlier 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 cases
LASER &PDT
 CO2 laser
 Multicentric lesion and difficult areas of oralLP
 Recurrences have been reported
 Excimer 308 nm laser
 Effective in the erosive OLP
 Even in difficult to control lesions
 Photodynamic therapy
 With methylene blue
 Case reports show 50% improvement in lesions
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
 HCV
Surgery
 Surgical excision
 Isolated non healing plaques and erosive lesions
 Suspected malignant transformation
 Free soft tissue grafts
Lifestyle modifications
 Avoid smoking alcohol
 Avoid acidic/spicy food substances
 To maintain good oral hygiene
Oral LP
Asymptomatic
Improve/control oral
hygiene. Avoid
precipitating factors,
drugs, food chemicals,
etc.
Erosive or
symptomatic
Positive for Candida
Smear for candida
No treatment
Follow up
every 6
months
Negative for Candida
Topical steroids + antifungals
Topical steroids
Satisfactory
response
Unsatisfactory
response
Systemic steroid
Maintenance
with topical
steroids
Unsatisfactory
response
Alternatives- tacrolimus, retinoids,
PUVA, ILS, steroid sparing drugs,
DAPSONE, Non-pharmacotherapy
MY SUGGESTION
 Algorithmic approach
Step 1: TCS/ Tacrolimus
in orabase
Step 2: Continue Step 1
+ Burst of Oral
Corticosteroids
Step 4: Continue Step 1 +
MMF/Retinoids/Dapsone/
Non-Pharmacotherapy
Step 3: Continue Step 1
+ Cyclosporin short
course
THANK YOU