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Pathogenesis of Pathogenesis of Atopic Dermatitis: Atopic Dermatitis: Rationale for Barrier Repair Therapy Rationale for Barrier Repair Therapy
Peter M. Elias, M.D.Peter M. Elias, M.D.Department of Dermatology, Department of Dermatology,
UCSFUCSF
& Dermatology Service, VAMC,& Dermatology Service, VAMC,
San FranciscoSan Francisco
March 30, 31 & April 1, 2010March 30, 31 & April 1, 2010
Atopic DermatitisAtopic Dermatitis
Common diseaseCommon disease ~30% children affected~30% children affected
What about adults?What about adults?
~~5% have classic AD5% have classic AD5% have classic AD5% have classic AD
True incidence in adultsTrue incidence in adults
is much higher is much higher same genetic abnormalitysame genetic abnormality
other eczemas, severe dry other eczemas, severe dry skin, ‘sensitive skin’ skin, ‘sensitive skin’
Atopic DermatitisAtopic Dermatitis
Common diseaseCommon disease
Associated with other atopic diseasesAssociated with other atopic diseasesAssociated with other atopic diseasesAssociated with other atopic diseases Asthma, Allergic rhinitisAsthma, Allergic rhinitis
IgEIgE sensitization to food and airborne allergens sensitization to food and airborne allergens (note: (note: these antigens initiate disease after penetrating these antigens initiate disease after penetrating the skin!)the skin!)
Atopic DermatitisAtopic Dermatitis
Common diseaseCommon disease
Associated with other atopic diseasesAssociated with other atopic diseasespp MultigenicMultigenic (Some shared with asthma (T(Some shared with asthma (THH2)2)
More common in Asians (over 50%)More common in Asians (over 50%)
Atopic DermatitisAtopic Dermatitis
Incidence and severity are increasingIncidence and severity are increasing
Atopic Disease: A Modern EpidemicAtopic Disease: A Modern Epidemic
10
15
Chi
ldre
n)
1964
19892002
0
5
Asthma Allergicrhinitis
Atopicdermatitis
Pre
vale
nce
(%
Ninan TK, Russell G. BMJ. 1992;304:873-875.NIAID Website. http://www.niaid.nih.gov/factsheets/allergystat.htm.
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Why Is Prevalence Rising?Why Is Prevalence Rising?
Hygiene hypothesis (HH)Hygiene hypothesis (HH)
‘inside‘inside outside’ perspectiveoutside’ perspectiveinsideinside--outside perspectiveoutside perspective
Busse WW, et al. NEJM 2001;344:350-362
Why is Prevalence Rising?Why is Prevalence Rising?
Hygiene hypothesis (HH)Hygiene hypothesis (HH)
‘inside‘inside--outside’ perspectiveoutside’ perspective
HH= ‘outsideHH= ‘outside--inside’ perspective: inside’ perspective: Crowded urban Crowded urban environment→sustainedenvironment→sustained dust mite exposuredust mite exposure
PercutaneousPercutaneous absorption across a defective barrierabsorption across a defective barrier
Excessive hygiene damages barrierExcessive hygiene damages barrier
The Traditional View of Atopic The Traditional View of Atopic Dermatitis: “From the InsideDermatitis: “From the Inside--Out”Out”
An Immunologic DisorderAn Immunologic Disorder IgEIgE response to antigensresponse to antigens
TT 2 cytokine production2 cytokine production TTHH2 cytokine production2 cytokine production
Epidermis is a downstream participant in the Epidermis is a downstream participant in the battlefront of the immune responsebattlefront of the immune response
INSIDE
(Body)
OUTSIDE(Environment)
Skin surface
Epidermis
‘Inside-Out’ View of AD Pathogenesis
“Immune Dysregulation”
TH2 cytokines: IL4,5,13
IgE production
(Antigen)
Genetic/ Constitutional
Atopic Dermatitis: Atopic Dermatitis: ‘Outside‘Outside--Inside’ ParadigmInside’ Paradigm
VulnerableVulnerable BarrierBarrier
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Genetic + Acquired Stressors
Atopic Dermatitis: Atopic Dermatitis: ‘Outside‘Outside--Inside’ ParadigmInside’ Paradigm
Vulnerable Vulnerable Barrier Barrier + Inflammation+ Inflammation
But What Do We Mean by ‘Barrier’?
Barrier FunctionBarrier Functionss of of Stratum Stratum CorneumCorneum(Abnormal in Atopic Dermatitis)(Abnormal in Atopic Dermatitis)
Permeability barrier Permeability barrier (also excludes noxious chemicals & (also excludes noxious chemicals &
allergens) allergens) g )g ) Mechanical barrierMechanical barrier
Antimicrobial defenseAntimicrobial defense Integrity & cohesion (desquamation)Integrity & cohesion (desquamation) Antioxidant defenseAntioxidant defense Cytokine activationCytokine activation Ultraviolet light barrierUltraviolet light barrier Hydration (pliability)Hydration (pliability)
} Stratum corneum
Stratum CorneumStratum Corneum
“Normal Basket Weave” = artifact of lipid extraction during tissue processing
}
Stratum CorneumStratum Corneum
Frozen section stained with hydrophobic dye
“Normal Basket Weave” = artifact of lipid extraction during processing
Stratum Corneum StructureStratum Corneum Structure
Bricks and Mortar AnalogyBricks and Mortar Analogy Bricks = anucleate corneocytesBricks = anucleate corneocytes
Stratum Corneum StructureStratum Corneum Structure
Bricks and Mortar AnalogyBricks and Mortar Analogy
Bricks = Bricks = anucleateanucleatecorneocytescorneocytes
FFilledilled ithith ker tinker tin
aaaa
aa
aa
aa
aaFFilled illed with with keratin keratin macrofibrilsmacrofibrils
OsmoticallyOsmotically--active active small small molecules derived from molecules derived from breakdown breakdown of of filaggrinfilaggrin
aa aaaa
aaaa
aa
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Stratum Stratum CorneumCorneum StructureStructure
Bricks and Mortar AnalogyBricks and Mortar Analogy
Bricks = Bricks = anucleateanucleate corneocytescorneocytes
aaaa
aa
aa
aa
aaIL 1
IL-1,
IL-1,
Surrounded Surrounded by a highly by a highly crosscross--linked linked protein shell, the protein shell, the cornifiedcornified envelopeenvelope
aa aaaa
aaaa
aaIL-1,IL-1, IL-1,
Stratum Stratum CorneumCorneum StructureStructure
‘Bricks’ = ‘Bricks’ = corneocytescorneocytes
‘Mortar’ = extracellular ‘Mortar’ = extracellular matrixmatrix
aaaa
aa
aa
aa
aa
IL-1,
IL-1,
IL-1,
NonNon--polar lamellar polar lamellar bilayersbilayers CholesterolCholesterol
LongLong--chain Fatty Acidschain Fatty Acids
CeramidesCeramides
aa aaaa
aaaa
aaIL-1,
IL 1,IL-1,
CeramideCeramide
Cer (sphingol + fatty acid)
HN
O C16-24 (epidermis C16-34)
**
OH
HO *OH* *
*4 6
Permeability BarrierPermeability Barrier
NonNon--polar lipid bilayers fill intercellular domainpolar lipid bilayers fill intercellular domain Repeating arrays of lamellar sheetsRepeating arrays of lamellar sheets
Lipids are very hydrophobic Lipids are very hydrophobic
Requirements for a Competent Requirements for a Competent Permeability BarrierPermeability Barrier
Correct 3 Lipids (cholesterol, free fatty acids, Correct 3 Lipids (cholesterol, free fatty acids, & & ceramidesceramides))
Sufficient amounts of lipid (10% of weight of SC) Sufficient amounts of lipid (10% of weight of SC)
Correct Proportion (1:1:1 molar ratio)Correct Proportion (1:1:1 molar ratio) Correct Proportion (1:1:1 molar ratio)Correct Proportion (1:1:1 molar ratio)
Lamellar structures in intercellular domainsLamellar structures in intercellular domains
Epidermal
Corneocyte
Intercellulardomain
Extracellular Processingp
Lamellar body
Granular cell
Corneocyte
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Non-polar ProductsLipid Precursors
STRATUM GRANULOSUM SG-SC INTERFACE LOWER SC
Sphingosine
Free Fatty AcidsPhospholipids
Gl l id
↓pH
Highly cohesive &anhydrous
Catabolic Enzymes
Antimicrobial Proteins
hBD2, LL-37
CeramidesGlucosylceramide
Cholesterol
Yellow= Antimicrobial Activity
INSIDE
OUTSIDE
Epidermis
Stratum corneum
Permeability Barrier: Normal
H2O
H2OAntigenInfectionX
TEWL
40
60
n +
/-S
EM
)
Permeability Barrier in Atopic Dermatitis
Severity of barrier dysfunction
0
20
‘Uninvolved’ MildlyInvolved
SeverelyInvolved
g/cm
2hr
(m
ean
Mean TEWLin non-atopics
dysfunction parallels severity of disease
Uninvolved Skin IS Involved!
Molecular Genetics Shows That AD Is Molecular Genetics Shows That AD Is Initiated by a Defect in Barrier FunctionInitiated by a Defect in Barrier Function
Broader Implication Is That Barrier Function Broader Implication Is That Barrier Function Is Clinically Relevant!Is Clinically Relevant!
Genes HighlyGenes Highly--Associated with Atopic Associated with Atopic Dermatitis Affect the BarrierDermatitis Affect the Barrier
Loss of Loss of FilaggrinFilaggrin, a Structural Protein of the , a Structural Protein of the Stratum Stratum CorneumCorneum (AD & (AD & IchthyosisIchthyosis VulgarisVulgaris))
Excessive Serine Protease ActivityExcessive Serine Protease Activity
1) Reduced Expression of the Serine Protease 1) Reduced Expression of the Serine Protease Inhibitor, LEKTI (Netherton syndrome)Inhibitor, LEKTI (Netherton syndrome)
2) Acquired LEKTI Deficiency in AD2) Acquired LEKTI Deficiency in AD
3) KLK 5 Activation of Th2 Cytokines 3) KLK 5 Activation of Th2 Cytokines
IchthyosisIchthyosis vulgarisvulgaris
AutosomalAutosomal dominantdominant Mild to moderate Mild to moderate scalescale
Assoc. w/ Atopic dermatitisAssoc. w/ Atopic dermatitis•• >50>50%%>50>50% %
Common Common •• 1/250 school kids w/ “dry 1/250 school kids w/ “dry
skin” (preskin” (pre--genotype era)genotype era)
•• Actual incidence must be Actual incidence must be much higher (‘uninvolved’much higher (‘uninvolved’
skin of AD=IVskin of AD=IV))
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Same Same FilaggrinFilaggrin Mutations Underlie Both Mutations Underlie Both AD and AD and IchthyosisIchthyosis VulgarisVulgaris (IV)(IV)
Same lossSame loss--ofof--function mutations in function mutations in FILAGGRINFILAGGRIN
in both IV and AD in both IV and AD
In large IV In large IV kindredskindreds, if: , if: One allele affected One allele affected → Most have (mild) IV and → Most have (mild) IV and some some
have AD (later onset, mild disease)have AD (later onset, mild disease)
Both alleles affected Both alleles affected → All have → All have IV and IV and most most have AD have AD (early onset, severe)*(early onset, severe)*
**Even some doubleEven some double--allele IV do not develop ADallele IV do not develop AD——why not?why not?
Ichthyosis VulgarisIchthyosis Vulgaris
AlleleAllele--dependent dependent absence of absence of granular granular layerlayer
Decreased Decreased FF--type type keratohyalinkeratohyalin granulesgranules
How Does Loss of How Does Loss of FilaggrinFilaggrin(an (an intraintracellular protein) Provoke a Barrier cellular protein) Provoke a Barrier
Abnormality?Abnormality?
StructurallyStructurally--defective defective corneocytecorneocyte? ? (No)(No)
Decreased SC hydrationDecreased SC hydration--accentuates accentuates
barrier abnormality (Yes)barrier abnormality (Yes)
↑pH (Yes)↑pH (Yes)
FLG mutations
↓ Profilaggrin
↓ Fil i
Consequences of Filaggrin Deficiency
↓ Filaggrin
↓ Corneocyte osmolytes
↓ Corneocyte hydration“Dry Skin”
↓ Organic acids(Urocanic acid; Pyrrolidone carboxylic acid)
↑ pH
Increased Water LossContributes To Barrier
Abnormality
glutamine pyrrolidonecarboxylic acid
↓ Hydration
100 % R H
↓Permeability Barrier
argininearginine
deiminasecitrulline
FilaggrinFilaggrin ProteolyticProteolytic Pathway: How Pathway: How Deficiency Contributes to AD PathogenesisDeficiency Contributes to AD Pathogenesis
↓Antimicrobial
↓filaggrin histidinehistidase
trans-UCA
UV-B
cis-UCA (immunosuppression)
Sunscreen
100 % R.H.
↓Integrity/Cohesion↑pH
Direct Evidence for Importance Direct Evidence for Importance of pH in ADof pH in AD
M int n n f n A idi pHM int n n f n A idi pHMaintenance of an Acidic pH Maintenance of an Acidic pH Prevents Development of AD!Prevents Development of AD!
((HatanoHatano, et al, JID 2009), et al, JID 2009)
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NethertonNetherton Syndrome:Syndrome:22ndnd Genetic Link to ADGenetic Link to AD
Atopic dermatitisAtopic dermatitis
↑↑ ↑↑ IgEIgE levelslevels
Anaphylactic reactions to Anaphylactic reactions to food antigensfood antigens
Severe barrier abnormalitySevere barrier abnormality
→Fluid & Electrolyte →Fluid & Electrolyte AbnormalitiesAbnormalities
→Growth Failure→Growth Failure
NethertonNetherton syndrome:syndrome:Genetic basisGenetic basis
Mutations in Mutations in SPINK5SPINK5
Encodes LEKTI 1Encodes LEKTI 1 Encodes LEKTI 1Encodes LEKTI 1•• Serine protease inhibitorSerine protease inhibitor
•• EpidermisEpidermis Normally localizes to lamellar bodies & SC intersticesNormally localizes to lamellar bodies & SC interstices
PATHOGENESIS OF NETHERTON PATHOGENESIS OF NETHERTON SYNDROMESYNDROME
LEKTI 1
S i
SPINK5 mutation
Barrier
Lipid processing enzymes
Lamellar bilayers
↓ SCcohesion
InflammationIL-1, activated
infections↓Antimicrobial peptides (HBD2, LL37)
SCCE
Serine proteaseActivity (SCTE, SCCE)
Corneodesmosomes
SPINK5 mutations
LEKTI 1
SCTE (Klk5)
SCCE (Klk7)
Corneodesmosomes
Pathogenesis of Netherton Syndrome
Lipid processing enzymes
Lamellar bilayers
SC cohesion
Thinning of SC
Barrier Dysfunction
SPINK5 mutations
LEKTI 1
SCTE (Klk5)
SCCE (Klk7)
Corneodesmosomes LL-37 Infections
Pathogenesis of Netherton SyndromeP
Lipid processing enzymes
Lamellar bilayers
SC cohesion
Thinning of SC
Barrier Dysfunction
IL-1/ activation
Th1 Th2 Inflammation
Cytokine cascadeTSLP
NethertonNetherton Syndrome: Syndrome: PathophysiologyPathophysiology
Gene defect leads to Gene defect leads to unopposed serine protease unopposed serine protease activityactivity
How is this relevant for atopic dermatitis?How is this relevant for atopic dermatitis?
Increased serine protease activity also in ADIncreased serine protease activity also in AD
(Due to ↑ pH)(Due to ↑ pH)
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Increased Serine Protease Activity in ADIncreased Serine Protease Activity in AD
Atopic DermatitisAtopic Dermatitis
Normal Epidermis
Atopic DermatitisIchthyosis V l i
Netherton S d
pH pH
Relationship of Ichthyosis Vulgaris and Netherton Syndrome to Atopic Dermatitis
LEKTI 1
Atopic DermatitisVulgaris Syndrome
Serine protease activity
SPINK5
Serine protease activity
? (inherited)
(acquired)
pHpH--Dependence of Serine Protease ActivationDependence of Serine Protease ActivationSP Bind To and Activate PAR2, a G-Protein-Coupled
Plasma Membrane Receptor
Serine Proteases Bind To PAR2, Which Is Expressed in Outer Nucleated Epidermis
‘‘SuperbaseSuperbase’’--Induced Increase in Primary Induced Increase in Primary Cytokine Production Is Reversible by SPICytokine Production Is Reversible by SPI
HD:Elias/Powerpoint/pH Chronic
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Basis for Lipid AbnormalityBasis for Lipid Abnormalityin Atopic Dermatitis in Atopic Dermatitis
Lipids are in wrong place Lipids are in wrong place (↓Total Lipids)(↓Total Lipids)
↓ lamellar body secretion→↓ lamellar body secretion→entombed in corneocytesentombed in corneocytes
Further ↓ in Further ↓ in ceramideceramide content (3 reasons)content (3 reasons) ↑Th2 cytokines → ↓↑Th2 cytokines → ↓ceramideceramide synthesis synthesis
↑↑pH →↓ activity of pH →↓ activity of CerCer--generating generating hydrolaseshydrolases
↑ pH → SP↑ pH → SP--mediated degradation of mediated degradation of
CerCer--generating generating hydrolaseshydrolases
Abnormal Lipids in AD Lead To Abnormal Lipids in AD Lead To ↓↓ Lamellar MembranesLamellar Membranes
Normal (Intact) Membranes Restrict Allergen Penetration
Decreased & Fragmented Membranes in AD Allow Allergen Ingress
Generation of Generation of CeramidesCeramides: : Role of pHRole of pH
SG/SC Lower SC
sPLA2sPLA2 ßGlcCer’aseßGlcCer’ase
7.37.37.37.3 ~ 5.0~ 5.0~ 5.0~ 5.0pHpHpHpH
SM’aseSM’aseSS’aseSS’ase
pH Serine SC
Corneo-
InflammationCytokine
Activation
Consequences of pH in Atopic Dermatitis
Both Acquired Stressors & FLGDeficiency
-Glucocerebrosidase, Acid Sphingomyelinase
p
Permeability Barrier
ProteaseActivity
SC Cohesion
desmosomes
↓ Ceramides
↓Lamellar BodySecretion
Serine Proteases (SP) Block Lamellar Body Secretion, While SP Inhibitors Accelerate Secretion OUTSIDE
The ‘Outside-to-Inside-(Back) to-Outside’ View
Epidermis
Stratum corneum
H2O
H2O
Antigen
Antigen
H2O
H2O
INSIDE
TH2 cytokines: IL 4, 5, 13
IgE production
Histamine
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INSIDE
OUTSIDE The ‘Outside-to-Inside-to-Outside’ View
Epidermis
Stratum corneum
H2O
H2O
Antigen
AntigenInfection
Exotoxins
Superantigen
H2O
H2O
TH2 cytokines: IL 4, 5, 13
IgE production
Histamine
Distinctive Lipid Abnormality in AD Distinctive Lipid Abnormality in AD
Total quantities of SC lipid are reducedTotal quantities of SC lipid are reduced
Further ↓ in Further ↓ in ceramideceramide contentcontent↓↓
Provides the rationale for therapy with Provides the rationale for therapy with ceramideceramide--dominant mixture of the 3 key dominant mixture of the 3 key physiologic lipids physiologic lipids
Conflict of Interest StatementConflict of Interest Statement
Barrier Repair Therapy Is Subject of a Barrier Repair Therapy Is Subject of a UC Patent (Dr. Elias is an inventor)UC Patent (Dr. Elias is an inventor)
Licensed to Licensed to PromiusPharmaPromiusPharma in USin US
Basis for Lipid Abnormalities in Basis for Lipid Abnormalities in Atopic DermatitisAtopic Dermatitis
Decreased extracellular lipids:Decreased extracellular lipids:
Lipids are in wrong place due to SP → PAR2Lipids are in wrong place due to SP → PAR2 entombed in corneocytesentombed in corneocytes
↓delivery to extracellular domains↓delivery to extracellular domains
↓ ↓ CeramideCeramide content content ↑Th2 cytokines → ↓↑Th2 cytokines → ↓ceramideceramide synthesis (Oita group)synthesis (Oita group)
↑↑pH →↓ activity of pH →↓ activity of CerCer--generating acid generating acid hydrolaseshydrolases
Sustained ↑ pH → Sustained ↑ pH → proteolyticproteolytic degradation ofdegradation of
CerCer--generating generating hydrolaseshydrolases
Sustained ↑ pH Eventually Destroys Ceramide-Generating Enzymes
De-Activation and Degradation of Lipid Processing Enzymes Results in ↓ & Immature Lamellar Bilayers
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Atopic Dermatitis: New Atopic Dermatitis: New ‘Outside‘Outside--Inside’ ParadigmInside’ Paradigm
Acquired Triggers : ↑pH soaps, ↓ambient humidity ↑ϕ stress
Inherited + Acquired
Vulnerable BarrierVulnerable Barrier
↓ambient humidity, ↑ϕ stress
Inherited Defects Alone May Produce Only IV: Acquired Insults, Which Further Degrade Barrier,
May Also Be Required
FLG pH SP PCAPAR2
LB secretion
FLG pH SP PCA
LB secretion
FLG pH SP PCAPAR2
↓ Barrier
FLG pH SP PCA
↓ LB↓ Barrier FLG pH SP PCA
PAR2
↓ Barrier
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FLG pH SP PCA
↓ LB↓ Barrier
PAR2
Th 1 Inflammation
IL-α/β
PAR2 FLG pH SP PCA
↓ Barrier
Th 1 Inflammation
IL-α/β→cytokine cascade
↓ LB
FLG pH SP PCA↓ Barrier
Th 1 2Inflammation
IL-α/βTSLP + allergens
↓ LB
FLG pH SP PCA↓ Barrier
PAR2
Th 2Inflammation
IL-α/βTSLP
PAR2 FLG pH SP PCA
↓ Barrier
Th 2Inflammation
IL-α/βTSLP
↓ LB
FLG pH SP PCA↓ Barrier
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PAR2
Th 1 2Inflammation
IL-α/β
IL-4, 13
TSLP
PAR2 FLG pH SP PCA
↓ BarrierPAR2
Th 1 2Inflammation
IL-α/β
IL-4, 13
TSLP
IL-4, 13↓ Ceramide
PAR2 FLG pH SP PCA
↓ Barrier
Th 2Inflammation
IL-α/β
IL-4, 13
TSLP
IL-4, 13↓ Ceramide
↓ LB
FLG pH SP PCA↓ Barrier
PAR2
Th 1 2Inflammation
IL-α/β
IL-4, 13
TSLP
IL-4, 13 ↓DSG →↓cohesion
PAR2 FLG pH SP PCA
↓ Barrier
PAR2
Th 1 2Inflammation
IL-α/β
IL-4, 13
TSLP
IL-4, 13↓ hBD2, LL-37
PAR2 FLG pH SP PCA
↓ Barrier
Th 2Inflammation
IL-α/β
IL-4, 13
TSLP
IL-4, 13↓ hBD2, LL-37
↓ LB
FLG pH SP PCA↓ Barrier
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Th 1 2Inflammation
IL-α/β
IL-4, 13
↓ ceramideIL-4, 13
↓ ceramide
TSLP
PAR2
↓ LB secretion FLG pH SP PCA ↓ Barrier
Pruritus
PAR2
Consequences for Barrier of Consequences for Barrier of Th2 InflammationTh2 Inflammation
↓ ↓ FilaggrinFilaggrin → ↑ pH (and defective → ↑ pH (and defective corneocytescorneocytes))
↓ ↓ CeramidesCeramides
↓ ↓ DesmogleinDesmoglein → ↓ SC Cohesion→ ↓ SC Cohesion
↓ Antimicrobial peptides↓ Antimicrobial peptides
PAR2
Th 1 2Inflammation
IL-α/β
IL-4, 13
TSLP
IL-4, 13↓ Ceramide
PAR2 FLG pH SP PCA
↓ Barrier
Acquired Stressors
Soaps
PAR2
Th 1 2Inflammation
IL-α/β
IL-4, 13
TSLP
IL-4, 13↓ Ceramide
PAR2 FLG pH SP PCA
↓ Barrier
Acquired Stressors
Soaps↓Humidity
PAR2
Th 1 2Inflammation
IL-α/β
IL-4, 13
TSLP
IL-4, 13↓ Ceramide
PAR2 FLG pH SP PCA
↓ Barrier
Acquired Stressors
Soaps↓Humidity
Psychological Stress
↑GC
Th 2Inflammation
IL-α/β
IL-4, 13
↓ ceramideIL-4, 13
↓ ceramide
TSLP
↓ LB secretion FLG pH SP PCA ↓ Barrier
Pruritus
PAR2 Scratch→excoriations
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Genetic/ Constitutional
Current Therapy Is Directed at Inflammatory Infiltrate
Disease Trigger Clinical Disease
Vulnerable Barrier Defective Barrier Inflammation
Genetic/ Constitutional Disease Trigger Clinical Disease
Current Therapy Is Directedat Inflammatory Infiltrate
Vulnerable Barrier Defective Barrier Inflammation
Corticosteroid or Immunomodulator
Genetic/ Constitutional Disease Trigger Clinical Disease
As AD Improves, Barrier Function Deteriorates
Vulnerable Barrier Defective Barrier Inflammation
Corticosteroid or Immunomodulator
Likely Explanation for Rebound Flares & Tachyphylaxis
Concerns about Concerns about ImmunomodulatorsImmunomodulators
••Increased Infections esp EczemaIncreased Infections esp Eczema HerpeticumHerpeticumIncreased Infections, esp. Eczema Increased Infections, esp. Eczema HerpeticumHerpeticum
••PhotocarcinogenicityPhotocarcinogenicity
••Other TumorsOther Tumors
Topical Immunomodulators Carcinogenic?
Tacrolimus and pimecrolimus are immunosuppressants
Both show blood levels after topical administration, which can be as high as in organ transplant patientsg g p p
Topical pimecrolimus and tacrolimus enter the lymphatic system (don’t need blood levels)
Lymphoma signal evident in mouse carcinogenicity studies
10
Tacrolimus Blood Levels Following Application of 0.1% Ointment
Adults (n=32)■ Peds (n=20)
2
4
6
8
Days0 5 10 15
Max
Ob
serv
ed C
(n
g/m
l)
■
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Blood Levels after 0.03% Tacrolimus Ointment in Children
12
1
6
(ng/
ml)
■
Days0 5 10 15
4
8
Max
Ob
serv
ed C
(
■■
Cutaneous Tumors with Topical Pimecrolimus(reported to FDA as of 2006)
Tumor type # cases
Lymphomas 14
Squamous cell CA 5
Basal Cell CA 1
Paget disease (breast CA) 1
Melanoma, metastatic 1
Other tumors 8
New Awareness of Importance of Barrier Function
New opportunities for dermatologic therapy: New opportunities for dermatologic therapy: pp g pypp g pyTreat inflammatory skin diseases by correcting Treat inflammatory skin diseases by correcting (primary) abnormalities in epidermal structure (primary) abnormalities in epidermal structure and functionand function
Approaches to Treat AD By Fixing the Barrier
Educate (soaps, hydration, ↓Educate (soaps, hydration, ↓ϕϕstress)stress) Hydrate (emollients→↓ steroid usage)Hydrate (emollients→↓ steroid usage) ↓Staph carriage ↓Staph carriage ↓ p g↓ p g Break ItchBreak Itch--Scratch cycle Scratch cycle (antihistamines(antihistamines--also good for the also good for the
barrier!)barrier!) Topical barrier repair (optimal ratio of Cer, FFA, Chol) Lower SC pH Serine protease inhibitors PAR2 inhibitors
Percent Changes in Mean SCORAD Scores – EpiCeram Vs. Fluticasone in Moderate-to-Severe AD:
Both products rapidly improved SCORAD scores. Cutivate rate of improvement was significantly better at 2 weeks, with both products equivalent at 4 weeks.
60%
70%
**
0%
10%
20%
30%
40%
50%
Baseline Day 14 Day 28
Fluticasone(n=62)Epiceram(n=59)
(n=113)
* p<0.01** NS
*
Barrier Repair TherapyBarrier Repair Therapy
Standard emollientsStandard emollientsAquaphorAquaphor®®, Eucerin, Eucerin®®, etc., etc.
NonNon--physiologic lipidsphysiologic lipidsNonNon physiologic lipidsphysiologic lipidsPetroleum based, lanolin, etc.Petroleum based, lanolin, etc.
Remain on skin surfaceRemain on skin surface Temporary Temporary ↓ TEWL↓ TEWL
Not incorporated into SC lamellar membranesNot incorporated into SC lamellar membranes
Do not correct underlying barrier defectDo not correct underlying barrier defect
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Corrective Barrier Corrective Barrier Repair TherapyRepair Therapy
Physiologic lipidPhysiologic lipid--based formulationsbased formulations CeramidesCeramides, FFA, cholesterol , FFA, cholesterol
Incorporated Incorporated into into lamellar lamellar bodies →secreted bodies →secreted
R i b i ONLY if t i t l tiR i b i ONLY if t i t l ti Repair barrier ONLY if present in correct molar ratiosRepair barrier ONLY if present in correct molar ratios e..g., e..g., ceramidesceramides alone will make barrier worse!alone will make barrier worse!
PHYSIOLOGIC LIPIDS TRAVERSE THE SC PHYSIOLOGIC LIPIDS TRAVERSE THE SC & ENTER THE NUCLEATED LAYERS& ENTER THE NUCLEATED LAYERS
Physiologic Lipids
Therapy That Corrects the Barrier Therapy That Corrects the Barrier Abnormality Is AntiAbnormality Is Anti--Inflammatory Inflammatory
By Which Mechanisms?By Which Mechanisms?
AntiAnti--inflammatory Mechanismsinflammatory Mechanismsof Barrierof Barrier--Corrective Therapy in ADCorrective Therapy in AD
Normalizing Barrier→↓ Cytokine CascadeNormalizing Barrier→↓ Cytokine Cascade
Prevents Allergen/Prevents Allergen/HaptenHapten IngressIngress
↑ Permeability Barrier →↑ Antimicrobial Defense↑ Permeability Barrier →↑ Antimicrobial Defense
Certain Free Fatty Acids Are AntiCertain Free Fatty Acids Are Anti--inflammatoryinflammatory
Normalizing pH→↓ Serine Protease Activity Normalizing pH→↓ Serine Protease Activity
(↓ Th2 inflammation; ↓ IL(↓ Th2 inflammation; ↓ IL--1 activation; ↓ PAR21 activation; ↓ PAR2--mediated mediated prurituspruritus))
Lamellar BodySecretion
Inhibitory Ions
Lipid and AMP
Barrier Perturbation
Cytokines/Growth Factors
DNA Synthesis
STRATUM CORNEUM
‘OUTSIDE-INSIDE’ PATHOGENESIS OF AD:
Barrier Abnormality Stimulates a Cytokine Cascade
IL-1, TNF, AR, NGEFVEGFSecretion
DERMIS
EPIDERMIS
Epidermal Hyperplasia
Inflammation
Fibroplasia, Endothelial Hyperplasia
Permeability & AntimicrobialBarrier Restoration Chemokines
AR = amphiregulin; NGF = nerve growth factor; AMP= antimicrobial peptide
Barrier Repair TherapyBarrier Repair Therapy
Physiologic lipidPhysiologic lipid--based formulationsbased formulations CeramidesCeramides, FFA, cholesterol , FFA, cholesterol
Incorporated into SC lamellar membranes Incorporated into SC lamellar membranes
Repair barrier ONLY if present in correct molar ratiosRepair barrier ONLY if present in correct molar ratiosRepair barrier ONLY if present in correct molar ratiosRepair barrier ONLY if present in correct molar ratios
CAVEATSCAVEATS ““ceramidesceramides”, “barrier repair” functioning as “Buzz words””, “barrier repair” functioning as “Buzz words”
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Barrier Repair TherapyBarrier Repair Therapy
Physiologic lipidPhysiologic lipid--based formulationsbased formulations CeramidesCeramides, FFA, cholesterol , FFA, cholesterol
Incorporated into SC lamellar membranes Incorporated into SC lamellar membranes
R i b i ONLY if i l iR i b i ONLY if i l i Repair barrier ONLY if present in correct molar ratiosRepair barrier ONLY if present in correct molar ratios
Remain SkepticalRemain Skeptical ““ceramidesceramides”, “barrier repair” ”, “barrier repair” have become ‘buzz have become ‘buzz
words’words’
Several new products here and on the waySeveral new products here and on the way Approved as “medical devices”Approved as “medical devices”
Often little data on Often little data on efficacy (don’t have correct lipids or efficacy (don’t have correct lipids or ratios)ratios)
Barrier Repair TherapyBarrier Repair Therapy
Physiologic lipidPhysiologic lipid--based formulationsbased formulations Ceramides, FFA, cholesterolCeramides, FFA, cholesterol
Incorporated into SC lamellar membranesIncorporated into SC lamellar membranes
Repair barrier ONLY if present in correct molar ratiosRepair barrier ONLY if present in correct molar ratios
CAVEATSCAVEATS Many “barrier repair” formulations on marketMany “barrier repair” formulations on market
Often little data to support claim Often little data to support claim “ceramides”, “barrier repair” functioning as “Buzz words”“ceramides”, “barrier repair” functioning as “Buzz words”
EpiCeramEpiCeram emulsion®emulsion® Physiologic lipid based formulationsPhysiologic lipid based formulations “Optimal” molar ratio of 3 key lipidsDeveloped at UCSF (Elias & Feingold labs)
EpiCeramEpiCeram® emulsion® emulsion→→High content of physiologic lipids (5 1%)→→High content of physiologic lipids (5.1%)→Ceramide-dominant→↓ pH→Slow-release delivery system (nanospheres)→Certain lipids (PPAR activators ) add
potency & prevent side effects of GC
40%
50%
60%
70%
Cutivate®
*
% Changes in Mean SCORAD Score
(Sugarman & Parish, J Drugs Dermatol, Dec., 2009)
0%
10%
20%
30%
Baseline % Change fromBaseline to Day
14
% Change fromBaseline to Day
28
Epiceram™
* Difference is not statistically significant.
Efficacy of EpiCeram in Comparison To Efficacy of EpiCeram in Comparison To MidMid--Strength Steroid Strength Steroid –– ModerateModerate--toto--Severe Childhood Severe Childhood
ADAD
Comparable Comparable ↓↓ SCORAD scoresSCORAD scores Comparable Comparable ↓ ↓ Reduction of ItchReduction of Itch
C blC bl I i Sl H biI i Sl H bi Comparable Comparable Improvement in Sleep HabitsImprovement in Sleep Habits Comparable Comparable % Patients % Patients ““Clear or Almost ClearClear or Almost Clear”” by by
Physicians’ Global Assessment Physicians’ Global Assessment Comparable % Patients with Comparable % Patients with >75% Reduction in >75% Reduction in
SCORAD scoresSCORAD scores
SugarmanSugarman & Parrish, J. Drugs & Parrish, J. Drugs DermatolDermatol 20092009
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EPIC studyEPIC study
bbOpen Label, 37 CentersOpen Label, 37 Centers
Over 250 patients enrolled to dateOver 250 patients enrolled to date
Ages 2 months to 86 yearsAges 2 months to 86 years
The “Atopic March”
Barnetson & Rogers, BMJ 2002, 324:1376-9
0 5 10 15Age (years)
Can Barrier Repair Strategies Prevent Progression of the Atopic March?
Bottom Line:Bottom Line:BARRIER FUNCTION IS BARRIER FUNCTION IS
CLINICALLY RELEVANT!CLINICALLY RELEVANT!CLINICALLY RELEVANT!CLINICALLY RELEVANT!
End Domination of Immuno-Centric Ideation
“Basta’ (= enough already) to ‘Hand-Me-Down’ Therapies from Other Medical Specialties
Over-Arching Theme: (Re)Capturing Respect for Dermatology
p
Identify Organ (Skin)-Specific Therapies
Reorganize & Reshape Cosmeceuticals as Pharmaceuticals (and validate accordingly)
Possible End-Result: Regain our self-respect & recapture portions of specialty lost to other medical and surgical subspecialties
Effects of Anti-InflammatoriesDiffer in Diseased vs. Normal Skin
Diseased skin: initially improve barrier function by : initially improve barrier function by decreasing inflammationdecreasing inflammation
Treated skin: As inflammation resolves, negative s inflammation resolves, negative effects on barrier function become evidenteffects on barrier function become evident
Atopic DermatitisIchthyosis V l i
Netherton S d
pH pH
Relationship of Ichthyosis Vulgaris and Netherton Syndrome to Atopic Dermatitis
LEKTI 1
Atopic DermatitisVulgaris Syndrome
Serine protease activity
SPINK5
Serine protease activity
? (inherited)
(acquired)
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EpiCeram Usage In the Treatment of Atopic Dermatitis (AD)
EpiCeram BID (Affected Area)
+/-
Steroid or TIM
EpiCeram BID (Affected Area)
+
Steroid / TIM
Mild-to- Moderate Moderate –to-Severe
EpiCeram QD to Affected Areas
and
Emollient to Unaffected Areas
Remission Remission
EpiCeram QD to Affected Areas
+/-
Emollient to Unaffected Areas
2 wks 2 wks
EpiCeram Usage In the Treatment of Atopic Dermatitis (AD)Additional Suggestions
- EpiCeram should be applied prior to a steroid or TIM
- Suggested use is EpiCeram + steroid/TIM in the mornings (after bathing) & evenings
- Emollient should not overlap areas of EpiCeramapplication
Dept of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Arch Dermatol 146: May 2010
Department of Veterans Affairs Medical CenterDepartment of Veterans Affairs Medical CenterSan Francisco, CaliforniaSan Francisco, California
Thank you for your attention!Thank you for your attention!