Pathogenesis of Atopic Dermatitis: Atopic Dermatitis ... · 6/28/2010 1 Pathogenesis of Atopic...

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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’


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!)


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%)


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


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


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


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


? (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


PAR2

Th 2Inflammation

IL-α/βTSLP

PAR2 FLG pH SP PCA

↓ Barrier

Th 2Inflammation

IL-α/βTSLP

↓ LB


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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


↓ LB


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


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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


PAR2 FLG pH SP PCA

↓ Barrier

Acquired Stressors

Soaps

PAR2

Th 1 2Inflammation

IL-α/β

IL-4, 13

TSLP


PAR2 FLG pH SP PCA

↓ Barrier

Acquired Stressors

Soaps↓Humidity

PAR2

Th 1 2Inflammation

IL-α/β

IL-4, 13

TSLP


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


Corticosteroid or Immunomodulator

Genetic/ Constitutional Disease Trigger Clinical Disease

As AD Improves, Barrier Function Deteriorates


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



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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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)


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


SPINK5


? (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!

Pathogenesis of Atopic Dermatitis: Atopic Dermatitis ... · 6/28/2010 1 Pathogenesis of Atopic...

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