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

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6/28/2010 1 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, UCSF UCSF & Dermatology Service, VAMC, & Dermatology Service, VAMC, San Francisco San Francisco March 30, 31 & April 1, 2010 March 30, 31 & April 1, 2010 Atopic Dermatitis Atopic Dermatitis Common disease Common disease ~30% children affected ~30% children affected What about adults? What about adults? ~5% have classic AD 5% have classic AD 5% have classic AD 5% have classic AD True incidence in adults True incidence in adults is much higher is much higher same genetic abnormality same genetic abnormality other eczemas, severe dry other eczemas, severe dry skin, ‘sensitive skin’ skin, ‘sensitive skin’ Atopic Dermatitis Atopic Dermatitis Common disease Common disease Associated with other atopic diseases Associated with other atopic diseases Associated with other atopic diseases Associated with other atopic diseases Asthma, Allergic rhinitis Asthma, Allergic rhinitis IgE IgE 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 Dermatitis Atopic Dermatitis Common disease Common disease Associated with other atopic diseases Associated with other atopic diseases Multigenic Multigenic (Some shared with asthma (T (Some shared with asthma (T H 2) 2) More common in Asians (over 50%) More common in Asians (over 50%) Atopic Dermatitis Atopic Dermatitis Incidence and severity are increasing Incidence and severity are increasing Atopic Disease: A Modern Epidemic Atopic Disease: A Modern Epidemic 10 15 Children) 1964 1989 2002 0 5 Asthma Allergic rhinitis Atopic dermatitis Prevalence (% Ninan TK, Russell G. BMJ. 1992;304:873-875. NIAID Website. http://www.niaid.nih.gov/factsheets/allergystat.htm.
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Transcript of Pathogenesis of Atopic Dermatitis: Atopic Dermatitis ... · 6/28/2010 1 Pathogenesis of Atopic...

  • 6/28/2010

    1

    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 FranciscoMarch 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)

    196419892002

    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 = anucleateanucleate

    corneocytescorneocytes

    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

    matrixmatrixaa

    aaaa

    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 +/

    -SEM

    )

    Permeability Barrier in Atopic Dermatitis

    Severity of barrier dysfunction

    0

    20

    ‘Uninvolved’ MildlyInvolved

    SeverelyInvolved

    g/cm

    2hr

    (mea

    n

    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 AD3) 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 FILAGGRINFILAGGRINin 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 PCA

    PAR2

    ↓ Barrier

    FLG pH SP PCA↓ LB

    ↓ Barrier FLG pH SP PCA

    PAR2

    ↓ Barrier

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    FLG pH SP PCA↓ LB

    ↓ BarrierPAR2

    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 ↓ Barrier

    PAR2

    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 ↓ BarrierPAR2

    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

  • 6/28/2010

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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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    16

    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

  • 6/28/2010

    17

    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”

  • 6/28/2010

    18

    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

  • 6/28/2010

    19

    EPIC studyEPIC study

    bbOpen Label, 37 CentersOpen Label, 37 CentersOver 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)

  • 6/28/2010

    20

    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!