Atopicdermatitisworkinprogress 151031110952 Lva1 App6891

Atopic dermatitis:
work in progress
Suda Sibunruang, M.D.
Outline
Pathogenesis
Phenotypes
Approach and management
Treatment
Prevention
Outline
Pathogenesis
Phenotypes
Treatment
Prevention
Two alternate hypotheses

Outside - in
Inside - out
Thyssen JP. and Kezic S. J Allergy Clin Immunol 2014;134:792-9

Figure courtesy of Boyd Jacobson, National Jewish Health, Denver, Colorado
Atopic dermatitis
Disrupted epidermal terminal
differentiation
- Reduced lipids
Abnormal skin barrier
Epicutaneous absorption of
environmental allergens
Systemic sensitization
Deficiency of structural proteins

ceramides
Development of food allergy

and asthma
Leung D. and Guttman-Yassky E. J Allergy Clin Immunol 2014;134:769-79

Benedetto AD. et. al. J Allergy Clin Immunol 2011;127:773-86
Outside - in
Inside - out
Cytokine-driven disease
Back to
outside
Outside
to inside

Complex dialog between immune dysregulation &

epidermal barrier defect
Complex causes of epithelial skin barrier dysfunction
Genetic
Environment
Abnormal
skin barrier
Allergens Diet
Irritant
Stress
Microbes
Onset
Heterogeneity
Severity
Natural history
Immunologic
factors
Innate & adaptive immune response
Mutation in filaggrin (FLG)
- Strongest known risk factor for atopic dermatitis (AD) in Northern European and Asian
- Associated with early onset, severe course, more persistent, and often associated with
asthma, food allergy, and microbial infection
Irvine AD. et. al. N Engl J Med 2011;365:1315-27
Keratin filaments
Filagrin; filament-aggregating protein

Boguniewicz M. and Leung D. Immunol Rev. 2011;242:23346
Major component of NMF
Trans-urocanic acid
Absorb UVB
Activates serine proteases
(kallikreins)
Higher incidence of nonmelanoma skin cancers

in patients with AD
Elias PM. and Wakefield JS. J Allergy Clin Immunol 2014;134:781-91
Human -defensin 2
Carboxyterminal cathelicidin peptide LL-37
Hold corneocytes together;

their degradation leads to desquamation
Irvine AD. et. al. N Engl J Med 2011;365:1315-27
Filaggrin (FLG) mutations

Multiple FLG mutations have been identified,
with loss-of-function (null) mutations being
the most abundant
FLG mutations are found in 10-50% of AD but
also in 9% of non-AD population
Reductions in filaggrin expression are
pronounced in nearly almost patients with AD
Czarnowicki T. et. al. J Allergy Clin Immunol Pract 2014;2:371-9
Leung D. Allergology International 2013;62:151-61

Skin barrier dysfunction: Beyond filaggrin gene

Double mutation
Animal model of AD with
spontaneous eczema under
pathogen-free conditions
It was originally thought that filaggrin deficiency

in flaky tail mice explained propensity of
these mice to have AD
Sasaki T. et. al. Nihon Rinsho Meneki Gakkai Kaishi 2014;37:160-5
Loss-of function mutation in

transmembrane protein 79
Tmem79/matt gene
Impaired barrier function but

no spontaneous eczema
Sasaki T. et. al. Nihon Rinsho Meneki Gakkai Kaishi 2014;37:160-5
Double-mutant (DM)
- stubbed tail
- shortened
ear pinnae
Cutaneous inflammation
Saunders SP. et. al. J Allergy Clin Immunol 2013;132:1121-9
Encodes lamellar granules that are required for

processing of filaggrin, lipids, proteases, and
antimicrobial peptides (AMPs)
Sasaki T. et. al. J Allergy Clin Immunol 2013;132:1111-20

Skin barrier dysfunction: beyond filaggrin

Variants in other genes that encode a cluster of
proteins in epidermal differentiation complex
(EDC) located on chromosome 1q21
Filaggrin 2
Hornerin
SPRR3 (cornified envelope precursor)
SPINK5 (serine protease inhibitor Kazal type 5)
However, biologic function of EDC gene variants
as it relates to AD is not well understood
AD
NA
Benedetto AD. et. al. J Allergy Clin Immunol 2011;127:773-86
Skin barrier dysfunction

Abnormalities in terminal differentiation
of epidermal epithelium leading to
defective stratum corneum
Arguments (1)
FLG mutation is absent in most patients with AD
Majority of children with AD outgrow their
disease, even in presence of an FLG mutation
Unlike ichthyosis vulgaris, in which entire skin is
affected at birth, in same genetic background
patients with AD with FLG mutations have both
lesional and nonlesional skin and disease
develops at some later time point and does not
start at birth
Arguments (2)
Both lesional and nonlesional AD skin exhibit a
broad range of differentiation abnormalities
beyond filaggrin (eg, loricrin, involucrin,
corneodesmosin, and claudins), suggesting
reactive epidermal differentiation/cornification
alterations
Treatment of keratinocytes with IL-4, IL-13, IL-22,
IL-25, and IL-31 directly downregulates filaggrin
expression and increases kallikrein function,
which can directly cause barrier dysfunction
Arguments (3)
Mice that are genetically engineered to
overexpress TH2 cytokines in their skin
spontaneously have AD and in vivo skin barrier
defects
Filaggrin expression is restored by using antiinflammatory regimens with either topical
calcineurin inhibitors or topical corticosteroids
Resolution of AD in patients with moderate-tosevere disease with broad-based
immunosuppressive therapies, which is coupled
with resolution of abnormal epidermal responses
Boguniewicz M. and Leung D. Middletons Allergy Principle and Practice. 8th edition, 2014
TSLP
Nonlesional AD skin lesions

contain immune infiltrates
Produce cytokines, such as IL-4 and IL-13

Defective epidermal barrier
Barrier defects lead to penetration by
epicutaneous allergens
Activated Langerhans cells
and dermal DCs
Migrate to lymph nodes
Colonizing pathogens
Thymic stromal
lymphopoietin
Impair function of tight junctions
Decrease production
prime naive T cells into Th2 cells

TWEAK:TNF-like weak
inducer of apoptosis
W. Peng and N. Novak. Clin Exp Allergy 2015;45:566-74
Release inflammatory mediators and

chemokines to attract immune cells
Th2 type responses contribute mainly
Keratinocytes & APC express PRRs
Stimulation of TLRs
Release of AMPs &
Enhanced strength of tight junctions
to limit penetration of allergens
and microbes
Patients with AD have reduced
TLR function

Kuo et. al. J Allergy Clin Immunol 2013;131:266-78
Innate Lymphoid Cells: ILCs
ILCs have been observed to infiltrate AD skin and

release Th2 type cytokines IL-5, -9, -13 to promote
local inflammation after stimulation
with allergen, TSLP or IL-33
Some forms of AD are primarily driven by polarized

immune pathways that downregulate keratinocyte terminal
differentiation, thereby creating a secondary skin barrier defect
Identification of immune pathway polarity will be

of particular importance as biologic agents become
more readily available
Noda S. et. al. J Allergy Clin Immunol 2015;135:324-36

Increased expression of tissue receptors

for S. aureus, which leads to colonization
from keratinocytes
Degrade skin barrier
Commensal bacteria also produce AMPs

capable of controlling S.aureus growth
Williams MR. and Gallo RL. Curr Allergy Asthma Rep 2015:15;65
Kobayashi T. et. al. Immunity 2015;42:756-66
Atopic skin is predisposed to colonization or infection

by pathogenic microbes
Staphylococcus aureus
Weidinger S. and Novak N. Lancet 2015 [Epub ahead of print]

Temporal shifts in the skin microbiome associated

with disease flares and treatment in children
with atopic dermatitis
A skin microbiome study of AD disease states (baseline , disease flare, and
post-treatment) in 12 pediatric patients with moderate-to-severe AD and
11 healthy controls using 16S ribosomal RNA bacterial gene sequencing performed
on DNA obtained directly from serial skin sampling of children with AD
Kong HH. et. al. Genome Res 2012;22:850-9
Proportion of Staphylococcus sequences, particularly S. aureus,

was greater during disease flares than at baseline or post-treatment,
and correlated with worsened disease severity
Kong HH. et. al. Genome Res 2012;22:850-9
Eczema herpeticum; herpes simplex virus

Eczema herpeticum is extremely rare and herpes simplex virus

exposure is very common, it is likely that additional immunologic
and genetic factors contribute to AD with eczema herpeticum (ADEH+)
PBMCs from patients with ADEH+ stimulated with HSV1 were deficient in their antiviral immune
response involving interferon regulatory factor 3 and 7 innate immune pathways.
This likely contributes to reduced interferon response in ADEH+ that predisposes to
increased susceptibility to disseminated viral infection
Bin L, et. al. J Allergy Clin Immunol 2014;134:848-55
Eczema vaccinatum; smallpox virus

For AD patients, even with quiescent
disease, smallpox vaccination or contact
with persons vaccinated with smallpox
can result in potentially fatal complication
of eczema vaccinatum from
dissemination and poor immune control
of virus
Lyons JJ. et. al. Immunol Allergy Clin N Am 2015;35:16183

A 28-month-old child with refractory AD

developed eczema vaccinatum after
exposure to his father, a member of
US military who had recently received
smallpox vaccine
Nonvariola orthopoxvirus was detected

in vesicular scrapings and viral culture
supernatant, confirmed by vaccinia
virusspecific PCR
Treatment included vaccinia immune
globulin
Vora S, et. al. Clin Infect Dis 2008;46:155561
Eczema coxsackium; Coxsackie A6 virus

Coxsackievirus A6 (CVA6) was identified as an important cause of
severe hand, foot, and mouth disease
Mathes EF, et. al. Pediatrics 2013;132:14957
Outline
Pathogenesis
Phenotypes
Treatment
Prevention
Time has come to distinguish various

AD phenotypes and endotypes
Bieber T. Allergy 2012;67:1475-82
These phenotypes often have overlapping features but

contain dominant characteristics that distinguish them from each other
Adult-onset AD has also been increasingly reported

Obj: classify different courses of AD and to correlate these with specific risk factors
Methods: clinical examination and retrospective evaluation of history of AD were

performed in 725 adolescent and adult patients (aged 12-89 yrs).
Total and specific IgE were evaluated
Garmhausen D. et. al. Allergy 2013;68:498506
x
x
x
x
Patients with an early onset and chronic

persisting course develop highest level of
total IgE and high frequency of
allergen-specific IgE
Non-allergic variant of AD is most
frequent in patients with onset of AD
after age of 20 years
Broad heterogeneity of AD in adolescence and adulthood

Need for careful stratification of patients with AD in
clinical practice as a first approach to individualized therapy
Boguniewicz M. and Leung D. Immunol Rev. 2011;242:23346
The Asian atopic dermatitis phenotype combines features

of atopic dermatitis and psoriasis with
increased TH17 polarization
European American (EA)
Noda S. et. al. J Allergy Clin Immunol 2015 (article in press)
Methods: performed genomic profiling (RT PCR) & immunohistochemistry on lesional & nonlesional skin biopsy from 52 patients with
AD (25 EAs and 27 Asians), 10 patients with psoriasis (all EAs), and 27 healthy subjects (12 EAs and 15 Asians)
Greater acanthosis, higher Ki67 counts, and frequent parakeratosis in Asian patients
Disease severity/SCORAD scores were similar between AD groups
TH2 skewing characterized both Asian & EA patients with AD

but not patients with psoriasis
Lower TH1/interferon (CXCL9, CXCL10, MX1, and IFNG)

in nonlesional skin in Asian patients
Significantly higher TH17 and TH22 (IL17A, IL19, and S100A12

in lesional and IL-22 in nonlesional skin in Asian patients
In the future, AD might be stratified by genotype

and biomarkers
Bieber T. et. al. Allergy 2012; 67:96975
Outline
Pathogenesis
Phenotypes
Treatment
Prevention
Weidinger S. and Novak N.Lancet 2015 [Epub ahead of print]
Cutaneous T cell lymphomas represent a heterogeneous group of

non-Hodgkin lymphomas, with mycosis fungoides and Sezary syndrome
being most common subtypes
Mycosis fungoides
Szary syndrome
Li JY. et. al. Cancer Management and Research 2012:4;7589
Comprehensive treatment plan with

extensive education are needed
Lyons JJ. et. al. Immunol Allergy Clin N Am 2015;35:16183
IMPORTANCE: AD is treated by dermatologists, allergists, pediatricians, and primary physicians.

Several guidelines and parameters exist. Health care professionals may be unaware of guidelines
created by specialty organizations other than their own
OBJECTIVE: To review, compare, and contrast most recent AD management guidelines;
American Academy of Dermatology 2014 work group
2012 Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma &
Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council
of Allergy, Asthma & Immunology
2012 European Task Force on Atopic Dermatitis
2013 AsiaPacific Consensus Group for Atopic Dermatitis
Mohan GC. and Lio PA. JAMA Dermatol 2015;151:1009-13

Lio PA. et. al. J Allergy Clin Immunol Pract 2014;2:361-9
Differences in subtypes of patients seen by the groups, with a

bias of those with allergic triggers being seen by allergists and those
with more intrinsic ADbeing seen preferentially by dermatologists,
could also help explain these different emphases.
Outline
Pathogenesis
Phenotypes
Treatment
Prevention
Principles of treatment
Maintenance of skin barrier integrity

Control of skin inflammation
Nutrition
Identification and management of
allergenic and microbial triggers
Stepwise approach
Leung D. Allergology International 2013;62:151-61
From Reactive to Proactive therapy
Long-term, low-dose intermittent applications of

anti-inflammatory topical treatments to previously
affected skin, combined with a daily application of
emollients to entire skin surface
Weidinger S. and Novak N.Lancet 2015 [Epub ahead of print]
Unclear mechanism, but UV light,

is a treatment for severe AD
Hypothesized that at least part of
benefit of UV light exposure was
due to improved vitamin D status
Picture from www.freehdw.com, access October 2015
Randomized trial of vitamin D supplementation for

winter-related atopic dermatitis in children
Design: Randomized, double-blind, placebo controlled trial
of 107 Mongolian children with winter-related AD
Methods: Subjects were enrolled in Ulaanbaatar during winter and
randomly assigned to oral cholecalciferol (vitamin D3 1000 IU/day) versus placebo
for 1 month. All children and parents received emollient and patient education
Outcomes : EASI score and Investigators Global Assessment (IGA)
Camargo CA Jr, et. al. J Allergy Clin Immunol 2014;134:831-5
Access from www.google.com/patents , October 2015
Randomized trial of vitamin D supplementation for

winter-related atopic dermatitis in children
Compared with placebo, vitamin D supplementation produced a clinically and

statistically significant improvement in EASI score (adjusted mean
change:-6.5 vs -3.3, respectively; P=.04)
Change in IGA favored vitamin D over placebo (P=.03)
Greatest benefits are likely in populations who have extremely low vitamin D levels,
such as persons living in upper latitudes during winter or
darkly pigmented persons
Camargo CA Jr, et. al. J Allergy Clin Immunol 2014;134:831-5
Biological agents for AD
PDE4 plays an important role in degrading cyclic AMP.

Thus inhibition of PDE4 leads to a persistent
increase in cyclic AMP levels and subsequently reduces T cell
receptormediated T-cell activation and cytokine production
Noda S. et. al. J Allergy Clin Immunol 2015;135:324-36
We screened > 1000 compounds in

bioactive chemical library to find candidates
that promote FLG mRNA expression using
human immortalized keratinocyte
cell line HaCaT
JTC801 is a 4-aminoquinoline derivative,
which is considered a nonpeptidergic ORL1 receptor
antagonist
(ORL1 receptor is a G proteincoupled receptor)
It remains unclear how JTC801 regulates FLG expression
Oral JTC801 increased FLG expression

in human and murine keratinocytes
Otsuka A, et. al. J Allergy Clin Immunol 2014;133:139-46
Novak N. and Simon D. Allergy 2011;66:83039
Outline
Pathogenesis
Phenotypes
Treatment
Prevention
Recent studies suggest prevention of AD can

be achieved through early interventions to
protect skin barrier
Simpson EL. et. al. J Allergy Clin Immunol 2014;134:818-23

Early intervention might improve long-term outcomes

for AD and reduce allergen sensitization that leads to
associated allergic diseases in gastrointestinal and
respiratory tract
Application of moisturizer to neonates prevents

development of atopic dermatitis
Obj: To investigate whether moisturizer application during neonates prevents development
of AD and allergic sensitization
Methods: Moisturizer was applied daily during the first 32 wks to neonates at
high risk for AD (having a parent or sibling with AD)
Primary outcome: cumulative incidence of AD/eczema at wk 32nd
Secondary outcome: allergic sensitization (allergen-specific IgE to egg white)
n = 59
N = 118
n = 59
Horimukai K et. al. J Allergy Clin Immunol 2014;134:824-30
32% fewer neonates who received

moisturizer had AD/eczema by wk 32nd
(P=.012)
Could not show a statistically

significant effect of emollient on
allergic sensitization based on
level of IgE against egg white
Horimukai K et. al. J Allergy Clin Immunol 2014;134:824-30
Emollient enhancement of the skin barrier from birth

offers effective atopic dermatitis prevention
RCT of 124 neonates at high risk for AD in US & UK
(high risks: having a parent or sibling who had physician-diagnosed
AD, asthma, or AR)
Parents in intervention arm were instructed to apply full-body emollient
therapy at least once per day starting within 3 wks of birth
Parents in control arm were asked to use no emollients
Primary outcome: cumulative incidence of AD at 6 months
Significant protective effect was found with use of

daily emollient on cumulative incidence of AD
with a relative risk reduction of 50%
Simpson EL, et. al. J Allergy Clin Immunol 2014;134:818-23
If confirmed to be effective in future studies,

emollient therapy from birth would be
a simple and low-cost intervention
that could reduce global burden of
allergic diseases

Picture from www.weknowyourdreams.com, access October 2015
Other preventive options

Probiotic therapy has inconsistent results:
Lack of standardization of bacterial
preparations
Lack of biomarkers to identify which AD
phenotype would benefit from this
approach
Take home messages

AD is a complex and heterogeneous
disorder
Defective skin barrier function and
immune dysregulation are
paramount to disease pathogenesis
Thank you for your attention

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Atopic dermatitis:

Suda Sibunruang, M.D.

Two alternate hypotheses

Thyssen JP. and Kezic S. J Allergy Clin Immunol 2014;134:792-9

Abnormal skin barrier

Deficiency of structural proteins

Development of food allergy

Leung D. and Guttman-Yassky E. J Allergy Clin Immunol 2014;134:769-79

Thyssen JP. and Kezic S. J Allergy Clin Immunol 2014;134:792-9

Complex dialog between immune dysregulation &

Figure courtesy of Boyd Jacobson, National Jewish Health, Denver, Colorado

Leung D. and Guttman-Yassky E. J Allergy Clin Immunol 2014;134:769-79

Complex causes of epithelial skin barrier dysfunction

Mutation in filaggrin (FLG)

Filagrin; filament-aggregating protein

Major component of NMF

Higher incidence of nonmelanoma skin cancers

Elias PM. and Wakefield JS. J Allergy Clin Immunol 2014;134:781-91

Elias PM. and Wakefield JS. J Allergy Clin Immunol 2014;134:781-91

Elias PM. and Wakefield JS. J Allergy Clin Immunol 2014;134:781-91

Hold corneocytes together;

Irvine AD. et. al. N Engl J Med 2011;365:1315-27

Filaggrin (FLG) mutations

Thyssen JP. and Kezic S. J Allergy Clin Immunol 2014;134:792-9

Leung D. Allergology International 2013;62:151-61

Skin barrier dysfunction: Beyond filaggrin gene

It was originally thought that filaggrin deficiency

Loss-of function mutation in

Impaired barrier function but

Saunders SP. et. al. J Allergy Clin Immunol 2013;132:1121-9

Encodes lamellar granules that are required for

Sasaki T. et. al. J Allergy Clin Immunol 2013;132:1111-20

Skin barrier dysfunction: beyond filaggrin

Benedetto AD. et. al. J Allergy Clin Immunol 2011;127:773-86

Skin barrier dysfunction

Leung D. and Guttman-Yassky E. J Allergy Clin Immunol 2014;134:769-79

Figure courtesy of Boyd Jacobson, National Jewish Health, Denver, Colorado

Nonlesional AD skin lesions

Produce cytokines, such as IL-4 and IL-13

Leung D. and Guttman-Yassky E. J Allergy Clin Immunol 2014;134:769-79

Impair function of tight junctions

prime naive T cells into Th2 cells

Release inflammatory mediators and

W. Peng and N. Novak. Clin Exp Allergy 2015;45:566-74

Leung D. and Guttman-Yassky E. J Allergy Clin Immunol 2014;134:769-79

Leung D. and Guttman-Yassky E. J Allergy Clin Immunol 2014;134:769-79

Keratinocytes & APC express PRRs

Leung D. and Guttman-Yassky E. J Allergy Clin Immunol 2014;134:769-79

Kuo et. al. J Allergy Clin Immunol 2013;131:266-78

Innate Lymphoid Cells: ILCs

ILCs have been observed to infiltrate AD skin and

Some forms of AD are primarily driven by polarized

Identification of immune pathway polarity will be

Noda S. et. al. J Allergy Clin Immunol 2015;135:324-36

Increased expression of tissue receptors

Degrade skin barrier

Commensal bacteria also produce AMPs

Kobayashi T. et. al. Immunity 2015;42:756-66

Atopic skin is predisposed to colonization or infection

Weidinger S. and Novak N. Lancet 2015 [Epub ahead of print]

Temporal shifts in the skin microbiome associated

Kong HH. et. al. Genome Res 2012;22:850-9

Proportion of Staphylococcus sequences, particularly S. aureus,

Eczema herpeticum; herpes simplex virus