Atopic dermatitis: work in progress

Atopic dermatitis:
work in progress
Suda Sibunruang, M.D.

Outline
• Pathogenesis
• Phenotypes
• Approach and management
• Treatment
• Prevention

Thyssen JP. and Kezic S. J Allergy Clin Immunol 2014;134:792-9
Figure courtesy of Boyd Jacobson, National Jewish Health, Denver, Colorado
Outside - in
Inside - out
Two alternate hypotheses

Abnormal skin barrier
Epicutaneous absorption of
environmental allergens
Systemic sensitization
Development of food allergy
and asthma
Atopic dermatitis
- Disrupted epidermal terminal
differentiation
- Reduced lipids
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
Deficiency of structural proteins
ceramides

Outside - in
Inside - out
Outside
to inside
Back to
outside
Cytokine-driven disease

Complex dialog between immune dysregulation &
epidermal barrier defect

Genetic Environment
Immunologic
factors
Allergens Diet
Irritant Stress
Microbes
Heterogeneity
Onset
Severity
Natural history
Abnormal
skin barrier
Complex causes of epithelial skin barrier dysfunction
Innate & adaptive immune response

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

Boguniewicz M. and Leung D. Immunol Rev. 2011;242:233–46
Filagrin; filament-aggregating protein
Keratin filaments

Elias PM. and Wakefield JS. J Allergy Clin Immunol 2014;134:781-91
Trans-urocanic acid
Absorb UVB
Major component of NMF
Higher incidence of nonmelanoma skin cancers
in patients with AD
Activates serine proteases
(kallikreins)

Human β-defensin 2
Carboxyterminal cathelicidin peptide LL-37

Irvine AD. et. al. N Engl J Med 2011;365:1315-27
Hold corneocytes together;
their degradation leads to desquamation

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

Sasaki T. et. al. Nihon Rinsho Meneki Gakkai Kaishi 2014;37:160-5
Skin barrier dysfunction: Beyond filaggrin gene
Animal model of AD with
spontaneous eczema under
pathogen-free conditions
Double mutation
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
Impaired barrier function but
no spontaneous eczema
Loss-of function mutation in
transmembrane protein 79
Tmem79/matt gene

Saunders SP. et. al. J Allergy Clin Immunol 2013;132:1121-9
Double-mutant (DM)
- stubbed tail
- shortened
ear pinnae
Cutaneous inflammation

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

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

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

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 anti-
inflammatory regimens with either topical
calcineurin inhibitors or topical corticosteroids
• Resolution of AD in patients with moderate-to-
severe disease with broad-based
immunosuppressive therapies, which is coupled
with resolution of abnormal epidermal responses

Boguniewicz M. and Leung D. Middleton’s Allergy Principle and Practice. 8th edition, 2014

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
TSLP

W. Peng and N. Novak. Clin Exp Allergy 2015;45:566-74
prime naive T cells into Th2 cells
TWEAK:TNF-like weak
inducer of apoptosis
Impair function of tight junctions
Thymic stromal
lymphopoietin
Colonizing pathogens
Decrease production

Release inflammatory mediators and
chemokines to attract immune cells
Th2 type responses contribute mainly

Boguniewicz M. and Leung D. Middleton’s Allergy Principle and Practice. 8th edition, 2014
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

Noda S. et. al. J Allergy Clin Immunol 2015;135:324-36
Identification of immune pathway polarity will be
of particular importance as biologic agents become
more readily available
Some forms of AD are primarily driven by polarized
immune pathways that downregulate keratinocyte terminal
differentiation, thereby creating a secondary skin barrier defect

Williams MR. and Gallo RL. Curr Allergy Asthma Rep 2015:15;65
Increased expression of tissue receptors
for S. aureus, which leads to colonization
from keratinocytes
Commensal bacteria also produce AMPs
capable of controlling S.aureus growth
Degrade skin barrier

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

Weidinger S. and Novak N. Lancet 2015 [Epub ahead of print]
Atopic skin is predisposed to colonization or infection
by pathogenic microbes
Staphylococcus aureus

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

Eczema herpeticum; herpes simplex virus

Bin L, et. al. J Allergy Clin Immunol 2014;134:848-55
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

Lyons JJ. et. al. Immunol Allergy Clin N Am 2015;35:161–83
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

Vora S, et. al. Clin Infect Dis 2008;46:1555–61
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
virus–specific PCR
Treatment included vaccinia immune
globulin

Eczema coxsackium; Coxsackie A6 virus
Mathes EF, et. al. Pediatrics 2013;132:149–57
Coxsackievirus A6 (CVA6) was identified as an important cause of
“severe” hand, foot, and mouth disease

Bieber T. Allergy 2012;67:1475-82
Time has come to distinguish various
AD phenotypes and endotypes

These phenotypes often have overlapping features but
contain dominant characteristics that distinguish them from each other
Adult-onset AD has also been increasingly reported

Garmhausen D. et. al. Allergy 2013;68:498–506
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

x
x
x
x
x
x
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

Boguniewicz M. and Leung D. Immunol Rev. 2011;242:233–46
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

Noda S. et. al. J Allergy Clin Immunol 2015 (article in press)
The Asian atopic dermatitis phenotype combines features
of atopic dermatitis and psoriasis with
increased TH17 polarization
European American (EA)

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)
Disease severity/SCORAD scores were similar between AD groups
Greater acanthosis, higher Ki67 counts, and frequent parakeratosis in Asian patients

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

Bieber T. et. al. Allergy 2012; 67:969–75
In the future, AD might be stratified by genotype
and biomarkers

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

Li JY. et. al. Cancer Management and Research 2012:4;75–89
Cutaneous T cell lymphomas represent a heterogeneous group of
non-Hodgkin lymphomas, with mycosis fungoides and Sezary syndrome
being most common subtypes
Mycosis fungoides Sézary syndrome

Lyons JJ. et. al. Immunol Allergy Clin N Am 2015;35:161–83
Comprehensive treatment plan with
extensive education are needed

Mohan GC. and Lio PA. JAMA Dermatol 2015;151:1009-13
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 Asia–Pacific Consensus Group for Atopic Dermatitis

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.”

Principles of treatment
• Maintenance of skin barrier integrity
• Control of skin inflammation
• Nutrition
• Identification and management of
allergenic and microbial triggers

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

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

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

Camargo CA Jr, et. al. J Allergy Clin Immunol 2014;134:831-5
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 Investigator’s Global Assessment (IGA)

Access from www.google.com/patents , October 2015

Camargo CA Jr, et. al. J Allergy Clin Immunol 2014;134:831-5
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

Noda S. et. al. J Allergy Clin Immunol 2015;135:324-36
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
receptor–mediated T-cell activation and cytokine production

Otsuka A, et. al. J Allergy Clin Immunol 2014;133:139-46
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 protein–coupled receptor)
It remains unclear how JTC801 regulates FLG expression
Oral JTC801 increased FLG expression
in human and murine keratinocytes

Novak N. and Simon D. Allergy 2011;66:830–39

Simpson EL. et. al. J Allergy Clin Immunol 2014;134:818-23
Recent studies suggest prevention of AD can
be achieved through early interventions to
protect skin barrier

Early intervention might improve long-term outcomes
for AD and reduce allergen sensitization that leads to
associated allergic diseases in gastrointestinal and
respiratory tract

Horimukai K et. al. J Allergy Clin Immunol 2014;134:824-30
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 = 118
n = 59
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

Simpson EL, et. al. J Allergy Clin Immunol 2014;134:818-23
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%

Picture from www.weknowyourdreams.com, access October 2015
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

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

Atopic dermatitis: work in progress

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Atopic dermatitis: work in progress