Update on Atopic Dermatitis

Lucretia Adina Frasin & Carlo Gelmetti

AD: an overview
Ch i i fl t di ith
AD: an overview
Chronic inflammatory disease with no
known cure
1,2
Both genetic and environmental causes
1
Intensely pruritic
1
Relapsing/remitting co rse often diffic lt Relapsing/remitting course, often difficult
to treat
1
1. Darsow U, et al. J Eur Acad Dermatol Venereol 2010; 24:317328;
2. Alomar A, et al. Br J Dermatol 2004; 151 (Suppl. 70):327.
AD: a definition of terms
Atopic
= atopy /atopy/ (atah-pe) a genetic predisposition toward
the development of immediate hypersensitivity reactions
against common environmental antigens (atopic allergy),
most commonly manifested as allergic rhinitis but also as
bronchial asthma atopic dermatitis or food allergy bronchial asthma, atopic dermatitis, or food allergy.
(Dorlands 2007)
A state of sensitivity to common antigens - eg, house dust,
animal dander, pollen, with production of allergen-specific animal dander, pollen, with production of allergen specific
IgE; (McGraw-Hill Concise Dictionary of Modern
Medicine. 2002)
AD: a definition of terms AD: a definition of terms
Dermatitis =
inflammation of the skin
(= eczema) ( eczema)
AD Classification -1980 (Brunello Wuthrich)
Atopic Dermatitis
Extrinsic Extrinsic
AD AD
Intrinsic Intrinsic
AD AD
==
Raised IgE Raised IgE
==
Normal IgE Normal IgE
More frequently More frequently
linked with other linked with other linked with other linked with other
allergic diseases allergic diseases
Classification EAACI, 2001
The Atopic Eczema/Dermatitis Syndrome = AEDS
AEDS
The Atopic Eczema/Dermatitis Syndrome AEDS
AEDS
All i AEDS N ll i AEDS Allergic AEDS Nonallergic AEDS
IgE-associated AEDS Non-IgE-associated AEDS
Johansson SG. A revised nomenclature for allergy. Allergy 2001;56:813-24.
2004
Intrinsic AD Extrinsic AD
J Allergy Clin Immunol 2004;113:832-836
How atopic is AD?
A systematic review was undertaken of
o atop c s
A systematic review was undertaken of
studies in children with AD in hospital and
community populations measuring specific community populations, measuring specific
and non-specific IgE
1
1
Atopy is clearly associated with AD
1
However, up to 2/3 of people with AD may , p p p y
not be immunologically atopic
2
1. Flohr C, et al. J Allergy Clin Immunol 2004; 114:150158;
2. Cork MJ, et al. J Allergy Clin Immunol 2006; 118:321.
AD in evolution: an hypothetic path
2008
E l i f
Intrinsic AD
Early infancy
IgE sensitization
Extrinsic AD
g
Autoallergic AD
Autoantigens sensitizations g
Bierber T. N Engl J Med 2008 358;14: 1483-94
Prevalence of AD has steadily increased y
Prevalence of AD has risen progressively since 1940s
1-4
30
27 3
30.8
Australia
4
35
Denmark
3
(
%
)
20
25
27.3
Australia
15
C
h
i
l
d
r
e
n

(
12.2
11.9
New Zealand
1
20
17.3
Denmark
3
16.7
5
10
5.1
7.3
British birth
cohort studies
1
4.4
5.6
8.3
3.1
USA
1
Western
1
Sweden
1
UK
1
1945
0
1975
Year of birth (median
1
/mean
3,4
)
UK
1
USA
1
Australia
1
1965 1995 1985 1955
1. Taylor B, et al. Lancet 1984; 2:12551257; 2. Diepgen TL. Is the prevalence of atopic dermatitis increasing?
In: Atopic Dermatitis, 2000. Ed: Williams HC. Cambridge: Cambridge University Press;
3. Stensen L, et al. Allergy Asthma Proc 2008; 29:392396; 4. Foley P, et al. Arch Dermatol 2001; 137:293300.
( )
Reasons for increasing prevalence of AD Reasons for increasing prevalence of AD
Geographical location
Western lifestyle factors: socio-economic
status, family size , y
Diminished exposure to infection/infestations
Environmental triggers
Diepgen TL. Is the prevalence of atopic dermatitis increasing?
In: Atopic Dermatitis, 2000. Ed: Williams HC. Cambridge: Cambridge University Press.
Irritants and allergens are key
environmental triggers environmental triggers
Irritants Allergens
Soaps/detergents
1
Foods, e.g. milk, eggs, p g
Heat and sweating
Abrasive clothing
2
g gg
peanuts, wheat, soy, fish
2
House dust mites
1
g
Perspiration
1
Chemicals
1
Weeds
1
Animal dander
1
Smoke
1
Chlorine
1
Mould
1
Pollen
3
Chlorine
1. Leung DY & Bieber T. Lancet 2003; 361:151160;
2. Boguniewicz M, et al. J Allergy Clin Immunol 2003;
112 (6 Suppl.):S140150; 3. Fleischer AB. Postgrad Med 1999; 106:4955.
Determinants of AD: population-based cross-
sectional study in Germany y y
Methods: Data from a nationwide cross-sectional representative
survey conducted between 2003 and 2006 including 17 641 survey conducted between 2003 and 2006 including 17,641
children aged 0-17
Results: The weighted prevalence of ever physician-diagnosed Results: The weighted prevalence of ever physician-diagnosed
AD was 13.2%. Significant positive associations of parental
allergies, parent-reported infection after birth and parent- g , p p p
reported jaundice after birth were revealed.
Being a migrant and keeping a dog showed significant inverse
associations with AD.
Other lifestyle (alcohol consumption during pregnancy) and
f ( f environmental factors (mould on the walls, pets, origin from
East/West Germany) were not significantly related to AD.
Apfelbacher CJ et al. Allergy. 2011;66:206-13
Meta-analyses of epidemiological studies demonstrate a
correlation between specific ambient exposures and a p p
reduction in allergic risk during childhood
Tse K. Horner A. Allergen tolerance versus the allergic march: The hygiene
hypothesis revisited. Curr Allergy Asthma Rep. 2008 ;8:475483
The hygiene hypothesis The hygiene hypothesis
Children raised on farms are less likely to develop
allergic diseases than children raised in cities
AD has both genetic and environmental origins
AD has a complex, multifactorial aetiology arising from
gene-gene and gene-environment interactions g g g
Changes in genes related to skin barrier function,
combined with exposure to environmental triggers,
b t ti ll i i k f AD substantially increase risk of AD
Dermatitis
g
g
e
r
s
s
,

e
t
c
.
)
n
m
e
n
t
a
l

t
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n
t
s
E
n
v
i
r
o
(
s
o
a
p
,

Healthy
skin
Genetic disposition to a defective skin barrier
Cork MJ, et al. J Allergy Clin Immunol 2006; 118:321.
AD has a strong genetic component AD has a strong genetic component
Two major groups of
genes implicated g p
Genes encoding major
elements of immune elements of immune
system
Genes encoding Genes encoding
epidermal or other
epithelial epithelial
structural proteins
Bieber T. N Engl J Med 2008; 558:14831494
AD: causality
Long-standing debate regarding causality of AD
Outside-inside hypothesis?
Skin barrier dysfunction enables allergen penetration leading to Skin barrier dysfunction enables allergen penetration, leading to
cytokine production, inflammation and disease flares
1
OR
Inside-outside hypothesis?
Inflammatory response to irritants/allergens drives
OR
More recently the pathophysiology has been found to involve
Inflammatory response to irritants/allergens drives
skin barrier dysfunction
1
More recently, the pathophysiology has been found to involve
genes encoding BOTH skin barrier proteins such as filaggrin
AND components of the immune system
2
1. Elias PM, et al. Am J Contact Dermat 1999; 10:119126;
2. Bieber T. N Engl J Med. 2008; 358:14831494.
A defective epidermal barrier is a poor permeability
barrier, which permits the entry of allergens and the , p y g
loss of moisture.
H
2
O
Defective
id l epidermal
barrier
Subclinical Subclinical
inflammation
Cork MJ, et al. J Invest Dermatol 2009; 129:18921908.
AD: immune dysfunction underlies the
pathobiology and etiology pathobiology and etiology
Distorted
adaptive immunity
Impaired
innate immunity adaptive immunity innate immunity
Viral skin infection
Protein allergen sensitisation
T cell response
IgE production
Autoimmunity
Bacterial colonisation
Autoimmunity
Hereditary skin
barrier defect
Dry and scaly skin
Facilitated penetration
Wollenberg A. Clin Rev Allergy Immunol. 2007;33:35-44
Facilitated penetration
of water and protein
Inflammatory cascade of AD:
explaining the itch scratch cycle explaining the itch-scratch cycle
1. Scratching triggers 4. Chronic itching ensues and the
Patient
scratches
Chronic
itching
keratinocytes to release an
array of cytokines and
chemokines
cycle begins again
scratches
itching
Cytokines
released from
Increased
i fl ti
keratinocytes
inflammation
2. Cytokines/chemokines activate
antigen-presenting cells and cause the
differentiation of Th0 cells, which in turn causes
additional cytokines to be produced
3. These cytokines lead to skin
inflammation in a similar manner
to allergen induced flares
Kang K & Stevens SR. Clin Dermatol 2003; 21:116121;
Leung DY & Bieber T. Lancet 2003; 361:151160.
additional cytokines to be produced to allergen-induced flares
AD in evolution: an hypothetic path
2008
E l i f
Intrinsic AD
Sensitization to
self proteins
Early infancy
self proteins
IgE sensitization
Extrinsic AD
g
Sensitization
Autoallergic AD
Autoantigens sensitizations
Se s t at o
to allergens
g
Bierber T. N Engl J Med 2008 358;14: 1483-94
Diagnosing AD
There is no gold
t d d f d fi it standard for a definite
diagnosis!!
Chronic itching is
g
Chronic itching is
key to diagnosing
AD
Common differential diagnoses of AD
Adults Children Infants

Nummular dermatitis
2

Scabies
1,2

Seborrheic dermatitis
1,2

Contact dermatitis (allergic)
2

P i i
2

Contact dermatitis (irritant)

2

Molluscum dermatitis
2

Perioral dermatitis
2

Psoriasis
2

Tinea corporis
2

Immunodeficiencies
1,2

Ichthyoses
2

Immunodeficiencies
1,2

Malignancies e.g. cutaneous T cell

l h (CTCL)
1 3

Metabolic disorders e.g. zinc deficiency
2
1. Eigenmann PA. Pediatr Allergy Immunol 2001; 12 (Suppl. 14):6974;
2. Krol A & Krafchik B. Dermatologic Therapy 2006; 19:7382;
3. Leung DYM & Bieber T. Lancet 2003; 361:15160.
lymphoma (CTCL)
1,3
European Task Force on Atopic
Dermatitis/EADV Eczema Task Force
Darsow U Wollenberg A Simon D Taeb A Werfel T Oranje A Gelmetti C Darsow U, Wollenberg A, Simon D, Taeb A, Werfel T, Oranje A, Gelmetti C,
Svensson A, Deleuran M, Calza AM, Giusti F, Lbbe J, Seidenari S, Ring J
ETFAD/EADV eczema task force
2009 iti di i 2009 position paper on diagnosis
and treatment of atopic dermatitis.
J Eur Acad Dermatol Venereol.
2010;24:317-28. ;
Goals of management of AD
Sh t t t l f t t
Goals of management of AD
Short-term control of acute symptoms
Long-term stabilisation flare Long-term stabilisation, flare
prevention and avoidance of side
effects
Atopic dermatitis is a chronic condition. The
treatment has to be planned with a long-term
perspective.
Darsow U, et al. J Eur Acad Dermatol Venereol 2010; 24:317328.
AD: a multifactorial disease requires a
multifactorial approach multifactorial approach
Basic skincare regimen to
cleanse and hydrate the skin
and aid barrier repair
1
Appropriate anti-inflammatory
treatment
1
Skin barrier
f
Patient/
Immune system
dysfunction
Atopic
dermatitis
Atopic
dermatitis
Patient/
parent/
carer
education
1
Emotional
support
1
dysfunction
Identification of triggers and
their subsequent avoidance
1
Behavioural modification
2
or
physical barriers
3
to break the
1. Darsow U, et al. J Eur Acad Dermatol Venereol 2005; 19:286295;
2. Hoare C & Williams H. Health Technol Assess 2000; 4:1191;
3. Leung DY & Bieber T. Lancet 2003; 361:151160.
q
itch-scratch cycle
Traditional stepwise flare treatment of AD
1
Systemic therapy (e.g.
Step 4: Recalcitrant, severe AD
y py ( g
ciclosporin A) or UV therapy
Midhigh potency TCS or TCI*
Step 3: Moderate to severe AD
g p y
(TCI if AD not adequately responsive
or intolerant to TCS)
Step 2: Mild to moderate AD
Lowmid potency TCS or TCI*
(TCI if moderate AD not adequately
responsive or intolerant to TCS)
Step 1: Dry skin only
Basic treatment: skin hydration, emollients,
avoidance of irritants, identification and
addressing of specific trigger factors addressing of specific trigger factors
1. Akdis C, et al. Allergy 2006; 61:969987;
2. Wollenberg A, et al. J Dtsch Dermatol Ges 2009; 7:117121.
Over the age of 2 years. TCS = topical corticosteroid
TCI = topical calcineurin inhibitor
*
Old paradigm: three steps of AD management
Step 3: Treatment of flares with TCS/TCI
+ Education
Step 2: Identification and avoidance of allergens/triggers
+ Education
Step 1: Complete emollient therapy Step 1: Complete emollient therapy
+ Education
New paradigm: four steps of AD management
Step 4: Prevention of flares with TCS/TCI twice weekly
+ Education
Step 3: Treatment of flares with TCS/TCI
+ Education
Step 2: Identification and avoidance of allergens/triggers
+ Education
St 1
Step 2: Identification and avoidance of allergens/triggers
+ Education
Step 1: Complete emollient therapy
+ Education
Rationale for ongoing active management:
non-lesional skin is not normal non-lesional skin is not normal
Lesional skin is characterised by clinical inflammation (flare)
Non-lesional skin shows signs of sub-clinical inflammation between Non lesional skin shows signs of sub clinical inflammation between
flares, which progresses to clinical inflammation and recurrence of
flares at irregular intervals
Inflammation (flare)
nn
Inflammation (flare)
a
m
m
a
t
i
o
n
a
m
m
a
t
i
o
n
Lesional
skin
e
e

o
f

i
n
f
l
a
e
e

o
f

i
n
f
l
a
Non-lesional
D
e
g
r
e
D
e
g
r
eNon-lesional
skin,
sub-clinical
inflammation
Non lesional
Sub-clinical inflammation
Wollenberg A & Bieber T. Allergy 2009; 64:276278.
Time
No inflammation
Time
No inflammation
Non-lesional
skin, no
inflammation
No inflammation
The final goal is to control subclinical
inflammation inflammation
Aim of active maintenance treatment is to prevent flares by p y
continuously controlling sub-clinical inflammation, even after
resolution of clinical signs of flare
Inflammation (flare)
nn
Inflammation (flare)
Short-term induction therapy with
intensive topical anti-inflammatory
+
a
m
m
a
t
i
o
a
m
m
a
t
i
o
Active maintenance treatment of
previously affected areas in combination
with emollient therapy of entire skin
Lesional
skin
+
r
e
e

o
f

i
n
f
l
r
e
e

o
f

i
n
f
lwith emollient therapy of entire skin
surface
Non-lesional
D
e
g
r
No inflammation
D
e
g
r
N i fl ti
skin,
sub-clinical
inflammation
Non-lesional
No inflammation
Sub-clinical inflammation
Wollenberg A & Bieber T. Allergy 2009; 64:276278.
Time
No inflammation
Time
No inflammation
skin, no
inflammation
No inflammation
AD: EBM THERAPY AD: EBM THERAPY
1. Topical Corticosteroids
2. Topical Calcineurin Inhibitors
3 UV therapy 3. UV-therapy
4. Cyclosporine A 4. Cyclosporine A
5. Psychotherapy
Fukuie T, Nomura I, Horimukai K et al.
Proactive treatment appears to decrease serum immunoglobulin-E levels in
patients with severe atopic dermatitis. patients with severe atopic dermatitis.
Br J Dermatol. 2010 Nov;163(5):1127-9.
There were no serious AE in any of the pts during tx; 8 pts y p g ; p
(32%) in the proactive tx group experienced fungal infection (2
pts in reactive group). Skin thinning and striae formation were
not seen in any patients Hypertrichosis was suspected in not seen in any patients. Hypertrichosis was suspected in
some pts before titration of frequency of topical CTS, but
normalized when the frequency of topical CTS was decreased
to twice a week or less.
We used proactive tx for the management of severe AD and
the serum IgE level appeared to decrease Continuous close the serum IgE level appeared to decrease. Continuous close
adherence to the proactive tx may suppress inflammatory cells
and lower the serum IgE. Decrease of egg white- and milk-
specific IgE was also seen, and may play an important role in
alleviating food allergies.
This is the first report to evaluate the effectiveness of proactive This is the first report to evaluate the effectiveness of proactive
therapy in reducing the serum IgE level.
Fig 1. Percentage changes of total IgE levels during the treatment. Baseline (just
before the start of inpatient treatment) total IgE of each patient was determined as
100% I th ti th t t l I E l l d d b 100%. In the proactive group, the total IgE level was reduced by our
comprehensive treatment and IgE levels at 2 years after treatment commencement
were significantly lower than in the reactive group. *Significant differences
b t th t ft 2 (P < 001 M Whit U t t) between the two groups after 2 years (P < 001, MannWhitney U-test).
Fig 2. Changes in egg white- and milkspecific IgE levels after the start of
treatment. Food-specific IgE levels in the patients in the proactive treatment group
(bl li ) d d i ifi tl d i f ll N i ifi t d (blue line) decreased significantly during follow-up. No significant decreases were
seen in the reactive treatment group patients (red lines). *Significant difference in
Wilcoxon signed rank test.
Meurer M, Eichenfield LF, Ho V, Potter PC, Werfel T, Hultsch T.
Addition of pimecrolimus cream 1% to a topical corticosteroid tx regimen in
paediatric patients with severe atopic dermatitis: a randomized double-blind trial paediatric patients with severe atopic dermatitis: a randomized, double-blind trial.
J Dermatolog Treat. 2010 May;21(3):157-66.
Pimecrolimus and topical corticosteroids combination tx may Pimecrolimus and topical corticosteroids combination tx may
provide an alternative tx for pts with severe AD.
To assess the safety profile of pimecrolimus cream 1% (PIM)
bi d i h fl i (F U) F U l i di i combined with fluticasone (FLU) versus FLU alone in paediatric pts
with severe AD.
Pts (n = 376) were randomized to a combination of PIM with FLU or ( )
vehicle plus FLU for 4 weeks. The primary outcome was the
frequency of clinically relevant pre-defined adverse events (AEs).
Erythematous rash was the only AE occurring more frequently in Erythematous rash was the only AE, occurring more frequently in
the combination group, while there were no noticeable differences
in the frequency of other AEs. Efficacy variables were comparable
b t th 2 A t d f t ti t l between the 2 groups. A trend for greater time to relapse was
observed for the combination of PIM with FLU in pts who were clear
at the end of tx, with a marked improvement in facial AD.
In paediatric pts with severe AD the overall safety profile of PIM
combined with FLU was similar to that of FLU alone.
Mandelin J, Remitz A, Virtanen H, Reitamo S.
One-year treatment with 0.1% tacrolimus ointment versus a corticosteroid
regimen in adults with moderate to severe atopic dermatitis: A randomized, g p ,
double-blind, comparative trial.
Acta Derm Venereol. 2010 Mar;90(2):170-4.
A one-year, randomized, double-blind study was conducted in 80
pts with AD treated with tacrolimus (TAC) ointment or a
corticosteroid (CTS) (hydrocortisone acetate 1% ointment for head ( ) ( y
and neck, hydrocortisone butyrate 0.1% ointment for trunk and
limbs) to compare efficacy and safety, and effects on Th2-reactivity.
The study was completed by 36/40 pts in the TAC group and 31/40 The study was completed by 36/40 pts in the TAC group, and 31/40
pts in the CTS group. In both groups affected BSA, eczema area and
severity index, and TEWL decreased at months 6 and 12. TAC was
i f ll ffi t th 6 d i th h d d k superior for all efficacy scores at month 6, and in the head and neck
area at month 12. Recall antigen reactivity increased at month 12 in
both groups. Adverse events were reported by 40/40 pts in the TAC,
and by 34/40 pts in the CTS group.
Long-term tx with topical TAC or a CTS regimen improves AD and
recall antigen reactivity, suggesting an improvement in the Th1/Th2- recall antigen reactivity, suggesting an improvement in the Th1/Th2
balance.
Chen SL, Yan J, Wang FS.
Two topical calcineurin inhibitors for the treatment of atopic dermatitis in
pediatric patients: a meta-analysis of randomized clinical trials. p p y
J Dermatolog Treat. 2010;21:144-56.
OBJECTIVE: To evaluate the efficacy and safety of tacrolimus
ointment and pimecrolimus cream for the treatment of AD in ointment and pimecrolimus cream for the treatment of AD in
pediatric patients.
METHODS: MEDLINE, Embase, the CNKI and Cochrane Library
databases were searched up to December 2008 databases were searched up to December 2008.
RESULTS: Twenty trials involving 6288 infants and children with AD
met the inclusion criteria. More patients using tacrolimus had a
good response than those in control groups including vehicle 1% good response than those in control groups including vehicle, 1%
hydrocortisone acetate and 1% pimecrolimus.
The effect difference between 0.03% tacrolimus and 0.1%
tacrolimus ointments was not statistically significant tacrolimus ointments was not statistically significant
The incidence of adverse events of tacrolimus ointment or
pimecrolimus cream was similar to the vehicle. The major adverse
t b i d it events were burning and pruritus.
CONCLUSIONS: Both tacrolimus ointment and pimecrolimus cream
are safe and effective in the treatment of AD in pediatric patients.
T li i t t i t i li Tacrolimus ointments were superior to pimecrolimus cream.
Anti-pruritic therapy (Darsow/ Stnder/ Gieler)
Itch is the most important clinical symptom Itch is the most important clinical symptom
in AD, with peculiar impact on emotional
dimensions of perception as compared to dimensions of perception as compared to
other pruritic dermatoses like urticaria.
C i it i AD l Concerning pruritus accompanying AD, only
few studies investigate the antipruritic effect
l I t t di it i t f th only. In most studies, pruritus is part of the
total symptom score using the EASI and
SCORAD SCORAD.
Specific antipruritic therapies Specific antipruritic therapies
1. Topical anesthetics
2 Cannabinoid receptor agonist 2. Cannabinoid receptor agonist
3. Capsaicin
4. Topical doxepin
5 Topical mast cell stabilizers 5. Topical mast cell stabilizers
6. Opioid receptor antagonists
7. Selective serotonin reuptake inhibitors
Searing DA, Leung DY.
Vitamin D in atopic dermatitis, asthma and allergic diseases.
I l All Cli N th A 2010 30(3) 397 409 Immunol Allergy Clin North Am. 2010;30(3):397-409
This review examines the scientific evidence behind the This review examines the scientific evidence behind the
hypothesis that vitamin D plays a role in the
pathogenesis of allergic diseases, along with a focus on
emerging data regarding vitamin D and AD emerging data regarding vitamin D and AD.
Elucidated molecular interactions of vitamin D with
components of the immune system and clinical data
regarding vitamin D deficiency and atopic diseases are regarding vitamin D deficiency and atopic diseases are
discussed.
The rationale behind the sunshine hypothesis, laboratory yp , y
evidence supporting links between vitamin D deficiency
and allergic diseases, the clinical evidence for and
against vitamin D playing a role in allergic diseases, and g p y g g ,
the emerging evidence regarding the potential use of
vitamin D to augment the innate immune response in
atopic dermatitis are reviewed. p
New therapeutic perspectives in AD New therapeutic perspectives in AD
PPAR (Peroxisome Proliferative-
Activated Receptors) Activators p )
Skin Protease Inhibitors
S l ti Gl ti id R t Selective Glucocorticoid Receptor
Agonists (SEGRA)
Chemokine Inhibitors
Complications of AD
Increased risk of
manifestation
Other atopic
conditions including
asthma and allergic
rhinitis
manifestation
of autoimmune
states later in life
8
rhinitis
(atopic march)
1
Increased susceptibility to
skin infections
Ocular complications:
skin infections
Bacterial infections,
e.g. Staphylococcus aureus
2
Viral infections,
e g herpes simplex virus
3
Ocular complications:
blepharitis,
keratoconjunctivitis,
keratoconus, uveitis,
subcapsular cataract,
e.g. herpes simplex virus
3
Fungal infections,
e.g. Malassezia furfur
4
retinal detachment,
ocular herpes simplex
6,7
1. Weinberg EG. Curr Allergy Clin Immunol
2005; 18:45; 2. du Vivier A. Dermatology In
Practice, 1990. London: Gower Medical Publishing;
3. Wollenberg A, et al. J Am Acad Dermatol 2003; 49:198205;
4 Leung DY & Bieber T Lancet 2003; 361:151 160;
Reduced quality of life,
e.g. sleep disturbance
ff i
4. Leung DY & Bieber T. Lancet 2003; 361:151160;
5. Lewis-Jones S. Int J Clin Pract 2006; 60:984992;
6. Garrity JA & Liesegang TJ. Can J Ophthalmol 1984; 19:2124;
7. Carmi E, et al. Acta Derm Venereol 2006; 86:515517;
8. Kokkonen J & Niinimki A. J Autoimmun 2004; 22:341344.
common, affecting
physical/mental states,
behaviour, childrens growth
5