Atopic dermatitis

ATOPIC DERMATITIS
Natthiya Pholmoo, MD
Sep 2021

Introduction
◦ Atopic dermatitis, also known as eczema
and atopic eczema
◦ 20% of children and 10% of adults in
high-income countries.
◦ Itching and recurrent eczematous lesions
and has a heterogeneous clinical
presentation.
◦ Atopic dermatitis can occur at any age,
the usual age of onset is in early
childhood, typically at age 3–6 months.
Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet. 2020;396(10247):345–60.

Introduction
◦ The causes of atopic dermatitis are
complex and multifactorial.
◦ The personal and family history regarding
allergies such as allergic rhinitis, and/or
asthma is related to AD.
◦ Individuals with atopic dermatitis are at
increased risk of having asthma, allergic
rhinitis, and food allergy.

Introduction
Atopic dermatits can be classified
• Intrinsic / non-IgE-associated AD
• Extrinsic / IgE-associated AD
: total IgE
: allergen-specific IgE in serum
: IgE-mediated sensitization from skin
prick test
Kulthanan K, Tuchinda P, Nitiyarom R, Chunharas A, Chantaphakul H, Aunhachoke K, et al.
Clinical practice guidelines for the diagnosis and management of atopic dermatitis. Asian Pac J Allergy Immunol. 2021;10.12932/AP-010221-1050.

Epidemiology
◦ Atopic dermatitis affects up to 20% of children and 10%
of adults in high-income countries
◦ Approximately 4% of adults had severe disease.
◦ Environmental factors are important in the etiology of
atopic dermatitis.
◦ Low prevalence of atopic dermatitis in areas with high
humidity, temperature, and ultraviolet light exposure.
◦ Higher prevalence in AfricanAmerican individuals
(17%) than in white people (11%)

Epidemiology
The prevalence of eczema symptoms in Bangkok
• 6-7 years : 16.7%
• 13-14 years : 9.6%
• There has been no study reporting the
prevalence of adult-onset AD in Thailand.

Natural history
◦ Early transient
◦ Relapsing–remitting
◦ Chronic persistent
◦ Long periods of remission followed by
recurrence

Predictors of persistent atopic
dermatitis activity into adulthood
◦ Concurrent asthma
◦ Hay fever
◦ Young age of onset
◦ Low socioeconomic status
◦ Nonwhite ethnicity

Pathophysiology and
mechanisms of disease
◦ Complex interplay between a dysfunctional epidermal
barrier, skin microbiome abnormalities, and a
predominantly type-2-skewed immune dysregulation.
◦ Skin barrier weakness attributable to a filaggrin
deficiency promotes inflammation and T cell infiltration.
◦ Colonization or infection with Staphylococcus aureus
damages the skin barrier and induces inflammatory
responses.

The complex interplay
among
◦ skin barrier
dysfunction
◦ skin inflammation
◦ itch
contributes to the
development, progression
and chronicity of AD
Nakahara T, Kido-Nakahara M, Tsuji G, Furue M. Basics and recent advances in the pathophysiology of atopic dermatitis. J Dermatol. 2021;48(2):130–9.

Puar N, Chovatiya R, Paller AS. New treatments in atopic dermatitis. Ann Allergy Asthma Immunol. 2021;126(1):21–31.

Genetic risk factors
◦ A family history of atopic disease, particularly
atopic dermatitis, is the strongest risk factor for
developing the disorder.
◦ Atopic dermatitis has strong heritability
approximately 75% in monozygotic twin studies

Filaggrin
◦ The strongest genetic risk for atopic dermatitis identified
is associated with mutations in the skin barrier protein
filaggrin, encoded by the FLG gene.
◦ Loss of function mutations in FLG cause a 50%
decrease in protein expression in the heterozygous state
and a total loss of protein expression in the
homozygous.
◦ FLG loss of function mutations confer a 3–5 times higher
risk of atopic dermatitis and predispose these individuals
to asthma and peanut allergy.

Filaggrin
◦ FLG deficiency has been reported to cause AD at an early
age, increase the sensitivity and severity of allergies, and
increase the vulnerability to infection.
◦ FLG abnormalities are closely related to controlling TEWL and
maintaining SC hydration in patients with AD.
◦ 40% of FLG mutation carriers do not develop AD.
◦ FLG mutations are only found in 15–50% of patients with AD.
◦ Thus, genetic abnormalities in FLG alone do not explain all of
the skin barrier dysfunctions of AD.

Filaggrin is an important
structural protein that is
responsible
for SC homeostasis
Plays a crucial role in
maintaining SC hydration
natural moisturizing factors

Epidermal
barrier
dysfunction
Elevated transepidermal water loss and pH
increased permeability, reduced water
retention and altered lipid composition.
Disruption of barrier function in atopic
dermatitis is multifactorial and includes
genetic factors, such as FLG mutations, and
physical damage from scratching.
The barrier is further damaged by microbial
dysbiosis, including colonisation with S
aureus and Malassezia yeasts.
Type 2 immune activity in the skin causes a
secondary downregulation of skin barrier
genes and stratum corneum lipids

Normal and effective barrier function cannot be established, resulting in an increase in
transepidermal water loss (TEWL) and a decrease in SC hydration in AD patients.

The role of the
microbiome
◦ S aureus being a dominant colonizer and
pathogen.
◦ Colonisation rates on bacterial cultures on non-
lesional skin (39%) and lesional skin (70%).
◦ Early colonization with S aureus preceded
development of atopic dermatitis in later life.
◦ S aureus contributes to atopic dermatitis
pathogenesis in many ways, including barrier
disruption and direct proinflammatory effects
such as type 2 immune activation.

Edslev SM, Agner T, Andersen PS. Skin microbiome in atopic dermatitis. Acta Derm Venereol. 2020;100(12):adv00164.

The role of the
microbiome
◦ Cutaneous yeasts such as Malassezia species
could trigger or exacerbate cutaneous inflam-
mation in atopic dermatitis.
◦ A subgroup of people with atopic dermatitis,
particularly those individuals with more severe
dermatitis of the head and neck, display
specific IgE reactivities to Malassezia antigens
and might benefit from topical or oral antifungal
therapy, or both, although evidence to support
these treatments is sparse.

Immunological
dysregulation
and
inflammation
◦ Cutaneous inflammation is central to the
pathogenesis of atopic dermatitis.
◦ Lesional skin of patients with atopic
dermatitis shows a T cell infiltrate
predominantly characterised by CD4
expression.
◦ Activated Th2 cells release IL-4 and IL-13,
promoting IgE class switching in B cells and
production of antigen-specific IgE.

◦ Non-lesional atopic dermatitis skin shows
immunohistological changes, including spongiosis
(abnormal accumulation of fluid between cells) and
T-cell infiltrations similar to those of lesional skin
◦ Lesional atopic dermatitis skin shows dysregulated
expression of a wide range of genes, mostly related to
keratinocyte activity and T-cell infiltration, especially for
Th2-associated (IL-4, IL-10, IL-13) and Th22-
associated (IL-22) genes.
◦ An activation of Th1mediated and Th17-mediated
responses has been reported in chronic skin lesions.
◦ Inhibition of Th1-cell or Th17-cell axes does not appear
to be an effective therapeutic intervention for atopic
dermatitis.

◦ Many patients with severe atopic dermatitis have
increased IgE-mediated reactivity to aeroallergens,
food proteins, microbial antigens, or keratinocyte-
derived auto-antigens.
◦ Environmental allergens such as house dust mites,
pollens, or animal epithelia allergens can contribute to
atopic dermatitis flares in IgE-sensitised patients.
◦ In infants with moderate-to-severe atopic dermatitis,
food allergens also induce flares, but most food
allergies resolve during childhood.

Neuroimmune interactions
◦ The dominant symptom of atopic dermatitis is itch,
contributing to pathogenesis through skin barrier damage,
allowing allergens and irritants to permeate, and activation of
alarm signals that perpetuate the itch–scratch cycle
◦ Itch is induced by a complex variety of pruritogens such as
type 2 cytokines.
◦ Histamine is the most studied pruritogen, predominantly
released from mast cells and basophils.
◦ There is no robust evidence that antihistamines are effective
in improving signs and symptoms of atopic dermatitis,
including itch.

Clinical signs
◦ Without definitive tests, Clinical signs are needed for
diagnosis.
◦ A clinician’s assessment is considered the gold
standard.
◦ Essential features are eczematous lesions, intense
pruritus, and a chronic or relapsing disease course.
◦ The eczematous lesions can be manifested in acute,
subacute, chronic features.
◦ Eczematous lesions typically show an age-related
distribution.
◦ Common features seen in most patients with atopic
dermatitis are generalised skin dryness.

Eczematous lesions
◦ Acute oozing, crusted, eroded vesicles, papules on
erythematous plaque
◦ Subacute scaly erythematous papules or plaques
◦ Chronic lichenified, slightly pigmented, excoriated plaques

Non-lesional Acute
Subacute Chronic

Infants
◦ Infants often present with acute lesions.
◦ Poorly defined erythema with edema, vesicles,
excoriations, and serous exudate.
◦ Typically involvethe face and the extensor
surfaces of the limbs.
◦ The trunk might be affected but the nappy area
is typically spared.

Childhood
(aged 2 years and older) older)
◦ Eczema becomes more localised and chronic
than in infancy.
◦ Paler erythema, dry skin (xerosis), poorly
defined lesions
◦ Commonly affecting flexor surfaces with
thickening (lichenification) of chronic areas.

Adults
◦ Adolescents and adults usually have
diffuse eczema.
◦ They can also have localised lesions typically
affecting hands, eyelids, and flexures.
◦ Adults can have chronic hand eczema only or
head-neck dermatitis as well, involving the
upper trunk, shoulders, and scalp.

◦ Hyperlinearity of palms
and soles
: mostly seen in patients
with FLG mutations or
ichthyosis vulgaris
◦ Dennie-Morgan
infraorbital folds
◦ Hertoghe’s sign.
Associated non-specific
features

Differential diagnoses of atopic dermatitis
https://www.facebook.com/EctodermalDysplasiaFamily
https://www.contemporarypediatrics.com/
view/ichthyosis-vulgaris-7-month-old-boy

https://www.alamy.com/pityriasis-rosea-is-a-type-of-dermatitis-with-a-mild-
pink-or-red-skin-rash-and-a-flaky-rash-maternal-plaque-image425950722.html
https://www.wikidoc.org/index.php/File:Pityriasis_rubra_pilaris06.jpg
https://www.pcds.org.uk/clinical-guidance/eczema-
asteatotic-eczema-syn-xerotic-eczema-eczema-craquele

Diagnostic
◦ The diagnosis of AD is based on one’s history and clinical
manifestations, such as morphology and the distribution of skin lesions.
◦ In 1980, major and minor criteria for a diagnosis of AD were proposed
by Hanifin and Rajka.
◦ Three of four major criteria and three of 23 minor criteria are required
for a diagnosis of AD.

Features to be considered in the diagnosis of patients
with atopic dermatitis by Hanifin & Rajka (1980)

Diagnostic
◦ AD is diagnosed according to its clinical presentation, rather than from
the results of diagnostic testing.
◦ The use of percutaneous skin or in vitro tests, ranging from SPT to
specific IgE to relevant allergens, can be used to identify potentially
allergic triggering factors.

Food allergy
◦ Food allergies relating to AD is commonly found in children under five years of age.
◦ The Food Allergy Expert Panel suggests that a food allergy test may be considered
in children with moderate-to-severe AD who do not respond well after proper
treatment.
◦ One-third of children with AD who test positive for food allergies do not have clinical
symptoms after sensitization.
◦ Thus, an oral food challenge test (elimination and re-challenge) should be
performed on children to confirm the diagnosis of food-induced eczema in patients
with AD in order to avoid unnecessary food avoidance.

Diagnostic algorithm
of oral food challenge
test in patients with
atopic dermatitis
Clinical practice guidelines for the diagnosis and management of atopic dermatitis. Asian
Pac J Allergy Immunol. 2021;10.12932/AP-010221-1050.

Management
The aims of AD treatment
◦ Reduce symptoms (pruritus and dermatitis)
◦ Prevent exacerbations
◦ Optimize treatment to prevent therapeutic risks

1. Patients and family education
2. Disease-severity assessment
3. Avoiding precipitating factors
4. Management of AD
5. Prevention
Management

Patients and family education
◦ Patients and their family should be educated in order to understand the
course of the disease and to know how to properly manage themselves to
control their symptoms and prevent an exacerbation of the disease.
◦ Interdisciplinary educational programs by dermatologists, allergists,
pediatricians, psychologists, and nursing staff help to significantly improve
their patients’ quality of life.

Disease-severity assessment
The most common scales for assessing disease severity in AD patients
◦ The Eczema Area and Severity Index (EASI)
◦ Scoring of Atopic Dermatitis (SCORAD)
These scales identify condition as
◦ Mild
◦ Moderate
◦ Severe

Avoiding precipitating factors
Many factors can contribute to the exacerbation of AD
◦ Infections
◦ Temperature
◦ Humidity
◦ Irritants
◦ Emotional stress
◦ Food allergens
◦ Aeroallergens

General recommendations for patients
with AD
Patients should avoid aggravating factors and substances
◦ Rough cloth textures
◦ Heavy sun exposure
◦ Hot temperatures, steam and hot vapors
◦ Body scrubbing and scratching
Patients are encouraged to wear loose clothing.
Keep their nails short and clean.

Bathing
◦ Hypoallergenic soap
◦ Water temperature of 27-30°C
◦ Limiting one’s exposure time to 5-10 minutes
◦ After gently drying the skin, topical emollients should be applied immediately
to slightly humid skin.
◦ Bathing with antiseptic soaps or solutions should be avoided, as they can
cause skin irritation.
◦ Some studies have reported the benefits of body washes containing diluted
sodium hypochlorite (0.006%) for 5-10 minutes two to three times a week and
then washing them with water can reduce the disease severity and the need
for topical corticosteroids or antibiotics especially in patients with a recurrent
skin infection.

Moisturizers
◦ Moisturizers for patients with AD should not contain any fragrance or
preservatives.
◦ It is recommended to use plain moisturizers such as cold cream, cream base,
3-10% urea, or petrolatum twice daily.
◦ It can keep the skin hydrated for 2-6 hours, depending on the type of
moisturizer.
◦ The amount that should be used
◦ Newborns : 100 g/week
◦ Infants : 150 g/week
◦ young children : 200 g/week
◦ adults : 250 g/week

Topical corticosteroids (TCS)
◦ A mild-to-moderate potency of TCS should be applied twice daily on the
inflamed skin during acute exacerbation, and then discontinued during
disease remission.
◦ A proactive therapy is a long-term, intermittent application of anti-inflammatory
agents to the previously affected skin, along with an ongoing emollient
treatment of the unaffected skin.
◦ Wet-wrap therapy has been reported to be safe and effective in children with
severe or refractory AD.

Topical calcineurin inhibitors (TCI)
◦ Second-line therapy in treating AD
◦ Can be used over TCS in sensitive skin areas such as the face and
intertriginous and anogenital sites, especially for topical long-term use.
◦ Typically, a twice-daily application is recommended during AD flares, followed
by once daily during improvement, and then it should be discontinued during
remission.

Topical calcineurin inhibitors (TCI)
Tacrolimus
◦ Tacrolimus can be used for any severity of AD.
◦ Tacrolimus 0.03% ointment is recommended in children aged 2-16,
◦ tacrolimus 0.1% ointment is recommended in patients aged over 16 years.
◦ Tacrolimus 0.1% showed no difference in potency when compared with moderate-to-
potent TCS.
Pimecrolimus
◦ Pimecrolimus 1% is effective for mild-to-moderate AD on the face and other
sensitive skin areas.
◦ Pimecrolimus 1% had similar efficacy to low-to-medium potent TCS.
◦ In Thailand, it is recommended to use on infants over three months old.

Topical phosphodiesterase 4 inhibitor
◦ Crisaborole 2% ointment has been approved by the EU and US FDA for
patients with mild-to-moderate AD.
◦ It acts by inhibiting phosphodiesterase 4 and reducing inflammatory cytokines,
resulting in a significant decrease in inflammatory skin and pruritic symptoms.
◦ It can be used twice daily in mild-to-moderate AD patients aged over three
months.
◦ Pain, burning, and stinging sensations have been reported regarding
application sites in some patients.
◦ Currently, it is not available in Thailand.

Antimicrobial therapy
◦ Antimicrobial therapy can be used in AD patients with a superimposed
bacterial infection.
◦ Suitable topical or systemic antibiotics should act against Staphylococcus
aureus (S. aureus) and Streptococcus pyogenes.
◦ The optimal duration of treatment is 1-2 weeks.
◦ The prolonged use of antibiotics is not recommended.
◦ Antibiotics are not recommended for the treatment of AD that does not have
superimposed bacterial infection.

Systemic antihistamines
◦ Sedating AHs may be helpful for the reduction of itches and sleepiness during
disease flares.
◦ It should be noted that topical AHs are not recommended because there are
no adequate evidences of topical AHs to control AD symptoms.

Systemic corticosteroids
◦ For patients with an uncontrolled disease with TCS, oral prednisolone or
intramuscular injections of triamcinolone can be administered as a short-term
treatment.
◦ Oral prednisolone at a dose of 0.5-1 mg/kg/day for up to maximum 2 weeks
can be given.
◦ Long-term use, especially in children, is not recommended, due to side effects
such as growth restriction and hormonal suppression.

Systemic immunomodulators
Ciclosporin
◦ Ciclosporin is suggested as a first-line, short-term treatment for moderate-to-
severe AD.
◦ Higher dosage of 5 mg/kg/day yields a better response and is more
efficacious than a lower dosage.
◦ Major concerned side effects are hypertension and renal impairment.
◦ Thus, treatment should be started with a dosage of 3 mg/kg/day, and then
slightly decreased at a dose of 0.5-1 mg/kg/day every two weeks.

Azathioprine
◦ Treatment for moderate-to-severe AD patients who are unresponsive or who
develop adverse effects from ciclosporin.
◦ The suggested initial dose is 50 mg/day in adult, and this dosage should be
titrated according to the clinical response and its possible side effects.
◦ The recommended dosages of azathioprine in adults and children are 1-3
mg/kg/day and 1-2 mg/kg/day.

Methotrexate
◦ Adults with severe AD.
◦ The starting doses are 5-15 mg/week in adults and 10-15 mg/m2/week in
children.
◦ The dosage should be increased weekly in steps of 2.5-5 mg/week, not
exceeding 25 mg/week.
◦ As methotrexate is teratogenic, men and women of childbearing potential
must use effective contraception during therapy.

Biologics
Dupilumab
◦ Dupilumab is a fully human monoclonal antibody that blocks the common α-
chain of IL-4 and IL-13 receptors.
◦ It has been approved as a first-line treatment by the EU and US FDA in 2017
for patients aged over six years with moderate-to-severe AD whose disease is
not adequately controlled with topical prescription therapies or when systemic
therapies are not advisable.
◦ For the treatment of Thai patients aged 12 years and older with moderate-to-
severe AD whose disease is not adequately controlled with topical prescription
therapies or when those therapies are not advisable.
◦ It can be used with or without TCS.

Biologics
◦Dupilumab
◦ The safety profile of dupilumab is favourable, with ocular complaints (in
particular conjunctivitis) being the most frequent side effect observed, in up to
28% of dupilumab users in clinical trials
◦ Most cases of conjunctivitis are transitory and can be managed successfully
with topical anti-inflammatory (ocular) agents without dupilumab withdrawal.

Phototherapy
◦ If disease control cannot be achieved with
topical measures, phototherapy (usually 4–8
weeks) can be considered.
◦ The most effective settings are narrow-band
ultraviolet B radiation and medium-dose
ultraviolet A1.
◦ Benefits have to be weighed against long-
term cumulative adverse effects, including
photodamage, skin carcinogenesis, and
melanoma induction, particularly for
ultraviolet A1.
◦ The need for frequent treatments
(usually 3–5 applications a week for a
total of 2–3 months).

Clinical practice guidelines for the diagnosis and management of atopic dermatitis. Asian Pac J Allergy
Immunol. 2021;10.12932/AP-010221-1050.

Treatment during
pregnancy and lactation
◦ There is no advice against the use of emollients, class
II and III topical corticosteroids, topical calcineurin
inhibitors, and phototherapy with ultraviolet A1 and
narrow-band ultraviolet B.
◦ Short-term systemic steroids and ciclosporin are
considered relatively safe with close monitoring, but
avoidance of azathioprine is recommended
◦ Methotrexate and mycophenolate mofetil are
contraindicated in pregnant and lactating women.

Long-term
outcomes
◦ US adults reported a striking increase in
conjunctivitis in people with atopic
dermatitis compared with healthy people
◦ A systematic review showed increased
risk of atopic dermatitis in people with
eosinophilic esophagitis compared with
controls

Bacterial, fungal, and viral
complications in atopic dermatitis
◦ Although true infection is less common, S aureus
remains the most common bacterial infection seen in
people with atopic dermatitis, with impetigo-like lesions
being the typical clinical appearance.
◦ Viral infections commonly seen in individuals with
atopic dermatitis include molluscum contagiosum,
herpes simplex virus infections (ranging from mild to
life-threatening forms of eczema herpeticum), herpes
zoster, and cutaneous warts.

Atopic dermatitis

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