2. INTRODUCTION
• Atopic dermatitis is a chronic, relapsing, pruritic, inflammatory skin disease
• often associated with an elevated serum level of immunoglobulin E (IgE)
• often associated with a personal or family history of atopy
• sensitization to environmental or food allergens is clearly associated with the
atopic dermatitis phenotype, it does not seem to be a causative factor
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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3. Epidemiology
• increased two- to threefold over the past 30 years
• 5–20% of children and 2–10% of adults are affected
• the first manifestation of the atopic march
--- Approximately 50% of affected children show symptoms in the first
year of life
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4. Current Insights into Atopic March
Children 2021, 8(11), 1067; https://doi.org/10.3390/children811106
P.1
5. Epidemiology
higher rates of atopic dermatitis :
• Africa, Oceania and Asia-Pacific --- overall prevalence of Taiwan is 4.6-
6.7%(2020台灣皮膚科醫學會異位性皮膚炎診療共識)
• slight female preponderance
• urban areas and high-income countries
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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6. Risk factors
Genetic risk factors
• Loss-of-function variants in the
FLG gene
• genes involved in the regulation
of innate host defenses and T
cell function
Environmental exposures
• Climate(溫度、濕度)
• air pollution
• inverse relationship with early
exposure to nonpathogen
microorganisms ---hygiene
hypothesis
• water hardness(high hardness)
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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7. Allergy, Parasites, and the Hygiene Hypothesis
MARIA YAZDANBAKHSH, PETER G. KREMSNER, AND RONALD VAN REEAuthors Info & Affiliations
SCIENCE 19 Apr 2002 Vol 296, Issue 5567 pp. 490-494 DOI: 10.1126/science.296.5567.490
8. Etiology
內因
• impaired skin barrier function
• immunologic abnormalities
• Neuroimmune interactions
外因
• environmental interactions
• Alteration of cutaneous
microbiome
• infectious triggers
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9. What Causes Eczema?
Reviewed by Mark Boguniewicz, MD (July 01, 2015)
https://www.nationaljewish.org/conditions/eczema-
atopic-dermatitis/what-causes-eczema
10. PATHOPHYSIOLOGY
impaired skin barrier function is caused by :
1.reduced filaggrin production
2.imbalance between stratum corneum protease and antiprotease
activity
3.tight junction abnormalities
4.altered composition and lamellar organization of epidermal lipids,
microbial colonization
5.itch-scratch cycle
6.release of proinflammatory cytokines
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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12. PATHOPHYSIOLOGY
FLG variants
• filaggrin precursor profilaggrin is encoded by the FLG gene, located in the
epidermal differentiation complex on chromosome 1q23.3
• associated with specific atopic dermatitis phenotypes---early-onset and
persistent disease…
• FLG genotype may also influence the response to treatment
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis AUTHOR:William Howe, MD
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13. PATHOPHYSIOLOGY
1.Stimulation of TLRs
2. Release of alarmins activate inflammatory type 2 immune cells
3. Activated Th2 cells release IL-4 and IL-13
4. Affecting the epidermal barrier function by suppressing the expression of
terminal keratinocyte differentiation genes(eg, FLG)
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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14. PATHOPHYSIOLOGY
immunologic abnormalities
• Both the innate and acquired immune responses have a role in the
pathogenesis of type 2 inflammation in atopic dermatitis
• cytokine cluster on chromosome 5q31.1 including genes encoding IL-13 and
IL-4
• the locus on chromosome 11q13.5 involved in the regulation of innate host
defenses and T cell function
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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15. PATHOPHYSIOLOGY
Neuroimmune interactions
• Itch is mediated by
1.unmyelinated, histamine-sensitive
2.non-histamine-sensitive peripheral C-nerve fibers
• Chronic itch results from complex interactions among non-histamine-
sensitive peripheral C-nerve fibers, keratinocytes, and Th2 immune cells.
• Type 2 cytokines, including IL-4, IL-13, and IL-31, are thought to be relevant
mediators of chronic itch in atopic dermatitis
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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16. Clinical Manifestations
Common features Acute 1.intensely pruritic
2.erythematous papules
3.vesicles with exudation
subacute or chronic 1.Dry, scaly, or excoriated,
erythematous papules
2.lichenification
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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17. Clinical
Manifestations
• In children and adults with deeply
pigmented skin, erythema may appear
dark brown
infants 1.pruritic, red, scaly, and crusted
lesions
2.face, scalp, cheeks, and
extensor surfaces of the
extremities
(diaper area沒有)
children 1. less exudation and often
demonstrates lichenified plaques
2.antecubital and popliteal fossae,
head, and neck
3. atopic dirty neck
adolescents and
adults
1.localized and lichenified plaques
2.flexural areas , head and neck
regions
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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18. Clinical Manifestations
Associated features---a variety of cutaneous findings
• Centrofacial pallor
• White dermographism(皮膚畫紋症)
• Keratosis pilaris (毛孔角化症)
• Palmar hyperlinearity
• Pityriasis alba (白色糠疹)
• Periorbital darkening ("allergic shiners") and Dennie-Morgan infraorbital folds
• Thinning or absence of the lateral portion of the eyebrows (Hertoghe's sign)
• Infra-auricular and retroauricular fissuring
• Nipple eczema
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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26. Clinical
variants
Regional and morphologic variants of atopic
dermatitis have been described in both
children and adults
• Atopic hand eczema
1.involving the volar wrists and dorsum of
the hands
2.most common in adults
3. exposed to "wet work" environments
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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28. Clinical variants
• Clinical variants
1.may be the only manifestation
2.associated with lichenification
3.presence of Dennie-Morgan lines
• Atopic cheilitis
1. characterized by dryness, peeling, and fissuring of the lips
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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30. Laboratory findings
• 80 percent of patients have increased serum IgE levels, often with
eosinophilia
• IgE level tends to vary with disease severity
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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31. Diagnosis
ESSENTIAL FEATURES
• Pruritus
• Facial and extensor eczema in
infants and children
• Flexural eczema in adults
• Chronic or relapsing dermatitis
FREQUENTLY ASSOCIATED FEATURES
• Personal or family history of atopic
disease
• Xerosis
• Cutaneous infections
• Nonspecific dermatitis of the hands
or feet
• Elevated serum IgE levels
• Positive immediate-type allergy
skin tests
• Early age of onset
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32. Diagnostic criteria
The United Kingdom Working Group on atopic dermatitis criteria
• itchy skin, plus three or more of the following :
History of skin creases being involved including antecubital fossae, popliteal fossae, neck, areas around eyes,
and fronts of ankles.
• History of asthma or hay fever (or history of atopic disease in a first-degree relative for children <4 years of
age).
• The presence of generally dry skin within the past year.
• Symptoms beginning in a child before the age of two years. This criterion is not used to make the diagnosis in a
child who is under four years old.
• Visible dermatitis involving flexural surfaces. For children under four years of age, this criterion is met by
dermatitis affecting the cheeks or forehead and outer aspects of the extremities
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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33. Diagnostic criteria
The American Academy of Dermatology
criteria for the diagnosis of atopic
dermatitis
Essential features 1.Pruritus
2.Eczema (acute,
subacute, chronic) with
typical morphology and
age-specific patterns
3.Chronic or relapsing
history
Important features 1.Early age of onset
2.Personal and/or family
history of atopy
3.IgE reactivity
4.Xerosis
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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38. Differential Diagnosis
2. Langerhans cell histiocytosis
• hemorrhagic or petechial lesions(小出血點<3mm)
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39. Differential Diagnosis
3.Seborrheic dermatitis
• most common differential diagnosis in infants.
• presence of salmon-red, erythematous skin patches with greasy scale,
involvement of the scalp
• little or no pruritus
• may coexist with atopic dermatitis
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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40. Differential Diagnosis
4.Allergic or irritant contact dermatitis
• history of exposure to irritants or potential sensitizers
• a relevant patch test positivity suggest the diagnosis of contact dermatitis.
• skin biopsy is not useful to distinguish irritant or allergic contact dermatitis
from atopic dermatitis(identical histopathologic features)
• may coexist with atopic dermatitis
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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41. Differential Diagnosis
5. Psoriasis
• often involves the diaper area, with well-demarcated, erythematous patches
with little scale in infants and young children
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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42. Differential Diagnosis
6.Scabies
• intensely pruritic skin
• presence of burrows(疥隧道) in interdigital spaces and flexor surfaces of the
wrists, elbows, axilla, or genitals
• presence of vesicopustules on the palms and soles suggest the diagnosis of
scabies
• The demonstration of mites or eggs by skin scraping or dermoscopy can
confirm the diagnosis
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43. Differential Diagnosis
Less common conditions may be confused
• Exanthematous (maculopapular) drug eruption
• Zinc deficiency
• Netherton syndrome
• Cutaneous T cell lymphoma
Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis
AUTHOR:William Howe, MD
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44. Treatment
• skin hydration with emollients
• lukewarm baths for 15–20 minutes+application of fragrance-free emollients
• avoidance of triggers
• pharmacologic therapy to reduce pruritus and inflammation
Nelson Essentials of Pediatrics
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45. Topical antiinflammatory agents
Topical corticosteroids
• effective for the acute and
chronic phases
• The least potent
corticosteroid should be used
• Low-potency
nonfluorinated(非氟化)
corticosteroids should be used
on the face, intertriginous
areas, and large areas
• Local adverse effects---skin
atrophy and striae
Immunomodulators(tacrolimus,
pimecrolimus and Crisaborole )
• second-line agents
• short-term and intermittent
treatment
• used on all body locations and
are especially useful on delicate
skin
• The most common adverse is
local skin irritation
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46. Severe, refractory atopic dermatitis
• systemic corticosteroids
• Cyclosporine
• dupilumab(IL-4、IL-13 inhibitor)
• rarely, antimetabolites such as mycophenolate mofetil or methotrexate
• Phototherapy
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47. Complications
• 90% of patients with atopic dermatitis have colonization of lesional skin with
Staphylococcus aureus (S. aureus)
• associated with disease severity. S. aureus secretes exotoxins that act as
superantigens
• infected atopic dermatitis often presents as impetiginous(膿痂疹), pustular
lesions with crusting and honey-colored exudate
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48. Complications
Herpes simplex superinfection(Kaposi varicelliform eruption)(eczema
herpeticum)
• A rare complication, occurring in less than 3 % of patients
• occasionally being recurrent
• misdiagnosed as bacterial infection and should be considered if skin lesions
fail to respond to antibiotics.
• Coxsackieviruses may produce similar lesions
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50. Prognosis
• Symptoms become less severe in two thirds of children, with complete remission for
approximately 20%
• More widespread early onset disease that is concomitant with asthma and allergic rhinitis,
family history of atopic dermatitis, and elevated serum IgE levels may predict a more
persistent course
• a single cause and cure for atopic dermatitis is unlikely
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51. Prevention
• identify and avoid allergens and irritants including soaps, detergents, fragrances, chemicals,
smoke, and extremes of temperature and humidity
• wool and synthetic fabrics can be irritating to the skin, 100% cotton fabric is preferred.
• Sweating is a recognized trigger.
• Fingernails should be trimmed
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Approximately 50% of affected children show symptoms in the first year of life, and 80% experience disease onset before 5 years of age
In the United States, the overall prevalence is approximately 16 percent 美國黑人19%
family history of atopy:70 percent of patients have a positive family history of atopic diseases. Children with one atopic parent have a two- to threefold increased risk of developing atopic dermatitis
FLG gene : including allergic contact dermatitis, asthma, and food allergy
Two systematic reviews provided evidence to support an inverse relationship between atopic dermatitis and exposure to endotoxin, early daycare, helminth(蠕蟲) infestation, number of siblings, farm animals, and pet dogs in early life(病毒、細菌沒用)
2021 meta-analysis of seven observational studies that included nearly 386,000 participants found a modest increase of risk of atopic dermatitis in children exposed to hard water (odds ratio [OR] 1.28, 95% CI 1.09-1.50). However, the authors considered the certainty of this estimate to be very low, due to high risk of bias and heterogeneity in the definition of “hard water.”對硬水定義不明確
A meta-analysis of 95 observational studies found that 70 percent of patients with atopic dermatitis carried S. aureus on lesional skin striking decrease in the skin microbial diversity during flares, with reduction of Streptococcus, Corynebacterium, and Propionibacterium genera and increase in S. aureus density
exaggerated cutaneous inflammatory response to environmental triggers
內因:A diverse set of genes encoding epidermal structural proteins (filaggrin) and elements of the immune system play a major role in atopic dermatitis
Activated Langerhans cells in the dermis expressing surface-bound immunoglobulin E (IgE) stimulate T cells
activated Th2 lymphocytes infiltrate the dermis
through interleukin 4 (IL-4), IL-13, and IL-5
stratum corneum(角質層), which consists of vertical stacks of anucleate corneocytes packed with keratin filaments embedded in a matrix of filaggrin breakdown products
results in increased transepidermal water loss, increased permeability, reduced water retention, and altered lipid composition
Tight junctions are located in the granular layer of the epidermis below the stratum corneum and are thought to seal the intercellular space to prevent the free diffusion of macromolecules
Inflammatory cytokines, such as interleukin (IL) 4, IL-13, IL-17A, IL- 22, IL-25, and IL-31, have also been shown to suppress filaggrin expression
stratum corneum(角質層), which consists of vertical stacks of anucleate corneocytes packed with keratin filaments embedded in a matrix of filaggrin breakdown products
results in increased transepidermal water loss, increased permeability, reduced water retention, and altered lipid composition
2.FLG不同variants影響表現型 包括early-onset and persistent disease; increased risk of asthma, allergic rhinitis, and food allergy; increased prevalence and persistence of hand and foot dermatitis during adulthood; and multiple contact allergies
3.3321delA in East Asian patients K4022X in Korean and Northern Chinese patients S2554X, S2889X, S3296X, and Q1701X in Japanese patients
1.Stimulation of TLRs by tissue damage or microorganisms leads to the release of a wide range of danger signals (alarmins) such as IL-1A
2. The release of alarmins triggered by epithelial barrier disruption activates inflammatory dendritic epidermal cells and type 2 immune cells, including Th2 cells
3. Activated Th2 cells release IL-4 and IL-13, which promote inflammation as well as B cell IgE class switching
4. Th2 cytokines (IL-4, IL-13, IL-31, and IL-22) affect the epidermal barrier function by suppressing the expression of terminal keratinocyte differentiation genes (eg, FLG, loricrin, involucrin)
responsiveness of itch to inhibition of the IL-4 receptor (dupilumab) and downstream IL-4 signaling (Janus kinase [JAK] inhibitors) supports the relevance of these neuroimmune interactions in the pathogenesis of chronic atopic itch
1.The sides of the neck may show a reticulate pigmentation
2. In all age groups, any area of the body can be involved in severe cases, although it is uncommon to see lesions in the axillary, gluteal, or groin area. Lesions in these locations should prompt consideration of other diagnoses, such as psoriasis, allergic contact dermatitis, or seborrheic dermatitis
1.Although considered minor diagnostic criteria, these findings are frequently seen and may be supportive of the diagnosis of atopic dermatitis in some patients
2.Regional and morphologic variants of atopic dermatitis have been described in both children and adults
may be the only manifestation of atopic dermatitis or occur in association with the classic age-related manifestations
Because of the high variability of clinical presentation, related to age, ethnicity, and severity, the diagnosis may be difficult, especially in infants and older adults.
皮膚切片:Skin biopsy is of little value, but may be performed to exclude other skin diseases
過敏原檢查:Skin testing or serum specific IgE testing may be helpful in assessing the contribution of food or environmental allergies to disease expression if history is suggestive
1.goals of eczema therapy are to reduce the number and severity of flares and to increase duration of disease-free periods
2.Prevention of xerosis(乾燥症) is important for pruritus control
3.Emollients should be ointments or creams. Lotions are not as effective because they contain water or alcohol and may have a drying effect owing to evaporation.
4.A mild nonsoap cleanser also is recommended
Corticosteroids are ranked by potency into seven classes
Higher potency corticosteroids should be used for limited periods
systemic adverse effects (hypothalamic-pituitary-adrenal axis suppression and hyperglycemia) ---緩解要降級
superantigens, stimulating T cells and increasing IgE production
Topical antibiotics, such as mupirocin or retapamulin, can be used to treat local areas of infection. Oral antibiotics such as cephalexin, dicloxacillin, or amoxicillin-clavulanate can be used for multifocal disease or for infection around the eyes and mouth that is difficult to treat topically
Bacterial cultures may be helpful in patients who do not respond to oral antibiotics or who have infection after multiple antibiotic courses given the increasing incidence of community-acquired methicillin-resistant S. aureus(MRSA)
A pooled analysis of 45 studies including over 110,000 subjects found that 20 percent of cases of childhood atopic dermatitis had persistent disease eight years after the diagnosis and less than 5 percent had persistent disease 20 years after the diagnosis
The age of onset was the main factor associated with persistence of atopic dermatitis. The hazard ratio was 2.65 (95% CI 2.54-2.75) for onset at age 2 to 5 years, 4.22 (95% CI 3.86-4.61) for onset at age 6 to 11 years, and 2.04 (95% CI 1.66-2.49) for onset at age 12 to 17 years compared with age of onset <2 years
Other risk factors for persistence were disease severity and duration and female sex
infants and younger children who do not respond to the usual therapies, identifying and removing a food allergen
Food allergy is not a common trigger for older patients.
In severe atopic dermatitis, 30% of patients may have a food allergy trigger; for moderate eczema, 15%; for mild, less than 10%
Other environmental exposures, such as dust mites
