ATOPIC DERMATITIS-CLINICAL FEATURES AND DIAGNOSIS
What is atopic dermatitis (AD)?
It is a most common chronic inflammatory skin disease common
in children and has a relapsing course.
It affects 10-30% of children worldwide.
Which is the common age group?
AD has an onset before 5 years of age.
AD typically begins in infancy. Approximately 50% of
patients experience symptoms in the 1st yr of life, and an additional 30% are
diagnosed between 1 and 5 yr of age.
F:M – 1.3:1
Persistent atopic dermatitis
may be present in approximately 50 percent of patients diagnosed with atopic
dermatitis during childhood.
What are the risk factors?
Family history (Approximately
70 percent of patients have a positive family history of atopic diseases)
Filaggrin gene loss of
function mutation
High levels of calcium carbonate
in water
Hygiene hypothesis has
protective role
What is the pathogenesis?
What are the different hypothesis for atopic dermatitis?
Whether skin
inflammation is initiated by skin barrier dysfunction ("outside-in"
hypothesis) or by immune dysregulation ("inside-out"
hypothesis) is still in debate.
How does skin barrier dysfunction lead to AD pathogenesis?
The epidermal skin
barrier prevents the allergen, irritant and microbes from entering the body. It
also prevents the loss of water.
Which layer of epidermis has the barrier function?
Stratum corneum.
It consists of
vertical stacks of anucleate corneocytes packed with keratin filaments embedded
in a matrix of filaggrin breakdown products.
The corneocyte
layers are embedded in an extracellular matrix replete with multiple lamellar bilayers
enriched in ceramides, cholesterol, and free fatty acids derived from secreted
lamellar body precursor lipids.
What determines the permeability of epidermis?
The complex
interactions between terminal differentiated keratinocytes on the surface of
the skin and groups of structural proteins, such as filaggrin, regulatory
enzymes, and lipids. Filaggrin deficiency is a major determinant of
defective barrier function.
Also, the imbalance between
protease and anti-protease activity of stratum corneum determines the skin
permeability.
The tight junctions
between cells of stratum granulosum are thought to seal the free diffusion of
macromolecules.
What happens in AD?
Genetically impaired
skin barrier function with increased transdermal water loss.
Higher levels of water loss is associated
with greater disease severity.
What is Filaggrin?
Filaggrin is a
protein produced by differentiating keratinocytes encoded by the FLG gene.
The cells of the
granular layer contain dense cytoplasmic granules primarily composed of pro-filaggrin,
with other protein components required for the formation of the corneocytes
that are responsible for the barrier function of the skin.
What is the function of filaggrin?
The hygroscopic free
amino acids and their derivatives, such as pyrrolidone carboxylic acid and
trans-urocanic acid, resulting from the breakdown of filaggrin, are major
components of the natural moisturizer factor (NMF).
NMF maintains skin
hydration and water retention within the stratum corneum in conditions of low
environmental humidity.
50% of patients with severe AD have FLG
mutation. FLG mutation is strongly associated with development of food allergy
and eczema herpeticum. Nonetheless, up to 60% of carriers of a FLG mutation do
not develop atopic diseases.
What are the other proteins in stratum corneum?
Corneodesmosin,
desmoglein-1, desmocollin-1, transglutaminase-3, and enzymes involved in the
production of natural moisturizing factor were found to be at lower levels in
children with AD.
What are the genetic mutations associated with AD?
FLG loss of function mutation leading
to defective Filaggrin protein.
SPINK5 mutation
What other disease FLG mutation is
associated with?
Ichthyosis vulgaris and pachyonychia congenita
What other disease is SPINK5 mutation is associated with?
Netherton syndrome
which is a rare autosomal recessive disorder characterized by severe atopic
dermatitis and a specific hair shaft abnormality.
How impaired immune function leads to AD?
Innate immune system
is first line of rapid response mechanism to prevent microbial invasions.
It consists of
Physical barrier
(stratum corneum and intercellular junctions);
Antimicrobial
peptides (AMPs), cytokines, and chemokines;
Antigen-presenting
cells, keratinocytes, mast cells, and PMNs; and
Skin-resident normal
microbial flora
Also, the keratinocytes and APCS in the skin express innate immune receptors called pattern recognition receptors which include toll like receptors (TLRs).
What is the function of TLRs?
Stimulation of TLRs
by tissue damage or microorganisms leads to the release of a wide range of
inflammatory mediators, including AMPs, cytokines, and chemokines, and enhances
the strength of tight junctions to further limit the penetration of allergens and
microorganisms
An additional
function of TLRs is to induce dendritic cell maturation, which determines the
character and magnitude of the adaptive immune response.
What happens in AD skin?
The defective innate
immune system is unable to prevent the microbial invasion leading to significant
skin damage, excessive allergen penetration and abnormal exaggerated adaptive
immune system activation.
What is atopic and non-atopic asthma?
Atopic
eczema is
associated with IgE-mediated sensitization (at onset or during the course of
eczema) and occurs in 70–80% of patients with AD.
Nonatopic
eczema is
not associated with IgE-mediated sensitization and is seen in 20–30% of
patients with AD. Both forms of AD are associated with eosinophilia.
What is the effect of adaptive immune system?
In AD the adaptive
immune system on exposure to allergen preferentially activates Th-2 cell and
Th-2 cytokines like IL-4,5 and 13.
IL-4 and 13 induces
isotype switching to IgE synthesis.
Il-5 induces
eosinophil development.
In patients with AD
the skin is found to have cells with high IL-4 and IL-13.
These cytokines, IL-4,13 appear
to modulate the epidermal barrier function by suppressing the expression of
terminal keratinocyte differentiation genes (e.g., FLG, loricrin,
involucrin), inhibiting the production of AMPs, and promoting epidermal
hyperplasia.
What is different in terms of cytokine and chemokine expression between acute and chronic AD?
Compared with the skin of healthy individuals, both unaffected skin and acute skin lesions of patients with AD have an increased number of cells expressing IL-4 and IL-13.Chronic AD skin
lesions, by contrast, have fewer cells that express IL-4 and IL-13, but
increased numbers of cells that express IL-5, granulocyte-macrophage
colony-stimulating factor, IL-12, and interferon (IFN)-γthan acute AD lesions.
What are differences between acute and chronic AD?
Acute AD is characterized
by spongiosis i.e. intercellular epidermal edema leading to stretching and
eventual rupture of the intercellular attachments with formation of vesicles. There
is marked perivenular T-cell and inflammatory monocyte-macrophage infiltration
in acute AD lesions.
Chronic, lichenified
AD is characterized by a hyperplastic epidermis with hyperkeratosis and minimal
spongiosis. There are predominantly IgE-bearing Langerhans cells in the
epidermis, and macrophages in the dermal mononuclear cell infiltrate. Mast cell
and eosinophil numbers are increased, contributing to skin inflammation.
What are the clinical features?
Dry skin and severe
pruritus are the cardinal signs of atopic dermatitis.
Acute eczema is
characterized by intensely pruritic erythematous papules and vesicles with
exudation and crusting, whereas subacute or chronic lesions present as dry,
scaly, or excoriated erythematous papules. Skin thickening from chronic
scratching (lichenification) and fissuring may develop over time.
In many patients,
lesions in different stages may be present at the same time.
Most patients with
atopic dermatitis have a cutaneous hyperreactivity to various environmental
stimuli, including exposure to food and inhalant allergens, irritants, changes
in physical environment (including pollution, humidity, etc.), microbial
infection, and stress.
How is the clinical feature of AD different in different age groups?
In infants and young
children (zero to two years), atopic dermatitis typically presents with
pruritic, red, scaly, and crusted lesions on the extensor surfaces and cheeks
or scalp. There is usually sparing of the diaper area .Acute lesions can
include vesicles, and there can be serous exudates and crusting in severe
cases.
In older children and adolescents (2 to
16 years), atopic dermatitis is characterized by less exudation and often
demonstrates lichenified plaques in a flexural distribution, especially of the
antecubital and popliteal fossae, volar aspect of the wrists, ankles, and neck.
The sides of the neck may show a
reticulate pigmentation, the so-called "atopic dirty neck".
In adults, atopic dermatitis is
considerably more localized and lichenified. The areas involved are in most cases
the skin flexures. Less frequently, the dermatitis may involve the face, neck,
or hands.
In all age groups any area of the body
can be involved in severe cases. However, the lesions are uncommon in the
axillary, gluteal or groin areas. Lesions in these areas should prompt consideration
of other diagnoses such as psoriasis, allergic contact dermatitis, or
seborrheic dermatitis.
What are the associated features of AD?
Patients with atopic dermatitis may
present a variety of cutaneous findings, so-called atopic stigmata, which
include
Centro facial pallor,
White dermographism,
Keratosis pilaris
Palmar hyperlinearity,
Pityriasis alba
Periorbital darkening and Dennie-Morgan
infraorbital folds
thinning or absence of the lateral
portion of the eyebrows (Hertoghe's sign)
Infra-auricular and retro-auricular
fissuring, and nipple eczema.
Although considered minor diagnostic
criteria, these findings are frequently seen and may be supportive of the
diagnosis of atopic dermatitis in some patients.
What are the clinical variants of AD?
Atopic hand eczema
Eyelid eczema
Atopic cheilitis
What is the clinical course of AD?
Atopic dermatitis follows a chronic
relapsing course over months to years. Patients with mild disease may
experience intermittent flares with spontaneous remission, but patients with
moderate to severe dermatitis rarely clear without treatment.
The majority of
patients are clear of eczema by late childhood, but the disease may persist
into adolescence and adulthood in a variable proportion of cases.
What clinical infections AD patient are predisposed to?
Patients with atopic dermatitis are
predisposed to the development of bacterial and viral skin infections.
Because Staphylococcus aureus colonizes nearly 100 percent of
patients, impetiginization of lesions of atopic dermatitis is frequent and is
associated with disease exacerbation.
However, infection from community-acquired methicillin-resistant Staphylococcus aureus is uncommon among children with atopic dermatitis.
What is eczema herpeticum?
It is also known as Kaposi’s varicelliform
eruption and is the rapid dissemination of a HSV infection on the affected skin
of patients with atopic dermatitis.
It is a rare condition occurring in
<3% cases of AD but can be recurrent.
Severe eczema, high levels of
serum IgE, and history of food allergy or asthma appear to be predisposing
factors.
What is atopic march?
Patients with atopic dermatitis and a
genetic predisposition to produce IgE following exposure to allergens may
develop a typical sequence of atopic dermatitis, allergic rhinitis, asthma, and
food allergy at certain ages (the "atopic march").
What are co-morbidities associated with AD?
Ichthyosis vulgaris in 10-30% cases
Vernal keratoconjunctivitis
May be associated with CVS disease
Microcytic anemia
ADHD
Depression
Suicidal tendency
What is the diagnostic criteria for AD?
What are the differential diagnosis?
Contact dermatitis-
The localization of dermatitis to a
specific skin area, history of exposure to irritants or potential sensitizers,
and a relevant patch test positivity suggest the diagnosis of contact
dermatitis.
Seborrheic dermatitis-
The presence of salmon-red erythematous
skin patches with greasy scale, involvement of the scalp, and little or no
pruritus support the diagnosis of seborrheic dermatitis.
Psoriasis-
Diaper area involvement with little
scaling
Scabies
Drug reactions
Acrodermatitis enteropathica
Netherton syndrome
LCH
Wiskott Aldrich syndrome
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