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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