dermatitis

Pathophysiology of Dermatitis

• Dermatitis is an inflammatory disruption of the epidermis, triggered by physical or immunological provocation.
• Dermatitis and eczema are frequently used interchangeably.
• Histologically, dermatitis appears as spongiosis.
• Impairment of the skin's barrier function causes increased transepidermal water loss.

Learning Outcomes

• Compare the pathophysiology of various forms of dermatitis (e.g., allergic, atopic, contact, irritant).
• Describe the etiology and pathogenesis of atopic dermatitis.
• Describe the etiology and pathogenesis of allergic contact dermatitis (type 4 delayed hypersensitivity).
• Describe the etiology and pathogenesis of irritant dermatitis and its relationship to atopic and contact dermatitis, relating it to clinical features.
• Describe the etiology and pathogenesis of seborrheic dermatitis, and relate it to clinical features.

Atopic Dermatitis

• A complex, familial transmitted skin disease caused by interactions between genetic, immune, and environmental risk factors.
• Primarily begins in childhood with variable progression.
• Itch is the hallmark symptom; in severe cases, it can be unrelenting and lead to sleep disturbance and excoriated, infection-prone skin.
• Often accompanied by atopic co-morbidities (e.g., allergic asthma and allergic rhinitis), resulting in impaired quality of life.
• Has a prevalence peak of 15% to 20% in early childhood in industrialized countries.
• Often has variable rates of remission with continuous or recurring symptoms into adulthood
• Characterized by eczematous dermatitis (acute, subacute, or chronic).
• Frequently involves the face and extensor surfaces of the extremities in infancy.
• In children and adults, flexural eczema or lichenification is common.
• Associated with personal or family history of atopy (allergic rhinitis, asthma, atopic dermatitis).
• Associated with xerosis (dry skin) or skin barrier dysfunction.
• Associated with immunoglobulin E (IgE) reactivity.
• Pathogenesis driven by skin barrier defects (most importantly in the FLG gene) and environmental effects, alterations in immune responses in T cells, antigen processing, inflammatory cytokines, host defense proteins, allergen sensitivity, and infection.

AD Clinical Features

• Acute: Characterized by erythematous papulovesicles (small red bumps or blisters), often with pinpoint crusting or weeping due to exudation and intense pruritus leading to scratching.
• Subacute/Chronic: Characterized by dry, scaly plaques, excoriation (scratching), and lichenification (thickened skin with exaggerated skin lines due to chronic rubbing).
• Lesions may appear simultaneously in multiple areas, or within the same lesion.
• Indistinguishable clinically or histologically from other eczematous conditions, such as allergic contact dermatitis or nummular dermatitis.
• Patients with darker skin tones often present with follicular accentuation, flat-topped papules in lichenified areas, and a tendency toward hyperpigmentation in inflamed areas.
• Distribution varies with age
• Infant lesions primarily affect the face, scalp, and extensor surfaces of the extremities
• The diaper area is usually spared.
• In older children and adults with long-standing AD the lesions are commonly located in flexural folds of the extremities.
• Chronic hand eczema is common in adults, and at least one third of patients exhibit filaggrin deficiency, resulting in ichthyosis vulgaris, keratosis pilaris, and hyperlinear palms.

AD & Skin Barrier

• A decrease in skin barrier function due to the downregulation of cornified envelope genes (e.g., keratin, filaggrin, loricrin) is associated with AD.
• Reduced ceramide levels, increased endogenous proteolytic enzyme activity, and enhanced transepidermal water loss lead to compromised skin barrier function.
• Exposure to exogenous proteases (e.g., from house dust mites and S. aureus) and scratching further damage the barrier, increasing allergen absorption and microbial colonization.
• This can lead to higher-level allergic responses and predispose those with compromised skin barriers to food allergies and respiratory allergies.

AD & Genetics

• Many genes are associated with AD but a critical loss of function mutation of the FILAGGRIN gene is often noted.
• The FILAGGRIN gene is located on chromosome 1q21, and is part of a larger complex involved in epidermal differentiation.
• Mutations impair skin barrier function, increasing transepidermal water loss (TEWL) and promoting allergen attachment and entry.
• Although filaggrin mutations are associated with AD, they are not present in all affected individuals, suggesting other factors are also involved in AD development.

Immunopathology of AD

• Clinical presentation and duration of illness help in characterizing AD as non-lesional, acute, or chronic.
• Nonlesional AD shows mild epidermal hyperplasia and sparse perivascular T-cell infiltrate.
• Acute AD lesions show epidermal spongiosis leading to kerotinocyte cohesion disruption. Increased infiltration of activated memory T-cells with skin-homing cutaneous lymphocyte-associated antigen (CLA) is also present.
• Other immune responses include mast cell activation that contributes to inflammation and itching, and the rare presence of eosinophils, basophils, and neutrophils.
• In nonlesional AD, fewer surface-bound IgE molecules are observed in dendritic cells compared to lesional skin.
• Chronic lichenified lesions display hyperplastic epidermis, prominent hyperkeratosis, and minimal spongiosis. Increased IgE-bearing Langerhans cells (LCs) are observed in the epidermis, with macrophages dominating the dermal mononuclear cell infiltrate. Chronic lesions also show increased mast cells.
• Neutrophils are generally absent, even with Staphylococcus aureus colonization; eosinophils are increased in chronic disease.

AD & Inflammation

• Atopic dermatitis (AD) inflammation is orchestrated by local expression of inflammatory cytokines causing significant immune dysregulation and affecting skin barrier function.
• Key differences in AD epidermis compared to normal epidermis include highly expressed Thymic Stromal Lymphopoietin (TSLP) which activates dendritic cells promoting Th2 immune responses, increasing inflammation.
• Interleukin-33 (IL-33) is released by damaged or stressed keratinocytes, which enhances type 2 immunity and amplifies allergic inflammation.
• Many cytokines, including IL-4, IL-5, IL-13, IL-25, IL-31, and IL-33 have been identified in AD lesions.
• Type 2 cytokines are present in all stages of AD, and innate lymphoid type 2 cells, mast cells, and basophils are involved in their secretion.
• Multiple cell types produce overlapping cytokines, which leads to increased redundancy in the allergic inflammatory process.
• Treating the disease by targeting cytokines is often more effective than targeting specific cells.
• Beyond Th2 pathways, cytokines such as IL-22 and IL-17 play a significant role in AD by affecting terminal keratinocyte differentiation, filaggrin expression, and contributing to skin barrier dysfunction by inhibiting the process.

AD & Chemokines

• CTACK (CCL27) is highly upregulated in AD, attracting skin-homing CLA⁺ CCR10⁺ T cells to the affected skin. This is similar to the chemokines CCR4 and CCL17, which are expressed on skin-homing CLA⁺ T cells and bind to CCL17 on cutaneous venules, supporting T-cell migration into the skin.
• Macrophage-derived chemokine (MDC) and Thymus and activation-regulated cytokine (TARC) are also involved, acting as chemokines in recruiting Th2 cells to AD lesions. Elevated levels of these chemokines are present in atopic dermatitis.
• T helper 1 cell migration is also influenced by elevated chemokines including Fractalkine and IFN-γ-inducible protein 10 (IP-10). Monokine induced by IFN-γ (MIG) is also involved in chronic disease
• Macrophage chemoattractant protein-4 (MCP-4), Eotaxin and Regulated on activation, normal T cell expressed and secreted (RANTES) attract macrophages, eosinophils, and T cells into skin lesions.
• Severity of atopic dermatitis frequently correlates with TARC levels.

Immune Effects on Epithelial Differentiation

• Dry skin in individuals with AD often results in increased transepidermal water loss and compromised skin barrier function, particularly from reduced natural moisturizing factors and a reduced rate in epidermal turnover.
• Only a minority of AD patients have FLG variants mutations
• Other genetic variants involved in the epidermal differentiation complex (EDC) and tight junctions are less frequent but still occur.
• The majority of patients likely exhibit immune-mediated reduction in epidermal turnover.
• Decreased production of epidermal structural proteins, filaggrin breakdown products, and epidermal lipids occur, along with the creation of antimicrobial peptides (AMPs).
• Key cytokines, including TSLP, IL-4, and IL-13 are potent inhibitors of filaggrin production in keratinocytes, causing additional dysfunction from synergistic action with additional cytokines like IL-17, IL-22, IL-25, and IL-33, which further suppress epidermal proteins and lipid expression.
• Activation of proteases and lipases combined with the above results in defective epidermal barrier function and altering epidermal acidification, and loss of moisturing, thereby increasing allergen and microbial penetration.

Basis of Pruritus in AD

• Pruritus is a major feature in atopic dermatitis and results from cutaneous hyperreactivity and scratching caused by exposure to allergens, fluctuations in humidity, sweating, and low irritant concentrations.
• Mechanical scratching injuries produce pro-inflammatory cytokine and chemokine release, perpetuating a vicious scratch-itch cycle.
• The cause of pruritus in AD is not fully understood, but the releases of histamine, stress-induced neuropeptides (e.g., substance P, CGRP), and proteases that act on protease-activated receptors (PARs), particularly PAR-2 are also implicated. Elevated protease activity is seen in inflamed atopic dermatitis.
• Eicosanoids which are derived from arachidonic acid, along with eosinophil-derived proteins such as major basic protein (MBP) and eosinophil-derived neurotoxin (EDN) have also been implicated as contributing factors in causing itching.

Allergic Contact Dermatitis

• Caused by a cell-mediated hypersensitivity reaction (Type IV) triggered by skin exposure to an environmental allergen.
• Prior sensitization to the allergen is required before a reaction is elicited.
• Allergens often bind to skin proteins to form antigens that the immune system recognizes..
• Sensitization results from T cell activation, leading to an inflammatory response on subsequent allergen exposure.
• Characteristic of atopic dermatitis, the acute phase is characterized by the presence of pruritus, erythema, edema, and vesicles. The vesicles are often confined to the area of direct exposure, although with chronic exposure, lesions may spread, resulting in lichenification and scaling. The skin can become thick and leathery.
• Identifying the causal allergen through patch testing is a crucial diagnostic approach.
• Treatment focuses on allergen avoidance and patient education.

Irritant Dermatitis

• Common in cold seasons due to wet-to-dry cycling.
• The duration and frequency of contact with irritants can help to improve symptoms. Conversely , the exposure to allergens often requires complete avoidance to clear irritant contact dermatitis.
• The cause can be physical damage to the epidermis, such as with solvents that remove lipids from the epidermal layers, or repeatedly drying the stratum corneum or minor skin injury.
• Danger signals are released from damaged keratinocytes, causing inflammation, and these can promote a link to an allergic response .
• Exposure to chemicals, such as solvents, detergents, disinfectants, and anti-wrinkle medicaments are common irritants. Gloves are a common occupational irritant in wet work.
• Emollients application over prolonged periods can predispose to irritant contact dermatitis.
• Often self-diagnosed as the reaction is relatively immediate following exposure and resolves quickly.

Seborrheic Dermatitis

• A common inflammatory skin disease that commonly affects various age ranges.
• Characterized by erythematous, greasy, scaling patches and plaques, often on the scalp, face, ears, chest, and intertriginous areas.
• Etiology is unclear, but possible causes include abnormalities in immune function, Malassezia, sebaceous glands, and individual susceptibility.
• Treatment typically focuses on symptomatic control.
• In adolescents and young adults, seborrheic dermatitis may be related to increased hormonal influence on sebaceous gland function.
• In infants, seborrheic dermatitis may affect infants as early as 2 weeks of age with peak incidence at 3 months of age.
• Prevalence varies from 2.35-11.3%.
• Male predominance occurs across all ages and No racial or regional predilection.
• Cold and dry climates can increase severity; sun exposure may reduce severity