Dermatology
Atopic Dermatitis — Eczema
~9 min read5 sections
Atopic dermatitis (AD), commonly known as eczema, is a chronic inflammatory skin disorder characterized by intense pruritus, impaired skin barrier function, and dysregulated immune responses. It represents one of the most common dermatologic conditions encountered in clinical practice, affecting approximately 10-20% of children and 1-3% of adults globally, with increasing prevalence over the past three decades. The disease shows strong genetic predisposition with environmental triggers, and typically begins in infancy or early childhood, though adult-onset disease occurs in 10-30% of patients. AD profoundly impacts quality of life through sleep disruption, school/work absenteeism, and psychological morbidity, making recognition and appropriate management crucial for all physicians. The condition has gained increasing attention in internal medicine as atopic march (progression to asthma, allergic rhinitis) and emerging systemic complications necessitate holistic patient care. Understanding AD pathophysiology, staging, and the expanding therapeutic armamentarium is essential for board examination success.
Atopic dermatitis results from a complex interplay of genetic susceptibility, impaired barrier function, and dysregulated innate and adaptive immunity. The disease pathogenesis represents a convergence of three critical defects:
- Filaggrin and Epidermal Barrier Dysfunction: Loss-of-function mutations in the FLG gene encoding filaggrin, a key structural protein in the stratum corneum, occur in 20-30% of AD patients and represent the strongest genetic risk factor. Filaggrin is essential for normal keratin filament aggregation and water-holding capacity of the stratum corneum. Its deficiency (or reduced expression from environmental factors like decreased pH or proteolytic degradation) leads to impaired skin barrier integrity, increased transepidermal water loss (TEWL), and enhanced penetration of allergens and pathogens. This barrier defect is mechanistically primary: even patients without FLG mutations demonstrate functional barrier impairment through reduced lipid content (particularly ceramides, cholesterol, and free fatty acids), abnormal lipid composition, and enhanced protease activity. The compromised barrier allows irritants and microbial antigens to penetrate more readily, creating a vicious cycle of inflammation.
- Type 2 Helper T Cell (Th2)-Skewed Adaptive Immunity: AD demonstrates striking Th2 polarization with elevated IL-4, IL-5, and IL-13 production, mediated by dendritic cells presenting antigens via OX40L signaling and enhanced by thymic stromal lymphopoietin (TSLP) released from epithelial cells responding to barrier disruption. IL-4 drives B cells to produce IgE, explaining the high prevalence of elevated serum IgE (80% of patients) and positive allergen-specific IgE or skin prick tests. IL-13 directly promotes further barrier dysfunction through suppression of filaggrin and tight junction proteins (claudins, occludin, zonula occludens-1). IL-5 recruits eosinophils, which release cationic proteins and lipid mediators perpetuating inflammation. Regulatory T cells (Tregs) are functionally impaired in AD, failing to suppress this Th2 response effectively. The acute phase of AD is primarily Th2-driven, while chronic lesions show accumulation of Th1 and Th17 cells as well, explaining disease evolution.
- Innate Immune Dysregulation and Reduced Antimicrobial Defenses: The epithelial barrier defect in AD is accompanied by impaired production of antimicrobial peptides (particularly cathelicidin and beta-defensins), increasing susceptibility to secondary bacterial infection with Staphylococcus aureus, which occurs in 80-100% of active lesions. Additionally, Toll-like receptor (TLR) signaling is dysregulated—reduced TLR-2 and TLR-4 signaling in response to bacterial products paradoxically impairs immune recognition of pathogens while simultaneously hyperreactivity of other TLR pathways (TLR-7, TLR-9) promotes excessive inflammation. PAR-2 (protease-activated receptor 2) is upregulated on epithelial cells and mast cells, and activated by serine proteases (from S. aureus), driving further IL-6 and thymic stromal lymphopoietin (TSLP) release. Mast cell activation is central to acute pruritus, with elevated tryptase and histamine release.
- Pruritus Mechanisms and Neurogenic Inflammation: The intense pruritus of AD exceeds what would be expected from visible inflammation alone, reflecting both increased density of sensory nerve fibers (particularly TRPV1+ C-nociceptors) and altered neuroimmune signaling. TSLP, IL-31 (derived from Th2 cells and mast cells), and neuropeptides (substance P, calcitonin gene-related peptide) activate pruritogenic pathways. Barrier dysfunction allows direct access of irritants and allergens to sensory endings. Chronic scratching worsens barrier dysfunction through mechanical trauma, creating a "itch-scratch-itch cycle." Importantly, IL-31, acting through the IL-31 receptor on dorsal root ganglion neurons, represents a key driver of itch independent of histamine, explaining why antihistamines provide only partial relief.
- Additional Mechanisms: Microbial dysbiosis with S. aureus overcolonization promotes inflammation through multiple toxins (alpha-hemolysin, Panton-Valentine leukocidin). Environmental factors including low humidity, harsh soaps, irritants, and psychological stress trigger flares through epidermal stress signaling. Polymorphisms in genes encoding immune regulators (IL-4, IL-13, STAT6, TSLP receptor) modulate disease risk and severity. Exposure to allergens (house dust mite, pollen, pet dander) in the context of barrier defect and Th2 skewing perpetuates Type I and Type IV hypersensitivity reactions.
- Genetic Predisposition (Primary Factor): Strong familial clustering with 60-80% of AD patients reporting a positive family history of atopy (AD, asthma, allergic rhinitis). Monozygotic twin concordance is 70-80%, while dizygotic is 20-30%. Beyond filaggrin mutations, genome-wide association studies have identified susceptibility loci involving immune regulation (STAT6, IL-4R, IL-13), barrier function (corneodesmosin), and lipid metabolism genes. Polymorphisms in IL-31, IL-13, and IL-4RA associate with disease severity.
- Filaggrin Loss-of-Function Mutations (strongest single genetic risk): Null mutations in FLG gene (common variants: R501X, 2282del4) increase AD risk 2-3 fold in heterozygotes and up to 10-fold in homozygotes. These mutations are more common in European ancestry populations (10% carrier frequency) and independently associate with ichthyosis vulgaris. FLG mutations also increase risk of asthma and allergic sensitization even in unaffected relatives.
- Environmental Triggers (Secondary Exacerbants):
- Low humidity and cold weather (winter flares common)
- Irritants: fragrances, dyes, harsh detergents, sodium lauryl sulfate, preservatives
- Allergens: dust mites (Der p 1), pollen, animal dander, food allergens in food-allergic individuals
- Infections: viral (particularly RSV, EBV, HSV—risk of eczema herpeticum), bacterial (S. aureus)
- Psychological stress: cortisol dysregulation impairs barrier repair and promotes Th2 differentiation
- Dietary factors: food allergens trigger flares in 30% of moderate-to-severe AD (eggs, milk, peanuts, tree nuts, fish, shellfish, soy, wheat)
- Systemic Atopic Diathesis: Elevated IgE, family history of asthma, allergic rhinitis, or food allergy. Patients with AD have 3-fold increased risk of asthma development (atopic march).
- Age of Onset: 60% begin before age 5 years; adult-onset typically associated with more severe disease and worse prognosis. Intrinsic AD (non-atopic variant, 10-20% of cases) occurs in patients without elevated IgE or atopic family history but with similar filaggrin mutations and barrier defects.
- Pruritus (Cardinal Symptom): Intense, often nocturnal itching that frequently disrupts sleep and precedes visible skin lesions. The pruritus is characteristically described as "relentless" and "agonizing," often worse in evening/night and exacerbated by heat, sweating, stress, and irritant exposure. The itch-scratch cycle results in lichenification and excoriation of lesions. Antihistamines provide inadequate relief, reflecting IL-31 and non-histaminergic mechanisms. Patients often report itching that awakens them multiple times nightly.
- Xerosis (Dry Skin): Generalized dry, sensitive skin even in uninvolved areas reflects global barrier dysfunction with elevated TEWL (2-3 fold higher than normal skin). Skin appears rough, dull, and scaly. May precede visible inflammatory lesions.
- Acute Phase Lesions: Well-demarcated erythematous patches and plaques with vesicles, exudation, and crusting. Typically oozing and weeping appearance. Most commonly affects face, neck, dorsal hands, and flexural surfaces (antecubital/popliteal fossae, neck, wrists, ankles). Lesions may be extremely pruritic and tender. Facial involvement often gives appearance of "allergic shiners" with periorbital edema and darkening.
- Chronic Phase Lesions: Lichenified (thickened, with exaggerated skin markings), hyperpigmented or hypopigmented plaques on flexural surfaces and hands. Skin appears leather-like with loss of normal elasticity. This represents repeated trauma from scratching and chronic inflammation. "Keratosis pilaris-like" follicular hyperkeratosis may be prominent on extensor surfaces.
- Physical Examination Findings:
- Xerosis and ichthyosis (mild scale)
- Flexural predominance (antecubital/popliteal fossae, neck, wrists)
- Facial erythema and periorbital edema ("allergic shiners")
- Dennie-Morgan folds (accentuated infraorbital creases) from chronic periorbital edema
- Lichenification in chronic lesions with accentuated skin markings
- Excoriations from scratching with sealing crusts (indicating secondary infection risk)
- "Dirty neck" sign: hyperpigmentation of neck from scratching
- Hand dermatitis (often sole manifestation in adults; see occupational dermatitis)
- Follicular hyperkeratosis on extensor surfaces (overlaps keratosis pilaris)
- Hypopigmented macules (post-inflammatory)
- Absence of vesicles in chronic stage (though may be present acutely)
- Important Clinical Variants:
- Infantile AD (2-12 months): Often begins on face/scalp and extensor surfaces (opposite of older children); may involve nappy area; typically less pruritic than older children but causes sleep disruption and parental stress
- Childhood AD (1-10 years): Classic flexural distribution, intensely pruritic, often associated with food allergies
- Adult-onset AD: Often occupational (hand dermatitis from water/irritant exposure); worse prognosis and more frequent severe flares
- Intrinsic AD: Seronegative (normal IgE, negative skin prick tests), similar appearance to extrinsic AD, may have worse prognosis
- Localized forms: Nummular dermatitis (coin-shaped lesions), dyshidrotic eczema (pompholyx—intensely pruritic vesicles on palms/soles), hand eczema (occupational)
- Severe/Erythrodermic AD: Widespread erythema covering >75% BSA, systemic symptoms, risk of infection and metabolic derangement
- Clinical Diagnosis Based on Hanifin and Rajka Criteria: AD is diagnosed clinically; no definitive laboratory test exists. The Hanifin and Rajka criteria (1980) require 3 of 4 major criteria plus 3 of 23 minor criteria (highly sensitive/specific but cumbersome in practice). Major criteria are: (1) Pruritus, (2) Typical morphology and distribution (flexural in children/adults, facial/extensor in infants), (3) Chronic or relapsing course, (4) Personal or family history of atopy. Minor criteria include: xerosis, elevated serum IgE, recurrent skin infections, etc.
- Newer Diagnostic Criteria—UK Working Party (More Practical): Requires pruritus plus 3 of 4 features: (1) Onset before age 2 years, (2) History of dry skin, (3) Recurrent skin infections, (4) Visible flexural dermatitis OR facial/extensor involvement in children <4 years. This criterion has >90% sensitivity and specificity and is recommended in practice guidelines.
- Severity Assessment—EASI Score (Eczema Area and Severity Index):
- Mild: EASI 0.1-7
- Moderate: EASI 7.1-21
- Severe: EASI >21
- Scored on erythema, edema/lichenification, excoriation, weeping/crusting graded 0-3 for each body region weighted by area affected (head, trunk, upper extremities, lower extremities). Sensitivity to change makes it useful for monitoring treatment response.
- SCORAD Index (Scoring Atopic Dermatitis): Integrates area affected (0-100), severity of key signs (erythema, edema, exudation, lichenification, scratching, dryness), and subjective symptoms (itch/sleeplessness 0-100). Total score: Mild <25, Moderate 25-50, Severe >50. Reproducible and accepted by regulatory agencies.
- Laboratory Tests (not required for diagnosis but informative):
- Serum IgE: Elevated (>150 IU/mL) in 80% of atopic AD, but normal in intrinsic AD; helps confirm atopic phenotype
- Allergen-specific IgE or skin prick testing: Positive in 80% of atopic AD; identifies specific triggers; consider in patients with food allergy suspicion or occupational exposure
- Eosinophil count: May be elevated during active disease
- Blood cultures/bacterial cultures: Only if systemic infection suspected (fever, lymphadenopathy, rapid progression)
- Immunoglobulin panel, lymphocyte subsets: Not routinely needed unless severe or recurrent infections suggest immunodeficiency
- Imaging: Generally not required. Consider chest imaging only if concurrent asthma suspected.
- Diagnostic Confirmation of Secondary Infection:
- Bacterial culture: Recommended if suspect impetiginization (honey-crusted lesions, pustules, increasing inflammation despite topical treatment)—obtain culture from lesion; S. aureus is predominant; also Screen for MRSA if healthcare-associated or unresponsive to beta-lactams
- HSV serology/PCR or viral culture: If eczema herpeticum suspected (painful vesicles with systemic symptoms, especially during primary HSV-1/HSV-2 infection)
- Fungal KOH preparation or culture: If atypical distribution or suspected superimposed tinea (especially hand/foot margin involvement)
- Differential Diagnosis Considerations:
- Contact dermatitis (allergic or irritant): History of exposure, more localized, well-demarcated boundaries, relatively less pruritic
- Seborrheic dermatitis: Greasy scale, involvement of seborrheic sites (scalp, nasolabial folds, ears), yellow/waxy appearance, less pruritic
- Psoriasis: Well-demarcated erythematous plaques with silvery micaceous scale, normal TEWL, negative family history of atopy, different distribution (extensor), less pruritic
- Nummular dermatitis: Coin-shaped lesions, may occur independently or as AD variant
- Dyshidrotic eczema: Intensely pruritic vesicles confined to palms/soles, periodic flares, relation to stress/dyshidrosis
- **Scab