Inflammatory Skin Disease Pathology — Eczema, Psoriasis

Eczema (Atopic Dermatitis)

Filaggrin Gene Mutations & Barrier Dysfunction

• Filaggrin (FLG) is a key structural protein that aggregates keratin filaments and breaks down into natural moisturizing factors (NMF) including pyrrolidone carboxylic acid and urocanic acid
• Loss-of-function mutations in FLG (homozygous or heterozygous) impair skin barrier function, leading to increased transepidermal water loss (TEWL) and penetration of allergens/irritants
• ~20-30% of patients with atopic dermatitis carry FLG mutations; defects correlate with early-onset, more severe disease
• Barrier dysfunction allows microbial colonization and antigen presentation, perpetuating inflammation

Type 2 Immune Dysregulation

• Th2 cell predominance with elevated IL-4, IL-5, IL-13, and IL-31 production (IL-31 directly mediates pruritus via IL-31 receptor on sensory neurons—a critical board concept)
• Dendritic cells in atopic individuals show enhanced response to allergens via upregulated OX40L expression, promoting Th2 differentiation
• Decreased interferon-gamma (IFN-γ) production (Th1 response) allows bacterial overgrowth, particularly Staphylococcus aureus colonization (found in 90% of lesional skin)
• IgE elevation and enhanced mast cell/basophil activation contribute to allergic sensitization
• IL-17-producing CD8+ T cells (Tc17) recently identified as contributors to chronic disease

Keratinocyte & Tight Junction Dysfunction

• Claudins (claudin-1 primarily) and occludin expression reduced, compromising tight junction integrity
• Impaired E-cadherin adhesion allows increased paracellular permeability
• Keratinocytes produce increased thymic stromal lymphopoietin (TSLP), which promotes Th2 differentiation through dendritic cell stimulation
• Loss of antimicrobial peptides (lactoferrin, lysozyme) contributes to bacterial dysbiosis

Pruritus Mechanisms

• IL-31 from Th2 cells activates IL-31 receptor on sensory C-fibers → intense pruritus
• Increased nerve fiber density and neurotrophin (NGF, BDNF) production lower itch threshold
• Scratching triggers further inflammation and barrier damage—the "itch-scratch cycle"

Psoriasis

Th1/Th17-Mediated Hyperinflammation

• IL-23-IL-17 axis is central: IL-23 (from dendritic cells and macrophages) drives differentiation of naive T cells into IL-17-producing Th17 cells
• IL-17A and IL-22 stimulate keratinocyte hyperproliferation and antimicrobial peptide production (β-defensins, cathelicidin)
• TNF-α and IFN-γ from Th1 cells amplify inflammation and activate additional immune cells
• Reduced IL-10 and TGF-β (regulatory T cell-derived) allow unchecked Th17 expansion

Keratinocyte Hyperproliferation

• Abnormally rapid keratinocyte turnover: normal ~28 days vs. psoriasis ~4-5 days
• IL-17 and IL-22 directly stimulate cyclin-dependent kinase activity and S-phase entry, driving proliferation
• Wnt/β-catenin signaling hyperactivation in psoriatic keratinocytes independently promotes proliferation
• Maturation defects: keratinocytes exit cell cycle prematurely, fail to fully differentiate, and accumulate → parakeratosis (retention of nuclei in stratum corneum—pathognomonic finding)

Angiogenesis

• Elevated VEGF (vascular endothelial growth factor) production promotes formation of dilated, tortuous capillary loops in dermal papillae
• These capillaries are friable and bleed easily with trauma (basis of Auspitz sign—pinpoint bleeding when scale removed)

Genetic Susceptibility

• HLA-Cw6 allele shows strongest association with early-onset psoriasis (Type 1; before age 40)
• Genome-wide association studies (GWAS) identified >60 susceptibility loci involving IL-23R, IL-17, CARD14, NF-κB pathway genes
• Suggests CD8+ T-cell mediated response to cutaneous antigens in genetically predisposed individuals

Triggering Factors

• Streptococcal infection (Group A Streptococcus throat infection 2-3 weeks prior to guttate psoriasis onset)
• Trauma (Koebner phenomenon), stress, NSAIDs, beta-blockers, lithium, withdrawal of systemic corticosteroids
• May involve molecular mimicry between streptococcal antigens and skin keratinocyte epitopes

Eczema (Atopic Dermatitis)

Genetic Predisposition

• Family history in ~80% of patients; monozygotic twin concordance ~70-80%
• Filaggrin mutations (as above); also polymorphisms in IL-4, IL-13, STAT3, and skin barrier genes
• "Atopic triad" association: eczema, asthma, allergic rhinitis suggesting shared Th2-skewed immune response

Environmental & Allergen Exposure

• Early-life exposure to allergens in setting of barrier dysfunction and Th2 bias
• Irritant contact dermatitis triggers: soaps, detergents, fragrances, topical antibiotics (neomycin), lanolin
• Allergic contact dermatitis: nickel, fragrance mix, preservatives (formaldehyde, methylchloroisothiazolinone), poison ivy
• House dust mites (Dermatophagoides species) antigens; pet dander; pollen
• Microbiome dysbiosis and reduced diversity (lower Faecalibacterium, increased Staphylococcus)

Infections

• Viral: HSV-1 (eczema herpeticum—disseminated infection in atopics), molluscum contagiosum
• Bacterial: Staph aureus superantigen production (enterotoxins) exacerbate disease

Demographic & Life Factors

• Age: typically onset before age 5; can persist into adulthood or present de novo
• Geography: higher prevalence in developed nations and urban environments
• Psychological stress elevates IL-31 and pruritus
• Reduced sun exposure (vitamin D deficiency)

Psoriasis

HLA Association

• HLA-Cw6 strong association with Type 1 (early-onset, often guttate or plaque morphology)
• HLA-Bw57, HLA-A2 also implicated; HLA-linkage disequilibrium with PSORS1 locus

Genetic Architecture

• Polygenic inheritance; ~80 concordance in identical twins
• Susceptibility loci in IL-23R, IL-17A/F, TNF-α, NF-κB pathway genes, CARD14 (activating mutations → familial psoriasis)
• No single Mendelian gene in most cases

Environmental Triggers

• Streptococcal pharyngitis: classic trigger of guttate psoriasis (1-3 weeks post-infection); Th17 cross-reactivity hypothesis
• Trauma/Koebner phenomenon: ~25% of patients; lesions appear at sites of injury within days to weeks
• Medications: beta-blockers (propranolol), ACE inhibitors, NSAIDs, lithium (exact mechanisms unclear; may involve IL-23 pathway), antimalarials
• Systemic corticosteroid withdrawal: rebound flare
• Infections: other bacterial, viral (HIV—severe psoriasis flares), fungal
• Psychological stress: triggers 30-40% of exacerbations via neurogenic inflammation and IL-31 upregulation
• Smoking: major risk factor (doubles risk, worsens severity)
• Alcohol consumption: associated with more severe disease
• Obesity: increased TNF-α from adipose tissue; weight loss improves outcomes

Metabolic Associations

• Metabolic syndrome, dyslipidemia, and cardiovascular disease (shared inflammatory pathways)
• Increased risk of myocardial infarction and stroke

Eczema (Atopic Dermatitis)

Cardinal Symptoms

• Severe pruritus: often worse at night, leading to sleep disturbance; "itch that rashes" vs. "rash that itches" in psoriasis
• Dry, sensitive skin (xerosis)
• Lichenification (thickening) with repeated scratching
• Exudation and crusting during acute flares

Acute Phase Morphology

• Erythematous patches and plaques (less sharply demarcated than psoriasis)
• Vesicles and bullae (serous fluid-filled; frank exudation and weeping in severe cases)
• Edema (spongiosis on histology)
• Crusting and secondary bacterial infection (golden crusts suggest Staph aureus)

Chronic Phase Morphology

• Dry, scaly patches with poorly demarcated borders
• Lichenification (accentuated skin markings, thickened epidermis from chronic rubbing)
• Hyperpigmentation or hypopigmentation (post-inflammatory changes)
• Keratosis pilaris-like follicular papules (common associated finding)
• Flexural distribution (antecubital fossae, popliteal fossae, neck) typical in older children and adults; face and extensor surfaces in infants

Associated Physical Examination Findings

• Dennie-Morgan fold (extra eyelid crease, also called Dennie fold) — highly suggestive but not pathognomonic
• Infraorbital darkening ("allergic shiners")
• Facial erythema and edema
• Ichthyosis (fine, whitish scaling) and follicular hyperkeratosis (keratosis pilaris)
• Palmar/plantar hyperlinearity (exaggerated skin markings)
• Nipple eczema (often pruritic, unilateral; must exclude Paget disease in older adults)

Lab Correlates

• Elevated serum IgE (>100 IU/mL in ~80% of patients)
• Elevated eosinophil count (if marked: consider hyperIgE syndrome)
• Positive allergen-specific IgE or skin prick tests (but presence doesn't prove causation)
• Normal or mildly elevated ESR

Psoriasis

Cardinal Features

• Pruritus (only ~15-30% of patients; when present, mild to moderate; absence doesn't exclude)
• Well-demarcated erythematous plaques (clear-cut borders—classic finding)
• Silvery-white scale (highly characteristic and pathognomonic when present)
• Symmetrical distribution on extensor surfaces

Lesion Morphology & Variants

Plaque Psoriasis (85-90% of cases)

• Sharply demarcated, erythematous plaques with thick, silvery-white scale
• Size: millimeters to centimeters; may coalesce into larger lesions
• Extensor surfaces: elbows, knees, shins, sacrum, scalp, buttocks
• Symmetric distribution (bilateral involvement of similar sites)

Guttate Psoriasis (7-10%)

• Sudden onset of numerous small (1-10 mm) "teardrop-shaped" papules and plaques
• Classically preceded 2-3 weeks prior by streptococcal pharyngitis
• Often trunk and proximal extremities; less on face/hands
• May transition to chronic plaque-type

Pustular Psoriasis (1-3%; can be generalized [GPP] or localized [acanthosis pustulosa])

• Sterile pustules on erythematous base (distinguish from infection)
• Generalized pustular psoriasis (von Zumbusch variant): life-threatening with fever, malaise, systemic toxicity
• Palmoplantar pustulosis: chronic localized pustules on palms and soles

Inverse Psoriasis (3-7%)

• Intertriginous areas (skin folds): axillae, groin, inframammary, intergluteal
• Smooth, shiny, non-scaly erythematous patches (scale removed by friction/moisture)
• Often mistaken for fungal infection or intertrigo

Erythrodermic Psoriasis (<3%; dermatological emergency)

• Generalized erythema and scaling involving >90% body surface area
• High risk of infection, fluid/electrolyte loss, thermoregulation failure

Nail Psoriasis (10-50% of patients)

• Pitting (small depressions in nail plate—hallmark; from focal parakeratosis in nail matrix)
• Onycholysis (nail bed separation, yellow-brown discoloration/"oil spots")
• Subungual hyperkeratosis (debris under nail)
• Can be sole manifestation

Arthropathy (Psoriatic Arthritis; 5-30% of patients)

• Asymmetric oligoarticular disease (often DIP and PIP joints of hands; also knees, ankles)
• May precede skin lesions (5-10% of cases)
• HLA-B27 not strongly associated (unlike ankylosing spondylitis)

Clinical Diagnostic Findings

Eczema (Atopic Dermatitis)

Clinical Diagnosis (Hanifin & Rajka Criteria / UK Working Party Criteria)

• Diagnostic Criteria (Simplified UK Working Party): Must have pruritus PLUS at least 3 of:

1. 1.Onset before age 2 (or age 4 if pediatric criteria)
2. 2.History of dry skin
3. 3.History of itchy skin rashes
4. 4.Visible flexural dermatitis (or cheeks/forehead/outer limbs if <4 years)
5. 5.Onset before age 2
6. 6.History of dry skin generally (not just in winter)
7. 7.History of skin infections requiring antibiotics
8. 8.Family history of atopy (asthma, allergic rhinitis, atopic dermatitis)

Histopathology (when biopsy needed)

• Acute/Active Lesions:
• Spongiosis: intercell

Immediate stabilisation (emergencies first)

• Erythrodermic and generalized pustular psoriasis: admit for fluid/electrolyte repletion, warming, and skin care; the AAD–National Psoriasis Foundation guidelines favor rapidly acting systemic agents (cyclosporine or infliximab) over slow-onset drugs. The anti–IL-36 receptor antibody spesolimab is FDA-approved for generalized pustular psoriasis flares.
• Eczema herpeticum: systemic acyclovir (IV if extensive, febrile, or periocular) plus ophthalmology consult — do not simply escalate topical steroids.

Atopic dermatitis — first line (AAD guidelines)

• Emollients/barrier repair: liberal thick ointments correct the filaggrin-related barrier defect and reduce transepidermal water loss; they are foundational maintenance therapy and reduce flare frequency and steroid requirement. Proactive twice-weekly topical steroid or calcineurin inhibitor applied to previously affected (healed) sites also reduces relapse.
• Topical corticosteroids: potency matched to site — low-potency (hydrocortisone) on face, eyelids, and folds; mid-potency (triamcinolone) on trunk/limbs.
• Topical calcineurin inhibitors (tacrolimus, pimecrolimus): steroid-sparing for face/folds; block calcineurin–NFAT and IL-2 transcription without causing atrophy. Crisaborole (PDE4) and topical ruxolitinib (JAK) are alternatives.
• Adjuncts: dilute bleach baths and intranasal mupirocin for recurrent S. aureus impetiginization; sedating antihistamines help sleep, not itch.

Psoriasis — first line (AAD–NPF)

• Limited plaque disease: topical corticosteroid plus a vitamin D analog (calcipotriene), which normalizes keratinocyte differentiation; tazarotene and tar are alternatives.
• Extensive skin disease (>5–10% BSA): narrowband UVB, methotrexate, acitretin, apremilast (PDE4), or biologics targeting TNF-α (adalimumab), IL-17 (secukinumab), IL-23 (guselkumab), or IL-12/23 (ustekinumab).
• Psoriatic arthritis: methotrexate, apremilast, or TNF/IL-17/IL-23 biologics — acitretin and phototherapy clear skin only and do not treat joint disease. Screen for latent TB and hepatitis B before biologics.

Contraindicated / avoid

• Systemic corticosteroids in psoriasis: withdrawal precipitates rebound pustular or erythrodermic flares.
• Teratogens: methotrexate and acitretin are contraindicated in pregnancy; acitretin additionally requires pregnancy avoidance for 3 years after stopping and alcohol avoidance (alcohol drives conversion to long-lived etretinate). Topical tazarotene is also contraindicated in pregnancy.
• Live vaccines should be avoided during biologic or systemic immunosuppressive therapy; avoid IL-17 inhibitors in inflammatory bowel disease and TNF inhibitors in advanced heart failure or demyelinating disease.

Atopic dermatitis — disease complications

• **Secondary S. aureus impetiginization**: barrier loss plus reduced antimicrobial peptides permits colonization; signalled by honey-colored/golden crusting, weeping, and rapid worsening despite steroids.
• Eczema herpeticum (emergency): HSV-1 disseminates through defective barrier; look for monomorphic punched-out erosions, fever, and pain out of proportion. Confirm with viral PCR (Tzanck smear shows multinucleated giant cells) and treat with acyclovir; ocular involvement threatens vision.
• Erythroderma: >90% BSA involvement causing high-output failure, hypothermia, and protein loss — also an emergency.
• Ocular disease: keratoconjunctivitis, keratoconus, and cataract, the latter compounded by chronic periocular steroids.
• Sleep deprivation, growth impairment in children, and allergic contact sensitization to topical agents (neomycin, fragrance).

Psoriasis — disease complications

• Psoriatic arthritis: erosive, seronegative (RF-negative); dactylitis and the pencil-in-cup deformity of arthritis mutilans signal joint destruction. AAD–NPF advise routine screening for psoriatic arthritis with a validated tool (e.g., PEST); screening is commonly performed at least annually, since joint erosion is irreversible.
• Generalized pustular (von Zumbusch) and erythrodermic psoriasis (emergencies): sterile neutrophilic pustules with fever, leukocytosis, hypoalbuminemia, hypocalcemia, and sepsis risk.
• Cardiometabolic disease: chronic TNF-α/IL-17 inflammation drives insulin resistance, metabolic syndrome, and accelerated atherosclerosis; the AAD–NPF and ACC/AHA advise treating psoriasis as a risk-enhancing factor when deciding on statin therapy.
• Depression, NAFLD, and uveitis.

Treatment complications

• Topical corticosteroids: dermal collagen loss → atrophy, striae, telangiectasia, tachyphylaxis, and HPA-axis suppression in infants using potent agents under occlusion.
• Calcineurin inhibitors: application burning; a boxed lymphoma warning that long-term data have not substantiated.
• Dupilumab: conjunctivitis and facial erythema.
• JAK inhibitors: boxed warnings for thrombosis, MACE, malignancy, serious infection.
• Methotrexate: hepatotoxicity and pancytopenia (worsened by TMP-SMX); cyclosporine: nephrotoxicity, hypertension; acitretin: teratogenicity, hyperlipidemia; PUVA: cutaneous squamous cell carcinoma; biologics: reactivation of latent TB or hepatitis B, IL-17-associated mucocutaneous candidiasis.

• Histology is the discriminator: spongiosis (intercellular epidermal edema) = eczema; acanthosis + parakeratosis + thinned/absent granular layer = psoriasis. If the stem gives you the biopsy, it has already given you the diagnosis.
• Neutrophil location separates the two psoriasis buzzwords: Munro microabscesses sit in the stratum corneum; spongiform pustules of Kogoj sit in the stratum spinosum. Examiners swap these deliberately.
• "Itch that rashes" (eczema) vs "rash that itches" (psoriasis), and poorly demarcated flexural lesions vs sharply demarcated extensor plaques with silvery scale.
• Teardrop papules in a child 2–3 weeks after sore throat = guttate psoriasis; the single best next step is documenting recent streptococcal infection (throat culture/rapid antigen or ASO titer), not a skin biopsy.
• Punched-out monomorphic erosions with fever in an atopic child = eczema herpeticum; the best next step is HSV PCR and starting systemic acyclovir — never escalate topical steroids.
• Never give systemic corticosteroids for plaque psoriasis: taper precipitates rebound generalized pustular or erythrodermic disease. This is the most frequently tested management trap.
• The one association to know: HLA-Cw6 with early-onset psoriasis; and the drug triggers beta blockers, lithium, antimalarials, NSAIDs, and steroid withdrawal.
• Mechanism pearls: filaggrin loss-of-function → barrier failure and the atopic march; IL-31 mediates pruritus; dupilumab works by blocking the shared IL-4Rα of IL-4/IL-13.
• Common distractors: nail pitting and oil spots are psoriasis, not onychomycosis (a KOH/PAS will be negative); psoriatic arthritis is seronegative (RF-negative) and is not strongly HLA-B27-linked in peripheral disease; unilateral persistent nipple "eczema" in an older adult is Paget disease until biopsy proves otherwise.