Clinical Dermatology - Learning Notes for Medical Students

1. PAPULOSQUAMOUS DISEASES

Definition & Concept

Psoriasis

Epidemiology

• Affects 1-3% of the population worldwide
• Bimodal age of onset: early (15-25 years) and late (50-60 years)
• Strong genetic component: HLA-Cw6 is the most significant susceptibility allele

Pathogenesis

1. Dendritic cells in the dermis produce TNF-α and IL-23
2. IL-23 drives differentiation of Th17 cells, which produce IL-17A
3. IL-17 acts on keratinocytes → stimulates antimicrobial peptides, defensins, and proinflammatory mediators
4. TNF-α augments IL-17 effects → feed-forward inflammatory loop
5. Result: Hyperproliferative epidermis with markedly reduced basal keratinocyte transit time and abnormal differentiation

• Acanthosis (epidermal thickening)
• Parakeratosis (nucleated cells in stratum corneum)
• Munro microabscesses (neutrophil collections in the superficial epidermis)
• Dilated capillary loops in the dermal papillae (Auspitz sign - pinpoint bleeding with scale removal)
• Predominantly Th1/Th17-polarized T-cell infiltrate

Psoriatic susceptibility loci are largely non-overlapping with those for atopic dermatitis, consistent with mechanistically distinct diseases. - Fitzpatrick's Dermatology

Clinical Features

• Auspitz sign: Pinpoint bleeding when scale is scraped off
• Koebner phenomenon: Lesions appear at sites of skin trauma

Psoriatic Arthritis

• Occurs in 10-30% of psoriasis patients
• Patterns: oligoarthritis, symmetric polyarthritis (RA-like), arthritis mutilans, axial (spondylitis), DIP joint predominance
• Seronegative (RF-negative)

Comorbidities

• Cardiovascular disease (major risk; psoriasis is an independent risk factor - systemic inflammation)
• Metabolic syndrome, obesity, diabetes
• Depression and anxiety
• Inflammatory bowel disease
• Decreased life expectancy in severe disease

Treatment

• Corticosteroids (mainstay)
• Vitamin D analogues (calcipotriol/calcitriol)
• Calcineurin inhibitors (tacrolimus, pimecrolimus) - particularly for face/folds
• Coal tar, anthralin

• Narrowband UVB (nbUVB) - first-line phototherapy
• PUVA (psoralen + UVA) - more effective but higher skin cancer risk

• Methotrexate: folate antimetabolite; anti-inflammatory + antiproliferative
• Cyclosporine: calcineurin inhibitor; rapid onset; useful for acute severe disease; nephrotoxic with long-term use
• Acitretin: oral retinoid; useful for pustular and erythrodermic subtypes

• Anti-TNF-α: etanercept, adalimumab, infliximab
• Anti-IL-12/23 (anti-p40): ustekinumab
• Anti-IL-17A: secukinumab, ixekizumab - FDA-approved; rapid, near-complete responses
• Anti-IL-23 (anti-p19): guselkumab, risankizumab

Lichen Planus

Pathogenesis

• Cell-mediated autoimmune attack on basal keratinocytes
• CD8+ T cells recognize altered keratinocyte antigens → interface dermatitis
• Lichenoid dermatitis = reaction pattern with CD8 infiltrate at dermal-epidermal junction

Clinical Features - "6 P's"

• Distribution: wrists, ankles, oral mucosa, genitalia
• Wickham's striae: lacy white network on surface (best seen on oral lesions)
• Koebner phenomenon present
• Oral lichen planus: bilateral white lacy patches/erosions - may progress to SCC (1-5% risk)

Key Associations

• Hepatitis C virus (in endemic regions: Southern Europe, East Asia, South America, Middle East)
• Autoimmune chronic active hepatitis, primary biliary cirrhosis
• Dyslipidemia and metabolic syndrome
• Systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, vitiligo, alopecia areata

Histology

• Band-like lymphocytic infiltrate at dermal-epidermal junction (interface dermatitis)
• Saw-tooth rete ridges
• Civatte bodies (colloid/hyaline bodies - apoptotic keratinocytes)
• Hypergranulosis (thickened granular layer, especially in oral lesions)

Treatment

• Potent topical corticosteroids (first-line)
• Oral corticosteroids for severe/widespread disease
• Calcineurin inhibitors for oral lesions
• Hydroxychloroquine for erosive/refractory cases
• Natural course: often resolves in 1-2 years (cutaneous); oral lesions are more chronic

Pityriasis Rosea

• Self-limited eruption; presumed viral etiology (HHV-6/HHV-7)
• Herald patch: solitary oval scaly plaque (2-5 cm), precedes the generalized eruption by 1-2 weeks
• Secondary lesions: smaller oval scaly patches along skin lines ("Christmas tree" distribution on trunk)
• Resolves spontaneously in 6-12 weeks
• Treatment: symptomatic (antihistamines, mid-potency topical steroids)

2. ATOPIC DERMATITIS

Definition & Epidemiology

• Chronic relapsing inflammatory skin disease; the most common inflammatory skin disease
• Prevalence: 15-20% in children in industrialized countries; increasing incidence
• Part of the atopic march: AD → food allergy → allergic rhinitis → asthma
• Term coined by Sulzberger & Wise (1933)

Pathogenesis - "Outside-Inside" + Immune Dysregulation

1. Epidermal barrier dysfunction (structural):
   • Filaggrin (FLG) gene mutations - most important genetic risk factor
   • Filaggrin is critical for cornified envelope formation and skin hydration
   • Loss of function → increased transepidermal water loss → allergen/irritant penetration
   • Associated with ichthyosis vulgaris, hyperlinearity of palms, keratosis pilaris
2. Immune dysregulation:
   • Th2-predominant in acute/initial lesions: IL-4, IL-13 drive IgE production and eosinophilia
   • Th22 (IL-22): promotes epidermal hyperplasia
   • Chronic lesions: shift toward Th1 polarization
   • Dupilumab (anti-IL-4Rα) blocks both IL-4 and IL-13 signaling - highly effective

Diagnostic Criteria (Hanifin-Rajka)

• Pruritus
• Typical morphology and age-specific distribution
• Chronic/relapsing course
• Personal or family history of atopy

• Dry skin (xerosis)
• Dennie-Morgan folds (extra fold below lower eyelid)
• Allergic shiners (periorbital darkening)
• Keratosis pilaris, ichthyosis vulgaris, hyperlinearity of palms
• White dermatographism (white line on stroking with blunt instrument)
• Elevated serum IgE, immediate skin test reactivity
• Nipple dermatitis, pityriasis alba
• Anterior subcapsular cataracts, keratoconus

Age-Specific Clinical Patterns

Complications

• Staphylococcus aureus colonization in >70% of lesional skin (major driver of flares); MRSA rates similar to general population
• Eczema herpeticum (Kaposi varicelliform eruption): widespread HSV infection - serious complication requiring IV aciclovir
• Bacterial superinfection: impetigo
• Ocular: atopic keratoconjunctivitis, vernal conjunctivitis, keratoconus, cataracts
• Exfoliative dermatitis (rare, potentially life-threatening)
• Psychiatric comorbidities: anxiety, depression, ADHD (sleep-disruption mediated)
• Occupational hand dermatitis in wet-work professions

Treatment

• Regular emollients (cornerstone of management) - applied liberally and frequently
• Avoid triggers (irritants, allergens, excessive bathing with harsh soaps)
• Lukewarm water; pat dry; emollient within 3 minutes of bathing ("soak and seal")

• Topical corticosteroids (TCS): mainstay; use lowest effective potency; risk of skin atrophy with prolonged use on thin skin
• Topical calcineurin inhibitors (TCI): tacrolimus 0.1%/0.03%, pimecrolimus 1% - steroid-sparing; safe for face/folds; no skin atrophy

• Dupilumab (anti-IL-4Rα monoclonal antibody): first-line biologic; highly effective; approved for age ≥6 months
• Other biologics: tralokinumab (anti-IL-13), lebrikizumab
• JAK inhibitors (abrocitinib, upadacitinib, baricitinib): oral small molecules; rapid onset
• Traditional immunosuppressants (less preferred): cyclosporine, methotrexate, azathioprine, mycophenolate
• Short courses of systemic corticosteroids (bridge therapy; avoid long-term use)

3. SEBORRHEIC DERMATITIS

Pathogenesis

• Chronic inflammatory condition related to Malassezia (Pityrosporum) yeast overgrowth in sebaceous gland-rich areas
• Malassezia metabolizes sebum triglycerides → free fatty acids → irritation and inflammation
• Host immune response (innate and adaptive) plays a role
• Not a true allergic reaction; colonization is normal but response is abnormal in affected individuals

Clinical Features

• Affects sebaceous gland-rich areas: scalp, face (nasolabial folds, eyebrows, glabella), chest (presternal), flexures (retroauricular, axillae)
• Greasy yellow scales on an erythematous base
• Scalp: dandruff (mild) → thick adherent scaly plaques (severe)
• Facial: erythema + greasy scales in nasolabial folds, eyebrows, forehead
• Often asymptomatic or mildly pruritic
• Infantile seborrheic dermatitis ("cradle cap"): scalp in first 3 months of life; benign, self-resolving

HIV Association

• Prevalence in HIV up to 83% (vs 3-5% general population)
• Severity correlates with immunosuppression (lower CD4 count)
• May be extensive, involving scalp, axillae, groin, flexures
• Extension beyond typical distribution, sometimes to erythroderma
• Superinfection is common

Differential Diagnosis

• Psoriasis (plaques more well-demarcated, silvery scale, nail/joint involvement)
• Atopic dermatitis (pruritus more prominent, different distribution)
• Tinea versicolor, tinea capitis
• Contact dermatitis
• Rosacea (central face but no greasy scale)

Treatment

• Antifungal shampoos/topicals: ketoconazole (2%), selenium sulfide, zinc pyrithione - mainstay
• Topical corticosteroids: for acute flares
• Topical calcineurin inhibitors: for facial lesions, maintenance
• Scalp: medicated shampoos (ketoconazole, coal tar, ciclopirox, selenium sulfide)
• Maintenance therapy required (relapsing condition)

4. CUTANEOUS DRUG ERUPTIONS

Overview

• Adverse cutaneous drug reactions are among the most common drug side effects
• Mechanisms: immunologic (types I-IV hypersensitivity) and non-immunologic
• Elderly patients are at higher risk due to polypharmacy and impaired drug metabolism

Classification of Drug Eruptions

DRESS - Key Details

• Full acronym: Drug Reaction with Eosinophilia and Systemic Symptoms
• Alternatively called Drug-induced Hypersensitivity Syndrome (DiHS)
• Life-threatening: mortality ~10%
• Systemic involvement: liver (most common), kidney, lung, heart, thyroid
• RegiSCAR score used for diagnosis
• HHV-6 reactivation occurs and may drive severity
• Management: stop offending drug + systemic corticosteroids + supportive care
• Risk factors: HLA type (e.g. HLA-B*5801 + allopurinol in Han Chinese)

SJS/TEN Spectrum

• SJS: <10% body surface area (BSA) detachment
• SJS/TEN overlap: 10-30% BSA
• TEN: >30% BSA; mortality 30-50%
• Key features: target lesions, mucosal erosions (oral, ocular, genital), Nikolsky sign positive
• SCORTEN score predicts mortality
• Management: ICU/burn unit; stop drug; IVIG or cyclosporine; wound care; ophthalmology consult

Drug-Induced Linear IgA Disease

• Morphology resembles erythema multiforme, bullous pemphigoid, or dermatitis herpetiformis
• Drug-induced form: mucosal involvement less common, resolves when drug stopped
• Vancomycin is the classic culprit
• Biopsy: subepidermal blisters with neutrophilic infiltrate; DIF shows linear IgA at BMZ

5. DISORDERS OF PIGMENTATION

Hyperpigmentation

Melasma

• Acquired, symmetric brown-gray patches on sun-exposed areas of the face (cheeks, forehead, upper lip, nose)
• Triggers: UV radiation, pregnancy ("mask of pregnancy"), oral contraceptives, hormonal therapy
• Pathogenesis: increased melanin production by melanocytes (normal number); UV-induced, estrogen-driven
• More common in darker skin types (Fitzpatrick types III-VI) and in people of Latin American, Asian, or African descent
• Wood's lamp: epidermal melasma accentuated (vs. dermal - not enhanced)
• Treatment: strict photoprotection (first-line), hydroquinone 4% (tyrosinase inhibitor), topical retinoids, azelaic acid, kojic acid, chemical peels; triple combination (hydroquinone + tretinoin + mid-potency steroid) most effective
• Chronic condition; prone to relapse

Post-Inflammatory Hyperpigmentation (PIH)

• Follows cutaneous injury/inflammation (acne, lichen planus, lupus, trauma)
• More pronounced in darker skin types
• Epidermal (responds to treatment) vs. dermal (very resistant)
• Treatment: photoprotection, hydroquinone, retinoids; patience (months-years for resolution)

Acanthosis Nigricans

• Velvety, hyperpigmented, thickened skin in body folds (axillae, neck, groin, antecubital fossae)
• Pathogenesis: insulin resistance/hyperinsulinemia → insulin binds IGF-1 receptors on keratinocytes → proliferation
• Associations:
  • Insulin resistance/Type 2 diabetes, obesity (most common)
  • Paraneoplastic (malignant type): gastric adenocarcinoma (most common); sudden onset, widespread, mucosal involvement, acral verrucous thickening → prompt workup for occult malignancy
  • Endocrinopathies (Cushing's, acromegaly, hypothyroidism, polycystic ovarian syndrome)
  • Drugs (nicotinic acid, glucocorticoids, oral contraceptives, protease inhibitors)

Hypopigmentation

Vitiligo

• Acquired, autoimmune destruction of melanocytes
• Prevalence ~1% worldwide; equal gender distribution; positive family history in ~30%
• Pathogenesis: autoimmune - cytotoxic CD8+ T cells target melanocytes; autoantibodies against melanocyte antigens; IFN-γ/CXCL9/CXCL10 pathway critical (therapeutic target)
• Clinical features:
  • Well-demarcated, chalk-white macules and patches
  • Segmental vitiligo: unilateral, dermatomal distribution; earlier onset, stable course; poor response to treatment
  • Non-segmental (generalized): bilateral, symmetric; chronic progressive course; most common
  • Mucosal involvement: lips, gingiva
  • Wood's lamp: bright white fluorescence
• Associations: thyroid disease (Hashimoto's, Graves'), type 1 diabetes, Addison's disease, pernicious anemia, alopecia areata, rheumatoid arthritis - screen for autoimmune comorbidities
• Koebner phenomenon positive
• Treatment:
  • Topical corticosteroids and calcineurin inhibitors (first-line for limited disease)
  • NB-UVB phototherapy (best for widespread disease)
  • Ruxolitinib cream (JAK1/2 inhibitor) - FDA approved; highly effective
  • Oral JAK inhibitors (ritlecitinib) - systemic disease
  • Surgical repigmentation (autologous melanocyte transplant) for stable segmental

Albinism

• Congenital disorder of melanin synthesis despite normal melanocyte numbers
• Oculocutaneous albinism (OCA): autosomal recessive; tyrosinase pathway mutations
• Features: diffuse hypopigmentation of skin, hair, and eyes; nystagmus; photophobia; increased risk of skin cancer
• Ocular findings: reduced visual acuity, strabismus, photophobia, nystagmus

Pityriasis Alba

• Common in children; hypopigmented scaly patches on face
• Associated with atopic dermatitis and dry skin
• Self-limiting; treatment: emollients + mild TCS

6. ACNE VULGARIS

Pathogenesis - 4 Key Factors

1. Increased sebum production (androgen-driven at puberty; permissive factor)
2. Follicular hyperkeratinization → microcomedone formation (earliest lesion)
3. Cutibacterium acnes (formerly Propionibacterium acnes): metabolizes sebum triglycerides → free fatty acids → inflammation + cyst rupture
4. Inflammation: foreign body reaction to extruded cyst contents + cytokine-mediated

Clinical Features

Primary Lesions

• Closed comedone (whitehead): 1-2 mm white papules; not easily expressed; precursor of inflammatory lesions
• Open comedone (blackhead): dilated follicular orifice filled with oxidized sebum; rarely inflamed

Inflammatory Lesions (in order of severity)

• Papules → pustules → nodules → cysts
• Scarring: atrophic (ice-pick, boxcar, rolling) or hypertrophic/keloidal

Distribution

• Face most common: forehead (earliest), cheeks, nose, chin
• Chest and back frequently involved
• Comedones are the hallmark of true acne vulgaris (distinguishes from rosacea)

Grading

• Mild: predominantly comedonal ± a few inflammatory lesions
• Moderate: mixed comedonal and inflammatory; papules/pustules
• Severe: nodules, cysts; risk of scarring

Exacerbating Factors

• Friction/trauma (headbands, chin straps, helmets - "acne mechanica")
• Comedogenic topical agents (heavy cosmetics, hair preparations)
• Drugs: glucocorticoids (systemic/topical), progestin-only OCP, lithium, isoniazid, androgenic steroids, halogens, phenytoin, phenobarbital
• PCOS, hyperandrogenism
• Psychological stress (neurogenic inflammation)

Treatment Algorithm

• Topical retinoids (tretinoin, adapalene, tazarotene): normalize follicular keratinization; prevent new comedones - cornerstone
• Topical benzoyl peroxide (BPO): antibacterial (oxidative); no resistance; essential in any antibiotic regimen
• Topical salicylic acid: comedolytic
• Topical antiandrogen: clascoterone cream (FDA-approved)

• Add topical antibiotics (clindamycin, erythromycin) ALWAYS combined with BPO to prevent resistance
• Topical azelaic acid: antibacterial + comedolytic + anti-inflammatory; good for PIH

• Oral antibiotics: doxycycline or minocycline 100 mg BID (or low-dose extended-release); anti-inflammatory effects independent of antibacterial effects
• Expected response at 3 months; limit duration to 3-6 months
• Females: oral contraceptives (combined estrogen-progestin; FDA-approved: Ortho Tri-Cyclen, Estrostep, Beyaz)
• Females: spironolactone 50-200 mg/day (antiandrogen; safe, effective, durable)

• Isotretinoin (13-cis-retinoic acid):
  • Weight-based dosing; cumulative dose-driven course
  • Mechanism: reduces sebaceous gland size/sebum production, normalizes keratinization, anti-inflammatory, anti-C. acnes
  • Side effects: cheilitis, dry skin (universal), xerophthalmia, elevated triglycerides/LFTs, depression (controversial), IBD (rare)
  • Teratogenicity: Category X - two negative pregnancy tests before starting; pregnancy prevention program (iPLEDGE in the USA) mandatory
  • Results: excellent; often curative after one course

Acne vs. Rosacea (Key Distinction)

7. CUTANEOUS MANIFESTATIONS OF INTERNAL DISEASES

Paraneoplastic Syndromes

Acanthosis Nigricans (Malignant Type)

• Sudden-onset, extensive, involving mucous membranes and acral verrucous changes
• Strongly suggests gastric adenocarcinoma (most common); also colorectal, lung, breast, ovarian
• Pathogenesis: tumor-secreted TGF-α and other growth factors stimulate keratinocyte proliferation via EGF receptors

Leser-Trélat Sign

• Sudden eruption of multiple seborrheic keratoses (or rapid increase in size/number)
• Associated with internal malignancy (GI adenocarcinoma, breast, lymphoma)
• Often accompanies malignant acanthosis nigricans

Necrolytic Migratory Erythema (NME)

• Pathognomonic of glucagonoma (α-cell pancreatic tumor); present in >2/3 at diagnosis
• Distribution: intertriginous areas (groin, perineum, buttocks, lower abdomen), perioral face, distal extremities
• Lesion evolution: erythematous patches → plaques → bullae → erosions → crusts → geographic areas
• Painful and pruritic; waxes and wanes
• Associated features of glucagonoma syndrome: weight loss, diabetes mellitus, anemia, deep vein thrombosis, diarrhea, stomatitis, angular cheilitis, neuropsychiatric disorders
• Pseudoglucagonoma syndrome: identical skin + no glucagonoma; associated with liver disease, pancreatitis, celiac disease, IBD
• Treatment: surgery (resection) or octreotide for unresectable tumor; zinc/amino acid supplementation

Acrokeratosis Paraneoplastica (Bazex Syndrome)

• Symmetrical erythematous-to-violaceous scaly plaques on helices, nose, cheeks, acral extremities, nails
• Nail changes: paronychia, dystrophy, onycholysis
• Almost exclusively males >40 years
• ~60% squamous cell carcinomas of upper aerodigestive tract (esophagus, pharynx, larynx)
• Lesions often predate detection of malignancy

Hypertrichosis Lanuginosa Acquisita ("Malignant Down")

• Sudden appearance of long, fine, non-pigmented lanugo hairs, particularly on face and ears
• Accompanies advanced/metastatic carcinomas
• Associated features: glossitis, hypertrophy of tongue papillae, oral hyperpigmentation, acanthosis nigricans
• Eruption may resolve immediately before death (generalized antemortem immunosuppression)

Paraneoplastic Pemphigus

• Life-threatening; high mortality
• Painful hemorrhagic oral erosions - earliest and characteristic finding
• Polymorphous skin eruption: pemphigus-like + bullous pemphigoid-like + erythema multiforme-like + lichen planus-like lesions
• Multiorgan involvement (lung - bronchiolitis obliterans, thyroid, kidney, GI)
• Underlying neoplasm in nearly all patients: non-Hodgkin lymphoma (most common), CLL, Castleman disease, thymoma
• Worse prognosis with malignancy; better with benign tumors
• Serology: antibodies against periplakin, envoplakin, desmoplakins, BP230

Dermatoses Associated with Systemic Disease

Dermatitis Herpetiformis (DH)

• Autoimmune blistering disease; intensely pruritic vesicular eruption on extensor surfaces (elbows, knees, buttocks, scalp)
• Pathogenesis: IgA antibodies against epidermal transglutaminase (eTG, TG3)
• Associated with gluten-sensitive enteropathy (celiac disease); small bowel villi may be flat even without GI symptoms
• Skin biopsy: granular IgA deposits at dermal papillae on DIF (diagnostic)
• Increased risk of non-Hodgkin lymphoma (especially with longstanding disease); enteropathy-associated T-cell lymphoma
• Treatment: gluten-free diet (also reduces lymphoma risk) + dapsone (dramatic symptomatic relief)

Bullous Pemphigoid in Systemic Context

• Associated with neurological diseases: dementia, Parkinson's disease, stroke, epilepsy
• Some drugs can induce BP (drug-induced BP): furosemide, spironolactone, PD-1/PD-L1 checkpoint inhibitors
• Polypharmacy increases risk in elderly

8. IMMUNE BULLOUS DISEASES

Classification

• Intraepidermal: desmoglein targeted (pemphigus group)
• Subepidermal: BMZ targeted (pemphigoid group, DH, EBA, LAD)

Pemphigus Vulgaris

Pathogenesis

• IgG autoantibodies against desmoglein 3 (DSG3) ± desmoglein 1 (DSG1)
• Desmogleins are desmosomal cadherins that provide keratinocyte-keratinocyte adhesion
• Antibody binding → loss of cell-cell adhesion → acantholysis (intraepidermal blister)
• DSG3 only: mucosal involvement predominantly
• DSG3 + DSG1: mucocutaneous involvement

Clinical Features

• Age: 50-60 years; higher incidence in Ashkenazi Jewish and Mediterranean populations
• Flaccid (fragile) blisters on normal-appearing or erythematous skin; rupture easily → erosions and crusting
• Mucosal involvement (oral) in >90%; often the initial presentation; painful erosions
• Nikolsky sign positive: lateral pressure on perilesional skin → new blister
• Other mucosae: nasal, conjunctival, esophageal, genital
• Untreated: potentially fatal (fluid loss, infection, sepsis)

Diagnosis

• Skin biopsy (H&E): intraepidermal acantholytic bullae; "row of tombstones" - basal cells still attached to dermis
• Direct Immunofluorescence (DIF): IgG (± C3) deposition in intercellular spaces (chicken-wire/net pattern) throughout epidermis
• Indirect Immunofluorescence (IIF): circulating anti-DSG antibodies; titer correlates with disease activity
• ELISA for anti-DSG3 and anti-DSG1: specific and sensitive

Treatment

• High-dose systemic corticosteroids (prednisone 1 mg/kg/day): initial control
• Rituximab (anti-CD20): now first-line (or early add-on); dramatically reduces corticosteroid requirement; depletes B cells
• Steroid-sparing agents: azathioprine, mycophenolate mofetil, dapsone
• IVIG for refractory cases or rapid deterioration
• Plasmapheresis (removes circulating autoantibodies - bridge therapy)

Pemphigus Foliaceus

• IgG autoantibodies against DSG1 only (desmoglein 1)
• DSG1 is predominantly superficial epidermis
• More superficial blisters → superficial crusted erosions ("corn flake" appearance), no intact blisters
• No mucosal involvement (DSG1 absent in mucosa; DSG3 compensates)
• Fogo Selvagem: endemic form in Brazil (triggered by Black fly bite)
• Treatment similar to PV but often responds to lower dose steroids

Bullous Pemphigoid

Pathogenesis

• IgG autoantibodies against BP180 (type XVII collagen, BPAG2) and BP230 (BPAG1)
• BP180/BP230 are hemidesmosomal proteins at the dermal-epidermal junction (BMZ)
• Antibody binding → complement activation → recruitment of eosinophils and neutrophils → protease release → subepidermal blister (lamina lucida cleavage)

Clinical Features

• Most common autoimmune bullous disease in Western countries
• Age >60 years (primary age group); incidence increases with age
• Initial phase: pruritic urticarial papules and plaques (may last weeks-months before blistering)
• Bullous phase: large, tense blisters on erythematous or normal skin; blisters intact (unlike PV) due to subepidermal location
• Distribution: inner thighs, abdomen, flexures, axillae; generalized
• Mucosal involvement: less common than PV (20-30%)
• Nikolsky sign NEGATIVE (subepidermal, not acantholytic)

Systemic Associations

• Neurological disorders: dementia, Parkinson's disease, stroke, epilepsy (best established associations)
• Psychiatric disorders (antipsychotic medications may trigger)
• Debated association with malignancy (routine cancer screening not universally recommended; consider in early-onset, treatment failure)

Diagnosis

• Biopsy (H&E): subepidermal bulla with eosinophil-rich infiltrate
• DIF: linear IgG and C3 at the BMZ (dermal-epidermal junction)
• Salt-split skin: antibodies bind the epidermal side ("roof") - distinguishes from EBA (dermal side/"floor")
• ELISA: anti-BP180 NC16A (most specific), anti-BP230

Treatment

• Topical super-potent corticosteroids (clobetasol propionate): first-line for moderate disease; may be as effective as oral steroids with less systemic toxicity
• Oral corticosteroids (prednisone 0.5-1 mg/kg/day): for severe/widespread disease
• Steroid-sparing agents: doxycycline + nicotinamide (milder disease), azathioprine, mycophenolate mofetil, methotrexate
• Rituximab: emerging role in refractory cases
• Mortality related to disease severity and treatment complications (especially in elderly)

Mucous Membrane Pemphigoid (Cicatricial Pemphigoid)

• IgG (and sometimes IgA) autoantibodies against BMZ proteins (BP180, BP230, laminin-332, α6β4 integrin, type VII collagen)
• Predominantly mucosal disease: oral, conjunctival, nasal, laryngeal, esophageal, genital
• Scarring is the hallmark - causes blindness (symblepharon, entropion), laryngeal stenosis, esophageal stricture
• Skin involvement in 25-30% (resembles BP)
• Ocular involvement requires urgent ophthalmology referral and aggressive treatment
• DIF: linear IgG/IgA/C3 at BMZ
• Treatment: dapsone, systemic steroids, cyclophosphamide + prednisolone (sight-threatening), rituximab

Dermatitis Herpetiformis

• IgA autoantibodies against epidermal transglutaminase (TG3); also against tissue TG2
• Cross-reacts with gliadin (gluten)
• Intensely pruritic vesicles and papules; elbows, knees, buttocks, scalp, back
• Blisters rarely seen clinically (scratched off); excoriations predominate
• DIF: granular IgA deposits in dermal papillae (pathognomonic)
• Associated with celiac disease (gluten-sensitive enteropathy)
• Increased risk of non-Hodgkin lymphoma (B-cell and T-cell; enteropathy-associated T-cell lymphoma)
• Gluten-free diet may reduce lymphoma risk
• Treatment: dapsone (dramatic relief within 24-48h) + strict gluten-free diet

Epidermolysis Bullosa Acquisita (EBA)

• IgG autoantibodies against type VII collagen (anchoring fibrils; dermal side of BMZ)
• Classic/mechano-bullous form: skin fragility, blisters at trauma sites, scarring, milia; resembles genetic EB
• Inflammatory form: widespread tense blisters resembling BP; accentuated in flexures
• Mucous membrane pemphigoid-like form: scarring mucosal lesions
• Brunsting-Perry-like form: head and neck; scarring
• DIF: linear IgG at BMZ
• Salt-split skin: IgG on dermal side ("floor") - distinguishes from BP (epidermal/roof)
• Treatment: difficult; dapsone, colchicine, cyclosporine, rituximab

Linear IgA Bullous Dermatosis (LABD)

• IgA antibodies against BP180 ectodomain (LAD-1)
• Children: chronic bullous disease of childhood - dramatic presentation, excellent prognosis, may remit spontaneously at puberty
• Adults: acquired chronic form
• String of pearls/crown of pearls pattern: annular arrangement of tense vesicles around central erosion
• DIF: linear IgA at BMZ
• Drug-induced LABD: vancomycin (classic); also penicillins, furosemide, captopril
• Treatment: dapsone (first-line); sulfonamides; systemic steroids for severe disease

Summary Comparison Table - Immune Bullous Diseases

HIGH-YIELD CLINICAL PEARLS

• Koebner phenomenon + Auspitz sign + silvery scales on extensor surfaces = psoriasis
• IL-17 and IL-23 are the dominant cytokines; biologics targeting these axes are the most effective treatments
• Always screen for psoriatic arthritis and cardiovascular risk factors

• Filaggrin mutation = leaky skin barrier = atopic march
• "Outside-in" theory: barrier failure → sensitization → systemic atopy
• Dupilumab (anti-IL-4Rα) targets the IL-4/IL-13 Th2 pathway - game-changing biologic

• DRESS onset: 2-6 weeks; SJS/TEN: 1-3 weeks; AGEP: 24-48 hours - timing is diagnostic
• Always stop the offending drug immediately in severe reactions
• Allopurinol is the most common cause of SJS/TEN in Asian populations (HLA-B*5801)

• Acanthosis nigricans sudden-onset + mucosal + verrucous = rule out malignancy
• Vitiligo: screen thyroid, adrenal, glucose - autoimmune co-morbidities
• Ruxolitinib cream (JAK inhibitor) is FDA-approved for non-segmental vitiligo

• Comedones are the hallmark - no comedones, think rosacea
• Isotretinoin requires iPLEDGE enrollment; two negative pregnancy tests; teratogenic
• Oral antibiotics + BPO always (resistance prevention)

• Nikolsky sign: intraepidermal (pemphigus group) = positive; subepidermal (pemphigoid group) = negative
• Salt-split skin: BP = epidermal/"roof"; EBA = dermal/"floor"
• DH granular IgA = pathognomonic; always think celiac disease; check anti-TG2 and anti-DGP antibodies
• Paraneoplastic pemphigus = hemorrhagic oral erosions + lymphoma

1. Papulosquamous Diseases - Psoriasis (pathogenesis via IL-23/IL-17 axis, all clinical variants, comorbidities, treatment ladder including biologics), Lichen Planus (6 P's, Wickham's striae, HCV association, histology), Pityriasis Rosea
2. Atopic Dermatitis - Filaggrin/barrier dysfunction + Th2 immune dysregulation, Hanifin-Rajka criteria, age-specific patterns, complications (eczema herpeticum, S. aureus, ocular), full treatment ladder including dupilumab and JAK inhibitors
3. Seborrheic Dermatitis - Malassezia pathogenesis, distribution, cradle cap, severe HIV association (up to 83% prevalence), treatment
4. Cutaneous Drug Eruptions - Complete table of all major patterns with timing, key drugs, features; DRESS detail (SCORTEN, HLA associations), SJS/TEN spectrum, AGEP, drug-induced lupus, linear IgA disease
5. Disorders of Pigmentation - Melasma, PIH, acanthosis nigricans (benign vs. malignant), vitiligo (segmental vs. non-segmental, JAK inhibitor therapy), albinism, pityriasis alba
6. Acne Vulgaris - 4-factor pathogenesis, lesion types, grading, step-wise treatment (retinoids → antibiotics+BPO → oral antibiotics/hormonal → isotretinoin/iPLEDGE), acne vs. rosacea comparison
7. Cutaneous Manifestations of Internal Disease - Paraneoplastic syndromes (acanthosis nigricans, Leser-Trélat, NME/glucagonoma, Bazex syndrome, hypertrichosis lanuginosa acquisita, paraneoplastic pemphigus), dermatitis herpetiformis, bullous pemphigoid systemic associations
8. Immune Bullous Diseases - Full coverage of PV, PF, BP, MMP, DH, EBA, LABD, paraneoplastic pemphigus with target antigens, DIF patterns, salt-split skin interpretation, and a comprehensive comparison table