Immunologically Mediated Skin Diseases¶

Chapter 62 | Harrison's 22e · Part 2 – Cardinal Manifestations & Presentation · Chapter 62

Key Clinical Points¶

Pemphigus vulgaris (PV) is an autoantibody-mediated intraepidermal blistering disease characterized by acantholysis and flaccid blisters, typically in patients >40 years of age.
Pyoderma gangrenosum presents as painful ulcers with a characteristic undermined necrotic violaceous edge and a peripheral erythematous halo; 30–50% are associated with inflammatory bowel disease (IBD).
Fever and rash require careful differentiation between infectious diseases and inflammatory conditions (e.g., DRESS, AGEP, or serum sickness-like reactions).
Purpura, necrosis, or impending necrosis (gunmetal-gray color) in a febrile patient may indicate sepsis or vasculitis.
PV involves IgG autoantibodies against desmogleins (Dsg3 for mucosal; Dsg1 and Dsg3 for mucocutaneous involvement).
Blistering diseases are distinguished by specific immunopathologies and target antigens, such as Pemphigoid gestationis (BPAG2) and Linear IgA (BPAG2).
Scleroderma presents with characteristic features including acral sclerosis, matlike telangiectasias, and focal digital ulcers.
Dermatomyositis is characterized by specific cutaneous findings like the heliotrope rash (periorbital violaceous erythema) and Gottron's papules.
Discoid lupus erythematosus (DLE) presents as erythematous to violaceous, dyspigmented, atrophic plaques with scarring on sun-exposed areas.

DEFINITION & CLASSIFICATION¶

• Immunologically Mediated Skin Diseases: A group of disorders characterized by morbidity (pain, pruritus, disfigurement) and, in some instances, risk of mortality. ◦ Risk Factors: Loss of epidermal barrier function and/or secondary infection. • Pemphigus: A group of autoantibody-mediated intraepidermal blistering diseases characterized by loss of cohesion between epidermal cells (acantholysis). ◦ Clinical Sign: Manual pressure may elicit the separation of the epidermis (Nikolsky sign). This is characteristic of pemphigus but not specific to it; it is also seen in toxic epidermal necrolysis and Stevens-Johnson syndrome.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Pemphigus Vulgaris (PV) Mechanism: Autoantibody-mediated loss of cohesion between epidermal cells. ◦ Histology: → Intraepidermal vesicle formation secondary to acantholysis. → Blister cavities contain acantholytic cells (round, homogeneous, hyperchromatic nuclei). → Basal keratinocytes remain attached to the epidermal basement membrane. ◦ Immunopathology: → Direct immunofluorescence shows deposits of IgG on the surface of keratinocytes. → Complement components are typically found in lesional but not in uninvolved skin. ◦ Autoantigens in PV: Targeting desmogleins (Dsgs), transmembrane desmosomal glycoproteins. → Dsg3: Target for early/mucosal disease. → D1 & Dsg3: Targets in advanced/mucocutaneous disease. → Pathogenicity: Titer of autoantibodies correlates with disease activity.

Pyoderma Gangrenosum¶

• Etiology & Clinical Presentation: Often associated with systemic conditions; 30–50% are recognized as distinct entities. ◦ Morphology: → Undermined necrotic violaceous edge. → Peripheral erythematous halo. → Often begins as pustules that expand rapidly to sizes up to 20 cm. ◦ Associated Disorders: → Inflammatory bowel disease (IBD). → Seropositive rheumatoid arthritis. → Myelodysplasia, acute myelogenous leukemia (AML), or monoclonal gammopathy (usually IgA). → Autoinflammatory disorders. ◦ Clinical Features: → Often found on lower extremities; can occur anywhere including sites of trauma (pathergy).

CLINICAL FEATURES¶

• Pemphigus Vulgaris: Mucocutaneous blistering disease, typically in patients >40 years of age. ◦ Skin Manifestations: Fragile, flaccid blisters that rupture to produce extensive denudation of mucous membranes and skin. ◦ Involved Sites: Mouth, scalp, face, neck, axilla, groin, and trunk. ◦ Symptoms: May include severe skin pain or pruritus. • Pyoderma Gangrenosum: ◦ Morphology: Undermined necrotic violaceous edge with a peripheral erythematous halo. ◦ Progression: Often begins as pustules that expand rapidly to sizes up to 20 cm. ◦ Location: Most common on lower extremities; can occur anywhere, including sites of trauma (pathergy). • Fever and Rash Differentiation: Critical distinction between inflammatory diseases vs. infectious diseases. ◦ Infectious Indicators: → Drug rash plus fever (e.g., DRESS, AGEP, or serum sickness-like reaction). → Examples of infectious diseases with rash/fever: Lyme disease, secondary syphilis, and viral/bacterial exanthems. ◦ Inflammatory Diseases with Fever: → Pustular psoriasis, erythema, and Sweet syndrome. ◦ Red Flags (Signs of Ischemia): → Purpura, necrosis, or impending necrosis (gunmetal-gray color) may indicate sepsis or vasculitis.

DIFFERENTIAL DIAGNOSIS¶

• Pyoderma Gangrenosum Differentials: Requires exclusion of similar-appearing ulcers: ◦ Vasculitis. ◦ Meleney’s ulcer (synergistic infection at a site of trauma or surgery). ◦ Dimorphic fungi. ◦ Cutaneous amebiasis. ◦ Spider bites. ◦ Factitial.

DIAGNOSTIC APPROACH¶

Clinical Correlation: Essential for pyoderma gangrenosum to distinguish from vasculitis or infections.
Histology (Pemphigus): Identify intraepidermal vesicle formation and acantholytic cells (round, homogeneous, hyperchromatic nuclei).
Direct Immunofluorescence (IF): Detect IgG deposits on keratinocytes; used to identify autoantibody presence in 80–90% of PV patients.
ELISA: Used to precisely quantify IgG autoantibodies to Dsg3 and Dsg1.

MANAGEMENT & TREATMENT¶

Pemphigus Vulgaris Management: Focus on identifying specific autoantigen involvement (Dsg3 vs. Dsg1) to correlate with disease activity.
Discoid Lupus Erythematoma (DLE) Treatment: Focused on control of local cutaneous disease. → Primary measures: Photoprotection. → Pharmacotherapy: Topical or intralesional glucocorticoids.

KEY PEARLS & HIGH-YIELD POINTS¶

• Pemphigus Vulgaris: Flaccid blisters + mucosal involvement = high suspicion for PV. Autoantibodies to Dsg3 indicate early/mucosal disease; Dsg1 and Dsg3 indicate advanced mucocutaneous disease. • Pyoderma Gangrenosum: Undermined violaceous edge is characteristic; 30–50% associated with IBD; check for hematologic malignancies or autoinflammatory disorders. • Fever/Rash Rule: Purpura, necrosis, or gunmetal-gray color in a febrile patient suggests sepsis or vasculitis. DRESS and AGEP are common drug reactions. • Blistering Disease Table (Table 62-1): Key distinctions include: → Pemphigoid gestationis (IgA in dermal papillae; BPAG2 antigen). → Linear IgA (Linear IgA in epidermal BMZ; BPAG2 antigen). → Mucous membrane pemphigoid (BPAG2, laminin-332 antigens).

Reference Tables¶

TABLE 62-1 Immunologically Mediated Blistering Diseases DISEASE Pemphigus vulgaris Pemphigus foliaceus¶

Harrison's 22e, p.410

DISEASE	CLINICAL MANIFESTATIONS	HISTOLOGY	IMMUNOPATHOLOGY	AUTOANTIGENSa
Pemphigus vulgaris	Oromucosal lesions, flaccid blisters, denuded skin	Acantholytic blister formed in suprabasal layer of epidermis	Cell surface deposits of IgG on keratinocytes	Dsg3 (plus Dsg1 in patients with skin involvement)
	Crusts and shallow erosions on scalp, central face, upper chest, and back	Acantholytic blister formed in superficial layer of epidermis	Cell surface deposits of IgG on keratinocytes
Paraneoplastic pemphigus	Painful stomatitis with papulosquamous or lichenoid eruptions that may progress to blisters	Acantholysis, keratinocyte necrosis, and vacuolar interface dermatitis	Cell surface deposits of IgG and C3 on keratinocytes and (variably) similar immunoreactants in epidermal BMZ	Plakin protein family members and desmosomal cadherins (see text for details)
	Large tense blisters on flexor surfaces and trunk	Subepidermal blister with eosinophil-rich infiltrate	Linear band of IgG and/or C3 in epidermal BMZ
Pemphigoid gestationis	Pruritic, urticarial plaques rimmed by vesicles and bullae on the trunk and extremities	Teardrop-shaped, subepidermal blisters in dermal papillae; eosinophil-rich infiltrate	Linear band of C3 in epidermal BMZ	BPAG2 (plus BPAG1 in some patients)
	Extremely pruritic small papules and vesicles on elbows, knees, buttocks, and posterior neck	Subepidermal blister with neutrophils in dermal papillae	Granular deposits of IgA in dermal papillae
Linear IgA disease	Pruritic papulovesicles on extensor surfaces; occasionally larger, arciform blisters	Subepidermal blister with neutrophil-rich infiltrate	Linear band of IgA in epidermal BMZ	BPAG2 (see text for specific details)
	Blisters, erosions, scars, and milia on sites exposed to trauma; widespread, inflammatory, tense blisters may be seen initially	Subepidermal blister that may or may not include a leukocytic infiltrate	Linear band of IgG and/or C3 in epidermal BMZ
Mucous membrane pemphigoid	Erosive and/or blistering lesions of mucous membranes and possibly the skin; scarring of some sites	Subepidermal blister that may or may not include a leukocytic infiltrate	Linear band of IgG, IgA, and/or C3 in epidermal BMZ	BPAG2, laminin-332, or others