Step 2 CK · Dermatology

Vesiculobullous & Autoimmune Skin Disease

Name: Vesiculobullous & Autoimmune Skin Disease
Creator: Veli Bakalov, MD

Where the blister splits tells you the antibody

Dermatology·Drug Reactions & Blistering Disease·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Intraepidermal split + flaccid bullae + painful oral erosions + Nikolsky positive = pemphigus vulgaris (IgG vs desmoglein 3 ± 1; acantholysis with a basal "row of tombstones").
Subepidermal split + tense, intensely pruritic bullae in the elderly + mucosa spared + Nikolsky negative = bullous pemphigoid (IgG vs hemidesmosomal BP180/BP230).
DIF of perilesional skin: pemphigus = intercellular fishnet IgG; pemphigoid = linear IgG and C3 along the basement membrane; dermatitis herpetiformis = granular IgA at dermal papillary tips.
Pemphigus vulgaris can be fatal (fluid loss, sepsis) and needs systemic corticosteroids plus rituximab; bullous pemphigoid responds to high-potency topical or systemic steroids.
Desmoglein 3 dominates in mucosa and desmoglein 1 in skin; isolated anti-desmoglein 1 = pemphigus foliaceus (superficial, no mucosal disease).
Dermatitis herpetiformis is the skin manifestation of celiac disease: grouped itchy vesicles on elbows, knees, buttocks, and scalp; IgA vs transglutaminase; HLA-DQ2/DQ8.
Dermatitis herpetiformis: dapsone gives the fastest relief (check G6PD first for hemolysis and methemoglobinemia risk), but a lifelong gluten-free diet is definitive.
Porphyria cutanea tarda (UROD deficiency, most common porphyria): blisters, fragility, milia, hypertrichosis on dorsal hands; coral-pink urine under a Wood lamp; triggers HCV, alcohol, estrogen, iron, HIV; treat with phlebotomy or low-dose hydroxychloroquine.
Nikolsky sign is positive in pemphigus vulgaris, staphylococcal scalded skin syndrome, and TEN; negative in bullous pemphigoid and dermatitis herpetiformis.

Approach: where the blister splits

Plane of cleavage predicts the phenotype. An intraepidermal split leaves only a thin roof, so blisters are flaccid, fragile, and Nikolsky positive; this is pemphigus vulgaris. A subepidermal split carries the whole epidermis as the roof, so blisters are tense, robust, and Nikolsky negative; this is bullous pemphigoid.

Confirming the diagnosis. Biopsy a fresh blister edge for routine histology, and biopsy normal-appearing perilesional skin for direct immunofluorescence (DIF), which shows the antibody class and its deposition pattern.

The three autoimmune blistering diseases

Feature	Pemphigus vulgaris	Bullous pemphigoid	Dermatitis herpetiformis
Split	Intraepidermal, suprabasal (acantholysis)	Subepidermal, eosinophil-rich	Subepidermal, at the dermal papillae
Target	Desmoglein 3 (± 1): desmosome	BP180 and BP230: hemidesmosome	Epidermal/tissue transglutaminase
DIF	Intercellular IgG, fishnet pattern	Linear IgG and C3 along the BMZ	Granular IgA at dermal papillary tips
Lesions	Flaccid bullae → painful erosions	Tense, intensely pruritic bullae	Grouped, itchy vesicles on extensors
Mucosa	Oral often first or only site	Usually spared	Spared
Nikolsky	Positive	Negative	Negative
Patient	Middle-aged adults	Elderly	Celiac disease (HLA-DQ2/DQ8)
Treatment	Systemic steroids + rituximab	High-potency topical or systemic steroids	Gluten-free diet + dapsone

Nikolsky sign. Lateral pressure shears off the epidermis where keratinocyte cohesion is lost.

Positive: pemphigus vulgaris, staphylococcal scalded skin syndrome, toxic epidermal necrolysis
Negative: bullous pemphigoid, dermatitis herpetiformis

Pemphigus vulgaris

Mechanism. IgG autoantibodies against desmoglein 3, plus desmoglein 1 in mucocutaneous disease, the desmosomal cadherins that bind keratinocytes to one another. Loss of adhesion (acantholysis) produces an intraepidermal suprabasal split. The basal cells stay attached to the basement membrane, like a "row of tombstones."

Desmoglein 3 predominates in mucosa and desmoglein 1 in skin. Isolated anti-desmoglein 1 antibodies cause pemphigus foliaceus: superficial crusted erosions with no mucosal disease.

Presentation. Middle-aged adults develop flaccid bullae that rupture into painful erosions, and the oral mucosa is often the first or only site. Nikolsky sign is positive.

Diagnosis. DIF shows IgG between keratinocytes throughout the epidermis in a net-like (reticular, fishnet, or chicken-wire) pattern. A Tzanck smear shows acantholytic keratinocytes, and serum anti-desmoglein antibodies support the diagnosis.

Untreated pemphigus vulgaris can be fatal from fluid loss and sepsis, like a burn. It needs systemic immunosuppression: corticosteroids plus rituximab. A topical steroid alone is inadequate.

Variants. Thiol drugs (penicillamine, captopril) can induce pemphigus. Paraneoplastic pemphigus, with severe stomatitis, accompanies lymphoproliferative disorders such as non-Hodgkin lymphoma and CLL.

Bullous pemphigoid

Mechanism. IgG against the hemidesmosome antigens BP180 (BPAG2, collagen XVII) and BP230 (BPAG1) at the dermoepidermal junction. Complement fixation recruits eosinophils and produces a subepidermal split.

The pemphigoid antigens anchor basal cells to the basement membrane; the pemphigus antigens (desmogleins) hold keratinocytes to each other.

Presentation. Elderly patients develop large, tense, intensely pruritic bullae on the flexures and trunk, often after an urticarial (itchy, hive-like) prodrome. The oral mucosa is usually spared, and Nikolsky sign is negative. DPP-4 inhibitors (gliptins) are a recognized drug trigger.

Diagnosis and treatment. DIF shows linear IgG and C3 along the basement membrane zone, in contrast to the intercellular pattern of pemphigus, and histology shows an eosinophil-rich subepidermal blister. BP is less lethal than pemphigus vulgaris and is treated with high-potency topical corticosteroids (such as clobetasol) or systemic corticosteroids.

Epidermolysis bullosa acquisita is another subepidermal disease, targeting type VII collagen (anchoring fibrils). It produces trauma-induced acral blisters that heal with scarring and milia.

Dermatitis herpetiformis

The skin face of celiac disease. Intensely pruritic, grouped ("herpetiform") vesicles and papules on the extensor surfaces: elbows, knees, buttocks, and scalp. Because of the itch, patients often present with excoriations rather than intact vesicles. IgA targets epidermal and tissue transglutaminase, and the disease is tied to HLA-DQ2/DQ8 and gluten-sensitive enteropathy, even when gut symptoms are mild.

Diagnosis. DIF of perilesional skin shows granular IgA deposits at the tips of the dermal papillae. Celiac serology (IgA anti-tissue transglutaminase) supports the diagnosis.

Check G6PDDapsone causes hemolysis in G6PD deficiency and can cause methemoglobinemia.
DapsoneRelieves the itch within 24–48 hours but does not treat the gut.
Lifelong gluten-free dietThe definitive therapy; it heals both skin and intestine, allows the dapsone dose to be tapered and lowers the risk of small-bowel lymphoma.

Treating dermatitis herpetiformis

Porphyria cutanea tarda

Mechanism. The most common porphyria, caused by deficient uroporphyrinogen decarboxylase (UROD) activity in the liver. Uroporphyrins accumulate and act as photosensitizers in the skin.

Presentation. Photosensitive vesicles and bullae, skin fragility, milia, hyperpigmentation, and hypertrichosis on sun-exposed skin, classically the dorsal hands. Urine is dark or tea-colored and fluoresces coral-pink (orange-red) under a Wood lamp from elevated uroporphyrins.

Triggers (and the workup they imply): hepatitis C, alcohol, estrogen, iron overload, and HIV. Check HCV and HIV serologies and iron studies.

Remove triggersStop alcohol and estrogen; protect from sun.
Phlebotomy or low-dose hydroxychloroquinePhlebotomy reduces hepatic iron; hydroxychloroquine mobilizes porphyrins.
Treat the driverTreat underlying hepatitis C.

Managing PCT

PCT causes skin disease only. Acute neurovisceral attacks (abdominal pain, neuropathy, psychiatric symptoms) point to acute intermittent porphyria instead.