A 48-year-old woman of South Asian descent presents with a 3-month history of painful oral erosions initially thought to be recurrent aphthous ulcers. Over the past 4 weeks, flaccid bullae have appeared on her trunk and flexural areas, rupturing easily with minimal trauma. On examination, gentle lateral pressure on apparently normal-appearing skin of the forearm results in immediate epidermal separation and blister formation, as marked **D** in the diagram. Which of the following best explains the pathophysiologic basis of this clinical finding?

Explanation

## Why "Loss of keratinocyte-to-keratinocyte adhesion due to IgG autoantibodies against desmogleins, resulting in acantholysis" is right The Nikolsky sign in pemphigus vulgaris reflects the fundamental pathology: IgG autoantibodies against desmoglein 3 (and/or desmoglein 1) bind to desmosomal adhesion molecules on keratinocytes, disrupting cell-to-cell adhesion. This causes acantholysis—loss of intercellular cohesion within the epidermis—leading to suprabasal blistering. The positive Nikolsky sign (epidermal shearing with gentle pressure on normal-appearing skin) is pathognomonic for this loss of adhesion and is a hallmark of pemphigus vulgaris. The clinical presentation (painful oral erosions as initial manifestation, flaccid bullae, South Asian ethnicity, middle-aged) and the positive Nikolsky sign together confirm the diagnosis (Robbins 10e Ch 25; Harrison 21e Ch 56). ## Why each distractor is wrong - **Subepidermal separation at the dermal-epidermal junction due to anti-BP180 and anti-BP230 antibodies**: This describes bullous pemphigoid, not pemphigus vulgaris. Bullous pemphigoid produces tense (firm, non-flaccid) bullae that do not rupture easily, and the Nikolsky sign is characteristically NEGATIVE. The split is subepidermal, not intraepidermal. - **Granular IgA deposition at the dermal-epidermal junction associated with tissue transglutaminase antibodies**: This describes dermatitis herpetiformis, which presents with intensely pruritic vesicles (not painful erosions) on extensor surfaces and buttocks, is almost always associated with celiac disease, and has a completely different immunofluorescence pattern. Nikolsky sign is not a feature. - **Disruption of hemidesmosomes leading to tense bullae that do not rupture with minor pressure**: This again describes bullous pemphigoid. Tense bullae and negative Nikolsky sign are the opposite of what is seen here. Hemidesmosomes are disrupted in subepidermal blistering disorders, not in pemphigus. **High-Yield:** Nikolsky sign POSITIVE = pemphigus (intraepidermal acantholysis, flaccid bullae); Nikolsky sign NEGATIVE = bullous pemphigoid (subepidermal, tense bullae). [cite: Robbins 10e Ch 25; Harrison 21e Ch 56]