A 64-year-old man presents to his primary care provider after noticing the development of a blistering rash. The patient states that his symptoms began 1 week ago after he noticed a blister develop on the inside of his mouth that eventually ruptured. Over the past several days, he has noticed several more blisters on his torso. The patient denies a fever or any other symptoms. He has a history of high blood pressure, for which he takes hydrochlorothiazide. He is otherwise healthy and denies any recent changes to his medication. Today, the patient’s temperature is 99.0°F (37.2°C), blood pressure is 124/84 mmHg, pulse is 66/min, and respirations are 12/min. On exam, the patient’s mouth is notable for a previously ruptured blister on his left buccal mucosa. On his left flank and anterior abdomen are scattered 10-15-cm bullae that appear flaccid and filled with serous fluid. The lesions are erythematous but there is no surrounding erythema. On manual rubbing of the skin near the lesions, new blisters form within minutes. Which of the following is involved in the pathogenesis of this disease?

IgG against transmembrane proteins between cells

IgA antibodies depositing in the dermal papillae

Autoantibodies against hemidesmosomes

Exotoxin destroying keratinocyte attachments

A 45-year-old man visits the office with complaints of severe pain with urination for 5 days. In addition, he reports having burning discomfort and itchiness at the tip of his penis. He is also concerned regarding a yellow-colored urethral discharge that started a week ago. Before his symptoms began, he states that he had sexual intercourse with multiple partners at different parties organized by the hotel he was staying at. Physical examination shows edema and erythema concentrated around the urethral meatus accompanied by a mucopurulent discharge. Which of the following diagnostic tools will best aid in the identification of the causative agent for his symptoms?

Nucleic acid amplification tests (NAATs)

Leukocyte esterase dipstick test

A 54-year-old man comes to the physician because of a cough with blood-tinged sputum for 1 week. He also reports fever and a 5-kg (11 lb) weight loss during the past 2 months. Over the past year, he has had 4 episodes of sinusitis. Physical examination shows palpable nonblanching skin lesions over the hands and feet. Examination of the nasal cavity shows ulceration of the nasopharyngeal mucosa and a depressed nasal bridge. Oral examination shows a painful erythematous gingival enlargement that bleeds easily on contact. Which of the following is the most likely cause of the patient's symptoms?

Metalloprotease enzyme deficiency

Malignant myeloid cell proliferation

A 72-year-old nursing home resident is complaining of pruritis. She is noted to have multiple, tense blisters on her trunk as well as the flexor surfaces of her extremities. The blisters have an erythematous base. You are unable to extend the blisters when you apply lateral traction. You suspect an autoimmune bullous dermatosis. Which of the following is the cause of the likely condition?

Antibodies to epidermal transglutaminase

A 50-year-old woman with rheumatoid arthritis on methotrexate develops rapidly progressive painful ulcers on her legs with violaceous undermined borders. Biopsy shows neutrophilic dermal infiltrate with areas of necrosis, but no vasculitis or infection. Wound cultures are negative. Despite debridement, the ulcers worsen. C-ANCA and P-ANCA are negative. Evaluate the diagnosis and determine the management that addresses both the cutaneous condition and systemic disease.

Continue methotrexate, add TNF-alpha inhibitor and systemic corticosteroids

Discontinue all immunosuppression to allow wound healing

Increase methotrexate dose and add wound care

Discontinue methotrexate, start cyclosporine and prednisone

Start broad-spectrum antibiotics and surgical debridement

Vesiculobullous diseases for USMLE Step 2 CK: High-Yield Pathology Lessons

Vesiculobullous Overview - Skin Splits & Bubbles

Vesicle: Fluid-filled blister < 1 cm
Bulla: Fluid-filled blister > 1 cm
Pathogenesis hinges on the anatomical level of skin separation.

Skin layers and bullous disease split levels

⭐ The blister's clinical stability reveals the split's depth. Intraepidermal splits create flaccid, easily ruptured bullae (positive Nikolsky sign), while subepidermal splits form tense, durable bullae as the entire epidermis is the roof.

📌 Bullous Pemphigoid = Below the epidermis (subepidermal). Pemphigus Vulgaris = Very fragile (intraepidermal).

Intraepidermal Blistering - Fragile Connections Falter

Pemphigus Vulgaris: Most common and severe. Autoantibodies against Desmoglein-3 (Dsg3) & Dsg1.
- Presents with painful, flaccid bullae that rupture easily, leaving erosions.
- Nikolsky sign positive: Gentle rubbing of skin causes blistering.
- Oral mucosa involvement is common and often the first sign.
- Histo: Suprabasal acantholysis (separation) with "tombstoning" of basal cells.
- IF: Reticular or "net-like" pattern of IgG deposits around keratinocytes.

Pemphigus Vulgaris: Immunofluorescence, Net-like Pattern

Pemphigus Foliaceus: Milder variant; targets Dsg1 only.
- Superficial blisters form scaly, crusted erosions; resembles cornflakes.
- No mucosal involvement.
Hailey-Hailey Disease (Familial Benign Pemphigus):
- Genetic (ATP2C1 mutation), not autoimmune.
- Affects intertriginous areas (axillae, groin).
- Histo: Extensive acantholysis shows a "dilapidated brick wall" appearance.

⭐ Exam Favorite: In Pemphigus Vulgaris, anti-Dsg3 antibodies dominate in mucosal lesions, while anti-Dsg1 antibodies are more prominent in skin lesions. Mucosal-dominant disease may only have anti-Dsg3.

Subepidermal Blistering - Deeper Troubles Bubble

Tense, durable bullae as the entire epidermis forms the roof. Caused by autoantibodies against dermal-epidermal junction (DEJ) components.

Bullous Pemphigoid (BP)
- Most common; affects elderly (>60 yrs). Intense pruritus precedes tense bullae.
- Autoantibodies to hemidesmosome proteins: BPAG1 (BP230) & BPAG2 (BP180).
- 📌 Bullous Pemphigoid = Below Pidermis.
Dermatitis Herpetiformis (DH)
- Intensely pruritic vesicles on extensor surfaces (elbows, knees, buttocks).
- Microabscesses with neutrophils at dermal papillae tips.
⭐ Strong association with celiac disease; skin lesions improve with a gluten-free diet.
Epidermolysis Bullosa Acquisita (EBA)
- Autoantibodies against Type VII collagen in anchoring fibrils.
- Trauma-induced blisters on hands/feet; heals with scarring/milia.

Diagnostic Workup - Clues in the Goo

Skin Biopsy: Gold standard. Two samples required:
- Edge of a fresh blister for H&E (in formalin) to identify the level of the split.
- Perilesional skin for Direct Immunofluorescence (DIF) (in Michel's medium).
Tzanck Smear: Rapid test for herpesvirus (multinucleated giant cells), but low sensitivity for autoimmune bullous diseases.

Immunofluorescence patterns of bullous disorders

⭐ DIF Pattern is Key: Pemphigus vulgaris shows a "chicken-wire" or "net-like" pattern of IgG deposition around keratinocytes. Bullous pemphigoid shows a linear band of IgG and/or C3 at the dermoepidermal junction.

High‑Yield Points - ⚡ Biggest Takeaways

Pemphigus vulgaris features intraepidermal bullae due to anti-desmoglein antibodies; Nikolsky sign is positive.

Bullous pemphigoid shows subepidermal bullae from anti-hemidesmosome antibodies along the basement membrane; Nikolsky sign is negative.

Dermatitis herpetiformis is strongly associated with celiac disease and shows granular IgA deposits in the dermal papillae.

Epidermolysis bullosa is a genetic disorder causing friction-induced blisters due to defects in keratin or collagen.

Porphyria cutanea tarda presents with photosensitivity and blisters, caused by uroporphyrinogen decarboxylase deficiency.

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