Autoimmune intraepidermal blistering disease with flaccid bullae and painful mucosal erosions.
Also known as: pemphigus, PV, intraepidermal blistering disease
Overview
Autoimmune mucocutaneous blistering disorder caused by IgG autoantibodies against desmoglein 1 and 3, producing loss of keratinocyte adhesion (acantholysis) in the suprabasal epidermis. Flaccid bullae rupture easily, leaving painful erosions; oral mucosa is almost always involved.
Epidemiology
Rare (1-5 cases per million per year). Peak onset 40-60 years. Increased prevalence in Ashkenazi Jewish, Mediterranean, and South Asian populations. Associations with HLA-DR4 and HLA-DR14.
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Question 1DermatologyMedium
A 52-year-old woman of Ashkenazi Jewish descent presents with 3 months of painful oral erosions followed by flaccid bullae and raw, ragged-bordered erosions on her scalp, axillae, and trunk. The blisters rupture with minimal pressure, and lateral traction on adjacent normal-appearing skin produces shearing of the epidermis. A perilesional skin biopsy is sent for direct immunofluorescence. Which of the following findings best supports the suspected diagnosis?
AIntercellular IgG and C3 deposition in a chicken-wire pattern
BGranular IgA deposition within the tips of the dermal papillae
CLinear IgG and C3 deposition along the basement membrane zone
DIntercellular IgA deposition in the superficial epidermis
EShaggy fibrinogen deposition along the basement membrane zone
Reveal answer & full explanation
Correct answer: A — Intercellular IgG and C3 deposition in a chicken-wire pattern
AIntercellular IgG and C3 deposition in a chicken-wire pattern✓
BGranular IgA deposition within the tips of the dermal papillae
CLinear IgG and C3 deposition along the basement membrane zone
DIntercellular IgA deposition in the superficial epidermis
EShaggy fibrinogen deposition along the basement membrane zone
Why Intercellular IgG and C3 deposition in a chicken-wire pattern is correct
The vignette is classic pemphigus vulgaris: a middle-aged adult of Ashkenazi descent with painful oral erosions preceding flaccid cutaneous bullae and a positive Nikolsky sign (epidermal shearing on lateral pressure on perilesional skin).
PV is driven by IgG autoantibodies against desmoglein 1 and 3 within the desmosomes between keratinocytes, causing suprabasal acantholysis. Perilesional direct immunofluorescence therefore shows IgG and C3 deposited in the intercellular spaces of the epidermis, producing the characteristic net-like "chicken-wire" pattern.
This intercellular (not basement-membrane) localization is the confirmatory immunofluorescence finding; serum anti-desmoglein 1/3 ELISA further confirms the diagnosis and tracks disease activity.
Why the others are wrong
Granular IgA deposition within the tips of the dermal papillae — This is the finding of dermatitis herpetiformis, an intensely pruritic vesicular eruption linked to celiac disease, not an acantholytic mucocutaneous blistering disorder.
Linear IgG and C3 deposition along the basement membrane zone — This is the DIF pattern of bullous pemphigoid (anti-BP180/230), which causes tense subepidermal bullae on flexural skin with pruritus and usual mucosal sparing, the opposite localization from PV.
Intercellular IgA deposition in the superficial epidermis — This is the DIF pattern of IgA pemphigus (subcorneal pustular dermatosis type), which causes pruritic flaccid pustules in annular or circinate groups on the trunk and flexures with usual mucosal sparing; PV deposits IgG, not IgA, and typically begins with painful oral erosions.
Shaggy fibrinogen deposition along the basement membrane zone — the DIF pattern of lichen planus, whose erosive oral form can also cause painful mucosal erosions, but LP does not cause flaccid cutaneous bullae with a positive Nikolsky sign; PV deposits IgG and C3 in the intercellular spaces of the epidermis, not fibrinogen at the basement membrane.
Question 2DermatologyMedium
A 54-year-old man with biopsy-confirmed pemphigus vulgaris has widespread flaccid bullae and raw erosions covering roughly 40% of his trunk and scalp, plus painful oral erosions. He was started on high-dose prednisone two weeks ago. He now presents with fever to 39.1°C, tachycardia, and hypotension. The eroded skin is malodorous with purulent, crusted borders. Which of the following complications is most likely responsible for his deterioration?
APneumocystis pneumonia from steroid therapy
BSepsis from secondary cutaneous infection
CUnderlying lymphoproliferative malignancy
DHypovolemia from transepidermal fluid loss
EAdrenal crisis from HPA-axis suppression
Reveal answer & full explanation
Correct answer: B — Sepsis from secondary cutaneous infection
APneumocystis pneumonia from steroid therapy
BSepsis from secondary cutaneous infection✓
CUnderlying lymphoproliferative malignancy
DHypovolemia from transepidermal fluid loss
EAdrenal crisis from HPA-axis suppression
Why Sepsis from secondary cutaneous infection is correct
The denuded epidermis in pemphigus vulgaris is a large open wound that loses its barrier function, so extensive erosions are readily colonized and invaded by skin flora (Staphylococcus aureus, Streptococcus, gram-negatives).
Secondary bacterial infection of erosions progressing to sepsis is the leading cause of death in pemphigus vulgaris; modern mortality is under 10%, and most of those deaths are infectious.
High-dose corticosteroids (and other immunosuppression) further blunt the immune response, and the fever, tachycardia, hypotension, and purulent malodorous erosions here point to wound-derived sepsis.
Why the others are wrong
Hypovolemia from transepidermal fluid loss - Extensive erosions do cause burn-like fluid and protein loss that can contribute to tachycardia and hypotension, but fluid loss does not explain a fever of 39.1°C or purulent, malodorous erosions, which point to invasive wound infection.
Underlying lymphoproliferative malignancy - This defines paraneoplastic pemphigus (anti-plakin antibodies, severe stomatitis, CLL/NHL/Castleman), not classic biopsy-confirmed pemphigus vulgaris, and would not explain acute infected erosions.
Pneumocystis pneumonia from steroid therapy - PJP is a real risk of prolonged high-dose glucocorticoids (prophylaxis is usually considered at prednisone 20 mg/day or more for 4 weeks or longer), but it presents with progressive dyspnea, dry cough, and hypoxemia, none of which is described; this patient's deterioration centers on purulent, malodorous skin erosions two weeks into therapy.
Adrenal crisis from HPA-axis suppression - tempting because hypotension in a patient on high-dose glucocorticoids raises concern for HPA-axis suppression, but adrenal crisis follows abrupt steroid withdrawal or an unmet stress requirement; he is still receiving supraphysiologic prednisone, and adrenal insufficiency would not explain purulent, malodorous erosions.
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Other autoimmune disease (myasthenia gravis, thymoma)
Middle-aged adults of Mediterranean or Ashkenazi descent
Pathophysiology
IgG4 autoantibodies against desmoglein 3 (mucosa-dominant) or both desmoglein 1 and 3 (mucocutaneous) disrupt desmosomal adhesion between keratinocytes. The resulting acantholysis produces flaccid intraepidermal blisters that rupture, leaving raw erosions prone to secondary infection and fluid/protein loss.
Clinical presentation
Symptoms
Painful, persistent oral erosions (often the presenting symptom, precede skin disease by months)
Burning, painful skin lesions rather than itch
Dysphagia, odynophagia, weight loss from oropharyngeal involvement
Hoarseness if laryngeal involvement
Signs / physical exam
Flaccid bullae that rupture easily on scalp, face, axillae, groin, trunk
Erosions with ragged borders, slow to heal, may crust
Positive Nikolsky sign (lateral pressure on perilesional skin produces shearing)
Positive Asboe-Hansen sign (pressure on intact bulla extends it peripherally)
Classic findings
Painful oral erosions preceding flaccid cutaneous bullae in a middle-aged adult; positive Nikolsky.
Differential diagnosis
Bullous pemphigoid — Tense subepidermal bullae on flexural skin, intense pruritus, mucosa usually spared, elderly; anti-BP180/230 antibodies; linear C3 + IgG along basement membrane
Paraneoplastic pemphigus — Severe stomatitis, polymorphic skin lesions, underlying lymphoproliferative malignancy (CLL, NHL, Castleman disease); antibodies against multiple plakin proteins
Stevens-Johnson syndrome / TEN — Acute febrile drug reaction, dusky targetoid macules, full-thickness epidermal necrosis, mucosal involvement, positive Nikolsky on inflamed skin only
Mucous membrane pemphigoid — Scarring erosions of mucosa (oral, ocular, genital), risk of blindness and esophageal strictures; subepithelial split
Erythema multiforme major — True targetoid lesions, post-HSV or Mycoplasma, limited mucosal involvement, self-limited
Aphthous stomatitis — Recurrent small round ulcers limited to non-keratinized oral mucosa; no skin involvement; not progressive
Diagnostic workup
Diagnostic criteria
Diagnosis requires clinical findings plus histology and immunofluorescence. Lesional biopsy: suprabasal acantholysis with 'tombstone' row of basal cells. Perilesional direct immunofluorescence (DIF): intercellular 'chicken-wire' IgG and C3 deposition. Serum anti-desmoglein antibodies confirm and track activity.
Labs
Serum indirect immunofluorescence and ELISA for anti-desmoglein 1 and 3 IgG (titers correlate with disease activity)
Wound cultures from eroded skin if secondary infection suspected
Imaging
No routine imaging required
Esophagogastroduodenoscopy if dysphagia or odynophagia suggests esophageal involvement
Chest imaging and age-appropriate cancer screening to exclude paraneoplastic pemphigus in atypical cases
Diagnostic algorithm
Feature
Pemphigus Vulgaris
Bullous Pemphigoid
Age
40-60
>60
Bulla type
Flaccid, ruptures easily
Tense, intact
Mucosal involvement
Almost always (often first)
Rare (10-30%)
Pruritus
Pain > itch
Intense itch
Histology split
Intraepidermal (suprabasal)
Subepidermal
Target antigen
Desmoglein 1 and 3
BP180 (BPAG2), BP230 (BPAG1)
DIF pattern
Intercellular 'chicken-wire' IgG/C3
Linear IgG/C3 at basement membrane
Nikolsky sign
Positive
Negative (usually)
Mortality untreated
High (60-90%)
Lower but morbid
Pemphigus vulgaris vs bullous pemphigoid — key clinical and immunopathologic distinctions.
Treatment
First-line
Systemic corticosteroid: prednisone 1 mg/kg/day, methylprednisolone IV for severe disease; taper slowly over months
Rituximab (anti-CD20) — now first-line with steroids per 2020 international consensus and Joly et al. 2017 RITUX 3 trial; 1 g IV days 0 and 14 (rheumatoid arthritis dosing) or 375 mg/m² weekly × 4 (lymphoma dosing)
Wound care: nonadherent dressings, gentle cleansing, treatment of secondary bacterial infection (mupirocin topical, oral cephalexin or doxycycline)
Nutritional support, soft diet, viscous lidocaine and 'magic mouthwash' for oral pain
Always exclude paraneoplastic pemphigus in patients with severe stomatitis or hematologic malignancy.
Rituximab has shifted PV from a chronic steroid-dependent disease toward durable remission in many patients.
References
EADV 2020 — Joly P, Horvath B, Patsatsi A, et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol 2020;34:1900-1913
RITUX 3 Trial — First-line rituximab combined with short-term prednisone versus prednisone alone for pemphigus (Joly et al., Lancet 2017)
International Panel — Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus (Murrell et al., JAAD 2008)
International Panel 2020 — Murrell DF, Peña S, Joly P, et al. Diagnosis and management of pemphigus: recommendations of an international panel of experts. J Am Acad Dermatol 2020;82(3):575-585
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