Pemphigus Vulgaris
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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Risk factors
- Genetic predisposition (HLA-DRB1*04, DRB1*14)
- Drug-induced: penicillamine, captopril, rifampin, NSAIDs
- 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)
- CBC, CMP, baseline glucose, hepatitis B/C, TB screen prior to immunosuppression
- 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 |
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
Second-line / adjunct
- Steroid-sparing agents: azathioprine (check TPMT first), mycophenolate mofetil, methotrexate, cyclophosphamide (severe refractory)
- IVIG 2 g/kg per cycle for refractory disease or when immunosuppression contraindicated
- Plasmapheresis or immunoadsorption for fulminant disease
- Dapsone (mainly for IgA pemphigus variant)
Complications
- Secondary bacterial infection of erosions; sepsis
- Fluid, electrolyte, and protein loss (similar to burns in extensive disease)
- Steroid-related morbidity (osteoporosis, diabetes, infections, AVN)
- Esophageal stricture; laryngeal scarring; chronic ocular involvement
- Mortality historically 60-90% pre-steroids; now <10% with modern therapy, mostly from infection
PANCE pearls
- Positive Nikolsky sign is shared with TEN and SSSS; combine with clinical context and biopsy.
- Oral lesions almost always precede skin disease — unexplained chronic oral erosions in a middle-aged adult should prompt biopsy.
- Desmoglein 3 antibodies → mucosal disease; addition of desmoglein 1 antibodies → mucocutaneous disease.
- 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
- AAD/EADV 2020 — Updated S2K guidelines on the management of pemphigus vulgaris (Joly et al., JEADV 2020)
- 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)
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