Pemphigus Vulgaris
A serious autoimmune blistering disease caused by IgG antibodies against desmoglein 3 (±desmoglein 1), leading to intraepidermal acantholysis. Presents with painful oral erosions and flaccid skin blisters. Nikolsky sign positive. Untreated mortality historically >75%; now ~5–10% with immunosuppressive therapy.
Key Facts
IgG autoantibodies against desmoglein 3 (mucosal) ± desmoglein 1 (mucocutaneous) — intraepidermal acantholysis Flaccid blisters: intraepidermal — rupture easily, leaving painful erosions Nikolsky sign POSITIVE: lateral pressure on normal skin → epidermal separation Oral erosions: often the first and most persistent feature — painful, impair eating DIF: intercellular IgG and C3 — 'fishnet' or 'chicken-wire' pattern in epidermis Treatment: systemic corticosteroids (prednisolone 1 mg/kg) + steroid-sparing agent (rituximab is first-line per RITUX 3 trial) RITUX 3 trial: rituximab superior to prednisolone alone as first-line — complete remission in 89% at 24 months Historically fatal: >75% mortality before corticosteroids; now ~5–10%
Overview
Key Facts
Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune blistering disease. It is less common than bullous pemphigoid but carries greater morbidity and mortality. Oral mucosal involvement is often the presenting feature and the most difficult to control.
Epidemiology
- Incidence: ~0.5–1.6 per 100,000/year
- Typically presents age 40–60 years (younger than BP)
- Increased incidence in Ashkenazi Jewish and South Asian populations
- M:F ~equal
Aetiology
- Autoimmune: IgG autoantibodies targeting desmoglein 3 (desmosome component) — causes loss of keratinocyte adhesion (acantholysis)
- Mucosal-dominant: anti-desmoglein 3 only
- Mucocutaneous: anti-desmoglein 3 AND anti-desmoglein 1
- Genetic: HLA-DRB104:02 and HLA-DRB114:01 associations
- Drug-induced pemphigus: penicillamine, captopril, NSAIDs (rare)
Pathophysiology
- IgG binds desmoglein 3 → disruption of desmosomal adhesion → intraepidermal acantholysis (suprabasal)
- 'Desmoglein compensation theory': explains why mucosal-only disease occurs (mucosa relies primarily on Dsg3, while skin has both Dsg1 and Dsg3)
- Suprabasal acantholysis → 'tombstone' appearance of basal cells on histology
- Blisters form within the epidermis → thin roof → rupture easily
Clinical Presentation
Oral Mucosa (Often First Manifestation)
- Painful erosions on buccal mucosa, palate, gingiva, tongue
- Blisters rupture immediately — rarely see intact blisters in mouth
- Difficulty eating, weight loss, drooling
- May precede skin involvement by weeks to months
Skin
- Flaccid blisters on normal or erythematous skin
- Rupture easily → painful, slow-healing erosions
- Any body site; often scalp, face, trunk, axillae, groin
- No scarring (unless secondary infection)
- Blisters may extend with lateral pressure (Nikolsky +ve)
Nikolsky Sign
- POSITIVE: gentle lateral pressure on perilesional skin → epidermal separation and new blister formation
- Asboe-Hansen sign: pressure on intact blister → lateral extension
Red Flags
- Widespread erosions with fluid loss and secondary infection (sepsis risk)
- Inability to eat/drink due to oral erosions
- Rapid deterioration — may need hospitalisation
- Laryngeal/oesophageal involvement: dysphagia, hoarseness
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Bullous pemphigoid | Tense blisters, Nikolsky −ve, elderly, minimal oral involvement | DIF: linear IgG at BMZ |
| Mucous membrane pemphigoid | Predominantly mucous membrane scarring, ocular involvement | DIF: linear IgG/C3 at BMZ |
| Erythema multiforme | Target lesions, acute onset, HSV/drug trigger | Clinical, biopsy |
| Oral lichen planus | White lacy pattern (Wickham's striae), chronic | Biopsy |
| Aphthous ulceration | Small, well-defined ulcers, self-limiting | Clinical |
| Herpetic stomatitis | Grouped vesicles, gingivostomatitis, HSV | Viral swab, PCR |
Diagnosis / Investigation
Bedside
- Nikolsky sign: positive — important clinical clue
- Oral examination: erosions, desquamative gingivitis
Bloods
- Desmoglein 1 and 3 ELISA antibodies: serum — diagnostic and for monitoring disease activity; titres correlate with clinical severity
- FBC, U&Es, LFTs, glucose: baseline before immunosuppression
- TPMT activity: before starting azathioprine
Biopsy
- Perilesional skin biopsy: suprabasal acantholysis, 'tombstone' row of basal keratinocytes
- Direct immunofluorescence (DIF): perilesional skin — intercellular IgG and C3 in a 'fishnet'/'chicken-wire' pattern — diagnostic gold standard
- Indirect immunofluorescence: serum IgG binding to intercellular substance of monkey oesophagus
Special Tests
- Tzanck smear: acantholytic (Tzanck) cells — supportive but not specific
- ELISA titre monitoring: desmoglein 1/3 levels guide treatment decisions
Management
Non-Pharmacological
- Wound care: non-adherent dressings, antiseptic washes for erosions
- Oral care: soft diet, chlorhexidine mouthwash, topical analgesics (benzydamine)
- Nutritional support: dietary supplements, NG feeding if severe oral involvement
Pharmacological
Induction:
- Prednisolone 0.5–1 mg/kg/day: initial disease control; taper once remission achieved
- Rituximab 1 g IV on days 0 and 14: now recommended as first-line alongside low-dose prednisolone per RITUX 3 trial — complete remission in 89% at 24 months
Maintenance/Steroid-Sparing:
- Azathioprine 2–3 mg/kg/day (check TPMT): most commonly used
- Mycophenolate mofetil 1–1.5 g BD: alternative
- Rituximab maintenance: 500 mg at 12 and 18 months
Refractory:
- IVIg 2 g/kg over 2–5 days: for acute flares or pre-operative
- Cyclophosphamide: severe refractory disease
- Plasmapheresis: acute severe disease unresponsive to other treatments
Referral Criteria
- All suspected PV: urgent dermatology referral for biopsy and DIF
- Specialist immunobullous centre for management
- Ophthalmology: if ocular involvement suspected
- Dietetics: if oral involvement impairs nutrition
Prognosis
- Pre-corticosteroid era: >75% mortality
- Current mortality: ~5–10% (due to disease complications and immunosuppressive treatment)
- RITUX 3 trial: rituximab as first-line → complete remission off therapy in 89% at 24 months (vs 34% with prednisolone alone)
- Many patients achieve long-term remission with appropriate treatment
- Relapse: common during steroid tapering; desmoglein titres help predict
- Causes of death: sepsis (most common), treatment complications (GI bleeding, osteoporosis)
Other Relevant Information
Pemphigus vs Pemphigoid Comparison
| Feature | Pemphigus Vulgaris | Bullous Pemphigoid |
|---|---|---|
| Age | 40–60 years | >70 years |
| Blister type | Flaccid, intraepidermal | Tense, subepidermal |
| Nikolsky sign | Positive | Negative |
| Oral involvement | Common (often first) | Rare (<20%) |
| Target antigen | Desmoglein 3 (±1) | BP180, BP230 |
| DIF pattern | Intercellular (fishnet) | Linear at BMZ |
| Treatment | Prednisolone + rituximab | Topical clobetasol |
| Mortality | 5–10% | 25–30% (1-year, elderly) |
RITUX 3 Trial (Lancet 2017)
| Outcome | Rituximab | Prednisolone Alone |
|---|---|---|
| Complete remission off therapy (24 months) | 89% | 34% |
| Serious adverse events | Lower | Higher |