Pemphigus Vulgaris
Summary
Pemphigus Vulgaris (PV) is a rare but serious autoimmune blistering disease characterised by the formation of flaccid bullae (Blisters) on the skin and mucous membranes. It is caused by IgG autoantibodies targeting Desmoglein 3 (Dsg3) (Mucosal adhesion molecule) and often also Desmoglein 1 (Dsg1) (Skin adhesion molecule), which are components of desmosomes that hold keratinocytes together. Antibody binding leads to acantholysis (Loss of cell-cell adhesion) → Intraepidermal blister formation. The condition typically affects middle-aged adults (40-60 years) and was fatal before the era of corticosteroids. Clinically, patients present with painful oral erosions (Often the first manifestation) followed by flaccid blisters that rupture easily leaving raw, weeping erosions on the skin. Nikolsky's Sign is positive (Gentle pressure on skin causes separation). Diagnosis is confirmed by skin biopsy (Histology: Intraepidermal blister, Acantholysis) and Direct Immunofluorescence (DIF) (IgG + C3 in intercellular pattern – "Fishnet" / "Chicken wire"). Treatment is with high-dose Corticosteroids ± Immunosuppressants (Azathioprine, Mycophenolate) ± Rituximab (Anti-CD20 – Increasingly first-line). [1,2,3]
Clinical Pearls
"Mouth First": ~50-70% of PV patients present with oral erosions before skin lesions. Painful mouth ulcers that don't heal.
"Flaccid Blisters → Erosions": Blisters are very fragile. By the time the patient is seen, they often have erosions, not intact blisters.
"Nikolsky's Sign": Gentle lateral pressure on skin causes epidermis to shear off = Positive.
"Rituximab Revolution": Anti-CD20 therapy (Rituximab) has transformed outcomes. Now often first-line alongside steroids.
Demographics
| Factor | Notes |
|---|---|
| Age | Middle-aged: 40-60 years. |
| Sex | Equal or slight female predominance. |
| Ethnicity | Higher incidence in Ashkenazi Jews, Mediterranean populations, South Asians. |
| Incidence | Rare: ~0.5-5 per million per year. |
Risk Factors
| Risk Factor | Notes |
|---|---|
| Genetic Predisposition | HLA-DR4, HLA-DRw14. |
| Drug-Induced (Rare) | Penicillamine, Captopril, ACE inhibitors (Can trigger pemphigus-like eruptions). |
Desmogleins and Desmosomes
- Desmosomes: Cell-cell junctions that hold keratinocytes together.
- Desmogleins (Dsg): Transmembrane glycoproteins that are key components of desmosomes.
- Dsg1: Predominant in superficial epidermis and skin.
- Dsg3: Predominant in deeper epidermis and mucous membranes.
Antibody-Mediated Acantholysis
- Autoantibodies: IgG antibodies bind to Dsg3 (And often Dsg1).
- Desmosome Disruption: Loss of cell-cell adhesion.
- Acantholysis: Keratinocytes separate from each other.
- Intraepidermal Blister: Blister forms WITHIN the epidermis (Suprabasilar = Just above basal layer).
Desmoglein Compensation Theory
| Antibody Target | Clinical Manifestation |
|---|---|
| Anti-Dsg3 Only | Mucosal-dominant PV. Dsg1 in skin compensates → No skin blisters. Oral erosions only. |
| Anti-Dsg3 + Anti-Dsg1 | Mucocutaneous PV. Both skin and mucosal lesions. Dsg1 in skin disrupted → Skin blisters. |
| Type | Antibody Target | Features |
|---|---|---|
| Pemphigus Vulgaris (PV) | Dsg3 ± Dsg1 | Most common. Flaccid bullae. Oral + Skin. |
| Pemphigus Foliaceus (PF) | Dsg1 only | Superficial blisters. Crusted, Scaly erosions. NO mucosal involvement. |
| Paraneoplastic Pemphigus | Multiple antigens | Associated with malignancy (Lymphoma, CLL, Thymoma). Severe oral involvement. Poor prognosis. |
| IgA Pemphigus | Desmocollin | Rare. Pustular. |
| Drug-Induced Pemphigus | Variable | Triggered by drugs (Penicillamine, Captopril). |
Symptoms
| Symptom | Notes |
|---|---|
| Oral Erosions | Often first manifestation (~50-70%). Painful. Difficulty eating, Swallowing, Speaking. May be mistaken for aphthous ulcers or herpes. |
| Skin Blisters | Flaccid (Floppy). Clear fluid. Rupture easily → Erosions. |
| Skin Erosions | Raw, Red, Weeping. Slow to heal. |
| Scalp Lesions | Can be crusted, Misdiagnosed as seborrhoeic dermatitis. |
| Other Mucosal Sites | Pharynx, Oesophagus, Conjunctiva, Genitalia. |
Examination Findings
| Finding | Notes |
|---|---|
| Flaccid Bullae | Thin-walled. Easily ruptured. Often see erosions rather than intact blisters. |
| Erosions | Superficial. Irregular borders. Weeping. Slow to heal. |
| Nikolsky's Sign | Positive: Gentle lateral pressure on perilesional skin causes epidermis to slide and shear off. |
| Asboe-Hansen Sign (Bulla Spread Sign) | Pressure on intact blister causes fluid to spread laterally. |
| Oral Erosions | Buccal mucosa, Palate, Gingiva, Pharynx. Ragged edges. May have food debris. |
Sites of Involvement
| Site | Notes |
|---|---|
| Oral Mucosa | Most common. Buccal, Palatal, Gingival. |
| Skin | Trunk, Flexures, Scalp, Face. |
| Pharynx / Larynx | Hoarseness. Dysphagia. |
| Oesophagus | Dysphagia. Odynophagia. |
| Conjunctiva | Rare. Scarring. |
| Genitalia | Erosions. |
Diagnosis
| Investigation | Findings |
|---|---|
| Skin Biopsy (Lesional) | Histology: Intraepidermal (Suprabasilar) acantholysis. "Tombstone" appearance of basal cells attached to basement membrane. |
| Perilesional Skin Biopsy | Direct Immunofluorescence (DIF): IgG and C3 deposited on keratinocyte cell surfaces in an Intercellular "Fishnet" / "Chicken Wire" pattern. Gold standard. |
| Serum | Indirect Immunofluorescence (IIF): Circulating IgG antibodies. OR ELISA: Anti-Dsg3 and Anti-Dsg1 antibodies. Titre often correlates with disease activity. |
Summary of Key Findings
| Test | Finding |
|---|---|
| Histology | Suprabasilar acantholysis, Tombstoning |
| DIF | Intercellular IgG + C3 (Fishnet/Chicken wire) |
| Serology | Anti-Dsg3 ± Anti-Dsg1 (ELISA) |
Management Algorithm
PEMPHIGUS VULGARIS DIAGNOSED
(Clinical + Histology + DIF + Serology)
↓
ASSESS SEVERITY
- Extent of skin involvement (% BSA)
- Oral involvement severity
- Ability to eat/drink
- Secondary infection
↓
GENERAL MEASURES
- Dermatology inpatient review for severe disease
- Nutritional support
- Wound care
- Infection prevention
↓
PHARMACOLOGICAL TREATMENT
┌──────────────────────────────────────────────────────────┐
│ FIRST-LINE (Modern Approach): │
│ **Rituximab + Prednisolone** │
│ - Rituximab 1g IV x2 doses (Day 1 and Day 15) │
│ OR 375mg/m² weekly x4 │
│ + Prednisolone 0.5-1mg/kg (Tapering) │
│ (RITUX 3 Trial: Rituximab + Low-Dose Pred superior to │
│ High-Dose Pred alone) │
│ │
│ OR Traditional Approach: │
│ **High-Dose Prednisolone** (1-2mg/kg/day) │
│ + Steroid-sparing agent: │
│ - Azathioprine OR Mycophenolate Mofetil │
│ (Taper steroids once disease controlled) │
└──────────────────────────────────────────────────────────┘
↓
REFRACTORY / RELAPSED DISEASE
- Rituximab (If not already used)
- IVIG (Intravenous Immunoglobulin)
- Plasmapheresis
- Cyclophosphamide (Rarely now)
↓
MONITORING
- Clinical response (Healing of erosions)
- Anti-Dsg3 / Dsg1 titres (May correlate with activity)
- Side effects of treatment
Medications
| Drug | Notes |
|---|---|
| Prednisolone (High Dose) | 1-2mg/kg/day initially. Rapid symptom control. Long-term side effects. Taper as disease controlled. |
| Rituximab | Anti-CD20 monoclonal antibody. Depletes B cells. Increasingly first-line. May induce long-term remission. Monitor for infection. |
| Azathioprine | Steroid-sparing. Check TPMT before starting. |
| Mycophenolate Mofetil | Alternative steroid-sparing agent. |
| IVIG | For refractory disease. Monthly infusions. |
| Cyclophosphamide | Rarely used now (Toxicity). |
Supportive Care
| Measure | Notes |
|---|---|
| Wound Care | Non-adherent dressings. Antiseptic washes. |
| Oral Care | Soft diet. Topical anaesthetics. Mouthwashes. |
| Nutritional Support | NG feeding or supplements if unable to eat. |
| Infection Prevention | Antibiotics for secondary infection. |
| Bone Protection | Calcium, Vitamin D, Bisphosphonates (Long-term steroids). |
| Complication | Notes |
|---|---|
| Secondary Infection | Skin erosions susceptible to bacterial infection. Sepsis. |
| Fluid and Electrolyte Loss | From extensive erosions. Similar to burns. |
| Malnutrition | From painful oral erosions. Difficulty eating. |
| Steroid Side Effects | Osteoporosis, Diabetes, Hypertension, Weight gain, Cushing's, Immunosuppression. |
| Rituximab Side Effects | Infusion reactions, Infection, PML (Rare). |
| Oesophageal Stricture | From oesophageal involvement. |
| Paraneoplastic Pemphigus | Associated with malignancy. Exclude in all cases. |
| Factor | Notes |
|---|---|
| Before Steroids | PV was frequently fatal (Mortality >75%). |
| With Modern Treatment | Mortality ~5-10%. Most due to immunosuppression complications. |
| Remission | Achievable in most patients. May require long-term maintenance. Rituximab may induce prolonged remission. |
| Relapse | Common if treatment withdrawn too quickly. Monitor titres. |
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Pemphigus Management | BAD / EDF | Rituximab + Steroid as first-line. Steroid-sparing agents. Multidisciplinary care. |
| RITUX 3 Trial | Joly et al. 2017 | Rituximab + Low-Dose Prednisolone superior to High-Dose Prednisolone alone for achieving complete remission off therapy. |
What is Pemphigus Vulgaris?
Pemphigus Vulgaris is a rare condition where your immune system mistakenly attacks the "glue" that holds skin cells together. This causes blisters and raw areas to form on the skin and inside the mouth.
What are the symptoms?
- Painful mouth sores (Often the first sign) – Difficulty eating and swallowing.
- Blisters on the skin – These are fragile and burst easily, leaving raw, weeping areas.
- Slow healing – Sores take a long time to heal.
Is it serious?
Yes. Before modern treatments, pemphigus was often fatal. Now, with treatment, most people can control the disease and live normal lives. However, it usually requires long-term medication.
What is the treatment?
- Steroids (Prednisolone) – To reduce inflammation.
- Rituximab – A newer treatment that targets the immune cells causing the problem. Often used now as part of first-line treatment.
- Other immune-suppressing drugs – To help reduce steroid doses.
Will it go away?
With treatment, many people achieve remission (No active disease). Some may need long-term medication to stay in remission.
Primary Sources
- Joly P, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (RITUX 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389(10083):2031-2040. PMID: 28342637.
- Kershenovich R, et al. Diagnosis of pemphigus. J Am Acad Dermatol. 2014;71(2):358-368. PMID: 24793222.
- Murrell DF, et al. Diagnosis and management of pemphigus: Recommendations of an international panel of experts. J Am Acad Dermatol. 2020;82(3):575-585.e1. PMID: 31733293.
Common Exam Questions
- First Manifestation: "Where does Pemphigus Vulgaris typically first present?"
- Answer: Oral Mucosa (~50-70% present with oral erosions first).
- Nikolsky's Sign: "What is Nikolsky's sign and when is it positive?"
- Answer: Gentle lateral pressure on skin causes epidermis to shear off. Positive in PV (and other blistering diseases like TEN).
- Immunofluorescence Pattern: "What is the DIF finding in Pemphigus?"
- Answer: Intercellular IgG and C3 in a "Fishnet" / "Chicken Wire" pattern.
- Antibody Target: "What antigens are targeted in PV?"
- Answer: Desmoglein 3 (Dsg3) ± Desmoglein 1 (Dsg1).
Viva Points
- Suprabasilar Acantholysis: Blister forms just above the basal layer. Basal cells remain attached → "Tombstone" appearance.
- PV vs PF: PV = Dsg3 ± Dsg1, Oral + Skin. PF = Dsg1 only, Skin only, NO oral.
- Rituximab: Anti-CD20. Increasingly first-line. RITUX 3 trial evidence.
- Paraneoplastic Pemphigus: Always consider underlying malignancy.
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