Pemphigus Vulgaris

Pemphigus vulgaris (PV) is the prototype of the intraepidermal autoimmune blistering diseases — a potentially fatal disorder in which IgG autoantibodies attack the desmosomal adhesion protein desmoglein-3, splitting the epidermis just above the basal layer. For NEET PG it is one of the highest-yield dermatology topics: examiners repeatedly test the site of the split, the target antigen, Nikolsky sign, tombstone appearance, Tzanck cells, direct immunofluorescence (DIF) pattern, and first-line therapy. Master the contrast with bullous pemphigoid and you have answered a recurring two-question pair.

Definition & classification

Pemphigus is a group of autoimmune diseases characterised by intraepidermal blisters due to acantholysis (loss of keratinocyte-to-keratinocyte adhesion). "Acantholysis" literally means dissolution (lysis) of the prickle-cell (acanthocyte) attachments. The flaccid blister sits within the epidermis, in contrast to the subepidermal, tense blister of pemphigoid.

Variant	Level of split	Target antigen	Mucosa	Nikolsky
Pemphigus vulgaris	Suprabasal (just above basal layer)	Desmoglein-3 (± Dsg-1 if skin involved)	Almost always (often first sign)	Positive
Pemphigus vegetans	Suprabasal	Desmoglein-3	Yes	Positive
Pemphigus foliaceus	Subcorneal / granular layer	Desmoglein-1	Spared	Positive
Pemphigus erythematosus (Senear–Usher)	Subcorneal	Dsg-1 (+ lupus features)	Spared	Positive
Paraneoplastic pemphigus	Suprabasal + interface	Dsg-3, Dsg-1, plakins (envoplakin, periplakin, desmoplakin), BP180	Severe, intractable stomatitis	Positive
IgA pemphigus	Subcorneal/intraepidermal	Desmocollin-1	Spared	Variable
Drug-induced	Variable	Dsg-1/3	Variable	Positive

High-yield: PV = suprabasal split + anti-Dsg-3. PF = subcorneal split + anti-Dsg-1. This single line answers the majority of pemphigus MCQs.

The "desmoglein compensation" theory (why mucosa vs skin)

• Oral mucosa expresses mainly Dsg-3 → in PV, anti-Dsg-3 alone causes mucosal-only disease (mucosal-dominant PV).
• Skin expresses both Dsg-1 (superficial) and Dsg-3 (deep). When only Dsg-3 is attacked, Dsg-1 compensates in upper layers, so skin may be spared.
• When the patient also makes anti-Dsg-1, both skin and mucosa blister → mucocutaneous PV.
• In pemphigus foliaceus, only Dsg-1 is targeted; in the mouth, Dsg-3 compensates, so mucosa is spared and the blister is superficial (subcorneal).

High-yield: "Mucosa only" ⇒ anti-Dsg-3 alone. "Skin only / superficial" ⇒ anti-Dsg-1 (foliaceus). "Both" ⇒ anti-Dsg-1 + anti-Dsg-3.

Etiology & pathophysiology

• Autoantibody: Pathogenic IgG (predominantly IgG4 subclass in active disease) directed against the extracellular domain of desmoglein-3, a calcium-dependent cadherin in the desmosome.
• Mechanism: Antibody binding → steric hindrance of Dsg trans-interaction + intracellular signalling (p38 MAPK activation, phosphorylation events) → desmosome disassembly → acantholysis. The blister therefore forms by loss of adhesion, not by inflammatory destruction — hence relatively scant inflammatory infiltrate early.
• HLA association: HLA-DR4 (DRB1*0402) and HLA-DRw6 (DQB1*0503). Notably common in Ashkenazi Jews and in Indian/Mediterranean populations.
• Triggers/associations: Drugs containing a thiol/sulfhydryl group — classically penicillamine and captopril (also rifampicin, ACE inhibitors); rarely thymoma/myasthenia gravis; UV light; emotional stress.
• Age: Typically 40–60 years; either sex.

High-yield: Drug-induced pemphigus — remember the SH (thiol) drugs: penicillamine and captopril.

Clinical features

• Onset: In >50% of patients the first lesion is in the oral cavity — painful, non-healing erosions (rarely seen as intact bullae because they rupture instantly). Buccal and palatal mucosa most common. May precede skin lesions by months.
• Skin lesions: Flaccid, thin-roofed bullae on normal (non-erythematous) skin that rupture easily to leave painful, weeping erosions and crusts. Distribution: scalp, face, axillae, groin, trunk, pressure points.
• Blisters are flaccid (not tense) because the roof is only the upper epidermis — a fragile covering.
• Other mucosae: conjunctiva, oesophagus, nasal, pharyngeal, laryngeal, genital, anal.
• Healing without scarring (intraepidermal process spares the dermis) but with post-inflammatory hyperpigmentation.

Bedside signs (very high-yield)

1. Nikolsky sign (positive): Lateral shearing pressure on perilesional normal-looking skin causes the superficial epidermis to slide off → reflects acantholysis. Positive in active PV.
2. Asboe-Hansen sign (Bulla-spread / indirect Nikolsky): Vertical pressure on an intact bulla makes it extend laterally into adjacent skin.
3. Pseudo-Nikolsky differs — seen in TEN where the split is subepidermal/full thickness.

High-yield: Nikolsky sign is positive in PV, pemphigus foliaceus, SSSS and TEN, but negative in bullous pemphigoid and dermatitis herpetiformis. Do not call it specific for pemphigus.

Diagnosis & investigation of choice

A combined histology + immunofluorescence + serology approach.

Diagnostic flow: Clinical suspicion (flaccid bullae + oral erosions + positive Nikolsky) → Tzanck smear (quick bedside) → Skin biopsy of fresh small blister edge for H&E → Perilesional skin biopsy for DIF (investigation of choice) → Serum ELISA/IIF for anti-Dsg-3/1 (titre = disease activity / monitoring).

1. Tzanck smear

• Scraping from the floor of a fresh blister, stained (Giemsa/Wright).
• Shows acantholytic cells (Tzanck cells) — rounded keratinocytes with a large hyperchromatic nucleus and perinuclear halo, having lost their spinous attachments.
• Quick and supportive, not confirmatory.

2. Histopathology (H&E)

• Suprabasal acantholysis — cleft just above the basal layer.
• Basal keratinocytes remain attached to the basement membrane but lose lateral attachments, lining up like a "row of tombstones" along the blister floor.
• Acantholytic keratinocytes float free within the blister cavity.

High-yield: "Tombstone appearance" = basal cells standing on the blister floor in PV. "Row of tombstones" is the classic exam phrase.

3. Direct immunofluorescence (DIF) — confirmatory / investigation of choice

• Biopsy from perilesional (normal-appearing) skin.
• Shows intercellular ("fish-net" / "chicken-wire" / lace-like) deposition of IgG and C3 throughout the epidermis.

High-yield: DIF in PV = intercellular IgG + C3, fish-net/chicken-wire pattern. This is the single most specific confirmatory test and the usual "investigation of choice" answer.

4. Indirect immunofluorescence (IIF) & ELISA

• IIF (substrate: monkey oesophagus) detects circulating intercellular antibodies; titre correlates with disease activity.
• ELISA for anti-Dsg-3 and anti-Dsg-1 is now the preferred serological tool for diagnosis confirmation and monitoring response to therapy.

Feature	Direct IF (DIF)	Indirect IF (IIF)
Sample	Patient's perilesional skin	Patient's serum + substrate (monkey oesophagus)
Detects	Tissue-bound IgG/C3	Circulating autoantibody
Use	Diagnosis (most specific)	Monitoring activity (titre)
Pattern	Intercellular fish-net IgG/C3	Intercellular fluorescence

Management / drug of choice

Goal: switch off autoantibody production, heal erosions, prevent sepsis and fluid loss. PV is fatal if untreated (historically ~70–90% mortality from sepsis/fluid loss).

Stepwise approach:

1. First-line: Systemic corticosteroids — oral prednisolone 1 mg/kg/day (drug of choice for inducing remission). Severe/extensive disease may need IV pulse (dexamethasone/methylprednisolone) regimens.
2. Steroid-sparing adjuvant / first-line immunomodulator: Rituximab (anti-CD20 monoclonal) is now recommended first-line in moderate-to-severe PV, combined with steroids, and produces durable remission. Other steroid-sparing agents: azathioprine, mycophenolate mofetil, cyclophosphamide.
3. Refractory/severe rescue: IVIG, plasmapheresis/immunoadsorption (rapidly removes circulating antibody).
4. Supportive: wound care, fluid–electrolyte balance, nutrition, oral antiseptic/anaesthetic rinses, infection surveillance, bone protection and PPI for chronic steroids.

High-yield: Drug of choice to induce remission = systemic corticosteroids (prednisolone). Rituximab is the key steroid-sparing/first-line adjuvant and is increasingly the favoured answer for moderate–severe PV. Check thiopurine methyltransferase (TPMT) before azathioprine.

High-yield: Disease activity and the decision to taper steroids are guided by anti-Dsg titres (ELISA) and clinical healing — not by blood counts.

Complications

• Secondary bacterial infection / septicaemia — the leading cause of death.
• Fluid, electrolyte and protein loss from extensive denuded skin.
• Oesophageal/laryngeal erosions → dysphagia, odynophagia, airway issues.
• Treatment-related: long-term steroid toxicity (Cushingoid features, diabetes, osteoporosis, peptic ulcer, opportunistic infection), immunosuppressant marrow suppression, rituximab-associated infections/PML (rare).
• Growth retardation and adrenal suppression in younger/long-treated patients.

Key differentials

Feature	Pemphigus vulgaris	Bullous pemphigoid	Dermatitis herpetiformis	SSSS / TEN
Blister level	Intraepidermal (suprabasal)	Subepidermal	Subepidermal (dermal papillae)	SSSS: subcorneal; TEN: subepidermal
Blister type	Flaccid	Tense	Grouped vesicles	Sheets/peeling
Antigen	Dsg-3 (±Dsg-1)	BP180, BP230 (hemidesmosome)	Tissue transglutaminase / epidermal TG	SSSS: Dsg-1 (toxin); TEN: drug
Mucosa	Frequent, often first	Uncommon	Spared	TEN: yes; SSSS: no
Nikolsky	Positive	Negative	Negative	Positive
DIF	Intercellular fish-net IgG/C3	Linear IgG/C3 at BMZ	Granular IgA at dermal papillae tips	Negative
Age	40–60	Elderly (>60–70)	20–40	SSSS: children; TEN: any
Itch	Pain > itch	Itchy	Intensely pruritic	Pain

High-yield: BP shows linear IgG along the basement membrane; DH shows granular IgA at the tips of dermal papillae; PV shows intercellular IgG. Remember the pattern, not just the antigen.

High-yield: Pemphigus foliaceus is the differential when blisters are superficial, crusted, scaly (corn-flake crust) with no oral involvement and subcorneal split.

Mnemonics

• PV is "low" and "Vulgar" deep: PV split is deep (suprabasal), targets Dsg-3; PF split is superficial (subcorneal), targets Dsg-1. (Numerically, the smaller number 1 sits "higher/superficial".)
• "BP is Big & Below, Tense & old" → Bullous Pemphigoid: subepidermal (below), tense bullae, elderly.
• Thiol drugs causing pemphigus = "Captain Penicillin" → Captopril + Penicillamine.

Recently asked / exam angle

• Level of split / target antigen pairing — the single most repeated stem: "intraepidermal suprabasal acantholysis with anti-Dsg-3" ⇒ PV.
• Histology image / phrase: "row of tombstones," "tombstone appearance," "acantholytic cells" ⇒ PV.
• DIF pattern matching: intercellular fish-net IgG (PV) vs linear BMZ IgG (BP) vs granular IgA papillary tips (DH) — frequently an image-based or matching question.
• Tzanck smear positive in pemphigus, herpes, and varicella — be careful: Tzanck cells in herpes are multinucleate giant cells, in pemphigus they are acantholytic keratinocytes.
• Investigation of choice = DIF; monitoring = anti-Dsg ELISA / IIF titre.
• Drug of choice / first line = systemic corticosteroids; newer recommendation = rituximab + steroids for moderate–severe disease.
• Nikolsky sign positive list — distinguishing PV/PF/SSSS/TEN from BP/DH.
• Drug-induced pemphigus — penicillamine/captopril stems.
• Desmoglein compensation reasoning for "why mucosa is spared in foliaceus."
• Paraneoplastic pemphigus — severe stomatitis + anti-plakin antibodies + underlying lymphoproliferative malignancy (Castleman disease, NHL); may show bronchiolitis obliterans.

Rapid revision

1. PV = intraepidermal, suprabasal acantholysis; target = desmoglein-3 (a desmosomal cadherin).
2. Flaccid bullae on normal skin that rupture into painful erosions; oral mucosa is often the first and most persistent site.
3. Nikolsky sign positive (and Asboe-Hansen/bulla-spread positive); negative in bullous pemphigoid and dermatitis herpetiformis.
4. Histology: suprabasal split with basal cells in a "row of tombstones."
5. Tzanck smear: acantholytic cells; quick but not confirmatory.
6. DIF (investigation of choice): intercellular IgG + C3 in a fish-net/chicken-wire pattern.
7. IIF/ELISA (monkey oesophagus / anti-Dsg titre): correlate with disease activity → used for monitoring.
8. Pemphigus foliaceus: subcorneal split, anti-Dsg-1, mucosa spared, superficial scaly crusts.
9. HLA-DR4 / DRw6; commoner in Ashkenazi Jews; age 40–60.
10. Drug triggers: thiol drugs — penicillamine, captopril.
11. Treatment: systemic corticosteroids (prednisolone 1 mg/kg/day) first line; rituximab as first-line steroid-sparing in moderate–severe disease; azathioprine/MMF, IVIG, plasmapheresis for refractory cases.
12. Death is usually from sepsis / fluid loss — PV is fatal if untreated; heals without scarring (but with hyperpigmentation).