Pemphigus Vulgaris (PV)

Definition

Epidemiology

• Incidence: 0.76–5 new cases per million/year worldwide; markedly higher in Ashkenazi Jews (16–32 per million/year)
• Equal sex distribution; mean age of onset 50–60 years (broad range)
• Higher incidence in Middle East, Southeast Europe, and India
• Most common form of pemphigus in most countries (~75% of cases in France, ~67% in Japan)
• HLA associations: DRB1*0402 and DQB1*0503 confer risk, particularly in Ashkenazi Jews

Pathogenesis

Target Antigens — Desmogleins

Desmoglein Compensation Theory

• In mucosal-dominant PV: anti-Dsg3 antibodies cause blistering only in mucosa (where Dsg3 predominates without compensatory Dsg1)
• In mucocutaneous PV: both anti-Dsg1 and anti-Dsg3 present → blisters in skin and mucosa; blisters are suprabasilar because antibodies diffuse from the dermis upward

Mechanism of Blister Formation

Immunogenetics

• CD4+ T follicular helper cells stimulate anti-Dsg B cells
• VH1-46 gene usage shared among anti-Dsg3 B cells in PV patients (early autoimmune selection)
• Regulatory T cells may suppress autoimmunity in HLA-susceptible individuals who do not develop disease

Clinical Features

Subtypes

1. Mucosal-dominant PV — oral/mucosal erosions, minimal skin lesions (anti-Dsg3 only)
2. Mucocutaneous PV — widespread skin blisters and erosions + mucosal involvement (anti-Dsg1 + anti-Dsg3)

Oral / Mucosal Lesions

• Present in essentially all PV patients — often the first manifestation (months before skin)
• Painful erosions most common (blisters are fragile and break immediately)
• Sites: buccal and palatine mucosae most common; also throat, nasal mucosa, esophagus, conjunctiva, vagina, labia, penis, anus
• Esophageal involvement can cause sloughing of the mucosal lining as a cast
• Laryngeal involvement (55% of patients on endoscopy) often asymptomatic
• Oral disease frequently misdiagnosed, delaying diagnosis by months

Cutaneous Lesions

• Flaccid blisters on normal-appearing or erythematous skin — thin-roofed, easily ruptured
• Blisters are NOT tense (unlike bullous pemphigoid)
• Fluid: initially clear → may become hemorrhagic, turbid, seropurulent
• Rupture → large, painful erosions that ooze and bleed easily; do not heal spontaneously
• Heal with hyperpigmentation, no scarring
• Distribution: any skin surface, typically sparing palms and soles

Extensive erosions with nearly denuded back. Intact flaccid blisters visible at lower border. (Fitzpatrick's Dermatology)

(a,b) Mucosal PV — oral erosions. (c) Mucocutaneous PV — flaccid blisters on skin. (e) Histology of mcPV — suprabasal split with tombstone basal cells. Compare with PF (f) — subcorneal split.

Clinical Signs

Pemphigus Vegetans (variant)

• Vegetating/papillomatous lesions in intertriginous areas (axillae, groin, scalp)
• Suprabasilar acantholysis + intense eosinophilic infiltrate + microabscesses
• Better prognosis than typical PV; higher chance of remission

Diagnosis

Histopathology

• Suprabasilar acantholysis — cleft just above the basal layer
• Basal cells remain attached to basement membrane → "tombstone row" appearance
• Rounded-up acantholytic keratinocytes within blister cavity
• No keratinocyte necrosis
• Dermal papillae protrude into blister cavity; eosinophils in cavity and dermis
• Biopsy site: Edge of fresh blister + perilesional skin (for DIF)

Immunofluorescence

Differential Diagnosis (key distinctions)

Management

Principles

• PV should be treated at onset — even if limited, it will generalize; early disease is easier to control; delayed therapy increases mortality
• Goal: suppress autoantibody production → halt acantholysis → control disease → achieve remission

First-line Therapy

• Depletes B cells → reduces anti-Dsg autoantibody production
• Complete remission off immunosuppressives in 50–90% of PV patients after 1+ courses
• Significantly superior to prednisolone alone in the landmark RITUX 3 trial

• Historically the mainstay; still used as adjunctive therapy
• Starting dose typically 0.5–1 mg/kg/day; tapered once disease controlled
• Before glucocorticoids, PV was almost invariably fatal

Steroid-sparing Immunosuppressives (adjuvants)

Other Therapies

• IVIg (intravenous immunoglobulin) — rapidly reduces antibody levels; used in refractory cases or acute severe disease
• Plasmapheresis — removes circulating antibodies; used with immunosuppressives to prevent rebound
• Topical corticosteroids — for localized or mild disease, especially oral

Emerging/Investigational

• BTK inhibitors (e.g., PRN1008/rilzabrutinib) — block mature B cell survival
• FcRn blockers (efgartigimod/ARGX-113) — accelerate IgG catabolism → rapidly lower autoantibody levels
• CAAR-T cell therapy — chimeric autoantibody receptor T cells expressing Dsg3, programmed to selectively kill Dsg3-specific B cells; preclinical success, disease-specific without broad immunosuppression

Prognosis

• Cause of death: most often infection (from the immunosuppressive therapy itself)
• Annual mortality rate (USA): ~0.023 per 100,000
• Inpatient mortality: 1.6–3.2%
• Risk of death 2.4–3.3× higher than controls (UK, Taiwan data)

Summary Mnemonic: "PEMPHIGUS"