Pemphigus Vulgaris (PV)

  • #1 type of pemphigus worldwide with few exceptions (see foliaceous)
  • Peak of onset at 40-60 y/o
  • Similar sex predilection to slightly more common in females
  • Incidence: 1–5 cases / million / year
  • More common in patients with Jewish ancestry
  • Associated diseases: Thymoma, autoimmune thyroiditis, and myasthenia gravis

  • Genetic predisposition: HLA class II DR4 and DR14, but depends on ethnicity
  • Ashkenazi: DRB1*0402,
  • European: DRB1*1401, 1404
  • Asian: DQB1*0503
  • IgG autoantibodies against Dsg1˃3 → impede adhesion → loss of keratinocyte cell-cell adhesion → acantholysis; can cross placenta
  • Dsg 1 / Dsg 3 belong to desmosomal cadherins (i.e. family of calcium dependent cell-cell adhesion molecules attach to cytoskeleton) → tissue integrity
  • Dsg3 ˃ Dsg1 found in mucosa and neonatal skin explains blistering predominantly in oral mucosa in PV and transient neonatal skin blistering in PV and NOT PF mothers
  • Desmoglein compensation theory: Dsg1 and Dsg3 compensate each other

Types
  1. Mucosal dominant (Dsg3) #1
  2. Mucocutaneous (Dsg1 and Dsg3)
  3. Variant: Pemphigus vegetans (see below)
  4. Rare variants:
    • Isolated crusted plaque on face/scalp
    • Paronychia/Onychomadesis
    • Foot ulcers
    • Dyshidrotic eczema or pompholyx
    • Macroglossia
Distribution
  • Mucosal erosions 100% of patients + ~50% have cutaneous involvement
  • Most common on buccal and palatine mucosa), +/- vermilion lip > throat (hoarseness/difficulty swallowing), gingivae, tongue, esophagus, conjunctivae, nasal mucosa, vagina, labia, penis, and anus
Morphology/Symptoms
  • Non-pruritic flaccid blisters on normal looking skin or erythematous base → erosions +/- crust
  • Painful erosions in oral mucosa, variable sizes, and irregular ill-defined borders
  • Nikolsky+, Asboe-Hansen+
  • No scarring +/- dyspigmentation
Pemphigus Vegetans
  • Rare vegetative variant → possibly reactive
  • 2 subtypes: Neumann (severe) and Hallopeau (mild)
  • Flaccid blisters → erosions → fungoid or papillomatous proliferations +/- pustules → large vegetative plaques especially intertriginous, scalp, and face
Course (Prognosis)
  • Untreated → absent epidermal barrier function, loss of fluids, bacterial infection → may be fatal (Preceding systemic corticosteroid use, death within 2-5 years)

H&E (lesional and favor the edge of a fresh blister/erosion)
  • Early: eosinophilic spongiosis
  • Pathognomonic: Suprabasal acantholysis with “row of tombstone” → hemidesmosomes sustain basal cell attachment. *May involve hair follicles.* Perivascular mononuclear cell infiltrate with eosinophils
  • Vaginal lesion may mimic malignancy
  • Pemphigus vegetans: Suprabasal acantholysis + papillomatosis + acanthosis + intraepidermal microabscesses & eosinophils
  • NB: Tzanck smear can show acantholysis
DIF (perilesional)
  • *Most sensitive test seen in ~100%
  • IgG4 to Dsg3, Dsg1 ± C3 in chicken wire pattern
Demonstration of circulating auto-antibodies by:
  1. IIF + in 80% *substrate is monkey esophagus*
  2. Immunoblotting
  3. Immunoprecipitation
  4. ELISA (useful to monitor disease activity, more sensitive and specific than IIF)
  5. CLEIA

Goal:
  • Reduce autoantibodies production, restore skin barrier
Topical:
  • Corticosteroid (class 1), immunomodulators (tacrolimus)
Systemic:
  • Systemic corticosteroids (prednisone: 1mg/kg/day, then taper). Therapeutic effects estimation: number of new blisters/day + rate of new lesions healing
  • Rituximab (1st line more severe pemphigus vulgaris) rheumatoid arthritis or lymphoma protocol
Other options:
  • Intravenous methylprednisolone 1g/day over 2-3 hours with continuous cardiac monitoring for 3-5 days
  • Azathioprine: 2-4 mg/kg/day (usually 100-300 mg/day)
  • Mycophenolate mofetil: 2-3 g/day
  • Cyclophosphamide: 1-3 mg/kg/day (usually 50-200 mg/day) orally or intravenous 500-1000 mg/m2 q4weeks
  • Cyclosporine (3-5 mg/kg/day)
  • Methotrexate 7.5-20 mg/week
  • Gold (rare)
  • Plasmapheresis: 1-2 x/week at onset
  • High-dose intravenous immunoglobulin (IVIg) (400 mg/kg/d x 5 days)
Intralesional:
  • Corticosteroids, Rituximab (5 mg/cm2)

Mucosal lesions:
  • Acute herpetic stomatitis
  • Aphthous stomatitis
  • Erythema multiforme
  • Stevens-Johnson syndrome
  • Lichen planus
  • Systemic lupus erythematosus
  • Cicatricial pemphigoid
Cutaneous lesions:
  • Other forms of pemphigus
  • Bullous pemphigoid
  • Linear IgA bullous dermatosis (LABD)
  • Erythema multiforme
  • Hailey-Hailey (on path clues it’s pemphigus vulgaris: Acantholysis with no dyskeratosis, acantholysis of hair follicle, no orthokeratosis)
  • Transient acantholytic dermatosis AKA “Grover’s” disease (on path: intraepidermalacantholysis)
Pemphigus Vegetans:
  • Pemphigoid vegetans
  • Hailey-Hailey
  • Blastomycosis-like pyoderma
  • Pyodermatitispyostomatitis vegetans
Eosinophilic spongiosis
  • Pemphigus vulgaris
  • Bullous pemphigoid
  • Mucous membrane pemphigoid
  • Pemphigoid gestationis
  • Linear IgA bullous dermatosis (LABD)
  • Insect-bite reaction
  • Drug eruption
  • Id reactions
  • Wells syndrome
  • Polymorphic eruption of pregnancy
  • Erythema toxicum neonatorum
  • Atopic dermatitis
  • Contact dermatitis
  • Eosinophilic folliculitis
  • Mycosis fungoid
  • Still’s disease
  • Prurigo pigmentosa