Pemphigus

Pemphigus

 

Pemphigus is an autoimmune blistering disease that affects the skin and mucous membranes.

Epidemiology

  • Incidence - 0.75-5 per million
  • Age of onset – any age including childhood, most commonly diagnosed 40-60 year old
  • Gender – M:F equal
  • Ethnicity
    • Pemphigus vulgaris is more common in patients of Jewish or Mediterranean descent, HLA association
    • Fogo Salvagem occurs in rural areas of Brazil, Tunisia and Columbia

Types of Pemphigus

  • IgG pemphigus
    • Pemphigus vulgaris
      • Spontaneous
      • Drug-induced
      • Pemphigus vegetans
    • Pemphigus foliaceus
      • Spontaneous
      • Fogo Salvagem (Brazilian or endemic pemphigus)
      • Drug-induced
    • Pemphigus erythematosus
  • Paraneoplastic pemphigus
  • IgA pemphigus
    • Subcorneal pustular dermatoses (SPD)
    • Intraepidermal neutrophilic IgA dermatosis (IEN)

Pathology, Immunopathology and Pathophysiology

  • Suprabasilar keratinocyte acantholysis
  • Eosinophil infiltration, including eosinophilic spongiosis and abscesses
  • IgG pemphigus types
    • IgG is deposited on the cell surfaces (formerly referred to as intercellular substance) of epidermal and stratified squamous epithelial cells in and around affected areas and is detectably by direct immunofluorescence of perilesional skin
    • Serum IgG cell surface antibodies are also present and are detectable by indirect immunofluorescence
      • IgG epithelial cell surface antibodies have demonstrated pathogenic activity and are not simply epiphenomena of the disease
      • Levels of IgG cell surface antibodies correlate with disease activity
    • The major antigenic targets for the pathogenic antibodies are desmogleins, cell adhesion components of desmosomes in keratinocytes
      • Detectable by Enzyme Linked Immunosorbent Assay (ELISA)
      • IgG desmoglein-1 antibodies predominate in pemphigus foliaceus, and pemphigus erythematosus
        • Associated with nonmucosal lesions
      • IgG desmoglein-3 antibodies predominate in pemphigus vulgaris (and pemphigus vegetans) and associated with mucosal lesions
      • Overlap occurs with antibodies to both desmoglein-1 and desmoglein-3 and relative predominance of antibodies change over time
      • Levels of IgG antibodies to desmoglein-1 and/or desmoglein-3 fluctuate with disease activity
    • In pemphigus erythematosus, features of lupus are also present on histologic examination of fixed tissue and show granular immune deposits at the basement membrane zone by direct immunofluorescence of tissue submitted in Michel’s medium with or without positive lupus serologies.
  • IgA pemphigus types
    • IgA epithelial cell surface antibodies detected by direct immunofluorescence of perilesional skin
    • Serum IgA cell surface antibodies detected by indirect immunofluorescence
    • Subcorneal pustular dermatosis (SPD) type  
      • Vesicles and pustules in a subcorneal or upper epidermal location
    • Intraepidermal neutrophilic IgA dermatosis (IEN) type
      • Pustules throughout the epidermis

Clinical Presentation

  • Flaccid blisters on face, scalp, upper body and intertriginous areas
    • Nikolsky sign – applying pressure on blister periphery extends the lesion laterally
  • Mucosal blisters and erosions
  • Pemphigus vulgaris – initial presentation is usually oral; mucosal involvement
    • Pemphigus vegetans – intertriginous and oral with involvement of tongue (cerebriform tongue)
      • Flaccid bullae and erosions (Neumann type)
      • Pustules (Hallopeau type).
  • Pemphigus foliaceus – blisters typically on neck and upper trunk
  • IgA pemphigus types
    • Pruritic vesicles and pustules in subcorneal pustular dermatosis (SPD) 
    • Variable skin lesions with numerous pustules in intraepidermal neutrophilic IgA dermatosis (IEN)

Diagnosis

  • Laboratory testing
    • Testing for IgG cell surface and desmoglein antibodies is highly sensitive and specific for IgG pemphigus types (not IgA pemphigus types)
    • The presence of IgG cell surface antibodies and desmoglein antibodies in serum correlates with disease activity
      • Up to 80% of patients with pemphigus have IgG antibodies present in sera
    • Desmoglein antibodies are pathogenic and are not simply epiphenomena of the disease
      • Desmoglein-1 autoantibodies predominate in pemphigus foliaceus (and likely pemphigus erythematosus)
      • Desmoglein-3 autoantibodies are present in pemphigus vulgaris (and likely pemphigus vegetans)
      • Although the predominate antibodies differentiate the subtypes of pemphigus, overlap may occur
      • Patients with both skin and mucosal lesions may have IgG antibodies to both desmogleins 1 and 3
      • Desmoglein antibodies may or may not be positive in paraneoplastic pemphigus; however, indirect immunofluorescence is often positive in paraneoplastic pemphigus showing cell surface antibody staining
    • Testing for IgA cell surface antibodies is important in establishing the diagnosis of IgA pemphigus; this testing is highly sensitive and specific
      • This testing can distinguish IgA pemphigus from other pemphigus variants and from other immune-mediated skin disease
  • Differential Diagnosis
    • Pemphigoid
    • Epidermolysis bullosa acquisita
    • Viral infection, herpes (simplex) and coxsackie A16 (hand-foot-and-mouth disease)
    • Candidiasis
    • Aphthous stomatitis
    • Drug reaction
    • Lichen planus
    • Behçet disease
    • Lupus erythematosus
    • Stevens Johnson syndrome
    • Paraneoplastic pemphigus

Disease Monitoring

  • Both IgG cell surface antibodies (by IFA) and IgG desmoglein (desmoglein-1 and desmoglein-3) antibodies (by ELISA) are useful in monitoring patient’s disease activity and response to therapy in IgG pemphigus types
  • IgA cell surface antibody monitoring (by IFA) is useful for monitoring disease activity and response to therapy in IgA pemphigus

Treatment

  • Treatment, disease course and prognosis may vary with disease type identified

See Also