Epidermolysis Bullosa Acquisita

Diagnosis

Indications for Testing

• Presence of chronic blistering, erosive and/or crusting skin disease
• More common diseases ruled out

Criteria for Diagnosis

The International Bullous Disease Group (IBDG) has defined nine diagnostic criteria for EBA (Prost-Squarcioni, 2018):

• Clinical presentation of bullous disorder
• Subepidermal or subepithelial blister revealed through histopathology
• Positive direct immunofluorescence (DIF) microscopy of perilesional skin with IgG, third component of complement (C3), and/or IgM deposits within epithelial basement membrane zone (BMZ)
• Circulating antibodies against collagen type VII detected on collagen type VII-expressing cells
• Anchoring fibrils identified by direct immunoelectron microscopy or negative indirect immunofluorescence on collagen type VII-expressing cells
• U-serration pattern detected by DIF
• Immune deposits within anchoring fibrils zone detected by direct immunoelectron microscopy
• In vivo bound immune deposits below type IV collagen
• As an alternate to items 4-8, dermal labelling by direct or indirect immunofluorescence on salt-split skin

Laboratory Testing

• Initial serum testing – test for either pemphigus, pemphigoid, and endomysial antibodies or epithelial skin antibodies
  • Broad screening recommended unless a specific immunobullous skin disease type is suspected
  • Serologic diagnosis – positive in 90% of cases
• Pemphigoid panel
  • IgG BMZ antibodies positive titer >1:10 with dermal pattern is diagnostic for EBA
  • Collagen type VII antibody IgG by enzyme-linked immunosorbent assay (ELISA) – order if IgG BMZ is diagnostic for EBA

Histology

• Immunohistology
  • Perilesional skin biopsy for DIF – gold standard for diagnosis
    • Linear BMZ deposition of IgG and/or third component of complement (C3) along BMZ of perilesional tissue
  • Dermal pattern localization of serum IgG BMZ antibodies on human split skin substrate by indirect immunofluorescence
    • Characteristically found in EBA
    • Also found in
      • Subset of bullous systemic lupus erythematosus (SLE)
      • Two subsets of pemphigoid
        • Anti-laminin 332 pemphigoid
        • Anti-laminin γ1 pemphigoid
    • Collagen VII IgG antibodies not increased
      • Up to one-third of laminin 332 antibody pemphigoid cases with dermal pattern BMZ antibody staining have underlying malignancy or will be diagnosed with malignancy within a few months
      • Further clinical evaluation should be pursued as indicated
    • Collagen VII antibodies increased
      • Unknown whether patients also may have laminin 332 antibodies
      • Association with malignancy and dermal pattern BMZ antibody staining should be considered

Differential Diagnosis

• Pemphigoid
• Pemphigus
• Linear IgA disease
• Porphyria cutanea tarda
• Dermatitis herpetiformis
• Contact dermatitis
• Drug eruption
• Bullous SLE
• Hereditary forms of EBA

Monitoring

Either collagen type VII IgG antibody and epithelial skin antibody or collagen type VII IgG antibody and IgG BMZ antibodies

Background

Epidemiology

• Incidence – 25/100,000
• Age – peak onset in 40s​
• Sex – M:F, equal

Pathophysiology

• Subepidermal blister formation characterized by autoantibodies to structural components of skin and adjacent mucous membranes (specifically collagen VII)
• Collagen VII – component of anchoring fibrils within epithelial BMZ (skin and mucous membranes)
  • Patients with EBA characteristically develop IgG antibodies to collagen VII
  • Major epitopes for EBA antibody reactivity reside in noncollagenous amino-terminal domain (NC1)
  • Minor epitopes reside in noncollagenous carboxy-terminal domain (NC2) of the three identical alpha chains that comprise collagen VII

Clinical Presentation

• Classical/mechanobullous – one subtype (Prost-Squarcioni, 2018)
  • Lesions induced by trauma
  • Bullous or vesicular lesions surrounded by noninflamed or scarred skin
  • Scarring or formation of milia, typically on trauma-prone sites
  • Possible nail dystrophy and/or scarring alopecia
• Nonclassical/nonmechanobullous – four subtypes (Prost-Squarcioni, 2018)
  • Bullous pemphigoid (BP)-like EBA
    • Eruption with features typical of BP, such as pruritus and involvement of truck and folds
    • Typically combined with atypical lesions for a BP such as bullae on normal skin and milia
  • Mucous membrane-EBA – primarily affects mucous membrane lined by squamous epithelium (eg, mouth, pharynx, esophagus)
  • IgA-EBA – presents with linear IgA deposits in BMZ
    • May resemble linear IgA bullous dermatosis
    • May be more aggressive
    • May result in mucosal scarring
  • Brunsting-Perry-type EBA – blistering dermatosis confined to head and neck