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Epidermolysis Bullosa Acquisita. ARUP Consult©. Retrieved May 29, 2020, https://arupconsult.com/content/epidermolysis-bullosa-acquisita

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Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita (EBA) is a rare, chronic autoimmune blistering disease. Broad serologic screening is recommended unless a specific immunobullous skin disease type is suspected.

Quick Answers for Clinicians

Which testing algorithms are related to this topic?
Epithelial Antibody-Associated Immunobullous Diseases Testing

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
      • 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

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

ARUP Lab Tests

Order concurrently with serum antibody testing and fixed tissue histopathology for assessment of patient with pruritic, urticarial, blistering, and/or erosive disorders, including possible pemphigoid and pemphigoid variants, pemphigus and pemphigus subtypes, dermatitis herpetiformis, epidermolysis bullous acquisita (EBA), porphyria, and pseudoporphyria

Order concurrently with fixed tissue histopathology for assessment of patient with inflammatory, immune-mediated cutaneous disease, including possible lupus and lupus variants, vasculitis, drug reactions, lichen planus, and lichenoid reactions

See Epithelial Antibody-Associated Immunobullous Diseases Testing algorithm

Tissue must be submitted in Michel’s or Zeus medium; test cannot be performed on formalin-fixed tissue

Initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria, including pemphigoid, pemphigoid variants, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, linear IgA disease variants, and IgG-pemphigus subtypes

Order concurrently with perilesional skin biopsy for direct immunofluorescence for initial diagnosis

Use for disease monitoring with semiquantitative antibody level assessments and tracking and for persistent unexplained disease and/or worsening disease activity

Initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria from suspected basement membrane zone antibody-associated disease (eg, bullous pemphigoid, pemphigoid variants, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, and linear IgA disease variants)

Order concurrently with perilesional skin biopsy for direct immunofluorescence for initial diagnosis

Use for disease monitoring with semiquantitative antibody assessments and tracking

Preferred antibody panel for initial diagnostic assessment and disease monitoring in pemphigoid, EBA, and linear IgA bullous dermatosis

Bullous pemphigoid and other pemphigoid variants, EBA, and linear IgA bullous dermatosis present with blistering, erosions, pruritus, and urticaria, which affect skin and mucous membranes

To order individual component tests, refer to antibody testing for IgG BMZ, IgA BMZ, and/or IgG bullous pemphigoid antigens (BP180 and 230)

To screen for pemphigoid along with other possible immunobullous diseases, order concurrently with pemphigus antibody panel, IgG collagen type VII antibody, AND perilesional skin biopsy for direct immunofluorescence

See Epithelial Antibody-Associated Immunobullous Diseases Testing algorithm

Panel components include IgG and IgA epithelial basement membrane zone (BMZ) antibodies and IgG bullous pemphigoid BP180 and 230 antigens

For initial diagnosis and disease monitoring of EBA

To further evaluate IgG BMZ antibodies, consider ordering with IgG antibody testing for epithelial BMZ and bullous pemphigoid (BP180 and 230) antigens

Consider other types of BMZ antibody-associated disease testing (ie, IgA epithelial BMZ and herpes gestationis factor)

To discriminate among immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease, order concurrently with testing for epithelial cell surface antibody or refer to antibody panel tests for pemphigoid and pemphigus

See Epithelial Antibody-Associated Immunobullous Diseases Testing algorithm

Preferred panel for initial assessment and disease monitoring in IgG-variant pemphigus

​Pemphigus vulgaris and pemphigus foliaceus are most common types of pemphigus with blistering and erosive disease affecting skin and mucous membranes

To screen for pemphigus along with other possible immunobullous diseases, order concurrently with antibody panel test for pemphigoid, IgG collagen type VII antibody, AND perilesional skin biopsy for direct immunofluorescence

See Epithelial Antibody-Associated Immunobullous Diseases Testing algorithm

Panel components include antibody testing for IgG epithelial cell surface and IgG desmoglein 1 and 3; to order individual component tests, refer to epithelial skin antibody and/or desmoglein 1 and 3 antibodies in pemphigus, IgG

Use along with pemphigoid and pemphigus panel tests and epidermal transglutaminase antibody, IgA, or use with epithelial skin antibody and epidermal transglutaminase antibody, IgA, testing to initially diagnose and discriminate among immunobullous skin diseases in patients suspected of having or known to have any type of immunobullous disease

See Epithelial Antibody-Associated Immunobullous Diseases Testing algorithm

General screen for immunobullous diseases

Consider ordering concurrently with IgG bullous pemphigoid (BP180 and 230) antigens for suspected pemphigoid and/or IgG desmoglein 1 and 3 antibodies for suspected pemphigus

For more sensitive and specific testing for pemphigoid or pemphigus, refer to antibody panels for pemphigoid or pemphigus

See Epithelial Antibody-Associated Immunobullous Diseases Testing algorithm

Includes IgG and IgA BMZ antibodies (pemphigoid, EBA, linear IgA disease) and IgG and IgA cell surface antibodies (IgG and IgA pemphigus subtypes)

Monitor disease in patient with pemphigoid or EBA who has positive IgG BMZ antibodies by indirect immunofluorescence, either epidermal (roof) pattern or dermal (floor) pattern, on split skin substrate

Consider ordering concurrently with IgG antibody testing for bullous pemphigoid (BP180 and 230) antigens and/or collagen type VII

May use to screen for pemphigoid and other immunobullous diseases; however, test has decreased sensitivity and specificity when compared to panel tests for pemphigus antibodies or pemphigoid antibodies and will not detect IgA BMZ antibodies

See Epithelial Antibody-Associated Immunobullous Diseases Testing algorithm

Medical Experts

Contributor

Leiferman

 

Kristin M. Leiferman, MD

Co-Director, Immunodermatology Laboratory, Professor of Dermatology, University of Utah

Consultant, Immunodermatology at ARUP Laboratories

Contributor

References

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