Epidermolysis Bullosa Acquisita

Chronic Autoimmune Blistering Disease

  • Diagnosis
  • Algorithms
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

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

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 basement membrane zone (BMZ) antibodies positive titer >1:10 with dermal pattern is diagnostic for epidermolysis bullosa acquisita (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 direct immunofluorescence (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

  • Collagen type VII IgG antibody and epithelial skin antibody

OR

  • Collagen type VII IgG antibody and IgG basement membrane zone (BMZ) antibodies

Epidermolysis bullosa acquisita (EBA) is a rare, chronic autoimmune blistering disease.

Epidemiology

  • Incidence – 25/100,000
  • Age
    • Peak onset in 40s for acquired form
    • Infancy for inherited form
  • Sex – M:F, equal
  • Genetics – mutation present in inherited forms
    • Multiple mutations may be responsible, including KRT5, KRT14, LAM3, LAMA3, LAMB3, LAMC2, COL17A2, ITGA3, ITGA6, ITGB4
    • Autosomal recessive inheritance

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 basement membrane zone (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 3 identical alpha chains that comprise collagen VII

Clinical Presentation

  • Acquired EBA – 4 forms
    • Classical variant
      • Mechanobullous – slight trauma elicits blistering and erosions, typically on extensor surfaces of elbows, knees, hands, and feet
      • Noninflammatory
      • Healing of lesions results in atrophy, milia, scars, and pigmentation
    • Inflammatory variant
      • Resembles pemphigoid
      • Tense blistering on urticarial base
    • Cicatricial pemphigoidlike variant
      • Mucous membranes affected
      • Blistering lesions that scar
    • Brunsting-Perry pemphigoidlike variant
      • Head and neck involvement
      • Minimal mucosal disease
      • Blistering lesions that scar
  • Inherited EBA – 4 forms
    • Epidermolysis bullosa (EB) simplex
    • Dystrophic EB
    • Kindler syndrome
    • Junctional EB
      • Herlitz
      • Non-Herlitz – generalized
      • Non-Herlitz – localized
      • With pyloric atresia
      • Inversa
      • Late onset
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence

Recommended Use 

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 Immunobullous Skin Diseases Testing algorithm

Limitations 

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

Pemphigoid Antibody Panel - Epithelial Basement Membrane Zone Antibodies, IgG and IgA, BP180 and BP230 Antibodies, IgG 0092001
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Recommended Use 

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

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

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 Immunobullous Skin Diseases Testing algorithm

Collagen Type VII Antibody IgG by ELISA 2010905
Method: Enzyme-Linked Immunosorbent Assay

Recommended Use 

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 Immunobullous Skin Diseases Testing algorithm

Pemphigus Antibody Panel - Epithelial Cell Surface Antibodies and Desmoglein 1 and Desmoglein 3 Antibodies, IgG 0090650
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Recommended Use 

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

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

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 Immunobullous Skin Diseases Testing algorithm

Tissue Transglutaminase (tTG) Antibody, IgA with Reflex to Endomysial Antibody, IgA by IFA 0050734
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Recommended Use 

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

Reflex pattern – if tTG IgA is ≥4 U/mL, then EMA IgA by IFA testing will be added

See Immunobullous Skin Diseases Testing algorithm

Epithelial Skin Antibody 0090299
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Recommended Use 

General screen for immunobullous diseases

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

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 Immunobullous Skin Diseases Testing algorithm

Epithelial Basement Membrane Zone Antibody IgG 0092056
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Recommended Use 

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 Immunobullous Skin Diseases Testing algorithm

General References

Baum S, Sakka N, Artsi O, Trau H, Barzilai A. Diagnosis and classification of autoimmune blistering diseases. Autoimmun Rev. 2014; 13(4-5): 482-9. PubMed

Gupta R, Woodley DT, Chen M. Epidermolysis bullosa acquisita. Clin Dermatol. 2012; 30(1): 60-9. PubMed

Intong LR, Murrell DF. Management of epidermolysis bullosa acquisita. Dermatol Clin. 2011; 29(4): 643-7. PubMed

Ishii N, Hamada T, Dainichi T, Karashima T, Nakama T, Yasumoto S, Zillikens D, Hashimoto T. Epidermolysis bullosa acquisita: what's new? J Dermatol. 2010; 37(3): 220-30. PubMed

Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: Clinical manifestations. J Dtsch Dermatol Ges. 2011; 9(10): 844-56; quiz 857. PubMed

Lara-Corrales I, Pope E. Autoimmune blistering diseases in children. Semin Cutan Med Surg. 2010; 29(2): 85-91. PubMed

Lehman JS, Camilleri MJ, Gibson LE. Epidermolysis bullosa acquisita: concise review and practical considerations. Int J Dermatol. 2009; 48(3): 227-35; quiz 235-6. PubMed

Parker SR, MacKelfresh J. Autoimmune blistering diseases in the elderly. Clin Dermatol. 2011; 29(1): 69-79. PubMed

Schmidt E, Zillikens D. The diagnosis and treatment of autoimmune blistering skin diseases. Dtsch Arztebl Int. 2011; 108(23): 399-405, I-III. PubMed

Medical Reviewers

Leiferman, Kristin M., MD, Consultant, Immunodermatology at ARUP Laboratories; Co-Director, Immunodermatology Laboratory, Professor of Dermatology, University of Utah

Tebo, Anne E., PhD, D(ABMLI), Medical Director, Immunology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Last Update: September 2017