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.

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Clinical Overview

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

ARUP Lab Tests

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

Medical Experts

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

References

Guidelines

Prost-Squarcioni C, Caux F, Schmidt E, Jonkman MF, Vassileva S, Kim SC, Iranzo P, Daneshpazhooh M, Terra J, Bauer J, Fairley J, Hall R, Hertl M, Lehman JS, Marinovic B, Patsatsi A, Zillikens D, International Bullous Diseases Group, Werth V, Woodley DT, Murrell DF. International Bullous Diseases Group: consensus on diagnostic criteria for epidermolysis bullosa acquisita. Br J Dermatol. 2018; 179(1): 30-41. PubMed

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

Testing Algorithms

Immunobullous Skin Diseases Testing Algorithm

Read more about Immunobullous Skin Diseases Testing Algorithm

Educational Videos

Last Update: September 2018

Epidermolysis Bullosa Acquisita

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

Differential Diagnosis

Monitoring

Background

Epidemiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Immunobullous Skin Diseases Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Epidermolysis Bullosa Acquisita. ARUP Consult^©. Retrieved December 16, 2018, from: https://arupconsult.com/content/epidermolysis-bullosa-acquisita