Linear IgA Disease

Linear IgA disease is a blistering disorder of the skin and mucous membranes that is also known as linear IgA bullous dermatosis (in adults) and chronic bullous disease of childhood (in children). Initially, broad serum testing, including pemphigoid and pemphigus panels and endomysial antibodies, should be performed unless a specific immunobullous skin disease type is suspected.

Quick Answers for Clinicians

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Diagnosis

Indications for Testing

Presence of chronic blistering, urticarial plaques, eczematous skin disease after other, more common diseases ruled out

Laboratory Testing

  • Initial serum testing – pemphigoid and pemphigus panels and endomysial antibodies (all 3 tests for initial screening) or epithelial skin antibodies testing
    • Broad testing recommended unless a specific immunobullous skin disease type is suspected
      • IgA antibodies localized to epidermal side of split skin or showing a combined epidermal-dermal pattern
        • IgA antibodies showing dermal localization alone are rare but do occur
  • Serum IgA basement membrane zone (BMZ) antibodies by indirect immunofluorescence
    • Bind to epidermal, dermal, or combined epidermal-dermal areas of split skin
    • Positive in 60-70% of patients with linear IgA disease

Histology and Immunohistology

  • Histopathology – bullae are subepidermal with neutrophils along the BMZ and occasionally in dermal papillary tips
  • Perilesional skin biopsy (cutaneous direct immunofluorescence)
    • IgA BMZ antibodies in linear pattern present in 100% of patients
    • Complement and lesser intense linear IgG and/or IgM BMZ staining also may be present 

Differential Diagnosis

Monitoring

Epithelial basement membrane zone IgA antibody testing or epithelial skin antibodies to monitor disease activity and response to therapy

Background

Epidemiology

  • Prevalence – rare disorder
  • Age
    • Adult – average age of onset >60 years
    • Childhood – birth-10 years (average 4.5 years)
  • Sex – M<F; minimal

Risk Factors

Pathophysiology

  • Neutrophil involvement – usually greater in linear IgA disease
  • Eosinophil involvement – usually greater in pemphigoid and epidermolysis bullosa acquisita
  • Serum IgA basement membrane zone (BMZ) antibodies bind to epidermal, dermal, or combined epidermal-dermal areas of split skin
    • The linear IgA bullous disease antigen of 97 kDa (LABD97) and the 120 kD linear IgA disease antigen-1 (LAD-1) are cleavage products of bullous pemphigoid antigen 2 (BP180) and are major antigenic targets for IgA autoantibodies
    • Type VII collagen IgA antibodies may account for dermal staining on split skin
  • Both IgA and IgG BMZ antibodies may be found in tissue and serum of a subset of patients

Clinical Presentation

  • Papulovesicles, bullae, or urticarial plaques on extensor, central, or flexural sites with truncal involvement
    • May also appear annular or herpetiform
  • Variable lesion types similar to pemphigoid or epidermolysis bullosa acquisita
  • Classic presentation – “string of pearls” lesion consisting of grouped vesicles
  • Oral mucosa involvement – common
    • Ocular involvement – indistinguishable from ocular cicatricial pemphigoid
  • May exhibit severe pruritus
  • Perineal and perioral involvement common in children
  • Association with vancomycin and other drug exposure in drug-induced cases

ARUP Lab Tests

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

Refer to Immunobullous Skin Diseases Testing algorithm

Tissue must be submitted in Michel’s or Zeus medium; this 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, epidermolysis bullosa acquisita, and linear IgA bullous dermatosis

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

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

Refer to Immunobullous Skin Diseases Testing algorithm

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

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

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 (DIF)

Refer to Immunobullous Skin 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 the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

Refer to Immunobullous Skin Diseases Testing algorithm

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

Assess and monitor patient with linear IgA disease, including linear IgA bullous dermatosis and positive IgA BMZ antibodies, either epidermal (roof) pattern or dermal (floor) pattern

Consider ordering concurrently with IgG antibody testing for epithelial BMZ, bullous pemphigoid BP180 and 230 antigens, and/or collagen type VII

Refer to Immunobullous Skin Diseases Testing algorithm

General screen for immunobullous diseases

Test includes IgG and IgA BMZ antibodies (pemphigoid, epidermolysis bullosa acquisita, 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 pemphigus or pemphigoid

Refer to Immunobullous Skin Diseases Testing algorithm

Medical Experts

Contributor

Leiferman

 

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

Consultant, Immunodermatology at ARUP Laboratories

References

Additional Resources