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.

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

Histopathlogy and Immunopathology

  • 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 Laboratory Tests

Additional detail about the tests below can be found in the ARUP Immunobullous Disease Testing Comparison table

Use with serum immunobullous disease/epithelial antibody testing and formalin-fixed tissue histopathology for assessment of pruritic, urticarial, blistering, and/or erosive disorders

Use with formalin-fixed tissue histopathology for assessment of inflammatory, immune-mediated cutaneous disease

Optimal specimen location and complementary serum testing and/or histopathology examination vary according to disease type; note that specimen location and transport medium/fixative are different for direct immunofluorescence testing and fixed-tissue histopathology

Use as initial comprehensive testing panel to aid in the diagnosis of and distinguishing among skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria

Use for assessment of suspected epithelial antibody-associated immunobullous diseases, pemphigoid and pemphigus and their variants, that are not clinically distinguishable, have nonspecific features, potentially express overlapping epithelial antibodies, and/or are indicated by concurrent DIF biopsy

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA; collagen type VII antibodies, IgG by ELISA; cell surface antibodies, IgG by IIF; desmoglein 1 and 3 antibodies, IgG by ELISA; cell surface antibodies, IgA by IIF

Use as the preferred initial diagnostic panel for suspected BMZ antibody-associated skin and mucous membrane disorders that present with blistering, erosions, eczema, urticaria, pruritus, and/or mucositis

May be indicated by concurrent DIF biopsy

Alternatively, order the comprehensive Immunobullous Disease Antibody Panel for initial serum diagnostic assessment of epithelial antibody-associated diseases, pemphigoid, pemphigus, and their variants

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA; collagen type VII antibodies, IgG by ELISA

Use to assess and monitor pemphigoid, pemphigoid variants, and linear IgA disease and to discriminate among the immunobullous diseases with epithelial BMZ antibodies

May be indicated by concurrent DIF biopsy; preferred initial diagnostic serum panel is Basement Membrane Zone Antibody Panel

 

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA

Use to assess and monitor IgA BMZ antibodies in patients with linear IgA disease, including linear IgA bullous dermatosis and chronic bullous disease of childhood, and IgA variant EBA 

Testing should be correlated initially with concurrent DIF biopsy 

For initial linear IgA disease diagnosis, serum Basement Membrane Zone Antibody Panel or Immunobullous Disease Antibody Panel is preferred

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA

Use to assess and monitor DH; testing should be correlated initially with concurrent DIF biopsy

Because most patients with DH have associated celiac disease (CD), testing should be performed in conjunction with testing for CD

For initial diagnosis and assessment of disease progression/changes and to distinguish from other immunobullous diseases with epithelial antibodies, order concurrently with serum Immunobullous Disease Antibody Panel 

Use as the preferred serum antibody panel to assess and monitor IgG pemphigus variants (includes pemphigus foliaceus and pemphigus vulgaris), which present with blistering and erosive disease affecting skin and mucous membranes

Testing should be correlated with concurrent DIF biopsy

 

Components: cell surface antibodies, IgG by IIF; desmoglein 1 and desmoglein 3 antibodies, IgG by ELISA

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 IIF testing will be added

Use to assess and monitor IgA BMZ antibodies in patients with linear IgA disease, including linear IgA bullous dermatosis and chronic bullous disease of childhood, and IgA variant EBA

Testing should be correlated with concurrent DIF biopsy 

For initial linear IgA disease diagnosis, serum Basement Membrane Zone Antibody Panel or Immunobullous Disease Antibody Panel is preferred 

 

Use to monitor linear IgG and IgA BMZ antibody-associated diseases and IgG and IgA cell surface antibody-associated diseases in which antibody levels by ELISAs may not be increased and/or to assess for changing patterns of epithelial antibody expression

May be used as general initial serum test for immunobullous diseases; however, for more sensitive and specific serum testing with ELISAs for pemphigoid and EBA or for IgG variant pemphigus, refer to Basement Membrane Zone Antibody Panel or Pemphigus Antibody Panel, IgG

 

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; cell surface antibodies, IgG by IIF; cell surface, IgA by IIF

References

Additional Resources

Medical Experts

Contributor

Leiferman

Picture of Kristin M. Leiferman, MD

 

Co-Director, Immunodermatology Laboratory, Professor of Dermatology, and Adjunct Professor of Pathology, University of Utah
Medical Director, Immunodermatology, ARUP Laboratories