Linear IgA Disease

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 the 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 the 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

Clinical Background

Linear IgA disease is a blistering disorder of the skin and mucous membranes.

  • Also known as linear IgA bullous dermatosis (in adults)
  • Also known as chronic bullous disease of childhood (in children)

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 the 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
  • Involvement of oral mucosa – 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

Treatment

  • Dapsone
  • Immunosuppressives – prednisone therapy; however, this disease is less responsive to prednisone than pemphigoid

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence
(Direct Fluorescent Antibody Stain)

Use to determine the presence and characteristic staining pattern of immunoglobulins (IgG, IgM, IgA), third component of complement (C3) and fibrinogen in skin or mucous membrane biopsy specimens (biopsy site is critical; see below) from patients suspected of having linear IgA disease (including chronic bullous disease of childhood and linear IgA bullous dermatosis) or mixed immunobullous disease; perform this test with serum pemphigoid and pemphigus panel tests

For skin involvement, biopsy perilesional skin

For mucous membrane involvement, biopsy nonlesional mucosa

See Immunobullous Skin Diseases Testing algorithm

May be inaccurate if tissue not taken from correct perilesional location; specimen must have epidermis/epithelium and basement membrane zone (BMZ)

Concurrent serum testing helpful to characterize basement membrane zone antibody localization

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

Initial concurrent and repeat serum testing with pemphigoid panel is the most sensitive for diagnosis, for determining antibody profiles, and for following disease activity

Patients with indeterminate results should have repeat DIF biopsy

Patients with changing clinical features should have repeat DIF biopsy because antibody profiles may change over time

See Immunobullous Skin Diseases Testing algorithm
Pemphigoid Panel - Epithelial Basement Membrane Zone IgG & IgA, BP180 & BP230 IgG Antibodies 0092001
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Panel includes epithelial basement membrane zone (BMZ) IgG & IgA antibodies by indirect immunofluorescence (IFA) on split human skin and monkey esophagus substrates, BP180 and BP230 IgG antibodies by ELISAs

Use to diagnose most types of pemphigoid, epidermolysis bullosa acquisita, linear IgA disease (including linear IgA bullous dermatosis and chronic bullous disease of childhood), mixed immunobullous disease

Use along with pemphigus panel and endomysial 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

May be useful to monitor disease activity and therapeutic response

Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity (85-100% of linear IgA cases are positive)

See Immunobullous Skin Diseases Testing algorithm

Clinical correlation is necessary because the incidence of false-positives, although rare, increases with age

Because of clinical overlap among immunobullous diseases and similar names, pemphigoid testing may be confused with pemphigus testing and inadvertently misordered

Use pemphigoid panel or epithelial IgA basement membrane zone IgA antibody tests to monitor pemphigoid disease activity and response to therapy

Repeat pemphigoid panel for indeterminate results and/or continuing clinical consideration of linear IgA disease

See Immunobullous Skin Diseases Testing algorithm
Pemphigus Panel - IgG Epithelial Cell Surface Antibodies and Levels of IgG Desmoglein 1 and Desmoglein 3 Antibodies, Serum 0090650
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Panel includes epithelial cell surface IgG antibodies by IFA on intact human skin and monkey esophagus substrates, IgG desmoglein 1 and IgG desmoglein 3 antibodies by ELISAs

Use to diagnose most major types of pemphigus and to monitor disease activity and therapeutic response

Use along with pemphigoid panel and endomysial IgA antibody tests to initially diagnose and distinguish various immunobullous disorders in patients suspected or known to have any type of immunobullous disease

See Immunobullous Skin Diseases Testing algorithm

Clinical correlation is necessary because cell surface antibodies by IFA, usually in low titers, may be found in normal individuals (possible blood group reactivity) or in patients with fungal infections, burns, drug reactions, and other dermatoses, including other immunobullous diseases

Because of clinical overlap among immunobullous diseases and similar names, pemphigoid testing may be confused with pemphigus testing and inadvertently misordered

Testing for IgG pemphigus antibody types (most common) also may be confused with IgA pemphigus testing (rare disorder)

  
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

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

Does not detect IgA or other basement membrane zone antibodies that characterize linear IgA diseases (linear IgA bullous dermatosis, chronic bullous disease of childhood) or mixed immunobullous disease

  
Epithelial Basement Membrane Zone IgA Antibodies 0092057
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

This test comprises components included in pemphigoid panel and epithelial skin antibody tests

Use to establish or confirm diagnosis of linear IgA bullous disease, chronic bullous disease of childhood, and mixed immunobullous disease

Use to discriminate among clinically similar immunobullous diseases, linear IgA disease (linear IgA bullous dermatosis, childhood immunobullous disease), pemphigoid, epidermolysis bullosa acquisita, mixed immunobullous disease, pemphigus, and dermatitis herpetiformis

Follow persistent or recurrent disease activity with antibody titers

Clinical correlation necessary because incidence of false positives, although rare, increases with age

Specific for IgA basement membrane zone antibodies found in linear IgA disease and will not detect IgG basement membrane zone antibodies found in pemphigoid and epidermolysis bullosa acquisita or cell surface antibodies found in pemphigus

Use epithelial IgA basement membrane zone IgA antibody or pemphigoid panel tests to monitor linear IgA disease activity and response to therapy

Repeat epithelial IgA basement membrane zone IgA antibody or pemphigoid panel for indeterminate results and/or continuing clinical consideration of linear IgA disease

See Immunobullous Skin Diseases Testing algorithm
Epithelial Skin Antibody 0090299
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Panel includes epithelial basement membrane zone (BMZ) IgG and IgA antibodies by IFA and IgG and IgA cell surface antibodies by IFA on split human skin, intact human skin, and monkey esophagus substrates

Use as alternate to pemphigoid and pemphigus panel tests to initially diagnose and discriminate among clinically similar immune-mediated skin diseases such as pemphigus, linear IgA disease, pemphigoid, epidermolysis bullosa acquisita, and dermatitis herpetiformis in patients suspected of having or known to have any type of subepidermal immunobullous disease

Although helpful in screening for immunobullous disease, test is not as sensitive as combination of pemphigus and pemphigoid panels

Use epithelial skin antibody test or both pemphigoid and pemphigus panels to follow patients with changing clinical features because antibody profiles may change over time

See Immunobullous Skin Diseases Testing algorithm