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 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

• Contact dermatitis
• Dermatitis herpetiformis (DH)
• Drug reaction
• Epidermolysis bullosa acquisita (EBA)
• Erythema multiforme
• Herpes simplex or varicella-zoster viral infection
• Pemphigoid
• Pemphigoid gestationis (if pregnant)
• Pemphigus
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

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

• Certain drugs – antibiotics (vancomycin), lithium, nonsteroidal anti-inflammatory agents (diclofenac, piroxicam), cyclosporine, diuretics (furosemide), and others
• Various infections
• Autoimmune diseases – ulcerative colitis, Crohn disease, gastric hypochlorhydria, thyrotoxicosis, systemic lupus erythematous, dermatomyositis, rheumatoid arthritis
• Malignancies
  • Lymphoma or chronic lymphocytic leukemia (rare in both)
  • Carcinoma of the bladder, thyroid, or esophagus

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
  • May also appear clinically similar to dermatitis herpetiformis
• 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