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FeedbackLinear 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
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
- IgA antibodies localized to epidermal side of split skin or showing a combined epidermal-dermal pattern
- Broad testing recommended unless a specific immunobullous skin disease type is suspected
- 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
- Contact dermatitis
- Dermatitis herpetiformis
- Drug reaction
- Epidermolysis bullosa acquisita
- 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
ARUP Lab Tests
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, 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
Direct Immunofluorescence
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
Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay
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
Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay
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
Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody
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)
Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
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
Indirect Immunofluorescence
(Indirect Fluorescent Antibody)
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
Indirect Immunofluorescence
(Indirect Fluorescent Antibody)
Medical Experts
Leiferman
Co-Director, Immunodermatology Laboratory, Professor of Dermatology, University of Utah
Consultant, Immunodermatology at ARUP Laboratories
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Panel components include IgG and IgA epithelial basement membrane zone (BMZ) antibodies and IgG bullous pemphigoid BP180 and 230 antigens