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Disease Categories > Autoimmune Disease > Immunobullous Disease

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Immunobullous Skin Diseases Screening

Immunobullous skin diseases are a group of autoimmune blistering diseases that affect skin and mucous membranes and are caused by or associated with the deposition of specific antibodies on cutaneous structures.

Clinical Presentation

Although the various immunobullous skin diseases have certain clinical and histological features that characterize them, often their presentation is atypical and/or shows overlap with each other and other diseases including common skin diseases such as eczema and urticaria

Diagnosis

Diagnosis of immune-mediated diseases of skin and other epithelial organs is aided by specific immunodermatologic testing
Because of overlap among immunobullous diseases with similar names, testing may be confused and misordered
Laboratory testing
- Perilesional skin biopsy for direct immunofluorescence along with appropriate serum antibody tests are very helpful for the initial diagnosis of immunobullous skin disease because of increased sensitivity with tissue studies and ability to distinguish diseases by serum studies
- Autoantibodies may be present in normal individuals, usually in low titers and/or levels; clinical correlation is needed

PEMPHIGUS Clinical Presentation and Diagnostic Testing
Clinical presentation	Serum autoantibodies*	Perilesional biopsy staining
Pemphigus vulgaris Mucosal involvement is prominent; flaccid bullae with Nikolsky sign, erosions and crusting Pemphigus vegetans variant with vegetating intertriginous plaques and oral involvement including cerebriform tongue	IgG epithelial cell surface by indirect immunofluorescence (IFA); correlates with disease activity IgG desmoglein-3 antibodies (also desmoglein-1 antibodies) by enzyme-linked immunosorbent assay (ELISA) also correlates with disease activity and can help distinguish pemphigus subtypes	Epidermal IgG and C3 cell surface (intercellular substance) staining
Pemphigus foliaceus Superficial bullae, erosions, and scale with crusting, Nikolsky sign present Pemphigus erythematosus variant with lupus features	IgG epithelial cell surface by IFA; correlates with disease activity IgG desmoglein-1 antibodies (also desmoglein-3 antibodies) by ELISA also correlates with disease activity and can help distinguish pemphigus subtypes	Epidermal IgG and C3 cell surface (intercellular substance) staining; in pemphigus erythematosus variant, IgG, IgM, IgA and/or complement granular immune deposits at the basement membrane zone
Drug-induced pemphigus Pemphigus vulgaris or pemphigus foliaceus Implicated drugs: Thiol containing medication implicated in 80% (Penicillamine or captopril, Pyritinol, thiopronine, piroxicam, thiamazole, and gold sodium thiomalate) Masked thiols (Penicillin, piroxicam, cephalosporins, rifampin) Others(Enapril and dipyrone)	IgG epithelial cell surface by IFA; correlates with disease activity IgG desmoglein-1 antibodies and desmoglein-3 antibodies) by ELISA also correlates with disease activity and can help distinguish pemphigus subtypes	Epidermal IgG and C3 cell surface (intercellular substance) staining
IgA pemphigus Pruritic vesicles and pustules in subcorneal pustular dermatosis (SPD) variant; variable skin lesions with numerous pustules in intraepidermal neutrophilic IgA dermatosis (IEN) variant	IgA epithelial cell surface by IFA; correlates with disease activity	Epidermal IgA cell surface staining
Paraneoplastic pemphigus Flaccid bullae, lichenoid or erythema multiforme-like, usually involves mucosa, often extensively esophageal and respiratory	IgG epithelial cell surface and basement membrane zone (staining on rodent bladder epithelium is characteristic) by IFA; correlates with disease activity	Epidermal IgG and C3 cell surface and basement membrane zone staining
PEMPHIGOID Clinical Presentation and Diagnosis
Bullous pemphigoid and variants (urticarial, localized, drug-induced) Tense bullae, often on urticarial base, prominent pruritus; variant forms may not have bullae and may resemble other and common dermatoses, oral involvement; most cases are idiopathic, minority are drug induced—Penicillins, Ciprofloxacin, Furosemide, angiotensin converting enzyme inhibitors (captopril, enalapril), Chloroquine, Sulfasalazine, Phenacetin, Nifedipine, Terbinafine	IgG basement membrane zone, epidermal or combined by IFA, BP180 and/or BP230 IgG antibodies by ELISA correlate with disease activity	Linear basement membrane zone IgG and C3; linear IgM, IgA and IgE may be present
Mucous membrane (cicatricial) pemphigoid Tense bullae and erosions, scarring sequelae, ocular and oral	IgG basement membrane zone, epidermal or combined, rare dermal	Linear basement membrane zone IgG and C3
Herpes gestationis Tense bullae, similar to bullous pemphigoid, onset during or immediately after pregnancy	Complement fixing, basement membrane zone, epidermal	Linear basement membrane zone C3 and, less commonly, IgG
EPIDERMOLYSIS BULLOSA ACQUISITA Clinical Presentation and Diagnosis
Tense bullae, commonly occur in areas of trauma and in oral mucosa	IgG basement membrane zone, rarely IgA, dermal	Linear basement membrane zone IgG and C3, may show linear IgA and IgM
LINEAR IgA DISEASE (Linear IgA bullous dermatosis and chronic bullous disease of childhood) Clinical Presentation and Diagnosis
Tense bullae, similar to bullous pemphigoid; oral involvement common in adult disease; annular blisters “cluster of jewels” or “string of pearls” Most idiopathic, some linear IgA bullous dermatosis is drug induced: vancomycin, Amiodarone, Captopril, benazepril, Ceftriaxone, Cefamandole, Cyclosporin, Furosemide, Lithium, Diclofenac, Atorvastatin, IL-2, Interferon g, Piroxicam, Penicillins, Rifampin, Trimethoprim sulfamethoxazole, Phenytoin, Somatostatin, Gemcitabine, Vigabatrin, Glibenclamide, Carbamazine	IgA basement membrane zone, epidermal or combined (rarely dermal)	Linear basement membrane zone IgA, may have IgG and C3 (less intense basement membrane zone staining)
DERMATITIS HERPETIFORMIS Clinical Presentation and Diagnosis
Small bullae or erythematous papules, patches, plaques on extensor surfaces (elbows and knees, also scalp and buttocks); markedly pruritic; associated with intestinal gluten-sensitivity	IgA endomysial and transglutaminase antibodies; correlate with disease activity and compliance with gluten-free diet	Granular basement membrane zone IgA with stippling in dermal papillae; occasionally fibrillar IgA staining
BULLOUS LUPUS ERYTHEMATOSUS Clinical Presentation and Diagnosis
Tense bullae, photodistributed	IgG basement membrane zone, dermal or combined	Linear basement membrane zone IgG, also may show granular IgM and C3 basement membrane zone as in lupus band
*Refer to individual immunobullous disease/s for further information including testing

Indications for Ordering

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
Herpes Gestationis Factor (IgG Complement-Fixing Basement Membrane Zone Antibodies) 0092283 Method: Indirect Immunofluorescence	Order along with perilesional skin biopsy for diagnosis of herpes gestationis Follow persistent or recurrent disease activity with antibody titers		Perilesional biopsy for cutaneous direct immunofluorescence is recommended See Immunobullous Skin Diseases Testing algorithm
Paraneoplastic Pemphigus Antibody Screen 0092107 Method: Indirect Immunofluorescence	Order along with perilesional skin biopsy to help in the diagnosis of paraneoplastic pemphigus Follow persistent or recurrent disease activity with antibody titers		Perilesional biopsy for cutaneous direct immunofluorescence is recommended 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 Immunofluorescence	Order along with the pemphigus panel, endomysial antibodies test and perilesional skin biopsy to screen for immunobullous skin disease (preferred screening test combination) Follow persistent or recurrent disease activity with antibody titers and levels	Clinical correlation necessary because incidence of false-positives, although rare, increases with age	Perilesional biopsy for cutaneous direct immunofluorescence is recommended 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 Immunofluorescence	Order along with the pemphigoid panel, endomysial antibodies test and perilesional skin biopsy to screen for immunobullous skin disease (preferred screening test combination) Follow disease activity and therapeutic response with antibody titers and levels	Clinical correlation necessary because cell surface antibodies may be found in normal individuals and in patients with burns, fungal infections, drug reactions and other dermatoses	Perilesional biopsy for cutaneous direct immunofluorescence is recommended See Immunobullous Skin Diseases Testing algorithm
Epithelial Skin Antibody 0090299 Method: Indirect Immunofluorescence	Order along with endomysial antibody test and perilesional skin biopsy to screen for immunobullous skin disease Follow persistent or recurrent disease activity with disease specific antibody titers and levels		Perilesional biopsy for cutaneous direct immunofluorescence is recommended See Immunobullous Skin Diseases Testing algorithm
Cutaneous Direct Immunofluorescence, Biopsy 0092572 Method: Direct Immunofluorescence	Order along with serum tests to screen for immunobullous skin disease		See Immunobullous Skin Diseases Testing algorithm
Tissue Transglutaminase Antibody, IgA with Reflex to Endomysial Antibody, IgA Titer by IFA 0050734 Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody	Order along with IgA tissue transglutaminase antibody test and perilesional skin biopsy to screen for presence of immunobullous skin disease Follow disease activity with antibody titers and levels		Perilesional biopsy for cutaneous direct immunofluorescence is recommended See Immunobullous Skin Diseases Testing algorithm

Additional Tests Available

Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Comments
Epithelial Basement Membrane Zone IgG Antibodies 0092056 Method: Indirect Immunofluorescence (IFA)
Epithelial Basement Membrane Zone IgA Antibodies 0092057 Method: Indirect Immunofluorescence
Bullous Pemphigoid (180 kDa & 230 kDa) Antigens, IgG 0092566 Method: Enzyme Linked Immunosorbent Assay
IgG Desmoglein 1 & Desmoglein 3 0090649 Method: Enzyme-Linked Immunosorbent Assay
IgG Epithelial Cell Surface Antibodies 0090266 Method: Indirect Immunofluorescence
Pemphigus IgA Antibodies 0092106 Method: Indirect Immunofluorescence

Additional Information

Predictive Value of Immunodermatology Tests
Disease	Serum Studies - Cutaneous Indirect Immunofluorescence and ELISA	Tissue Studies– Cutaneous Direct Immunofluorescence
Bullous pemphigoid	70-80% of patients demonstrate IgG antibodies to BMZ components by indirect immunofluorescence, with epidermal staining on split skin 80% or more have BP230 (BP Ag1) and/or BP180 (BP Ag2) IgG antibodies by ELISA which correlate with disease activity	>90% of patients have characteristic linear deposition of IgG and C3 (also IgA) along the BMZ in perilesional skin
Dermatitis herpetiformis	Approximately 85% of patients demonstrate IgA endomysial antibodies by indirect immunofluorescence which is highly sensitive and specific for the disease IgA tissue transglutaminase antibodies by ELISA, slightly less specific but highly sensitive Respective antibodies correlate with disease activity	>95% of patients have granular and/or fibrillar IgA in dermal papillae of perilesional skin
Epidermolysis bullosa acquisita	Approximately 50% of patients demonstrate IgG antibodies to BMZ components, dermal staining on split skin by indirect immunofluorescence	>95% of patients show strong IgG and C3 in a thick linear BMZ band in perilesional skin; other immunoglobulins may also be present
Herpes gestationis	Approximately 85% of patients demonstrate HG factor (HG IgG) by complement fixing indirect immunofluorescence and BP180 (BPAG2) antibodies by ELISA Approximately 25% have IgG at the BMZ	>95% of patients have intense linear C3 at BMZ; 25% show linear IgG BMZ in perilesional skin
Pemphigus	70-80% of patients demonstrate IgG antibodies to epithelial cell surface components by indirect immunofluorescence, 90% or more have IgG desmoglein-1 and/or desmoglein-3 antibodies by ELISA (IgG desmoglein-1 antibodies predominate in pemphigus foliaceus and IgG desmoglein-3 antibodies predominate in pemphigus vulgaris). Respective antibodies correlate with disease activity	>90% of patients have cell surface IgG and/or C3 staining in perilesional skin
Vasculitis	Antinuclear antibodies and/or antineutrophilic cytoplasmic antibodies	50-60% of patients with immune-mediated vasculitis demonstrate antibody in dermal blood vessels in early lesion