Pemphigoid

Diagnosis

Indications for Testing

  • Presence of chronic blistering skin disease after more common diseases ruled out
  • Unexplained pruritus, erythroderma, eczema, urticaria, desquamative gingivitis, and mucositis (including stomatitis and conjunctivitis)

Laboratory Testing

  • Initial serum testing – pemphigoid and pemphigus panels and endomysial antibodies (all 3 test series initially), or epithelial skin antibodies testing
    • Unless specific disease is suspected, broad screening recommended because of overlap in clinical immunobullous disease presentations
  • Serum basement membrane zone (BMZ) antibodies and IgG BP180 and BP230 antibodies testing (IgG BMZ antibodies present in serum in 80% of bullous pemphigoid and 20% of mucous membrane pemphigoid patients)
    • Testing is highly sensitive and specific for pemphigoid
    • Testing can distinguish pemphigoid from linear IgA disease and epidermolysis bullosa acquisita
    • Detection of IgG antibodies to both BP180 and BP230 antigens increases sensitivity and specificity in diagnosing pemphigoid
  • Serum epithelial skin antibodies demonstrate epidermal or combined epidermal and dermal localization on BMZ-split human skin

Histology

  • Skin biopsy
    • Microscopy – subepidermal blister with superficial dermal inflammation consisting of lymphocytes, histocytes, and eosinophils; eosinophils often prominent with blistering
    • Electromicroscopy – blister formation within lamina lucida of the BMZ
  • Perilesional skin biopsy – cutaneous direct immunofluorescence submitted in Michel’s (or Zeus) medium
    • Linear IgG BMZ and linear C3 staining in 90% or more
    • Linear IgA or IgM may also be present

Differential Diagnosis

Monitoring

  • Basement membrane zone (BMZ) antibodies and, particularly, IgG BP180 and BP230 antibody levels by ELISA
    • Antibodies to either or both BP180 and BP230 antigens may be increased, and IgG BP180 levels correlate more closely to clinical activity than do titers of BMZ antibodies
    • Some patients’ antibody profiles change over time with transition from IgG to IgA BMZ antibodies, from IgA to IgG, or both classes of antibodies may develop which can have implications for disease severity and treatment considerations
  • Levels of IgG antibodies to BP180 antigens may be useful in monitoring disease activity and response to therapy

Clinical Background

Pemphigoid is a chronic autoimmune blistering disease of the skin and mucous membranes.

Epidemiology

  • Incidence – 4-22/1,000,000
  • Age – onset is ≥60 years; rare in children
    • ≥70 years – incidence significantly increases
    • ≥90 years – relative risk is 300-fold higher than ≤60 years
  • Sex – M:F, equal

Pathophysiology

  • Subepithelial (subepidermal or submucosal) blister with or without inflammation (eosinophils are characteristic, but a cell-poor variant exists)
  • IgG and complement are found at the basement membrane zone (BMZ) in perilesional tissue; IgE BMZ antibodies are difficult to detect but are likely important in pathophysiology
  • Two major molecular structures in hemidesmosomes to which pemphigoid antibodies bind – termed BP180 (BP Ag2) for a 180 kD bullous pemphigoid antigen and BP230 (BP Ag1) for a 230 kD bullous pemphigoid antigen
    • IgG antibodies to one or both target antigens commonly present (other BMZ antigens may be targets as well)
      • BP180 is a transmembrane component of the BMZ with collagen-like domains
      • BP230 is an intracellular hemidesmosomal plaque protein
  • Mucous membrane pemphigoid variant has antibodies to other BMZ components, including laminin-332 (previously known as laminin-5 and epiligrin), laminin-311 (previously known as laminin-6), and beta 4 integrin subunit
    • Pemphigoid with laminin-332 antibodies is associated with internal malignancy
  • Association with HLA genotype DOB1*0301 in Caucasians and DRB1*04, DRB1*1101, and DOB1*0302 in Japanese

Clinical Presentation

  • Flexural distribution (predominantly) of tense bullae with clear fluids or erosions on erythematous and/or urticarial base, or on normal appearing skin
  • Mucosal involvement occurs in 10-40% of cases
  • Pruritus is common
  • Involvement of ocular conjunctivae may lead to scarring and blindness in mucous membrane (ocular cicatricial) pemphigoid
  • Scarring alopecia may occur in mucous membrane (cicatricial) pemphigoid
    • On scalp, known as Brunsting-Perry pemphigoid
  • Variants include the following
    • Acral blisters in infants and vulvar lesions in prepubertal girls
    • Childhood pemphigoid
    • Drug-induced pemphigoid
    • Dyshidrosiform pemphigoid resembling dyshidrotic eczema
    • Eczematous pemphigoid
    • Erythrodermic pemphigoid
    • Lichen planus pemphigoides
    • Localized pemphigoid, pretibial pemphigoid
    • Mucous membrane pemphigoid (previously referred to as cicatricial pemphigoid)
    • Noninflammatory pemphigoid
    • Pemphigoid nodularis or nodular pemphigoid resembling prurigo nodularis
    • Urticarial pemphigoid resembling chronic urticaria
    • Vesicular pemphigoid, dermatitis herpetiformis-like

Treatment

  • Prednisone, other immunosuppressives, and steroid-sparing agents such as azathioprine and mycophenolate

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 (C3) of complement and fibrinogen in skin or mucous membrane biopsy specimens (biopsy site is critical; see below) from patients suspected of having pemphigoid; perform this test with serum pemphigoid panel

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 (attached/intact epithelium or epidermis is needed)

Not possible to distinguish pemphigoid from epidermolysis bullosa acquisita by direct immunofluorescence (DIF); concurrent serum testing needed

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 distinguishing pemphigoid from other subepithelial immunobullous disease, 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 & 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

Use to monitor disease activity and therapeutic response

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

See Immunobullous Skin Diseases Testing algorithm

Clinical correlation 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 Bullous Pemphigoid (180 kDa and 230 kDa) Antigens, IgG to monitor pemphigoid disease activity and response to therapy

Repeat pemphigoid panel for indeterminate results and/or continuing clinical consideration of the 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 IgG or IgA BMZ antibodies that characterize subepidermal immunobullous diseases other than dermatitis herpetiformis

  
Epithelial Skin Antibody 0090299
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Panel includes epithelial 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 pemphigoid, linear IgA disease, epidermolysis bullosa acquisita, pemphigus, and dermatitis herpetiformis in patients suspected of having or known to have any type of subepidermal immunobullous disease

Does not include testing for antibodies to target pemphigoid antigens, BP180 and BP230; which may be more sensitive diagnostic markers in some cases and the levels correlate with disease activity

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
Epithelial Basement Membrane Zone IgG Antibodies 0092056
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

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

Use to establish or confirm diagnosis of pemphigoid or epidermolysis bullosa acquisita in patients suspected of having or known to have any type of disorder with IgG BMZ antibodies

Use to distinguish pemphigoid from epidermolysis bullosa acquisita

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

This test does NOT detect IgA BMZ antibodies; linear IgA disease and dermatitis herpetiformis will NOT be detected

IgG BP180 and BP230 antibody levels, which may increase sensitivity in diagnosing pemphigoid and are useful to establish baseline for monitoring disease activity and response to therapy, are NOT included in this test

Use epithelial basement membrane zone IgG antibodies test to follow patients with pemphigoid, particularly those with normal bullous pemphigoid (180 kDa and 230 kDa) antigens IgG antibody tests

Repeat epithelial basement membrane zone IgG antibodies test for indeterminate results and/or continuing clinical consideration of pemphigoid

See Immunobullous Skin Diseases Testing algorithm
Bullous Pemphigoid (180 kDa and 230 kDa) Antigens, IgG 0092566
Method: Enzyme-Linked Immunosorbent Assay

This test comprises components included in the pemphigoid panel and pemphigoid gestationis factor test

Use to test for IgG BP180 (BP Ag2) and BP230 (BP Ag1) antibodies in patients suspected of having or known to have any type of pemphigoid, including bullous pemphigoid and variant forms, mucous membrane (cicatricial) pemphigoid, and herpes gestationis

Use to measure relative levels of BP180 and BP230 IgG antibodies to support a diagnosis of pemphigoid and to monitor disease activity and therapeutic response

Use along with epithelial BMZ antibodies by IFA to identify patients with pemphigoid antibodies  to epitopes other than those in the assay

Negative, positive, and borderline/indeterminate results should be correlated and confirmed with IFA, either epithelial skin antibody test or epithelial BMZ, IgG test and indeterminate/borderline levels should be monitored

Patients with pemphigoid may show reactivity to multiple BMZ components; therefore, negative/normal IgG BP180 and BP230 antibody levels do not rule out pemphigoid or another subepidermal immunobullous disease

Up to 7% of individuals unaffected by pemphigoid (including those with other immunobullous diseases) have increased IgG BP 180 and/or IgG BP 230 antibody levels

These tests are components of pemphigoid panel; pemphigoid panel is optimal for initial diagnosis of pemphigoid and monitoring response to therapy; otherwise, concurrent testing is advised with one of the following

  • Epithelial BMZ IgG antibody test
  • Epithelial skin antibody test

Correlations with IFA (epithelial antibody test), DIF findings, and clinical presentation are important for initial diagnosis

Use bullous pemphigoid (180 kDa and 230 kDa) antigens IgG antibody tests  to follow disease activity in pemphigoid

Patients with pemphigoid may show antibody reactivity that changes over time; therefore, testing by both IFA for BMZ antibodies and BP 180 and BP 230 ELISAs with the pemphigoid panel is strongly recommended periodically to follow disease activity

See Immunobullous Skin Diseases Testing algorithm