Pemphigoid Gestationis - Gestational Pemphigoid

Diagnosis

Indications for Testing

  • Urticarial, blistering, and/or pruritic lesions during pregnancy
  • Prompt, accurate diagnosis is essential for planning therapy to minimize morbidity and patient discomfort

Laboratory Testing

  • Histology
    • Biopsy 
      • Subepidermal blister
      • Eosinophilic spongiosis
      • Dermal infiltrate of eosinophils and lymphocytes
    • Immunohistology
      • Perilesional skin biopsy for cutaneous direct immunofluorescence
        • Characteristic pattern shows linear C3 basement membrane zone (BMZ) staining with or without linear IgG BMZ staining
      • Serum testing for complement-fixing IgG BMZ antibodies by indirect immunofluorescence (IFA) with fresh complement demonstrates C3 on the epidermal side of human split skin substrate (herpes gestationis factor or HGF)
        • Highly sensitive and specific testing for pemphigoid gestationis
      • Testing by ELISA for IgG antibodies to BP180 supplements testing by IFA
        • BP180 (BP Ag2) has been identified as a major antigenic target
        • BP230 (BP Ag1) is less commonly an antigenic target

Differential Diagnosis

Monitoring

  • Antibody levels may be helpful but may lag behind clinical response and may not reflect disease activity

Clinical Background

Pemphigoid gestationis (herpes gestationis) is a rare disease of pregnancy and puerperium.

Epidemiology

  • Incidence – 1/40,000-50,000 pregnancies; 1-2/1,000,000 people (Huilaja, 2014)
  • Age – onset in childbearing years
  • Sex – exclusively females
  • Ethnicity – no racial distribution

Risk Factors

  • Previous pregnancy with pemphigoid gestationis
  • HLA-DR3, HLA-DR4 or both
    • DRB1*0301 and DRB1*0401/040X
  • C4 null allele
  • Increased HLA-DR2 in father

Pathology and Immunopathology

  • Subepidermal blistering process
  • Linear C3 at the basement membrane zone (BMZ) on direct immunofluorescence of perilesional tissue in all cases; also linear IgG in 25-30%
  • Complement fixing IgG BMZ serum antibodies (herpes gestationis factor, HGF) – 50% of patients show epidermal localization on split skin substrate
  • IgG BP180 (BP Ag2) and, less commonly, IgG BP230 (BP Ag1) antibodies present by ELISA

Clinical Presentation

  • Typically presents in the second to third trimester
    • Often flares with labor
    • Resolves within several weeks to months after delivery
    • Rarely – chronic, severe disease
  • Variable skin lesions ranging from urticaria to vesicles to tense blisters on skin
    • Abdominal lesions common; usually begins with periumbilical lesions
    • Usually spares mucous membranes, face
    • Pronounced pruritus
  • Recurrence
    • Likely in subsequent pregnancies – earlier and greater severity
    • May also recur with
      • Menstrual cycles
      • Hormonal medications (oral contraception)
  • Infants of affected mothers
    • Increased risk of preterm birth
    • Intrauterine growth retardation
    • ~10% of infants have lesions from passive transfer of transplacental antibodies
      • Mild disease – urticarial and/or vesicular skin lesions
      • Usually resolves spontaneously within days or weeks
    • Blisters in small percentage of infants
  • May develop or recur in gestational trophoblastic disease
    • Molar pregnancy (hydatidiform mole)
    • Choriocarcinoma
  • Autoimmune-associated diseases

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)

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

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 reliably distinguish pemphigoid from epidermolysis bullosa acquisita or to distinguish pemphigus subtypes based on 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

Monitor herpes gestationis factor, including IgG BP180 antibody levels in serum

Herpes Gestationis Factor (Complement-Fixing Basement Membrane Zone Antibody IgG) 0092283
Method: Quantitative Indirect Immunofluorescence

Assess and monitor patient with possible pemphigoid gestationis (herpes gestationis); consider other types of immunobullous disease testing, (eg, IgA epithelial BMZ, IgG collagen type VII, and/or pemphigus antibody panel)

Use along with perilesional skin biopsy for DIF to diagnose pemphigoid (herpes) gestationis

Use to follow persistent or recurrent disease activity with antibody titers

See Immunobullous Skin Diseases Testing algorithm

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

Use herpes gestationis factor test to monitor disease, including IgG BP180 antibody levels; use relevant tests to monitor other immunobullous disease activity
Pemphigoid Antibody Panel - Epithelial Basement Membrane Zone Antibodies, IgG and IgA, BP180 and BP230 Antibodies, IgG 0092001
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Preferred antibody panel for initial diagnostic assessment and disease monitoring in pemphigoid, epidermolysis bullosa acquisita, and linear IgA bullous dermatosis

Panel components include IgG and IgA epithelial BMZ antibodies and IgG bullous pemphigoid BP180 & 230 antigens

To order individual component tests, refer to antibody testing for IgG BMZ, IgA BMZ, and/or IgG bullous pemphigoid BP 180 & 230 antigens

To screen for pemphigoid along with other possible immunobullous diseases, order concurrently with the pemphigus antibody panel  IgG collagen type VII antibody, AND perilesional skin biopsy for DIF

Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity (85-100% of pemphigus, pemphigoid, linear IgA disease, epidermolysis bullosa acquisita, and dermatitis herpetiformis 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 to monitor pemphigoid disease activity; use relevant tests to monitor other immunobullous disease activity

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

Pemphigus Antibody Panel - Epithelial Cell Surface Antibodies and Desmoglein 1 and Desmoglein 3 Antibodies, IgG 0090650
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Preferred panel for initial assessment and disease monitoring in IgG-variant pemphigus

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

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 DIF

Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity (85-100% of pemphigus, pemphigoid, linear IgA disease, epidermolysis bullosa acquisita, and dermatitis herpetiformis cases are positive)

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)

Use pemphigus panel to monitor pemphigus disease activity; use relevant tests to monitor other immunobullous disease activity

Repeat pemphigus panel for indeterminate results and/or continuing clinical consideration of immunobullous disease

Epithelial Skin Antibody 0090299
Method: 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 & 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

See Immunobullous Skin Diseases Testing algorithm

Does not include testing for antibodies to target pemphigoid antigens, BP180 and BP230, or to target pemphigus antigens desmoglein 1 and 3 which may be more sensitive diagnostic markers in some cases (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 Antibody IgG 0092056
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Monitor disease in patient with pemphigoid or epidermolysis bullosa acquisita who has positive IgG BMZ antibodies by indirect immunofluorescence, either epidermal (roof) pattern or dermal (floor) pattern, on split skin substrate

Consider ordering concurrently with IgG antibody testing for bullous pemphigoid (BP180 & 230) antigens and/or collagen type VII

May use to screen for pemphigoid and other immunobullous diseases; however, this test has decreased sensitivity and specificity when compared to the panel tests for pemphigus antibodies or pemphigoid antibodies and will not detect IgA BMZ antibodies

See Immunobullous Skin Diseases Testing algorithm

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Bullous Pemphigoid Antigens (180 kDa and 230 kDa), IgG 0092566
Method: Enzyme-Linked Immunosorbent Assay

Monitor disease in patient previously diagnosed with pemphigoid and increased antibodies for IgG BP180 and/or BP230; IgG BP180 antibody levels correlate with disease activity

For initial diagnosis and assessment of disease progression or changes, the preferred test is the pemphigoid antibody panel; panel components include IgG and IgA epithelial BMZ antibodies and IgG bullous pemphigoid (BP180 and 230) antigens

To determine the involvement of IgG BMZ antibodies and pattern of reactivity on split skin substrate, order with antibody testing for IgG epithelial BMZ; also, consider other types of BMZ antibody-associated disease testing, (ie, IgA epithelial BMZ, IgG collagen type VII, or herpes gestationis factor