Pemphigoid Gestationis - Herpes Gestationis

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 – 1/50,000 pregnancies; 2 per million population
  • Age – onset in childbearing years
  • Sex – exclusively females

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 (2/3 of patients)
    • 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
    • In subsequent pregnancies – earlier and with greater severity
    • May also recur with
      • Menstrual cycles
      • Hormonal medications (oral contraception)
  • Infants of affected mothers
    • Increased risk of prematurity
    • May be small for gestational age
    • ~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
  • May develop or recur in gestational trophoblastic disease
    • Molar pregnancy (hydatidiform mole)
    • Choriocarcinoma
  • Autoimmune-associated diseases

Treatment

  • Glucocorticoids
    • Topical steroids in early stages and in limited disease
    • Systemic steroids when blisters are widespread
      • Typically responsive to oral medication (prednisone, 0.5-1 mg/kg/day); higher oral doses or intravenous glucocorticoids administered with obstetrician approval
  • Multiple other therapies from antihistamines to immunosuppressives to intravenous immunoglobulin may be considered in severe disease
    • Must be administered in cooperation with obstetrician because of potential maternal-fetal effects

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

For skin involvement, biopsy perilesional skin

For mucous membrane involvement, biopsy nonlesional mucosa

May be inaccurate if tissue not taken from correct perilesional location (attached/intact epithelium or epidermis is needed)

Concurrent serum testing helpful to characterize epithelial antibody profile

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

Test includes complement-fixing basement membrane zone antibodies, IgG basement membrane zone antibodies, and IgG BP180 antibody level

Use for  patients suspected of having or known to have any type of pregnancy-related skin eruption (blisters) to diagnose pemphigoid (herpes) gestationis and to monitor disease activity

Use to diagnose pemphigoid (herpes) gestationis and to discriminate it from other pruritic dermatoses of pregnancy

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

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

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

Although pemphigoid gestationis is considered in the pemphigoid group of subepithelial immunobullous diseases and components of the pemphigoid panel are part of the herpes gestationis test, the pemphigoid panel is not as sensitive as pemphigoid (herpes) gestationis factor for the diagnosis of pemphigoid gestationis

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

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

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

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

    
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 basement membrane zone antibodies

Use to distinguish pemphigoid from epidermolysis bullosa acquisita

    
Additional Tests Available
 
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
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 tests

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