Pemphigoid Gestationis - Gestational Pemphigoid

Pemphigoid gestationis (herpes gestationis) is a rare disease of pregnancy and puerperium. Biopsy and immunohistology are both used in the workup of the disease.

Diagnosis

Indications for Testing

Urticarial, blistering, and/or pruritic lesions during pregnancy

Laboratory Testing

  • Prompt, accurate diagnosis is essential for planning therapy to minimize morbidity and patient discomfort
  • Histopathology
    • Biopsy 
      • Subepidermal blister
      • Eosinophilic spongiosis
      • Dermal infiltrate of eosinophils and lymphocytes
    • Immunopathology
      • Perilesional skin biopsy for cutaneous direct immunofluorescence (DIF) – 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 (IIF) testing with fresh complement
        • Demonstrates C3 on epidermal side of human split skin substrate (herpes gestationis factor [HGF])
        • Highly sensitive and specific testing for pemphigoid gestationis
      • Serum testing by enzyme-linked immunosorbent assay (ELISA) for IgG antibodies to BP180 supplements testing by IIF
        • BP180 (BPAg2) has been identified as a major antigenic target
        • BP230 (BPAg1) is less commonly an antigenic target
      • Consider serum testing for celiac disease (CD) because positive CD serologies have been identified in a subset of patients with pemphigus gestationis

Differential Diagnosis

  • Polymorphic eruption of pregnancy (PEP) – also known as pruritic urticarial papules and plaques of pregnancy (PUPPP)
  • Atopic eruption of pregnancy – also known as prurigo gestationis (prurigo of pregnancy or PP) and pruritic folliculitis of pregnancy
  • Intrahepatic cholestasis of pregnancy
  • Viral exanthems (eg, varicella)
  • Urticaria
  • Scabies
  • Autoimmune skin disorders
  • Bullous or urticarial drug reaction
  • Contact dermatitis
  • Erythema multiforme
  • Impetigo herpetiformis
  • Bullous lupus erythematosus

Monitoring

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

Background

Epidemiology

  • Incidence (Huilaja, 2014)
    • 1/40,000-50,000 pregnancies
    • 1-2/million people
  • 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 (BPAg2) and, less commonly, IgG BP230 (BPAg1) antibodies present by enzyme-linked immunosorbent assay (ELISA)

Clinical Presentation

  • Typically presents in the second to third trimester
    • Often flares with labor
    • Resolves within several weeks to months after delivery
    • Chronic, severe disease is rare
  • 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

ARUP Laboratory Tests

Additional detail about the tests below can be found in the ARUP Immunobullous Disease Testing Comparison table.  

Use with serum immunobullous disease/epithelial antibody testing and formalin-fixed tissue histopathology for assessment of pruritic, urticarial, blistering, and/or erosive disorders

Use with formalin-fixed tissue histopathology for assessment of inflammatory, immune-mediated cutaneous disease

Optimal specimen location and complementary serum testing and/or histopathology examination vary according to disease type. Note that specimen location and transport medium/fixative are different for direct immunofluorescence testing and fixed-tissue histopathology

Use as the preferred panel to assess and monitor pemphigoid gestationis (herpes gestationis) or other immunobullous disease with complement-fixing BMZ antibodies

Testing should be correlated initially with concurrent DIF biopsy 

Consider other types of immunobullous disease serum testing concurrently 

 

Components: complement-fixing BMZ antibodies; BP180 antibody, IgG by ELISA; BMZ antibodies, IgG by IIF

Use as initial comprehensive testing panel to aid in the diagnosis of and distinguishing among skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria

Use for assessment of suspected epithelial antibody-associated immunobullous diseases, pemphigoid and pemphigus and their variants, that are not clinically distinguishable, have nonspecific features, potentially express overlapping epithelial antibodies, and/or are indicated by concurrent DIF biopsy

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA; collagen type VII antibodies, IgG by ELISA; cell surface antibodies, IgG by IIF; desmoglein 1 and 3 antibodies, IgG by ELISA; cell surface antibodies, IgA by IIF

Use as the preferred initial diagnostic panel for suspected BMZ antibody-associated skin and mucous membrane disorders that present with blistering, erosions, eczema, urticaria, pruritus, and/or mucositis

May be indicated by concurrent DIF biopsy

Alternatively, order the comprehensive Immunobullous Disease Antibody Panel for initial serum diagnostic assessment of epithelial antibody-associated diseases, pemphigoid, pemphigus, and their variants

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA; collagen type VII antibodies, IgG by ELISA 

Use to assess and monitor pemphigoid, pemphigoid variants, and linear IgA disease and to discriminate among the immunobullous diseases with epithelial BMZ antibodies

May be indicated by concurrent DIF biopsy; preferred initial diagnostic serum panel is Basement Membrane Zone Antibody Panel

 

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA

Use as the preferred serum antibody panel to assess and monitor IgG-variant pemphigus (includes pemphigus foliaceus and pemphigus vulgaris), which present with blistering and erosive disease affecting skin and mucous membranes

Testing should be correlated initially with concurrent DIF biopsy

 

Components: cell surface antibodies, IgG by IIF; desmoglein 1 and desmoglein 3 antibodies, IgG by ELISA

Use to monitor linear IgG and IgA BMZ antibody-associated diseases and IgG and IgA cell surface antibody-associated diseases in which antibody levels by ELISAs may not be increased and/or to assess for changing patterns of epithelial antibody expression

May be used as general initial serum test for immunobullous diseases; however, for more sensitive and specific serum testing with ELISAs for pemphigoid and EBA or for IgG variant pemphigus, refer to Basement Membrane Zone Antibody Panel or Pemphigus Antibody Panel, IgG

 

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; cell surface antibodies, IgG by IIF; cell surface antibodies, IgA by IIF

Use to assess and monitor IgG basement membrane zone antibodies in patients with pemphigoid, pemphigoid variants/subtypes, and epidermolysis bullosa acquisita (EBA), especially those with normal relevant IgG BP180, IgG BP230, and IgG type VII collagen antibody levels by ELISAs

Testing should be correlated with concurrent DIF biopsy

For initial pemphigoid or EBA diagnosis, a more comprehensive serum panel is preferred; refer to Immunobullous Disease Antibody Panel

 

Related Tests

Use to monitor disease in patients diagnosed with pemphigoid and increased IgG BP180 and/or BP230 antibody levels

For initial pemphigoid diagnosis that discriminates among immunobullous diseases and for assessment of disease progression/changes and intermittent monitoring, the Basement Membrane Zone Antibody Panel or Immunobullous Disease Antibody Panel is preferred

Use to assess for the subset of patients with pemphigoid gestationis who have celiac disease antibodies

Components: quantitative nephelometry for IgA with one or more reflexive tests that may include IIF for IgA endomysial antibodies; ELISAs for IgA and IgG antibodies to tissue transglutaminase and deamidated gliadin peptide (DGP)  

Use to assess and monitor DH; testing should be correlated initially with concurrent DIF biopsy

Because most patients with DH have associated CD, testing should be performed in conjunction with testing for CD

For initial diagnosis and assessment of disease progression/changes and to distinguish from other immunobullous diseases with epithelial antibodies, order concurrently with serum Immunobullous Disease Antibody Panel 

References

Additional Resources

Medical Experts

Contributor

Leiferman

Picture of Kristin M. Leiferman, MD

 

Co-Director, Immunodermatology Laboratory, Professor of Dermatology, and Adjunct Professor of Pathology, University of Utah
Medical Director, Immunodermatology, ARUP Laboratories