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.

Quick Answers for Clinicians

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
  • 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 fluorescent antibody (IFA) 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
      • Testing by enzyme-linked immunosorbent assay (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

  • 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 (BP Ag2) and, less commonly, IgG BP230 (BP Ag1) 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 Lab Tests

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

Refer to Immunobullous Skin Diseases Testing algorithm

Tissue must be submitted in Michel’s or Zeus medium; this test cannot be performed on formalin-fixed tissue

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)

Refer to Immunobullous Skin Diseases Testing algorithm

Initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria, including pemphigoid, pemphigoid variants, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, linear IgA disease variants, and IgG-pemphigus subtypes

Order concurrently with perilesional skin biopsy for direct immunofluorescence for initial diagnosis

Use for disease monitoring with semiquantitative antibody level assessments and tracking and for persistent unexplained disease and/or worsening disease activity

Initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria from suspected basement membrane zone antibody-associated disease (eg, bullous pemphigoid, pemphigoid variants, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, and linear IgA disease variants)

Order concurrently with perilesional skin biopsy for direct immunofluorescence for initial diagnosis

Use for disease monitoring with semiquantitative antibody assessments and tracking

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 and 230 antigens

To order individual component tests, refer to antibody testing for IgG BMZ, IgA BMZ, and/or IgG bullous pemphigoid BP180 and 230 antigens

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

Refer to Immunobullous Skin Diseases Testing algorithm

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

Refer to Immunobullous Skin Diseases Testing algorithm

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 and 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

Refer to Immunobullous Skin Diseases Testing algorithm

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 and 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 panel tests for pemphigus antibodies or pemphigoid antibodies and will not detect IgA BMZ antibodies

Refer to Immunobullous Skin Diseases Testing algorithm

Related Tests

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, preferred test is pemphigoid antibody panel; panel components include IgG and IgA epithelial basement membrane zone (BMZ) antibodies and IgG bullous pemphigoid (BP180 and 230) antigens

To determine 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)

Medical Experts

Contributor

Leiferman

 

Co-Director, Immunodermatology Laboratory, Professor of Dermatology, University of Utah

Consultant, Immunodermatology at ARUP Laboratories

References

Additional Resources