Pemphigoid Gestationis - Gestational Pemphigoid

  • Diagnosis
  • Algorithms
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Content

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

  • 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

Immunobullous Skin Diseases Testing Algorithm

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

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

Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence
(Direct Fluorescent Antibody Stain)

Limitations

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

Follow Up

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

Limitations

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

Follow Up

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

Limitations

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

Follow Up

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

Limitations

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)

Follow Up

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)

Limitations

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

Follow Up

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)

Additional Tests Available

Bullous Pemphigoid Antigens (180 kDa and 230 kDa), IgG 0092566
Method: Enzyme-Linked Immunosorbent Assay

Comments

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

General References

Huilaja L, Mäkikallio K, Tasanen K. Gestational pemphigoid. Orphanet J Rare Dis. 2014; 9: 136. PubMed

Intong L, Murrell D. Pemphigoid gestationis: pathogenesis and clinical features. Dermatol Clin. 2011; 29(3): 447-52, ix. PubMed

Lipozenčić J, Ljubojevic S, Bukvić-Mokos Z. Pemphigoid gestationis. Clin Dermatol. 2012; 30(1): 51-5. PubMed

Roth M. Pregnancy dermatoses: diagnosis, management, and controversies. Am J Clin Dermatol. 2011; 12(1): 25-41. PubMed

Semkova K, Black M. Pemphigoid gestationis: current insights into pathogenesis and treatment. Eur J Obstet Gynecol Reprod Biol. 2009; 145(2): 138-44. PubMed

Medical Reviewers

Last Update: December 2015