Pemphigoid Gestationis - Herpes Gestationis

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 zones (BMZ) staining with or without linear IgG1 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)
Viral exanthems (eg, varicella)
Pemphigus vulgaris
Bullous pemphigoid
Linear IgA disease
Bullous or urticarial drug reaction
Dermatitis herpetiformis
Atopic eruption of pregnancy also known as prurigo gestationis (prurigo of pregnancy or PP) and pruritic folliculitis of pregnancy
Epidermolysis bullosa acquisita
Urticaria
Scabies
Contact dermatitis
Intrahepatic cholestasis of pregnancy
Erythema multiforme
Impetigo herpetiformis
Bullous lupus erythematosus

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

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

Epidemiology

Incidence – 1/50,000 pregnancies
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
- Have 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
- Systemic steroids when blisters are widespread
  - Typically responsive to oral (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 (IvIG) may be considered in severe disease
- Must be administered in cooperation with obstetrician because of potential maternal-fetal effects

Tests generally appear in the order most useful for common clinical situations

Test name: Cutaneous Direct Immunofluorescence, Biopsy

ARUP #: 0092572

Methodology: Direct Immunofluorescence
(Direct Fluorescent Antibody Stain)

Use:

Determine presence and staining pattern of immunoglobulins (IgG, IgM, IgA), third component of complement (C3) and fibrinogen in perilesional skin or mucosal biopsy specimens from patients suspected of having pemphigus; perform this test with serum pemphigus panel

Limitations:

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

Not possible to reliably distinguish pemphigus subtypes based on direct immunofluorescence (DIF); serum testing helpful for subtyping

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 BP 180 antibody levels in serum

Test name: Herpes Gestationis Factor (IgG Complement-Fixing Basement Membrane Zone Antibodies)

ARUP #: 0092283

Methodology: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Use:

Order for patients suspected of having or known to have any type of pregnancy-related skin eruption (blisters) to:

▪ Diagnose pemphigoid (herpes) gestationis
▪ Distinguish pruritic dermatoses of pregnancy
▪ Monitor disease activity

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

Limitations:

Perilesional skin biopsy evaluated by DIF is standard of diagnosis (>90% of cases are positive for C3 basement membrane zone staining); positive serum herpes gestationis factor in up to 50% of patients, increased IgG BP180 antibodies in at least 50%; antibody levels may lag behind clinical activity

Because of overlap among immunobullous diseases with similar names, testing for pemphigoid (herpes) gestationis may be confused with testing for other immunobullous diseases and misordered; the pemphigoid group is often confused with the pemphigus group

Follow-up:

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

Test name: Pemphigoid Panel - Epithelial Basement Membrane Zone IgG & IgA, BP180 & BP230 IgG Antibodies

ARUP #: 0092001

Methodology: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Use:

Supplements ELISA BP180 testing

Limitations:

Not as sensitive as herpes gestationis factor

Follow-up:

Monitor herpes gestationis factor with IgG BP180 antibody levels