Pemphigoid Gestationis - Gestational Pemphigoid

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Contributor

Leiferman

Professor, Dermatology; Medical Director, Regulatory Compliance and the Immunodermatology Laboratory, University of Utah

Medical Director, Immunodermatology, ARUP Laboratories

Pemphigoid gestationis (herpes gestationis) is a rare autoimmune subepidermal blistering disorder that occurs during pregnancy or the puerperium. It is mediated by autoantibodies directed against BP180 (also known as BPAG2 or collagen XVII), a hemidesmosomal protein expressed in both the skin and placenta. Aberrant expression of major histocompatibility complex (MHC) class II molecules in the placenta is thought to expose this antigen to the maternal immune system, triggering an autoimmune response. These autoantibodies, along with complement activation, lead to damage at the basement membrane zone (BMZ) and separation at the dermal-epidermal junction, resulting in the characteristic blistering eruption. Clinically, patients typically present with a pruritic urticarial eruption that progresses to tense blisters. The disease has been associated with an increased risk of preterm delivery and fetal growth restriction, as well as other obstetric complications/adverse pregnancy outcomes, and coordinated prenatal monitoring with obstetrics is recommended. Diagnosis is based on clinical presentation, skin biopsies with histopathology and direct immunofluorescence (DIF), and serum testing.

Quick Answers for Clinicians

How does pemphigoid gestationis typically present?

Pemphigoid gestationis typically presents in the second to third trimester. It can present with variable skin lesions such as urticaria, vesicles, and tense blisters on the skin. Abdominal skin lesions are common and demonstrate a periumbilical distribution. Mucous membranes and the face are usually spared. Pruritus may be pronounced and prodromal. Clinical manifestations often flare with labor but tend to resolve within several weeks or months after delivery. Chronic, severe disease is rare.

What conditions should be considered in the differential diagnosis for pemphigoid gestationis?

Other pregnancy-associated dermatoses are important to consider in the differential diagnosis for pemphigoid gestationis, such as 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 and pruritic folliculitis of pregnancy), and intrahepatic cholestasis of pregnancy. These disorders may be difficult to distinguish symptomatically and histopathologically in the early stages. The Pregnancy Dermatoses Clinical Scoring System can be helpful in distinguishing pemphigoid gestationis from PEP/PUPPP, as these conditions share clinical and histopathological features. Additional differential diagnostic considerations include urticaria, scabies, impetigo, autoimmune skin disorders (e.g., bullous pemphigoid, linear IgA disease, dermatitis herpetiformis), bullous or urticarial drug reaction, contact dermatitis, and erythema multiforme.

What are risk factors for pemphigoid gestationis?

Risk factors for pemphigoid gestationis include a history of pemphigoid gestationis in a previous pregnancy and specific maternal human leukocyte antigen (HLA) associations, particularly HLA-DR3, HLA-DR4, or the combination of DRB1*0301 and DRB1*0401/040X. Additional genetic predispositions include a C4 null allele in the mother and increased frequency of paternal HLA-DR2.^, Pemphigoid gestationis is more common in African American individuals and those with thyroid disease.

Indications for Testing

Laboratory testing for pemphigoid gestationis is indicated in the presence of urticarial, blistering, and/or pruritic lesions during pregnancy.

Laboratory Testing

Laboratory evaluation plays a central role in confirming the diagnosis of pemphigoid gestationis, as prompt and accurate identification is essential for planning therapy and minimizing morbidity and patient discomfort.

Histopathologic features depend on the disease phase and severity and range from nonspecific to characteristic. Eosinophilic spongiosis with dense superficial dermal eosinophils at the dermal-epidermal junction are consistent with pemphigoid gestationis. Papillary edema and mixed inflammatory cell infiltration, often eosinophil predominant, are found in prebullous lesions. Subepidermal blistering is usually observed in the bullous stage. The histopathological findings can be observed in other dermatoses.

Immunopathologic studies are needed to confirm the diagnosis of pemphigoid gestationis. A perilesional skin biopsy for cutaneous DIF is highly sensitive and specific and typically shows characteristic linear C3 BMZ localization with or without linear immunoglobulin G (IgG) BMZ reactivity. DIF is the testing standard for diagnosis of pemphigoid gestationis. However, serum testing by indirect immunofluorescence (IIF) can also be informative; using fresh complement and human split-skin substrate, complement-fixing BMZ antibodies (historically termed herpes gestationis factor [HGF]) localize C3 to the epidermal side and demonstrate high sensitivity and specificity for the disease. In contrast, conventional IgG BMZ antibody detection by IIF is less sensitive, with positivity in only about 25% of patients. Serum testing by enzyme-linked immunosorbent assay (ELISA) for IgG antibodies to BP180 has high sensitivity and specificity, noting that BP180 (BPAG2 or collagen XVII) is the major antigenic target for the IgG1 and IgG3 subclass autoantibodies that develop in the disease. Serum testing for celiac disease also may be considered, as positive celiac serologies have been identified in a subset of patients with pemphigoid gestationis.

Monitoring

Increased IgG BP180 antibody levels in the first trimester of pregnancy precede pemphigoid gestationis and may remain increased for a long time after remission/resolution of clinical disease. Moreover, IgG BP180 antibody levels at the time of diagnosis correlate with adverse pregnancy outcomes in pemphigoid gestationis, particularly when combined with blistering. Therefore, antibody levels are helpful but may lag behind clinical response and may not reflect disease activity.