Pemphigoid Gestationis: Practice Essentials, Pathophysiology, Epidemiology

Pemphigoid gestationis (PG) is a rare autoimmune bullous dermatosis of pregnancy. The original name “herpes gestationis” (for the herpetiform morphology of the blisters) is a misnomer because pemphigoid gestationis is not associated with herpes virus infection.

Causes

Pemphigoid gestationis is a pregnancy-associated autoimmune disease. Autoantibodies to the hemidesmosomal protein BPAG2 deposit in the skin and cause C3 deposition along the dermal-epidermal junction. Circulating antibodies and T cells are directed against an epitope located in the extracellular region of BPAG2 near the membrane, called the MCW-1 domain. This region of BPAG2 is also an immunodominant epitope in bullous pemphigoid, a closely related autoimmune blistering disease.

The trigger for autoantibody production is poorly understood. As described in Pathophysiology, autoantibodies to amniotic basement membrane may cross-react with BPAG2 antigen in the skin, leading to an immune response. Pemphigoid gestationis has also been described in association with trophoblastic tumors, such as hydatiform mole or choriocarcinoma, and in women with egg-donated pregnancies. ^{[1, 2]}

Complications

Women with pemphigoid gestationis have increased incidences of premature delivery and small-for-gestational age (SGA) neonates. Their lifetime risk of other autoimmune conditions, especially Graves disease, is increased.

Up to 10% of infants born to affected women have transient blisters. These infants are at risk for infection, thermoregulatory difficulties, and fluid and electrolyte abnormalities. At least one report details a neonate with pemphigoid gestationis born to an asymptomatic mother without PG. ^[3]

Treatment

Pemphigoid gestationis is a self-limited disease and the primary goal of treatment is symptom management. Topical and systemic corticosteroids are the mainstay of therapy. To minimize the risk for the mother and fetus, the lowest effective doses of medications are used. Even with optimum control, some blisters may continue to develop, and patients may have persistent pruritus. The risks and benefits of therapy must always be evaluated for the mother and the fetus.

Also see Medical Care and Medication Summary.

Consultations

Both a dermatologist and an obstetrician should be involved in caring for patients with pemphigoid gestationis. The pediatrician should also be made aware of the diagnosis and the medications the mother is receiving. Because pemphigoid gestationis is an uncommon disease, referral to immunodermatologists with expertise in the treatment of patients with severe or persistent disease may be appropriate.

Pemphigoid gestationis is a pregnancy-associated autoimmune disease. Most patients develop antibodies against the hemidesmosomal protein BP180, also known as BPAG2 or collagen XVII. However, in some cases, antibodies also form against another hemidesmosomal protein, BP230. ^[4]  The role of anti-BP180 is well defined in the pathogenesis of pemphigoid gestationis, though the clinical significance of anti-BP230 is uncertain. ^{[5, 6]}  Historically known as herpes gestationis factor, these circulating antibodies belong to the complement-fixing immunoglobulin G1 subclass. The binding of immunoglobulin G to the basement membrane results in C3 deposition at the dermo-epidermal junction and triggers an immune response by neutrophils and eosinophils, leading to the formation of subepidermal vesicles and blisters. In 1999, Chimanovitch et al. demonstrated that pemphigoid gestationis sera recognize five distinct epitopes within BP180 NC16A, four of which have been reported as major antigenic sites targeted by bullous pemphigoid antibodies. ^[7]

The trigger for the development of autoantibodies in persons with pemphigoid gestationis remains elusive. Cross-reactivity between placental tissue and skin may play a role. Pemphigoid gestationis has a strong association with HLA-DR3 (61%), HLA-DR4 (52%), or both (43%), and virtually all patients with a history of pemphigoid gestationis have anti-HLA antibodies. ^[8]  The placenta is known to be the main source of disparate (paternal) antigens and can thus present an immunologic target during gestation. One possible mechanism for autoantibody generation may be aberrant expression of fetal major histocompatibility complex (MHC)–II on trophoblasts and amniochorionic stromal cells permits maternal detection of paternal MHC-II. ^[9]  BP180 is expressed on both amniotic epithelial cells of the placenta and keratinocytes at the dermoepidermal junction. Thus, BP180 may be presented to maternal MHC-II in the presence of paternal MHC-II and recognized as a foreign antigen, leading to the formation of antibodies that are cross-reactive toward BP180 in the epidermis. ^[10]

In the United States, pemphigoid gestationis has an estimated prevalence of 1 case in 50,000 pregnancies. ^[6] Findings from European studies suggest that pemphigoid gestationis has an overall incidence of 0.5 cases per million people per year. ^[11]

Pemphigoid gestationis only affects pregnant individuals and is more common in multigravida pregnancies than primigravida. Additionally, it is less common among Blacks than Whites, which might reflect its association with specific HLA haplotypes. ^[12]

Pemphigoid gestationis is self-limited and typically regresses without scarring within weeks to months after delivery. It is likely to recur in subsequent pregnancies and may be precipitated by menses and the use of oral contraceptives.

Mortality/morbidity

No increase in fetal or maternal mortality has been demonstrated. A greater prevalence of premature and small-for-gestational-age (SGA) neonates is associated with pemphigoid gestationis. Five to 10 percent of infants born to affected mothers may present with transient cutaneous involvement that resolves as maternal autoantibodies are cleared.

Patients with pemphigoid gestationis have a higher relative prevalence of other autoimmune diseases, including Hashimoto thyroiditis, Graves disease, and pernicious anemia, which are also associated with HLA-DR3 and DR-4 haplotypes. ^{[2, 13, 14]}

Mothers with pemphigoid gestationis should be counseled regarding potential sequelae for their infant, such as small-for-gestational-age (SGA), prematurity, and transient blistering. Patients also should be aware that pemphigoid gestationis may recur with subsequent pregnancies, resumption of menses, and use of oral contraceptive agents.

The goals of therapy (ie, control pruritus, suppress extensive blistering but not totally eliminate blister formation) should be discussed with the patient prior to treatment. Patients should understand the benefits and potential adverse effects of all prescribed medications.