A 33-year-old Hispanic woman who was 5 months pregnant came to the hospital complaining of nausea and vomiting. She had a history of anticardiolipin antibody syndrome, diagnosed originally in 1993 after 2 spontaneous abortions. She had stopped taking warfarin (Coumadin) at the start of her pregnancy, and had been taking heparin for 3 months.
After 4 days of close monitoring, the patient had labor induced for severe life-threatening preeclampsia. One day after induction and delivery of a still-born fetus, she began to develop painful swelling of both hands and feet along with targetoid, urticarial, edematous, deep pink, slightly dusky papules and plaques on her hands, abdomen, lower extremities, and proximal thighs. Some of the edematous sites began to form vesicles and bullae (FIGURES 1 AND 2). When asked about this eruption, the patient mentioned having a similar rash after delivery of one of her children about 10 years before.
Interestingly, she noted that she only experienced these cutaneous findings during pregnancies with her second husband and not with her first. Biopsies were performed and showed prominent eosinophils in the dermis and a subepidermal vesicle.
FIGURE 1 Blisters on wrist…
Vesicles and bullae on the wrist after miscarriage.
FIGURE 2 …and abdomen
Similar bulla in the umbilicus.
What is your diagnosis?
Dx: Pemphigoid gestationis
The patient had pemphigoid gestationis, also known as herpes gestationis, a rare autoimmune bullous disease of pregnancy and the puerperium.1 Clinically and immunopathologically, pemphigoid gestationis is related to the pemphigoid disorders and is not virally mediated.2
In the United States, pemphigoid gestationis has an incidence of 1:10,000 to 1:50,000 pregnancies.3 Clinically, it manifests during the second or third trimester, with a sudden onset of extremely pruritic urticarial papules and plaques usually located around the umbilicus. These lesions often progress to tense vesicles and blisters and spread peripherally to the trunk, often sparing the face, palms, and soles.4 Worsening of the lesions at the time of delivery occurs in 75% of cases, and usually recurs with subsequent pregnancies.5 Occasionally, however, subsequent pregnancies are unaffected, so-called “skip pregnancies.”6 This occurs most often when there has been a change in paternity.7
The exact cause of pemphigoid gestationis is unknown. Investigative efforts led to the identification of an immunoglobulin G (IgG) autoantibody, which binds to bullous pemphigoid (BP) antigen 2, also called BP180, which is a protein associated with hemidesmosomes of basal keratinocytes.8-10 These hemidesmosomes form the central portion of the dermal–epidermal anchoring complex, whose function is to establish a connection between the basal keratinocytes and the upper dermis.11,12 This is critical for maintaining dermal–epidermal adhesion. It is hypothesized that binding of autoantibodies to BP180 initiates an inflammatory reaction, leading to blister formation at the dermal–epidermal junction.13
Histopathologic findings demonstrate subepidermal vesicles, spongiosis, and perivascular infiltrates of lymphocytes and histiocytes with a preponderance of eosinophils.3 The sine qua non of the disease, though, is demonstration through direct immunofluorescence of complement deposition and IgG in a linear band along the basement membrane.14
There appears to be a genetic predisposition toward the development of pemphigoid gestationis. Associations with human leukocyte antigens (HLAs) DR3 (61%–85%), DR4 (52%), or both (43%–50%) have been reported.3,15,16 Interestingly, 85% of persons with a history of pemphigoid gestationis were found to have anti-HLA antibodies, some of which were directed against paternal HLAs expressed in their placentae.17 These findings raised speculation about a possible immunologic insult against placental antigens during pregnancy. Evidence suggests that circulating auto-antibodies in patients with pemphigoid gestationis bind to the dermal–epidermal junction of skin and amnion in which BP180 antigen is also present.18-20
It has been demonstrated that in patients with pemphigoid gestationis the cells of the placenta stroma express abnormal major histocompatibility complex (MHC) class II molecules.21,22 This led to the proposition of 2 possible mechanisms for the initiation of an autoimmune response in pemphigoid gestationis. The first proposes that placental BP180 is presented to the maternal immune system in association with abnormal MHC molecules, which then trigger the production of autoantibodies that cross-react with the skin. Alternatively, the placental stromal cells may evoke an allogeneic reaction against the BP180 antigen presented by paternal MHC molecules of the placental stroma, which then cross-reacts with the skin.23 The latter theory supports the findings in this patient, who developed pemphigoid gestationis during the 2 pregnancies with her second husband and not during the pregnancies with her first husband.