Pemphigoid Gestationis 

Updated: Jun 02, 2017
Author: Victor A Teran; Chief Editor: William D James, MD 

Overview

Background

Pemphigoid gestationis (PG) is a rare autoimmune bullous dermatosis of pregnancy (see the image below). The disease was originally named herpes gestationis for the herpetiform morphology of the blisters, but this term is a misnomer because pemphigoid gestationis is not related to or associated with any active or prior herpes virus infection.

Tense bullae are present on the arms of this other Tense bullae are present on the arms of this otherwise healthy 32-year-old primigravida woman.

See Diagnosing Dermatoses in Pregnant Patients: 8 Cases to Test Your Skills, a Critical Images slideshow, for help identifying several types of cutaneous eruptions associated with pregnancy.

Pathophysiology

Pemphigoid gestationis is a pregnancy-associated autoimmune disease. Most patients develop antibodies against the hemidesmosomal protein BP180 (BPAG2, collagen XVII), and, in some cases, antibodies also form against another hemidesmosomal protein, BP230.[1] However, whereas the role of anti-BP180 is well defined in the pathogenesis of pemphigoid gestationis,[2] BP230 is intracellular and the clinical significance of anti-BP230 is uncertain.[3] Historically known as herpes gestationis factor, these circulating antibodies belong to the heat-stable immunoglobulin G1 subclass. The binding of immunoglobulin G to the basement membrane at the dermoepidermal junction triggers an immune response by neutrophils and eosinophils, leading to the formation of subepidermal vesicles and blisters. In 1999, Chimanovitch et al[4] 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.

The trigger for the development of autoantibodies in persons with pemphigoid gestationis remains elusive. Cross-reactivity between placental tissue and skin has been proposed to play a role. Pemphigoid gestationis has a strong association with HLA-DR3 (61%) and HLA-DR4 (52%), or both (43%),[5] and virtually all patients with a history of pemphigoid gestationis have demonstrable anti-HLA antibodies. 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 is that aberrantly expressed fetal major histocompatibility complex (MHC)–II on trophoblasts and amniochorionic stromal cells permits maternal detection of paternal MHC-II.[6] BP180 is expressed on both amniotic epithelial cells of the placenta and keratinocytes at the dermoepidermal junction.[7] 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.

Epidemiology

Frequency

United States

In the United States, pemphigoid gestationis has an estimated prevalence of 1 case in 50,000 pregnancies.[3]

International

Findings from European studies suggest that pemphigoid gestationis has an overall incidence of 0.5 cases per million people per year. In 1999, Jenkins et al[8] described the largest cohort of 87 patients in the United Kingdom with a total of 278 pregnancies, of which 142 were complicated by pemphigoid gestationis.

Race

Pemphigoid gestationis is less common among blacks than whites, which might reflect its association with specific HLA haplotypes.

Sex

This condition only affects females.

Age

Pemphigoid gestationis occurs in women of childbearing age.

Prognosis

Pemphigoid gestationis typically regresses without scarring within weeks to months after delivery. Pemphigoid gestationis may 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) babies is associated with pemphigoid gestationis. Of infants, 5-10% 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

Patient Education

Mothers with pemphigoid gestationis should be counseled regarding potential sequelae for their infant, such as 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.

 

Presentation

History

Pemphigoid gestationis typically manifests during late pregnancy, with an abrupt onset of extremely pruritic urticarial papules and blisters on the abdomen and trunk. Unrelenting pruritus often interferes with daily activities.

Lesions may appear any time during pregnancy, but they most commonly develop during the second and third trimesters.

Symptoms may abate at the end of pregnancy; however, dramatic flares can occur at or immediately after delivery. Pemphigoid gestationis usually resolves spontaneously within weeks to months after delivery and possibly quicker with breastfeeding. The persistence of disease activity for years postpartum has been reported.

Pemphigoid gestationis may recur with the resumption of menses, use of oral contraception, and subsequent pregnancies. The 1999 cohort study by Jenkins et al[8] showed no association between change in partner and development of pemphigoid gestationis in subsequent pregnancies.

Physical Examination

The initial clinical manifestations are erythematous urticarial patches and plaques, which are typically periumbilical; this is distinct from the presentation of pruritic urticarial papules and plaques of pregnancy, another dermatosis of pregnancy that spares the umbilicus.[9] These lesions progress to tense vesicles and blisters. However, some patients may present with urticarial plaques and may never develop blisters (see the images below). These hivelike plaques differ from true urticaria because of their relatively fixed nature. The rash spreads peripherally, often sparing the face, palms, and soles. Mucosal lesions occur in less than 20% of cases. Patients may have secondary infections at blister sites.

Tense bullae are present on the arms of this other Tense bullae are present on the arms of this otherwise healthy 32-year-old primigravida woman.
Urticarial or hivelike plaques, as seen on the pos Urticarial or hivelike plaques, as seen on the posterolateral neck of this woman in her third trimester, can be observed in patients with pemphigoid gestationis.
A close-up view of a blister reveals the tense pri A close-up view of a blister reveals the tense primary lesion filled with clear fluid.

Causes

Pemphigoid gestationis is a pregnancy-associated autoimmune disease. The autoantibodies are deposited in the skin and detectable in the circulation, and they are predominantly specific for the hemidesmosomal protein BPAG2.

Circulating antibodies and T cells are directed against an immunodominant epitope. This epitope, located in the extracellular region of BPAG2 near the membrane, is called the MCW-1 domain. This region of BPAG2 is also an immunodominant epitope in a closely related autoimmune blistering disease, bullous pemphigoid.

The trigger for autoantibody production is still poorly understood. As described in Pathophysiology, autoantibodies to amniotic basement membrane (paternal major histocompatibility class II antigens) may cross-react with BPAG2 antigen in the skin, leading to the immune response.

Pemphigoid gestationis has also been described to occur in association with trophoblastic tumors, such as hydatiform mole or choriocarcinoma.

Complications

Women with pemphigoid gestationis have increased incidences of premature delivery and SGA neonates. An increased lifetime risk of other autoimmune conditions, such as Graves disease, is documented.

Infants born to affected women rarely have transient blistering disease. These infants are at risk for infection, thermoregulatory difficulties, and fluid and electrolyte abnormalities.

 

DDx

Diagnostic Considerations

Pemphigoid gestationis shares common features with other dermatoses of pregnancy; these similarities make diagnosis more difficult. The criteria for diagnosis include a compatible clinical picture, the observation of a subepidermal blistering disease upon histopathologic evaluation, and a linear band of C3 at the epidermodermal junction detected with direct immunofluorescence (DIF) testing. An accurate diagnosis is important before therapy is initiated.

Differential Diagnoses

 

Workup

Laboratory Studies

Routine laboratory studies are not helpful in diagnosing pemphigoid gestationis. The results of most hematologic studies are within normal limits, although peripheral eosinophilia is seen in some cases.[10] Laboratory values that may be elevated include immunoglobulin levels, erythrocyte sedimentation rates, acute-phase reactant levels, and antithyroid antibodies.

The criteria for the diagnosis of pemphigoid gestationis include an appropriate clinical presentation, histologic findings of a subepidermal blistering process (as described below), and direct immunofluorescence (DIF) showing a linear band of C3 deposition with or without immunoglobulin G (present in 25-50% of patients[11] ) along the basement membrane. DIF is the key assay to differentiate pemphigoid gestationis (positive DIF) from pruritic urticarial papules and plaques of pregnancy (negative DIF). However, a similar pattern of DIF is observed in patients with pemphigoid gestationis, BP, and epidermolysis bullosa acquisita (EBA). DIF should be performed using samples from uninvolved perilesional skin.

Indirect immunofluorescence (IIF) testing of the patient's serum can be used to detect circulating immunoglobulin G1 antibodies for the basement membrane zone.[12] In 2004, Sitaru et al[13] demonstrated that immunoblotting and enzyme-linked immunosorbent assay testing are sensitive tools for the detection of autoantibodies to BP180 antigen in patients with pemphigoid gestationis and that enzyme-linked immunosorbent assay is useful to monitor autoantibody serum levels, which correlate to disease activity.

In 2013, Kwon et al[14] described an immunohistochemistry assay to detect C4d at the dermoepidermal junction in formalin-fixed, paraffin-embedded tissue. Visualization of C4d, an activation product of the classical complement pathway, at the dermoepidermal junction is specific for pemphigoid gestationis relative to other dermatoses of pregnancy, particularly pruritic urticarial papules and plaques of pregnancy. The advantage of this technique is that it allows for a single skin biopsy to serve the purposes of both histopathological examination and immunohistochemistry.

HLA-DR3/DR4 is present in 45% of patients with pemphigoid gestationis, as compared with 3% of the general population.

Histologic Findings

Biopsy samples from the edge of an early blister classically reveal a subepidermal blister with an eosinophil-predominant infiltrate. The inflammatory infiltrate is localized to the dermoepidermal junction and perivascular areas (see image below).

Upon histologic evaluation, an incipient blister i Upon histologic evaluation, an incipient blister is present at the junction of the epidermis and dermis, as is a moderately dense perivascular inflammatory infiltrate.

Keratinocyte necrosis and dermal edema are often present. These histologic features can also be observed in association with other autoimmune subepidermal blistering diseases, including BP and EBA (inflammatory type), cicatricial pemphigoid, and linear immunoglobulin A bullous dermatosis.

The salt-split technique demonstrates antibody deposition along the base of the epidermal fragment. IIF reveals a similar localization in patients with BP, whereas patients with EBA have circulating autoantibodies that bind to the blister floor.

 

Treatment

Medical Care

The goals of treatment are to relieve pruritus and to suppress extensive blister formation. To minimize the risk for the mother and fetus, use the lowest effective dose of medication to suppress disease activity. 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.

Consultations

A dermatologist and an obstetrician must coordinate care for patients with pemphigoid gestationis. The pediatrician also must be 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 is appropriate.

 

Medication

Medication Summary

Tepid baths, compresses, and emollients may help alleviate pruritus. Patients with mild disease can be treated with antihistamines and midpotency topical steroids, such as triamcinolone. However, these are usually ineffective in more severe cases, and systemic steroids remain the mainstay of therapy. Prednisone at 0.5 mg/kg/d is usually started, and the response to therapy is gauged by the abatement of pruritus and blister formation. Once blistering has ceased and lesions have begun to heal, the dose of prednisone is tapered to the minimum dose required to control the disease. Reported steroid-sparing agents used as the adjuvant therapy in the treatment of pemphigoid gestationis include azathioprine, dapsone, methotrexate, intravenous immunoglobulin, cyclosporine, pyridoxine, plasmapheresis, and minocycline/nicotinamide. Chemical oophorectomy with goserelin (a luteinizing hormone–releasing analog) also may hold promise.

Although there is a paucity of data regarding prophylaxis against recurrent pemphigoid gestationis, in a 2017 case report, Tourte et al[15] described the off-label use of rituximab to lower anti-BP180 titers and prevent clinical recurrence of pemphigoid gestationis.

The risks and benefits of each medication must be assessed for each patient before a therapeutic regimen is chosen. Patients should be made aware of the risks, adverse effects, contraindications, and drug interactions of their medications.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, they modify the body's immune response to diverse stimuli.

Triamcinolone (Aristocort)

Triamcinolone treats inflammatory dermatosis that is responsive to steroids. It decreases inflammation by suppressing the migration of PMN leukocytes and reversing capillary permeability.

Prednisone (Deltasone)

Prednisone is an immunosuppressant used for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. In patients with severe blistering in whom topical steroids fail to elicit a response, oral prednisone may be indicated.

Antihistamines

Class Summary

Antihistamines prevent histamine response in sensory nerve endings and blood vessels. They are more effective in preventing histamine response than in reversing it.

Diphenhydramine (Benadryl, Belix)

Diphenhydramine is used for symptomatic control of severe unremitting pruritus not controlled with previous therapeutic regimens. It should be administered orally rather than used topically, as topical diphenhydramine may cause allergic contact dermatitis.