Pemphigoid Gestationis

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.

Pemphigoid gestationis classically 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 most commonly develop during the second and third trimesters; however, they may appear any time during pregnancy. Dramatic flares often occur at or immediately after delivery, and may fully onset within hours. Symptoms usually abate by the end of pregnancy or resolve spontaneously within weeks to months after delivery, although the persistence of disease activity for years postpartum has been reported. In subsequent pregnancies, pemphigoid gestationis is very likely to recur and tends to present earlier and more intensely. Additionally, pemphigoid gestationis may recur with the resumption of menses or with the use of oral contraception.[2, 15, 16]

The initial clinical manifestation is erythematous, urticarial patches and plaques, classically located on the periumbilical abdomen. This is distinct from the presentation of polymorphic eruption of pregnancy (formerly called pruritic urticarial papules and plaques of pregnancy), which spares the umbilicus.  These hivelike plaques differ from true urticaria because of their relatively fixed nature. Lesions typically progress to clustered vesicles and tense bullae (see the images below), which may spread peripherally, sparing only the mucous membranes.[2, 13, 17]

Urticarial plaques, as shown in the image below, are typically the first dermatologic manifestation of pemphigoid gestationis.

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.

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

Routine serologic studies are not helpful in diagnosing pemphigoid gestationis, although peripheral eosinophilia may be seen in some cases.Laboratory values that may be non-specifically elevated include immunoglobulin levels, erythrocyte sedimentation rates, acute-phase reactant levels, and antithyroid antibodies.[17]

Immunoblotting and enzyme-linked immunosorbent assay (ELISA) testing are sensitive tools for the detection of autoantibodies to BP180 antigen in patients with pemphigoid gestationis. ELISA may have utility for monitoring autoantibody serum levels, which correlate to disease activity.[18]

Notably, HLA-DR3/DR4 is present in 45% of patients with pemphigoid gestationis, as compared with 3% of the general population.[8]

Histologic features vary with the clinical lesion present. In urticarial plaques, there is a predominantly perivascular infiltrate composed of lymphocytes, histiocytes, and eosinophils with marked papillary dermal edema (which may result in a “teardrop” appearance), with occasional spongiosis and basal keratinocyte necrosis. Vesicles and bullae of pemphigoid gestationis classically exhibit subepidermal blister formation with an eosinophilic infiltrate. The affected dermis contains a perivascular infiltrate composed of eosinophils, lymphocytes, histiocytes, and rare neutrophils.

Direct immunofluorescence (DIF) should be performed using samples from uninvolved perilesional skin and will show linear C3 along the basement membrane zone (essentially universally present) with linear IgG in 30-50% of patients. DIF is key to differentiate pemphigoid gestationis from polymorphic eruption of pregnancy, also known as pruritic urticarial papules and plaques of pregnancy (PUPPP).

Using the salt-split skin technique, indirect immunofluorescence (IIF) can be used to detect linear immunoglobulin G deposition along the epidermal side (roof), which is seen in approximately 30% of patients. Complement-added indirect immunofluorescence will detect circulating anti-basement membrane immunoglobulin G1 antibodies in the serum for virtually all patients with pemphigoid gestationis.[2, 19, 20]

Recently, immunohistochemical staining for C4d at the dermoepidermal junction on routine H&E tissue has been demonstrated to be sensitive and specific for PG, allowing a single skin biopsy to serve the purposes of both histopathological examination and immunohistochemistry.[21]

Treatment for pemphigoid gestationis is aimed at relieving pruritus and preventing the formation of new blisters. Initially, tepid baths, compresses, and emollients may help alleviate pruritus.

While there are no established guidelines for pemphigoid gestationis treatment, patients with mild disease can be treated with oral antihistamines and mid-potency topical corticosteroids, such as triamcinolone 0.1% cream or ointment. Short courses of topical steroids over limited body surface areas are generally considered safe to use during pregnancy and decrease inflammation by reversing capillary permeability and suppressing the migration of polymorphonuclear (PMN) leukocytes.[22]  Low to medium potency steroids are generally preferred to stronger ones. Antihistamines prevent histamine response in sensory nerve endings and blood vessels, decreasing pruritus. Of the first-generation histamines, diphenhydramine and chlorpheniramine are considered safe for use in pregnancy. Nonsedating, second-generation antihistamines that are safe to use during pregnancy include loratadine, cetirizine, and levocetirizine. In general, first-generation antihistamines are preferred over second-generation antihistamines due to the greater availability of safety data.

In more severe cases that are resistant to topical treatment or exceed 10% of body surface area, systemic corticosteroids may be needed. An initial regimen of 0.5 mg/kg/d of prednisone is typically used. Corticosteroids have anti-inflammatory properties, modify the body’s immune response to diverse stimuli, and can cause profound and varied metabolic effects. Prednisone is an immunosuppressant used to treat autoimmune disorders that may decrease inflammation by reversing capillary permeability, suppressing PMN activity, limiting antibody production, and stabilizing lysosomal membranes. Use of short courses of medium-dose prednisone is considered fairly safe during pregnancy, though increased risk of oral clefts have been reported when oral steroids are used in the first trimester. 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, and patients may or may not need to remain on a suppressive dose.

If patients are still unresponsive to treatment, steroid-sparing agents can be added as adjuvant therapy. The most commonly used steroid-sparing agents include intravenous immunoglobulin, azathioprine, dapsone, cyclosporine, and pyridoxine.[23, 24, 25, 26, 27]

Although there is a paucity of data regarding prophylaxis against recurrent pemphigoid gestationis, rituximab has been used to lower anti-BP180 titers and prevent clinical recurrence of pemphigoid gestationis.[28]

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.

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[28] 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.

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.

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.