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Dermatology > BULLOUS DISEASES
Pemphigoid Gestationis
Article Last Updated: Jan 26, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Anatoli Freiman, MD, CM, Senior Resident, Division of Dermatology, University of Toronto, Toronto, Canada
Anatoli Freiman is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, Canadian Dermatology Association, Royal College of Physicians and Surgeons of Canada, and Women's Dermatologic Society
Coauthor(s):
Anju Pabby, MD, Consulting Staff, LK Dermatology and Laser Center
Editors: Russell Hall, MD, Chief, Professor, Department of Internal Medicine, Division of Dermatology, Duke University; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Julia R Nunley, MD, Professor, Program Director, Dermatology Residency, Department of Dermatology, Virginia Commonwealth University Medical Center; Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
herpes gestationis, PG, autoimmune dermatosis of pregnancy, pregnancy-associated autoimmune disease, bullous pemphigoid antigen 2, BPAG2, herpetiform blisters, herpes gestationis factor, pruritic urticarial papules, pruritic urticarial blisters
Background
Pemphigoid gestationis (PG) is a rare autoimmune bullous dermatosis of pregnancy. The disease was originally named herpes gestationis on the basis of the morphological herpetiform feature of the blisters, but this term is a misnomer because PG is not related to or associated with any active or prior herpes virus infection.
Pathophysiology
PG is a pregnancy-associated autoimmune disease. Most patients develop antibodies against 2 hemidesmosomal proteins, BP180 (BPAG2, collagen XVII) and less frequently BP230. 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 triggers an immune response, leading to the formation of subepidermal vesicles and blisters. In 1999, Chimanovitch et al1 demonstrated that PG sera recognize 5 distinct epitopes within BP180 NC16A, 4 of which have been reported as major antigenic sites targeted by bullous pemphigoid antibodies. The trigger for the development of autoantibodies in persons with PG remains elusive. Cross-reactivity between placental tissue and skin has been proposed to play a role. PG has a strong association with HLA-DR3 (61-80%) and HLA-DR4 (52%), or both (43-50%), and virtually all patients with a history of PG have demonstrable anti-HLA antibodies. The placenta is known to be the main source of disparate (paternal) antibodies and can thus present an immunologic target during gestation.
Frequency
United States
In the United States, PG has an estimated prevalence of 1 case in 50,000-60,000 pregnancies.
International
Findings from European studies suggest that PG has an overall incidence of 0.5 cases per million people per year. In 1999, Jenkins et al2 described the largest cohort of 87 patients in the United Kingdom with a total of 278 pregnancies, of which 142 were complicated by PG.
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 PG.
- 5-10% of infants born to affected mothers may present with transient cutaneous involvement that resolves as maternal autoantibodies are cleared.
- Patients with PG 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.
Race
PG is less common among blacks than whites, which might reflect its association with specific HLA haplotypes.
Sex
This condition only affects females.
Age
PG occurs in women of childbearing age.
History
- PG 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. PG 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.
- PG may recur with the resumption of menses, use of oral contraception, and subsequent pregnancies. The 1999 cohort study by Jenkins et al2 showed no association between change in partner and development of PG in subsequent pregnancies.
Physical
- The initial clinical manifestations are erythematous urticarial patches and plaques, which are typically periumbilical.
- These lesions progress to tense vesicles and blisters (see Media File 1 and Media File 4).
- Some patients may present with urticarial plaques and may never develop blisters (see Media File 2). 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.
Causes
PG 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, BP.
- 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.
- PG has also been described to occur in association with trophoblastic tumors, such as hydatiform mole or choriocarcinoma.
Bullous Pemphigoid
Cicatricial Pemphigoid
Linear IgA Dermatosis
Pruritic Urticarial Papules and Plaques of Pregnancy
Urticaria, Acute
Other Problems to be Considered
Allergic contact dermatitis
Dermatitis herpetiformis
Drug-induced bullous disorders
Erythema multiforme
Papular dermatitis of pregnancy
Prurigo gestationis of Besnier
Pruritic folliculitis of pregnancy
Lab Studies
- Routine laboratory studies are not helpful in diagnosing PG.
- The results with most hematologic studies are within normal limits, although peripheral eosinophilia is not uncommon and may correlate with disease severity.
- 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 PG include an appropriate clinical presentation, histologic findings of a subepidermal blistering process (as described below), and direct immunofluorescence (DIF) results that show a linear band of C3 deposition with or without immunoglobulin G (present in 20-25% of patients) along the basement membrane.
- The DIF test is the key assay to differentiate PG (positive DIF findings) from pruritic urticarial papules and plaques of pregnancy (negative DIF findings). However, a similar pattern of DIF results is observed in patients with PG, BP, and epidermolysis bullosa acquisita (EBA).
- DIF should be performed using samples from noninvolved perilesional skin.
- Indirect immunofluorescence (IDIF) testing of the patient's serum can be used to detect circulating antibodies for basement membrane zone. In 2004, Sitaru et al3 demonstrated that immunoblotting and enzyme-linked immunosorbent assay testing are sensitive tools for the detection of autoantibodies to BP180 antigen in patients with PG and that enzyme-linked immunosorbent assay is useful to monitor autoantibody serum levels.
- HLA-DR3/DR4 is present in 45% of patients with PG, as compared with 3% of the general population.
Histologic Findings
Biopsy samples from the edge of an early blister typically reveal a subepidermal blister with an eosinophil-predominant infiltrate. The inflammatory infiltrate is localized to the dermal-epidermal junction and perivascular areas (see Media File 3). 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. IDIF reveals a similar localization in patients with BP, whereas patients with EBA have circulating autoantibodies that bind to the blister floor.
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 PG.
- The pediatrician also must be aware of the diagnosis and the medications the mother is receiving.
- Because PG is an uncommon disease, referral to immunodermatologists with expertise in the treatment of patients with severe or persistent disease is appropriate.
Tepid baths, compresses, and emollients may help alleviate pruritus. Patients with mild disease can be treated with antihistamines and midpotency topical or intralesional 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 PG 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.
Drug Category: Corticosteroids
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, they modify the body's immune response to diverse stimuli.
| Drug Name | Triamcinolone (Aristocort) |
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| Description | Treats inflammatory dermatosis that is responsive to steroids. Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability. Apply water-based creams sparingly and rub into skin until they disappear. Ointments, which are in a petrolatum-based vehicle, are used to treat chronic dermatoses. Use 0.1% cream or ointment. |
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| Adult Dose | Apply thin film after bathing bid/tid until response is achieved |
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| Pediatric Dose | 6-12 years: 0.03-0.2 mg/kg IM q1-7 d
>12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity; fungal, viral, and bacterial skin infections; use in neonates; use in intertriginous areas (eg, groin, armpits) or on face; use on areolas in breastfeeding women; decreased skin circulation |
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| Interactions | None reported |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | Prolonged use, applications over large areas, and use of potent steroids and occlusive dressings may result in systemic absorption, which may cause Cushing syndrome, reversible HPA axis suppression, hyperglycemia, and glycosuria; at typically doses, topical steroids pose no significant risks for the fetus or breastfeeding infants |
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| Drug Name | Prednisone (Deltasone) |
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| Description | Immunosuppressant used for the treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. In patients with severe blistering in whom topical or intralesional steroids fail to elicit a response, oral prednisone may be indicated. |
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| Adult Dose | 20-60 mg PO qd; usually administered as single morning dose; if no response or if disease worsens after 4–7 d, increase dose by 50% q3-5d until response occurs. |
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| Pediatric Dose | 4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid. |
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| Contraindications | Absolute: Systemic fungal infection, herpes simplex keratitis, hypersensitivity (usually with corticotropin, occasionally with IV preparations)
Relative: HTN, active TB, CHF, prior psychosis, positive IPPD test result, glaucoma, severe depression, DM, active PUD, cataracts, osteoporosis, recent bowel anastomosis, pregnancy |
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| Interactions | Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
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| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
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| Precautions | May unmask hypertension or gestational diabetes; frequently monitor blood sugar, blood pressure, and weight; at typically doses, amount secreted in breast milk is minimal and poses no significant risk to neonate; abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur
Use lower dose in hypothyroidism, liver disease, obesity (decrease cortisol-binding globulin and increase free fraction of steroid
Pregnancy, hyperthyroidism, and concurrent estrogen therapy may increase cortisol-binding globulin |
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Drug Category: Antihistamines
Antihistamines prevent histamine response in sensory nerve endings and blood vessels. They are more effective in preventing histamine response than in reversing it.
| Drug Name | Diphenhydramine (Benadryl, Belix) |
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| Description | For symptomatic control of severe unremitting pruritus not controlled with previous therapeutic regimens. |
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| Adult Dose | 25-50 mg PO bid/qid |
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| Pediatric Dose | 12.5-25 mg PO tid/qid; alternatively, 5 mg/kg/d or 150 mg/m2/d divided tid/qid; not to exceed 300 mg/d
5 mg/kg/d IV/IM or 150 mg/m2/d divided qid; not to exceed 300 mg/d |
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| Contraindications | Documented hypersensitivity; MAOI use; cardiovascular compromise in neonates |
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| Interactions | Potentiates effect of CNS depressants; do not give syrup with medications that can cause disulfiramlike reactions (due to alcohol content) |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, and urinary tract obstruction; may decrease milk production secondary to anticholinergic effect of antihistamines and decrease cardiovascular response to stress in breastfeeding neonates |
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Complications
- Women with PG 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. Infants so affected are at risk for infection, thermoregulatory difficulties, and fluid and electrolyte abnormalities.
Prognosis
- PG typically regresses without scarring within weeks to months after delivery.
- PG may recur in subsequent pregnancies and may be precipitated by menses and the use of oral contraceptives.
- Cutaneous involvement in infants is rare (5-10%) and abates with clearance of the maternal antibodies.
Patient Education
- Patients should understand the benign nature of PG. No adverse sequelae, except SGA neonates and prematurity, are noted to date.
- Patients should be aware that PG 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.
Special Concerns
- PG shares common features with other dermatosis 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 epidermal-dermal junction detected with DIF testing.
- An accurate diagnosis is important before therapy is initiated.
- 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.
| Media file 1:
Tense bullae are present on the arms of this otherwise healthy 32-year-old primigravida woman. |
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Media type: Photo
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| Media file 2:
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. |
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Media type: Photo
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| Media file 3:
Upon histologic evaluation, an incipient blister is present at the junction of the epidermis and dermis, as is a moderately dense perivascular inflammatory infiltrate. |
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Media type: Photo
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| Media file 4:
A close-up view of a blister reveals the tense primary lesion filled with clear fluid. |
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Media type: Photo
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- Chimanovitch I, Schmidt E, Messer G, Dopp R, Partscht K, Brocker EB, et al. IgG1 and IgG3 are the major immunoglobulin subclasses targeting epitopes within the NC16A domain of BP180 in pemphigoid gestationis. J Invest Dermatol. Jul 1999;113(1):140-2. [Medline].
- Jenkins RE, Hern S, Black MM. Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol. Jul 1999;24(4):255-9. [Medline].
- Sitaru C, Powell J, Messer G, Brocker EB, Wojnarowska F, Zillikens D. Immunoblotting and enzyme-linked immunosorbent assay for the diagnosis of pemphigoid gestationis. Obstet Gynecol. Apr 2004;103(4):757-63. [Medline].
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- Powell AM, Sakuma-Oyama Y, Oyama N, Albert S, Bhogal B, Kaneko F, et al. Usefulness of BP180 NC16a enzyme-linked immunosorbent assay in the serodiagnosis of pemphigoid gestationis and in differentiating between pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy. Arch Dermatol. 2005;141:705-10. [Medline].
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Pemphigoid Gestationis excerpt Article Last Updated: Jan 26, 2007
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