Case: blisters after deliveries (but only with husband no. 2): stillbirth is followed by skin changes that implicate the patient's spouse. What's going on?
After 4 days of close monitoring, the patient had labor induced for severe life-threatening preeclampsia. One day after induction and delivery of a stillborn 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.
[FIGURE 1 OMITTED]
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.
What is your diagnosis?
[FIGURE 2 OMITTED]
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 auto-antibodies 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.
Exploring the differential
It is important to differentiate the prebullous stage of pemphigoid gestationis from other pregnancy-related dermatoses. (24) These include polymorphic eruption of pregnancy (PEP), pruritic urticarial papules and plaques of pregnancy (PUPPP), erythema multiforme, prurigo annularis, intrahepatic cholestasis of pregnancy, and impetigo herpetiformis. Impetigo herpetiformis is not related to bacterial or viral causes, but is rather a manifestation of pustular psoriasis during pregnancy. The target lesions that form in pemphigoid gestationis look just like the target lesions of erythema multiforme.
When there is no blister formation, it is impossible to distinguish pemphigoid gestationis from many of the other cutaneous eruptions of pregnancy. If uncertain, the clinician should perform punch biopsies of the involved skin, with one specimen sent for immunofluoresence studies. The biopsy should not pass directly through a bulla, due to risk of losing the overlying epidermis in the specimen. Do the punch biopsy at the edge of the bulla including some normal skin. Other important laboratory exams to perform would include liver function tests to look for an upward trend associated with intrahepatic cholestasis, and herpes simplex virus antibody testing for the association with erythema multiforme. The cutaneous findings and pertinent tests are listed in order of increasing potential as a life-threatening dermatosis (TABLE).
Treating blisters and itch
Pemphigoid gestationis should resolve spontaneously within 2 to 3 months after delivery. Treatment is aimed at preventing new blisters and relieving pruritus, with topical corticosteroids and oral antihistamines in mild cases. (2,25) In advanced lesions as seen in this case, 0.3 to 0.5 mg/kg prednisolone daily is usually sufficient. 3,25) Alternative medications include sulfapyridine, dapsone, and cyclosporine, though disease response is variable and their safety is questionable. (3)
When the skin condition began, the patient was treated with oral antihistamines and topical steroids. On day 2, the diagnosis of pemphigoid gestationis was clear, and she was started on oral prednisone at 60 mg/day, which resulted in rapid symptom improvement in her lesions and swelling. New lesions stopped forming, and systemic steroids were tapered off over the 3 months after delivery. The skin lesions healed.
Our patient had classic findings of pemphigoid gestationis with many characteristic lesions (including the umbilicus), making the diagnosis possible before biopsy confirmation. This was fortunate for her because her painful swelling responded quickly to the corticosteroids. When cases are less clinically obvious, biopsy for histopathology and immunofluorescence facilitates differentiation of pemphigoid gestationis from other dermatoses of pregnancy. Although it is interesting that our patient also had the anticardiolipin syndrome, most patients do not have both conditions.
(1.) Coupe RL. Herpes gestationis. Arch Dermatol. 1965;91:633-636.
(2.) Jenkins RE, Hern S, Black MM. Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol. 1999;24:255-259.
(3.) Al-Fouzan AW, Galadari I, Oumeish I, et al. Herpes gestationis (Pemphigoid gestationis). Clin Dermatol. 2006;24:109-112.
(4.) Shornick JK. Herpes gestationis. J Am Acad Dermatol. 1987;17:539-556.
(5.) Holmes RC, Black MM, Dann J, et al. A comparative study of toxic erythema of pregnancy and herpes gestationis. Br J Dermatol. 1982;106:499-510.
(6.) Cozzani E, Basso M, Parodi A, Rebora A. Pemphigoid gestationis post partum after changing husband. Int J Dermatol. 2005;44:1057-1058.
(7.) Shornick JK, Black MM. Fetal risks in herpes gestationis. J Am Acad Dermatol. 1992;26:63-68.
(8.) Diaz LA, Ratrie H III, Saunders WS, et al. Isolation of a human epidermal cDNA corresponding to the 180kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome. J Clin Invest. 1990;86:1088-1094.
(9.) Giudice GJ, Emery DJ, Diaz LA. Cloning and primary structural analysis of the bullous pemphigoid autoantigen BP180. J Invest Dermatol. 1992;99:243-250.
(10.) Zillikens D, Giudice GJ. BP180/type XVIII collagen: its role in acquired and inherited disorders of the dermal-epidermal junction. Arch Dermatol Res. 1999; 91:187-194.
(11.) Borradori L, Sonnenberg A. Hemidesmosomes: roles in adhesion, signaling and human diseases. Curr Opin Cell Biol. 1996;8:647-656.
(12.) Zillikens D. Acquired skin disease of hemidesmosomes. J Dermatol Sci. 1999;20:134-154.
(13.) Schmidt E, Zillikens D. Autoimmune and inherited subepidermal blistering diseases: advances in the clinic and the laboratory. Adv Dermatol. 2000;16:113-157.
(14.) Shornick JD. Dermatoses of pregnancy. Semin Cutan Med Surg. 1998;17:172-181.
(15.) Holmes RC, Black MM, Jurecka W, et al. Clues to the aetiology and pathogenesis of herpes gestationis. Br J Dermatol. 1983;109:131-139.
(16.) Shornick JK, Stastny P, Gilliam JN. High frequency of histocompatibility antigens DR3 and DR4 in herpes gestationis. J Clin Invest. 1981;68:553-555.
(17.) Shornick JK, Stastny P, Gilliam JN. Paternal histocompatibility (HLA) antigens and maternal anti-HLA antibodies in herpes gestationis. J Invest Dermatol. 1983;81:407-409.
(18.) Ortonne JP, Hsi BL, Verrando P, et al. Herpes gestationis factor reacts with the amniotic epithelial basement membrane. Br J Dermatol. 1987;117:147-154.
(19.) Kelly SE, Bhogal BS, Wojnarowska F, Black MM. Expression of a pemphigoid gestationis-related antigen by human placenta. Br J Dermatol. 1988;118:605611.
(20.) Fairley JA, Heintz PW, Neuburg M, et al. Expression pattern of the bullous pemphigoid-180 antigen in normal and neoplastic epithelia. Br J Dermatol. 1995;133:385-391.
(21.) Kelly SE, Black MM, Fleming S. Antigen-presenting cells in the skin and placenta in pemphigoid gestationis. Br J Dermatol. 1990;122:593-599.
(22.) Borthwick GM, Holmes RC, Stirrat GM. Abnormal expression of class II MHC antigens in placentae from patients with pemphigoid gestationis. Placenta. 1988;9:81-94.
(23.) Kelly SE, Black MM, Fleming S. Pemphigoid gestationis: a unique mechanism of initiation of an autoimmune response by MHC class II molecules. J Pathol. 1989;158:81-82.
(24.) Borradori L, Saurat JH. Specific dermatoses of pregnancy. Toward a comprehensive view. Arch Dermatol. 1994;130:778-780.
(25.) Shimanovich I, Brocker EB, Zillikens D. Pemphigoid gestationis: new insights into the pathogenesis lead to novel diagnostic tools. Br J Obstet Gynaecol. 2002;109:970-976.
When there are no blisters, it is impossible to distinguish pemphigoid gestations from other cutaneous eruptions of pregnancy
Biopsy and immunofluorescence help differentiate pemphigoid gestationis from other dermatoses of pregnancy
Maria Villegas, MD, Heather Woodworth Goff, MD, MPH, Eric W. Kraus, MD, and Richard P. Usatine, MD University of Texas Health Science Center at San Antonio
The authors report no financial relationships relevant to this article.
TABLE Blisters in pregnancy: Six principal considerations DISEASE ASSOCIATION DIAGNOSIS Polymorphous Nonspecific pruritic Biopsy to differentiate eruption eruption of pregnancy from prebullous stage of pregnancy of pemphigoid (herpes) gestationis Pruritic urticarial Occur in stretch Unless history is very papules and plaques marks, spare clear, biopsy to of pregnancy umbilicus; more differentiate from common in prebullous stage of primigravidas pemphigoid gestationis Erythema multiforme Can involve mucous Viral, bacterial, or membranes; targetoid drug-related eruption; lesions; absence of most often with herpes pruritus; centripetal simplex I or II virus; spread; favors biopsy to differentiate palms/soles from pemphigoid gestationis Pemphigoid Blistering, Biopsy for histologic gestationis urticarial papules diagnosis and and plaques, pruritus immunofluorescence Intrahepatic With or without Elevation of liver cholestasis jaundice; otherwise, function tests, of pregnancy no cutaneous findings cholesterol, other than triglycerides; dark generalized pruritus; urine; risk of preterm birth right-upper-quadrant pain; nausea; greasy stools Impetigo Extremely ill with Biopsy if uncertain; herpetiformis fever, chills, pustules sterile; risk (pustular psoriasis nausea; vascular of hypocalcemia of pregnancy) instability; pustules hypoparathyroidism rather than vesicles DISEASE TREATMENT Polymorphous Mild to mid-potency eruption topical steroid; of pregnancy oral antihistamine Pruritic urticarial Emollient; pulse-dye papules and plaques laser during violaceous of pregnancy stage of striae; topical steroid; oral antihistamine Erythema multiforme Acyclovir, valacyclovir if HSV-related; treatment of bacterial infection; or removal of offending drug Pemphigoid Prednisone for short gestationis course, starting at 1 mg/kg, then tapering over 2-3 months; topical steroid Intrahepatic Ursodeoxycholic acid; cholestasis S-adenosyl-L-methionine of pregnancy Impetigo High-dose oral steroid herpetiformis or cyclosporine (pustular psoriasis of pregnancy)
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|Author:||Villegas, Maria; Kraus, Eric W.; Usatine, Richard P.|
|Article Type:||Medical condition overview|
|Date:||May 1, 2007|
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