Maria Villegas, MD, Case: Blisters after deliveries Heather Woodworth Goff, MD, MPH, Eric W. Kraus, MD, and (but only with husband no. 2) Richard P. Usatine, MD University of Texas Health is followed by skin changes that implicate Science Center at San Antonio The authors report no fi nancial the patient’s spouse. What’s going on? relationships relevant to this article.

33-year-old Hispanic woman plaques on her hands, abdomen, lower who was 5 months pregnant extremities, and proximal thighs. Some A came to the hospital complain- of the edematous sites began to form ing of nausea and vomiting. She had a vesicles and bullae (FIGURES 1 AND 2). history of anticardiolipin antibody syn- When asked about this eruption, the drome, diagnosed originally in 1993® Dowdenpatient mentioned Health having Mediaa similar rash after 2 spontaneous . She had after delivery of one of her children stopped taking warfarin (Coumadin) at about 10 years before. the start of her ,Copyright and hadFor been personalInterestingly, use she notedonly that she only taking heparin for 3 months. experienced these cutaneous fi ndings dur- After 4 days of close monitoring, ing with her second husband the patient had labor induced for severe and not with her fi rst. Biopsies were per- life-threatening preeclampsia. One day formed and showed prominent eosino- IN THIS ARTICLE after induction and delivery of a still- phils in the dermis and a subepidermal born , she began to develop painful vesicle. ❙ Differential dx: swelling of both hands and feet along 6 possibilities with targetoid, urticarial, edematous, Page 47 deep pink, slightly dusky papules and What is your diagnosis? ❙ Treatment options FIGURE 1 FIGURE 2 Page 48 Blisters on wrist...... and abdomen

Vesicles and bullae on the wrist after . Similar bulla in the umbilicus. CONTINUED

www.obgmanagement.com May 2007 • OBG MANAGEMENT 43

For mass reproduction, content licensing and permissions contact Dowden Health Media. Blisters after deliveries

Dx: Pemphigoid gestationis ease, though, is demonstration through The patient had pemphigoid gestationis, direct immunofl uorescence of comple- also known as herpes gestationis, a rare ment deposition and IgG in a linear band autoimmune bullous disease of preg- along the basement membrane.14 nancy and the puerperium.1 Clinically There appears to be a genetic pre- and immunopathologically, pemphigoid disposition toward the development of gestationis is related to the pemphigoid pemphigoid gestationis. Associations disorders and is not virally mediated.2 with human leukocyte antigens (HLAs) In the United States, pemphigoid ges- DR3 (61%–85%), DR4 (52%), or both tationis has an incidence of 1:10,000 to (43%–50%) have been reported.3,15,16 In- 1:50,000 pregnancies.3 Clinically, it mani- terestingly, 85% of persons with a histo- fests during the second or third trimester, ry of pemphigoid gestationis were found with a sudden onset of extremely pruritic to have anti-HLA antibodies, some of urticarial papules and plaques usually lo- which were directed against paternal cated around the umbilicus. These lesions HLAs expressed in their placentae.17 often progress to tense vesicles and blis- These fi ndings raised speculation about ters and spread peripherally to the trunk, a possible immunologic insult against often sparing the face, palms, and soles.4 placental antigens during pregnancy. Worsening of the lesions at the time of de- Evidence suggests that circulating auto- livery occurs in 75% of cases, and usually antibodies in patients with pemphigoid recurs with subsequent pregnancies.5 Oc- gestationis bind to the dermal–epidermal casionally, however, subsequent pregnan- junction of skin and amnion in which cies are unaffected, so-called “skip preg- BP180 antigen is also present.18–20 nancies.”6 This occurs most often when It has been demonstrated that in pa- there has been a change in paternity.7 tients with pemphigoid gestationis the cells The exact cause of pemphigoid ges- of the placenta stroma express abnormal tationis is unknown. Investigative efforts major histocompatibility complex (MHC) led to the identifi cation of an immuno- class II molecules.21,22 This led to the prop- FAST TRACK globulin G (IgG) autoantibody, which osition of 2 possible mechanisms for the When there are binds to bullous pemphigoid (BP) anti- initiation of an autoimmune response in gen 2, also called BP180, which is a pro- pemphigoid gestationis. The fi rst proposes no blisters, it is tein associated with hemidesmosomes of that placental BP180 is presented to the impossible to basal keratinocytes.8–10 These hemides- maternal immune system in association distinguish mosomes form the central portion of the with abnormal MHC molecules, which pemphigoid dermal–epidermal anchoring complex, then trigger the production of autoan- gestationis from whose function is to establish a connec- tibodies that cross-react with the skin. tion between the basal keratinocytes and Alternatively, the placental stromal cells other cutaneous the upper dermis.11,12 This is critical for may evoke an allogeneic reaction against eruptions of maintaining dermal–epidermal adhesion. the BP180 antigen presented by paternal pregnancy It is hypothesized that binding of autoan- MHC molecules of the placental stroma, tibodies to BP180 initiates an infl amma- which then cross-reacts with the skin.23 tory reaction, leading to blister formation The latter theory supports the fi ndings in at the dermal–epidermal junction.13 this patient, who developed pemphigoid gestationis during the 2 pregnancies with her second husband and not during the Autoimmune basis? pregnancies with her fi rst husband. Histopathologic fi ndings demonstrate subepidermal vesicles, spongiosis, and perivascular infi ltrates of lymphocytes Exploring the differential and histiocytes with a preponderance of It is important to differentiate the pre- eosinophils.3 The sine qua non of the dis- bullous stage of pemphigoid gestationis CONTINUED

44 OBG MANAGEMENT • May 2007 Blisters after deliveries

TABLE Blisters in pregnancy: Six principal considerations DISEASE ASSOCIATIONS DIAGNOSIS TREATMENT

Polymorphous eruption Nonspecifi c pruritic Biopsy to differentiate Mild to mid-potency of pregnancy eruption of pregnancy from prebullous stage topical steroid; of pemphigoid (herpes) oral antihistamine gestationis

Pruritic urticarial papules Occur in , Unless history is very Emollient; pulse-dye and plaques of pregnancy spare umbilicus; more clear, biopsy to differentiate laser during violaceous common in primigravidas from prebullous stage of stage of striae; topical pemphigoid gestationis steroid; oral antihistamine

Erythema multiforme Can involve mucous Viral, bacterial, or drug- Acyclovir, valacyclovir if membranes; targetoid related eruption; most often HSV-related; treatment lesions; absence of with herpes simplex I or II of bacterial infection; or pruritus; centripetal virus; biopsy to differentiate removal of offending drug spread; favors palms/soles from pemphigoid gestationis

Pemphigoid gestationis Blistering, urticarial papules and Biopsy for histologic Prednisone for short plaques, pruritus diagnosis and course, starting at 1 mg/kg, immunofl uorescence then tapering over 2–3 months; topical steroid

Intrahepatic cholestasis With or without jaundice; Elevation of liver function tests, Ursodeoxycholic acid; of pregnancy otherwise, no cutaneous cholesterol, triglycerides; dark S-adenosyl-L-methionine fi ndings other than generalized urine; right-upper-quadrant pain; pruritus; risk of nausea; greasy stools

Impetigo herpetiformis Extremely ill with fever, chills, Biopsy if uncertain; pustules High-dose oral steroid (pustular nausea; vascular instability; sterile; risk of hypocalcemia, or cyclosporine of pregnancy) pustules rather than vesicles hypoparathyroidism

from other pregnancy-related dermato- uncertain, the clinician should perform ses.24 These include polymorphic erup- punch biopsies of the involved skin, tion of pregnancy (PEP), pruritic urti- with one specimen sent for immuno- carial papules and plaques of pregnancy fl uoresence studies. The biopsy should (PUPPP), erythema multiforme, prurigo not pass directly through a bulla, due annularis, intrahepatic cholestasis of to risk of losing the overlying epidermis pregnancy, and impetigo herpetiformis. in the specimen. Do the punch biopsy Impetigo herpetiformis is not related to at the edge of the bulla including some bacterial or viral causes, but is rather a normal skin. Other important labora- manifestation of dur- tory exams to perform would include ing pregnancy. The target lesions that liver function tests to look for an up- form in pemphigoid gestationis look ward trend associated with intrahepatic just like the target lesions of erythema cholestasis, and herpes simplex virus multiforme. antibody testing for the association with When there is no blister formation, erythema multiforme. The cutaneous it is impossible to distinguish pemphi- fi ndings and pertinent tests are listed in goid gestationis from many of the other order of increasing potential as a life- cutaneous eruptions of pregnancy. If threatening dermatosis (TABLE). CONTINUED

www.obgmanagement.com May 2007 • OBG MANAGEMENT 47 Blisters after deliveries

Treating blisters and itch 5. Holmes RC, Black MM, Dann J, et al. A comparative study of toxic erythema of pregnancy and herpes ges- Pemphigoid gestationis should resolve tationis. Br J Dermatol. 1982;106:499–510. spontaneously within 2 to 3 months after 6. Cozzani E, Basso M, Parodi A, Rebora A. Pemphigoid delivery. Treatment is aimed at prevent- gestationis post partum after changing husband. Int J Dermatol. 2005;44:1057–1058. ing new blisters and relieving pruritus, 7. Shornick JK, Black MM. Fetal risks in herpes gestatio- with topical corticosteroids and oral anti- nis. J Am Acad Dermatol. 1992;26:63–68. histamines in mild cases.2,25 In advanced 8. Diaz LA, Ratrie H III, Saunders WS, et al. Isolation of a human epidermal cDNA corresponding to the 180- lesions as seen in this case, 0.3 to 0.5 mg/kg kD autoantigen recognized by bullous pemphigoid prednisolone daily is usually suffi cient.3,25 and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome. J Clin Invest. Alternative medications include sulfapyri- 1990;86:1088–1094. dine, dapsone, and cyclosporine, though 9. Giudice GJ, Emery DJ, Diaz LA. Cloning and primary disease response is variable and their structural analysis of the bullous pemphigoid autoan- tigen BP180. J Invest Dermatol. 1992;99:243–250. 3 safety is questionable. 10. Zillikens D, Giudice GJ. BP180/type XVIII collagen: When the skin condition began, the its role in acquired and inherited disorders of the der- mal–epidermal junction. Arch Dermatol Res. 1999; patient was treated with oral antihista- 91:187–194. mines and topical steroids. On day 2, the 11. Borradori L, Sonnenberg A. Hemidesmosomes: roles diagnosis of pemphigoid gestationis was in adhesion, signaling and human diseases. Curr Opin Cell Biol. 1996;8:647–656. clear, and she was started on oral predni- 12. Zillikens D. Acquired skin disease of hemidesmo- sone at 60 mg/day, which resulted in rap- somes. J Dermatol Sci. 1999;20:134–154. id symptom improvement in her lesions 13. Schmidt E, Zillikens D. Autoimmune and inherited sub- epidermal blistering diseases: advances in the clinic and swelling. New lesions stopped form- and the laboratory. Adv Dermatol. 2000;16:113–157. ing, and systemic steroids were tapered 14. Shornick JD. . Semin Cutan off over the 3 months after delivery. The Med Surg. 1998;17:172–181. 15. Holmes RC, Black MM, Jurecka W, et al. Clues to the skin lesions healed. 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 Summing up gestationis. J Clin Invest. 1981;68:553–555. Our patient had classic fi ndings of pem- 17. Shornick JK, Stastny P, Gilliam JN. Paternal histo- FAST TRACK phigoid gestationis with many charac- compatibility (HLA) antigens and maternal anti-HLA antibodies in herpes gestationis. J Invest Dermatol. Biopsy and teristic lesions (including the umbilicus), 1983;81:407–409. making the diagnosis possible before 18. Ortonne JP, Hsi BL, Verrando P, et al. Herpes gestatio- immunofl uorescence biopsy confi rmation. This was fortunate nis factor reacts with the amniotic epithelial basement help differentiate membrane. Br J Dermatol. 1987;117:147–154. for her because her painful swelling re- 19. Kelly SE, Bhogal BS, Wojnarowska F, Black MM. Ex- pemphigoid sponded quickly to the corticosteroids. pression of a pemphigoid gestationis-related antigen by human placenta. Br J Dermatol. 1988;118:605– gestationis from When cases are less clinically obvious, 611. other dermatoses biopsy for histopathology and immuno- 20. Fairley JA, Heintz PW, Neuburg M, et al. Expres- fl uorescence facilitates differentiation sion pattern of the bullous pemphigoid-180 antigen of pregnancy in normal and neoplastic epithelia. Br J Dermatol. of pemphigoid gestationis from other 1995;133:385–391. dermatoses of pregnancy. Although it is 21. Kelly SE, Black MM, Fleming S. Antigen-presenting cells in the skin and placenta in pemphigoid gestatio- interesting that our patient also had the nis. Br J Dermatol. 1990;122:593–599. anticardiolipin syndrome, most patients 22. Borthwick GM, Holmes RC, Stirrat GM. Abnormal do not have both conditions. ■ expression of class II MHC antigens in placentae from patients with pemphigoid gestationis. Placenta. 1988;9:81–94. References 23. Kelly SE, Black MM, Fleming S. Pemphigoid gesta- 1. Coupe RL. Herpes gestationis. Arch Dermatol. tionis: a unique mechanism of initiation of an autoim- 1965;91:633–636. mune response by MHC class II molecules. J Pathol. 2. Jenkins RE, Hern S, Black MM. Clinical features and 1989;158:81–82. management of 87 patients with pemphigoid gestatio- 24. Borradori L, Saurat JH. Specifi c dermatoses of preg- nis. Clin Exp Dermatol. 1999;24:255–259. nancy. Toward a comprehensive view. Arch Dermatol. 3. Al-Fouzan AW, Galadari I, Oumeish I, et al. Herpes 1994;130:778–780. gestationis (Pemphigoid gestationis). Clin Dermatol. 25. Shimanovich I, Bröcker EB, Zillikens D. Pemphigoid 2006;24:109–112. gestationis: new insights into the pathogenesis lead 4. Shornick JK. Herpes gestationis. J Am Acad Derma- to novel diagnostic tools. Br J Obstet Gynaecol. tol. 1987;17:539–556. 2002;109:970–976.

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