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PHOTO ROUNDS

Maria Villegas, Medical Blisters during — Student, Heather Woodworth Goff, MD, MPH, Eric W. Kraus, MD, and just with the second husband Richard P.Usatine, MD University of Texas Health Science Center at San Antonio 33-year-old Hispanic woman who After 4 days of close monitoring, the was 5 months pregnant came to the patient had labor induced for severe life- A hospital complaining of nausea and threatening pre-. One day after vomiting. She had a history of anticardi- induction and delivery of a stillborn , olipin antibody syndrome, diagnosed origi- she began to develop painful swelling of both nally in 1993 after 2 spontaneous abor- hands and feet along with targetoid, urticar- tions. She had stopped taking warfarin ial, edematous, deep pink, slightly dusky (Coumadin) at the start of her pregnancy,® papulesDowden and plaques Health on her hands, Media abdomen, and had been taking heparin for 3 months. lower extremities, and proximal thighs. Some of the edematous sites began to form FIGURE 1 CopyrightFor vesiclespersonal and bullae use (FIGURE only 1 AND 2). When Blisters on the wrist... asked about this eruption, the patient men- tioned having a similar rash after delivery of one of her children about 10 years before. Interestingly, she noted that she only experienced these cutaneous findings during with her second husband and not with her first. Biopsies were performed and showed prominent eosinophils in the der- mis and a subepidermal vesicle (FIGURE 3).

Vesicles and bullae on the wrist after . ❚ What is your diagnosis?

FIGURE 2 FIGURE 3 ...and the abdomen Biopsy results

FEATURE EDITOR Richard P.Usatine, MD, University of Texas Health Sciences Center at San Antonio. E-mail: [email protected]

CORRESPONDENCE Richard P.Usatine, MD, University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229- Histology showing prominent eosinophils in the der- 3900. E-mail: Similar bulla in the umbilicus. mis and a sub-epidermal vesicle (arrow). [email protected]

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❚ Diagnosis: eosinophils.3 The sine qua non of the dis- ROUNDS Pemphigoid gestationis ease, though, is the demonstration through The patient had pemphigoid gestationis, direct immunofluorescence of complement also known as herpes gestationis, a rare deposition and IgG in a linear band along PHOTO autoimmune bullous disease of pregnancy the basement membrane.14 and the puerperium.1 Clinically and There appears to be a genetic predispo- immunopathologically, pemphigoid gesta- sition toward the development of pem- tionis is related to the pemphigoid group of phigoid gestationis. Associations with disorders and is not virally mediated.2 human leukocyte antigens (HLAs) DR3 In the United States, pemphigoid ges- (61%–85%), DR4 (52%), or both tationis has an incidence of 1:10,000 to (43%–50%) have been reported.3,15,16 1:50,000 pregnancies.3 Clinically, it mani- Interestingly, 85% of persons with a history fests during the second or third trimester, of pemphigoid gestationis were found to with a sudden onset of extremely pruritic have anti-HLA antibodies, some of which urticarial papules and plaques usually were directed against paternal HLAs located around the umbilicus. These expressed in their placentae.17 These find- lesions often progress to tense vesicles and ings raised speculation about a possible blisters and spread peripherally to the immunologic insult against placental anti- trunk, often sparing the face, palms, and gens during pregnancy. Evidence suggests soles.4 Worsening of the lesions at the time that circulating autoantibodies in patients of delivery occurs in 75% of cases, and with pemphigoid gestationis bind to the der- usually recurs with subsequent pregnan- mal-epidermal junction of skin and amnion cies.5 Occasionally, however, subsequent in which BP180 antigen is also present.18–20 pregnancies are unaffected, so-called “skip It has been demonstrated that in pregnancies.”6 This occurs most often patients with pemphigoid gestationis the when there has been a change in paternity.7 cells of the placenta stroma express abnor- The exact cause of pemphigoid gesta- mal major histocompatibility complex tionis is unknown. Investigative efforts (MHC) class II molecules.21,22 This lead to FAST TRACK lead to the identification of an immuno- the proposition of 2 possible mechanisms When there are globulin G (IgG) autoantibody, which for the initiation of an autoimmune binds to bullous pemphigoid (BP) antigen response in pemphigoid gestationis. The no blisters, 2, also called BP180, which is a protein first proposes that placental BP180 is pre- it is impossible to associated with hemidesmosomes of basal sented to the maternal immune system in distinguish keratinocytes.8–10 These hemidesmosomes association with abnormal MHC mole- form the central portion of the dermal- cules, which then trigger the production of pemphigoid epidermal anchoring complex, whose autoantibodies that cross-react with the gestationis from function is to establish a connection skin. Alternatively, the placental stromal other cutaneous between the basal keratinocytes and the cells may evoke an allogeneic reaction eruptions upper dermis.11,12 This is critical for main- against the BP180 antigen presented by taining dermal-epidermal adhesion. It is paternal MHC molecules of the placental of pregnancy hypothesized that binding of autoantibod- stroma, which then cross-reacts with the ies to BP180 initiates an inflammatory skin.23 The latter theory supports the find- reaction, leading to blister formation at the ings in this patient, who developed pem- dermal-epidermal junction.13 phigoid gestationis during the 2 pregnan- cies with her second husband and not dur- ing the pregnancies with her first husband. ❚ Pathology and immunology Histopathologic findings demonstrate subepidermal vesicles, spongiosis, and ❚ Differential diagnosis perivascular lymphocyte, and histiocyte It is important to differentiate the prebul- infiltrates with a preponderance of lous stage of pemphigoid gestationis from

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Blisters during pregnancy ▲

TABLE Differential diagnosis for blisters in pregnancy

DISEASE ASSOCIATIONS DIAGNOSIS TREATMENT

Polymorphous eruption Nonspecific pruritic Biopsy to differentiate Mild to mid-potency of pregnancy eruption of pregnancy from prebullous stage topical steroids, of pemphigoid (herpes) oral antihistamines gestationis

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

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/ Biopsy sent for histologic Prednisone for short plaques, pruritus diagnosis and course starting at 1 mg/kg, immunofluorescence then tapering over 2–3 months, topical steroids

Intrahepatic cholestasis +/- jaundice, otherwise no Elevation in liver function Ursodeoxycholic acid, of pregnancy cutaneous findings other tests, cholesterol, S-adenosyl-L-methionine than generalized pruritus, triglycerides, dark urine, risk of right upper quadrant pain, nausea, greasy stools

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

other pregnancy-related dermatoses. These the clinician should perform punch biop- include polymorphic eruption of pregnan- sies of the involved skin, with one speci- cy (PEP), pruritic urticarial papules and men sent for immunofluoresence studies. plaques of pregnancy (PUPPP), erythema The biopsy should not pass directly multiforme, prurigo annularis, intrahepat- through a bullae, due to risk of losing the ic cholestasis of pregnancy, and impetigo overlying epidermis in the specimen. Do herpetiformis. is the punch biopsy at the edge of the bulla not related to bacterial or viral causes, but including some normal skin. Other impor- is rather a manifestation of pustular psori- tant laboratory exams to perform would asis during pregnancy. The target lesions include liver function tests to look for an that form in pemphigoid gestationis look upward trend associated with intrahepatic just like the target lesions of erythema cholestasis, and herpes simplex virus anti- multiforme. body testing for the association with ery- When there is no blister formation, it thema multiforme. The cutaneous findings is impossible to distinguish pemphigoid and pertinent tests are listed in the table gestationis from many of the other cuta- below in order of increasing potential as a neous eruptions of pregnancy. If uncertain, life-threatening dermatosis (TABLE).

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❚ Treatment 3. Al-Fouzan AW,Galadari I, Oumeish I, et al. Herpes gestation-

ROUNDS is (Pemphigoid gestationis). Clinics 2006; Pemphigoid gestationis should resolve spon- 24:109–112. taneously within 2 to 3 months of delivery. 4. Shornick JK. Herpes gestationis. J Am Acad Dermatol 1987; Treatment is aimed at preventing new blis- 17:539–556. PHOTO 5. Holmes RC, Black MM, Dann J, et al. A comparative study of ters and relieving pruritus, with topical cor- toxic erythema of pregnancy and herpes gestationis. Br J ticosteroids and oral antihistamines in mild Dermatol 1982; 106:499–510. cases.2,25 In advanced lesions as seen in this 6. Cozzani E, Basso M, Parodi A, Rebora A. Pemphigoid ges- tationis post partum after changing husband. Intn J case, 0.3 to 0.5 mg/kg of prednisolone daily Dermatol 2005; 44:1057–1058. 3,25 is usually sufficient. Alternative medica- 7. Shornick JK, Black MM. Fetal risks in herpes gestationis. tions include sulfapyridine, dapsone, and J Am Acad Dermatol 1992; 26:63–68. cyclosporine, though disease response is 8. Diaz LA, Ratrie H, III Saunders WS, et al. Isolation of a human 3 epidermal cDNA corresponding to the 180-kD autoantigen variable and their safety is questionable. recognized by bullous pemphigoid and herpes gestationis When the began, the sera. Immunolocalization of this protein to the hemidesmo- some. J Clin Invest 1990; 86:1088–1094. patient was treated with oral antihistamines 9. Giudice GJ, Emery DJ, DiazLA. Cloning and primary struc- and topical steroids. On day 2, the diagno- tural analysis of the bullous pemphigoid autoantigen BP180. sis of pemphigoid gestationis was clear, and J Invest Dermatol 1992; 99:243–250. she was started on oral prednisone at 60 10. Zillikens D, Giudice GJ. BP180/typeXVIII collagen: its role in acquired and inherited disorders of the dermal-epidermal mg/d, which resulted in rapid symptom junction. Arch Dermatol Res 1999; 291:187–194. improvement in her lesions and swelling. 11. Borradori L, Sonnenberg A. Hemidesmosomes: roles in adhesion, signaling and human diseases. Curr Opin Cell Biol New lesions stopped forming, and systemic 1996; 8:647–656. steroids were tapered off over the 3 months 12. Zillikens D. Acquired skin disease of hemidesmosomes. J after delivery. The skin lesions healed and Dermatol Sci 1999; 20:134–154. she was given supportive counseling to help 13. Schmidt E, Zillikens D. Autoimmune and inherited subepi- dermal blistering diseases: advances in the clinic and the her cope with her pregnancy loss. laboratory. Adv Dermatol 2000; 16:113–157. 14. Shornick JD. . Semin Cutan Med ❚ Surg 1998; 17:172–181. Conclusion 15. Holmes RC, Black MM, Jurecka W, et al. Clues to the aetiol- We have described a rare case of a patient ogy and pathogenesis of herpes gestationis. Br J Dermatol with no cutaneous eruptions during her 1983; 109:131–139. FAST TRACK 16. Shornick JK, Stastny P, Gilliam JN. High frequency of histo- pregnancies with her first husband, who compatibility antigens DR3 and DR4 in herpes gestationis, J Biopsy and developed pemphigoid gestationis in 2 Clin Invest 1981;68:553–555. pregnancies with her second husband. 17. Shornick JK, Stastny P, and JN Gilliam, Paternal histocom- immuno- patibility (HLA) antigens and maternal anti-HLA antibodies in fluorescence helps While it is interesting that our patient also herpes gestationis. J Invest Dermatol 1983; 81:407–409. had the anticardiolipin syndrome, most 18. Ortonne JP, Hsi BL, Verrando P, et al. Herpes gestationis fac- differentiate patients do not have both conditions. tor reacts with the amniotic epithelial basement membrane. pemphigoid Our patient had the classic findings of Br J Dermatol 1987; 117:147–154. 19. Kelly SE, Bhogal BS, Wojnarowska F,Black MM. Expression gestationis from pemphigoid gestationis with many charac- of a pemphigoid gestationis-related antigen by human pla- teristic lesions (including the umbilicus) centa. Br J Dermatol 19 8 8 ; 118 : 6 0 5 – 611. other dermatoses making the diagnosis possible before biopsy 20. Fairley JA, Heintz PW, Neuburg M, et al. Expression pattern of the bullous pemphigoid-180 antigen in normal and neo- of pregnancy confirmation. This was fortunate for her plastic epithelia. Br J Dermatol 1995; 133:385–391. because her painful swelling responded 21. Kelly SE, Black MM, Fleming S. Antigen-presenting cells in quickly to the corticosteroids. When cases the skin and placenta in pemphigoid gestationis. Br J Dermatol 1990; 122:593–599. are less clinically obvious, biopsy for histo- 22. Borthwick GM, Holmes RC, Stirrat GM.Abnormal expression pathology and immunofluorescence facili- of class II MHC antigens in placentae from patients with tates differentiation of pemphigoid gestatio- pemphigoid gestationis. Placenta 1988; 9:81–94. ■ 23. Kelly SE, Black MM, Fleming S. Pemphigoid gestationis: a nis from other dermatoses of pregnancy. unique mechanism of initiation of an autoimmune response by MHC class II molecules. J Pathol 1989; 158:81–82. REFERENCES 24. Borradori L, Saurat JH. Specific dermatoses of pregnancy. 1. Coupe RL. Herpes gestationis. Arch Dermatol 1965; Toward a comprehensive view. Arch Dermatol 1994; 91:633–636. 130:778–780. 2. Jenkins RE, Hern S, Black MM. Clinical features and man- 25. Shimanovich I, Bröcker EB, Zillikens D. Pemphigoid gestatio- agement of 87 patients with pemphigoid gestationis. Clin nis: new insights into the pathogenesis lead to novel diag- Exp Dermatol 1999; 24:255–259. nostic tools. Br J Obstet Gynaecol 2002; 109:970–976.

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