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ABSTRACTHerpes gestationis, also known as pemphigoid

gestationis (PG) is an extremely rare autoimmune bullousdermatosis of the gestation and postpartum period. The dis-ease was originally named herpes gestationis on the basisof the morphological herpetiform feature of the blisters. Wereport a 21-year-old woman, pregnant in the third trimes-ter, who presented with a pruritic bullous cutaneous erup-tion of two weeks duration. The disease started with a redplaque in the abdominal area accompanied by mild itch-ing. Soonafter, blisters appeared and affected almost theentire body. Physical examination revealed a primiparouswoman in good general state, pregnant in 36 weeks of ges-tation. The skin changes affected the abdomen, back of thetrunk, upper and lower extremities, hands and feet. Theywere manifested by a polymorphous eruption, consistingof erythematous urticaria-like plaques, small tense vesiclesand multiple excoriations. Mucous membranes were not af-fected. Routine laboratory examinations were within nor-mal limits. Direct immunofluorescence (DIF) onperilesional skin showed linear deposition of IgG (++) andC3 (++) at the cutaneous basement membrane zone (BMZ).Indirect immunofluorescence (IIF) on human esophagussubstrate revealed circulating IgG anti-BMZ antibodies ata titer of 1:80. ELISABP180 NC16A was strongly positive.The diagnosis of PG was confirmed and a treatment withsystemic methylprednisolone 60 mg/day was initiated, latergradually tapered to 20 mg/day, together with topicalcorticosteroids. As a result on the 10th day of the treatmentwe already achieved significant improvement with reduc-tion of erythema and itching, absence of new skin lesions.The pregnancy ended in term with successful childbirth.No flare of the skin disease was observed in the puerperalperiod.

Key word: Pemphigoid gestationis, herpes gestatio-nis, pregnancy, direct and indirect immunofluorescence,methylprednisolone.

INTRODUCTION:Herpes gestationis (HG), currently known as pemphi-

goid gestationis (PG), is a rare autoimmune blistering der-matosis of pregnancy with an incidence ranging up to 1:50000 pregnancies.[1] The term PG was introduced byHolmes and Black in 1982 and is largely used in Europebut in the USA the former name HGis still preferred.[2, 3]

HERPES GESTATIONIS

Ivelina Yordanova1, Valentin Valtchev1, Kossara Drenovska2, Dimitar K.Gospodinov1, Snejina Vassileva2

1) Department of Dermatology and Venereology, Faculty of Medicine, MedicalUniversity, Pleven, Bulgaria2) Department of Dermatology and Venereology, Faculty of Medicine, MedicalUniversity, Sofia, Bulgaria.

Journal of IMAB - Annual Proceeding (Scientific Papers) 2014, vol. 20, issue 6Journal of IMABISSN: 1312-773Xhttp://www.journal-imab-bg.org

PG typically affects pregnant women in the second or thirdtrimester but may appear at any time during pregnancy oreven during the immediate postpartum period.

CASE REPORT:We present a 21-year-old woman pregnant in the third

trimester. The disease started two weeks before her admis-sion in the Department of dermatology with red plaquesonthe abdominal skin, around the umbilicus, accompanied byitching. Soonafter, blisters appeared on this backgroundand quickly spread to affect almost the entire body.

The physical examination revealed a woman in goodgeneral condition, afebrile, pregnant at the 36 weeks of ges-tation. Cardiovascular and respiratory systems were with-out pathological changes - blood pressure 120/70 mmHg,heart rate 80 beats/min. The neurological status was nor-mal. The dermatological examination found pathologicalskin changes affecting the skin of the abdomen, the back,upper and lower extremities, hands and feet. The eruptionconsisted of erythematous, urticaria-like plaques with smalltense vesicles upon them and multipleexcoriations. (Fig.1a, b) The mucous membranes and skin appendages werenot affected. Routine laboratory investigations were withinnormal limits. Histological examination of a biopsy speci-men from a fresh vesicular lesion showed edema in the der-mis, mixed perivascular inflammatory infiltrate with a pre-dominance of eosinophils (Fig. 2). Direct immunofluores-cence (DIF) on perilesional skin showed linear depositionof IgG (++) and C3 (++) at the cutaneous basement mem-brane zone (BMZ) (Fig. 3). Indirect immunofluorescence(IIF) on human esophagus substrate revealed circulatingIgG anti-BMZ antibodies at a titer of 1:80 (Fig. 4).ELISABP180NC16A (ELISA kit, MBL, Nagoya, Japan) wasstrongly positive - 88.2 U/ml (cut off <9 negative; ≥ 9 posi-tive). Based on the data from the medical history, the clini-cal features and the results from the laboratory studies,thediagnosis PG was confirmed. Treatment with systemic meth-ylprednisolone 60 mg/daywas initiated, later gradually ta-pered to 20 mg/day, together with topical corticosteroids.Significant improvement was achieved about the 10th dayof the treatment with reduction of erythema and itching andabsence of new skin lesions (Fig. 5a, b). The pregnancyended in term with successful childbirth. A healthy femalenewborn with anthropometric parameters within the nor-mal ranges was born. No flare of the skin disease was ob-served in the mother in the puerperal period.

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Fig. 2. Histopathology: A marked edema, with adense inflammatory infiltrate (predominantly with eosino-phils) in the dermis.

Fig. 1a, b. Confluent urticaria-like plaques coveredwith tense vesicules and excoriations on the abdomen andback of the trunk.

Fig. 3. Direct immunofluorescence (DIF) on peri-lesional skin: linear deposition of IgG (++) and C3 (++) atthe cutaneous basement membrane zone (BMZ).

Fig. 4. Indirect immunofluorescence(IIF) on humanesophagus substrate: circulating IgG anti-BMZ antibodiesat a titer of 1:80.

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Fig. 5a, b. 10 daysafter treatment with systemicglucocorticosteroids: reduction of erythema and absenceof new skin eruptions.

DISCUSSION:PG is a self-limiting, autoimmune subepidermal bul-

lous dermatosis of pregnancy. Its pathogenic mechanism re-mains unclear but is considered to result from lack of rec-ognition of the fetoplacental unit by the maternal immunesystem. This leads tosubsequent production of anti-placen-tal antibodies. Similarly to bullous pemphigoid, the maintarget antigen in PG is BP antigen II (also known asBP180), in particular its non-collagenous 16A (NC16A)domain, which is constituent of both the placenta and theskin. The skin pathology in PG results from the ability ofthe anti-placental antibodies to cross-react with the sameproteins of the skin.Blister formation results from a com-plex mechanism involving TH2lymphocytes, cytokines andpolymorphonuclear cells.[4, 5, 6] PG has also been reportedin association with MHC class II HLA antigens DR3 andDR4.[1] The disease usually starts in the second or thirdtrimester of pregnancy and is characterized with an acuteonset of erythematous, urticarial papules and plaques thatprogress to tense vesicles and blisters, followed byseverepruritus. The lesions usually arise on the abdomen, ofteninvolving the umbilicus, and spread centrifugally. Recov-ery occurs generally in a few weeks after delivery but re-lapses are frequent in subsequent pregnancies.[7, 8] The di-agnosis of PG relies on theappropriate clinical presentation,the histologic findings of a subepidermal blistering andlinear C3 deposition along the BMZ, with or without depo-sition of IgG on DIF. ELISA BP180NC16A may be veryuseful in such casesdue to its high sensitivity to detect cir-culating auto-antibodies against NC16A domain of BP180,which is the major antigenic epitope in PG.[9]

The treatment of PG depends on the severity of thedisease. Mild cases may be treated with topical cortico-steroids and oral antihistamines. Potent topical glucocor-ticoids and oral corticosteroids (prednisone 0.5-1 mg/kg/day) are reserved for more serious cases.[1] Several casesresistant to corticosteroid therapy have been described, butsuccessfully treated with intravenous immunoglobulin andazathioprine or with adjuvant immunoadsorption.[10, 11,12] Fetal prognosis is good, but early onset in 2nd trimes-ter and blister formation are risk factors for prematurity andlow birth weight. Rarely the newborn may be affected byvery transitory blisters.[7]

In our case, clinical suspicion of PG was confirmedby DIF and IIF findings, as well as by ELISA BP180NC16A,the latter beingstrongly positive. Systemic treatment withmethylprednisolone (0,5mg/kg/day) was initiated duringthe pregnancy with gradual clinical improvement until de-livery. A healthy asymptomatic infant was born in termwithout cutaneous lesions. To date the patient has not re-ported a flare.

CONCLUSIONThe presented case highlights the importance of a

timely clinical and immunohistological diagnosis of PG.Differentiation of PG from other conditions like pruritic ur-ticarial papules and plaques of pregnancy (PUPPP) is es-sential because management and outcomes differ. In casesinwhich the clinical diagnosis is difficult, immunofluores-

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1. Burgdorf WHC, Plewig G, WolffHH, Landthaler M. (Eds.) Braun-Falco’sDermatology. 3rd ed. 2009, XXXVIII.p. 656-7.

2. Kroumpouzos G, Cohen LM.Dermatoses of pregnancy. J Am AcadDermatol. 2001 Jul;45(1):1-19; quiz19-22. [PubMed]

3. Lin MS, Arteaga LA, Diaz LA.Herpes gestationis. Clin Dermatol.2001 Nov-Dec;19(6):697-702.[PubMed] [CrossRef]

4. Fabbri P, Caproni M, Berti S,Bianchi B, Amato L, De Pita O, etal. The role of T lymphocytes andcytokines in the pathogenesis of pem-phigoid gestationis. Br J Dermatol.2003 Jun;148(6):1141-8. [PubMed][CrossRef]

5. Lin MS, Gharia MA, Swartz SJ,Diaz LA, Giudice GJ. Identificationand characterization of epitopes recog-nized by T lymphocytes and autoanti-bodies from patients with herpesgestationis. J Immunol. 1999 Apr;162(8):4991-7. [PubMed]

cence tests and ELISA studies for anti-BMZ antibodies areuseful in establishing the diagnosis. An interdisciplinaryapproach is also of crucial importance for the benefit ofthe mother and child during pregnancy, as well as duringthe postpartum period.

REFERENCES:6. Semkova K, Black M. Pemphig-

oid gestationis: current insights intopathogenesis and treatment. Eur JObstet Gynecol Reprod Biol. 2009Aug;145(2):138–144. [PubMed][CrossRef]

7. Ambros-Rudolph CM, MulleggerRR, Vaughan-Jones SA, Kerl H, BlackMM. The specific dermatoses of preg-nancy revisited and reclassified: re-sults of a retrospective two-centerstudy on 505 pregnant patients. J AmAcadDermatol. 2006 Mar;54(3):395-404. [PubMed] [CrossRef]

8. Boulinguez S, Bedane C, ProstC, Bernard P, Labbe L, BonnetblancJM. Chronic pemphigoid gestationis:comparative clinical and immun-opathological study of 10 patients.Dermatology. 2003; 206(2):113-9.[PubMed] [CrossRef]

9. Kobayashi M, Amagai M,Kuroda-Kinoshita K, HashimotoT, Shirakata Y, Hashimoto K, et al.BP180 ELISA using bacterial re-combinant NC16a protein as a diag-

nostic and monitoring tool for bullouspemphigoid. J DermatolSci. 2002 Dec;30(3):224–32. [PubMed] [CrossRef]

10. Gan DC, Welsh B, WebsterM.Successful treatment of a severepersistent case of pemphigoid gesta-tionis with antepartum and postpartumintravenous immunoglobulin followedby azathioprine. Australas J Dermatol.2012 Feb;53(1):66-9. [PubMed][CrossRef]

11. Kreuter A, Harati A,Breuckmann F, Appelhans C, AltmeyerP. Intravenous immune globulin in thetreatment of persistent pemphigoidgestationis. J Am Acad Dermatol. 2004D e c ; 5 1 ( 6 ) : 1 0 2 7 - 8 . [ P u b M e d ][CrossRef]

12. Westermann L, Hügel R, MeierM, Weichenthal M, Zillikens D, GläserR, Schmidt E. Glucocorticosteroid-re-sistant pemphigoid gestationis: suc-cessful treatment with adjuvant immu-noadsorption. J Dermatol. 2012 Feb;39(2):168-71. [PubMed]

Address for correspondence:Ivelina Yordanova, PhD. MD, Assoc. Prof.Department of Dermatology and Venereology, Faculty of Medicine, MedicalUniversity, Pleven,91, Gen. Vladimir Vazov str., 5800 Pleven, Bulgaria.E-mail: ivelina_yordanova@abv.bg,

Please cite this article as: Yordanova I, Valtchev V, Drenovska K, Gospodinov DK, Vassileva S. Herpes gestationis.J of IMAB. 2014 Oct-Dec;20(6):552-555. doi: http://dx.doi.org/10.5272/jimab.2014206.552

Received: 03/08/2014; Published online: 10/12/2014