This bullous disorder of pregnancy is also known as pemphigoid gestationis. It is rare occurring in approximately 1 in 50,000 pregnancies. It usually occurs in the second and third trimesters beginning with urticarial papules and plaques around the periumbilical region. With time, the lesions spread to the trunk and extremities becoming bullous. They usually subside with delivery but rarely may persist for months to years. It may recur in subsequent pregnancies. It is controversial whether the disease is associated with an increased fetal morbidity and mortality with premature delivery. However, there have been rare documented cases of vertical transmission to the infant with similar appearing lesions.
Like other autoimmune diseases, there is an association with other disorders such as Grave's disease. There is a close association with HLA DR3-DR4. All patients posess a circulating IgG antibody directed against a placental matrix antigen. This antibody crossreacts with a 180 kd protein sharing homology with the bullous pemphigoid antigen (BPAg2). This binding leads to complement activation and bullae formation.
In early lesions, there may be papillary dermal edema with a mixed perivascular infiltrate of lymphocytes and eosinophils. With time, eosinophilic microabscesses form around dermal papillae leading to subepidermal blister formation. Direct immunoflurorescence shows strong linear C3 binding at the dermoepidermal junction with a lesser amount of IgG, the reverse staining pattern for bullous pemphigoid. Salt split skin assay localizes the reactants to the epidermal side, like bullous pemphigoid.
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DISEASE ASSOCIATIONS CHARACTERIZATION VERTICAL TRANSMISSION
- Herpes Gestationis in a Mother and Newborn: Immunoclinical Perspectives Based on a Weekly Follow-up of the Enzyme-Linked Immunosorbent Assay Index of a Bullous Pemphigoid Antigen Noncollagenous Domain.
Department of Dermatology, Gifu University School of Medicine, Yanagido 1-1, Gifu City 501-1194, Japan.
- Arch Dermatol. 2007 Sep;143(9):1168-72. Abstract quote
BACKGROUND: Herpes gestationis (HG) is a rare, autoimmune, bullous disease that occurs during the second or third trimester and usually resolves over weeks or months after delivery. Neonates with HG are rare (estimated at 1 per 100 000 cases). Although anti-180-kDa bullous pemphigoid (BP180) autoantibody and transfer of this autoantibody are known as the cause, to our knowledge, no coordinated analysis of clinical symptoms and anti-BP180 antibody enzyme-linked immunosorbent assay titers has been reported in a mother and neonate with HG.
OBSERVATIONS: We describe a 33-year-old woman with HG and her neonate with vesicular erythematous lesions and the weekly follow-up results of the BP180 noncollagenous domain (NC16a) enzyme-linked immunosorbent assay.
CONCLUSIONS: Almost the same titer of pathogenic antibody as that in the mother is transferred to the neonate. The plasma elimination half-life of anti-BP180 antibody is approximately 15 days in mother and neonate. An abrupt twin peak increase in the BP180 enzyme-linked immunosorbent assay index from maternal serum was observed just before and after delivery, possibly explaining why HG usually occurs in the last trimester of pregnancy and exacerbates postpartum. Lesions in the neonate resolve without treatment far before pathogenic antibody disappears, suggesting that factors other than anti-BP180 antibodies may be involved in the generation of eruptions. Frequent testing of the BP180 enzyme-linked immunosorbent assay greatly facilitates therapeutic planning.
Herpes gestationis with transient bullous lesions in the newborn.
Bonifazi E, Meneghini CL.
Pediatr Dermatol 1984 Jan;1(3):215-8 Abstract quote
A case of severe bullous dermatosis in the newborn son of a mother with herpes gestationis is reported. Bullous lesions appeared in the child about 2 hours after delivery and regressed completely without specific treatment by the end of the first month, leaving numerous epidermal cysts. The immunologic phenomena were both qualitatively and quantitatively comparable to those obtained in the mother, i.e., deposition of complement (C3) and smaller amounts of IgG at the dermo-epidermal junction of the affected skin. A transient increase of the total serum IgE was demonstrated in the mother, while the serum IgE level in the newborn was less than 5 U/ml.
The pathogenetic role of IgG autoantibodies in herpes gestationis and, more generally, in autoimmune diseases is discussed.
Herpes gestationis in a mother and child.
Chen SH, Chopra K, Evans TY, Raimer SS, Levy ML, Tyring SK.
Department of Dermatology, UTMB, Galveston, Texas 77555-1070, USA.
J Am Acad Dermatol 1999 May;40(5 Pt 2):847-9 Abstract quote
Herpes gestationis (pemphigoid gestationis) is a rare autoimmune disease that appears during pregnancy or in the immediate postpartum period.
We report the cases of a mother and neonate with immunofluorescence confirmed herpes gestationis both of whom had extensive cutaneous involvement.
PATHOGENESIS CHARACTERIZATION EOSINOPHILS
Out Evidence for eosinophil degranulation in the pathogenesis of herpes gestationis.
Scheman AJ, Hordinsky MD, Groth DW, Vercellotti GM, Leiferman KM.
Department of Dermatology, University of Minnesota, Minneapolis.
Arch Dermatol 1989 Aug;125(8):1079-83 Abstract quote
Herpes gestationis is a pregnancy-related bullous dermatosis of unknown origin with associated tissue and peripheral blood eosinophilia.
In this report, eosinophil degranulation in herpes gestationis was studied, and the role that the eosinophil may have as an effector cell that induces tissue damage through deposition of toxic cationic proteins is discussed.
Using indirect immunofluorescence with antibody to human eosinophil granule major basic protein, major basic protein was observed both within tissue eosinophils and deposited extracellularly outside eosinophils in the dermis of eight patients with herpes gestationis. Possible mechanisms whereby eosinophils might be activated to degranulate in herpes gestationis are reviewed.
Clues to the aetiology and pathogenesis of herpes gestationis.
Holmes RC, Black MM, Jurecka W, Dann J, James DC, Timlin D, Bhogal B.
Br J Dermatol 1983 Aug;109(2):131-9 Abstract quote
In a study of twenty-five patients with herpes gestationis we found that 80% possessed the HLA antigen DR3, which confers increased immune responsiveness and a predisposition to 'auto-immune disease'.
In five patients the development of herpes gestationis coincided with a change in sexual partner, suggesting that the development of herpes gestationis may depend on exposure to an antigen derived from the father. This might share determinants with a component of the basement membrane zone of skin. Although anti-basement membrane zone antibodies are present in HG it is not clear whether they play a pathogenic role.
The infrequency of neonatal involvement and the lack of correlation between immunofluorescence findings and clinical activity in our patients suggested that the antibodies might be a result of tissue damage rather than its cause. Two patients in our study were exceptional in that episodes of herpes gestationis were followed by normal pregnancies. In these patients the relationship of their DR antigens to those of the fetus may have been important in determining whether or not the pregnancy would be affected by herpes gestationis.
Department of Dermatology, Group Health Cooperative of Puget Sound, Seattle, Washington.
Dermatol Clin 1993 Jul;11(3):527-33 Abstract quote
HG expresses a broader clinical range than previously thought. Disease may be mild and nonvesicular during one pregnancy, followed by explosive vesiculobullous disease during another. On the other hand, patients with extensive HG during one pregnancy may experience mild or even subclinical disease during a subsequent gestation. The broad range of clinical signs and the lack of demonstrable fetal or maternal risk associated with HG have important ramifications for patients desirous of further children.
There is a genetic predisposition to HG. DRB1*0301 (HLA-DR3) is increased and 90% of patients express either DRB1*0301 (HLA-DR3) or DRB1*0401/040X (HLA-DR4). Ninety percent of patients also carry a C4 null allele, which may be due to linkage dysequilibrium with DRB1*0301 or DRB1*0401/040X. The disease appears to be mediated by an IgG1 specific for a 180-kD component of hemidesmosomes. This protein is distinct from the 240-kD hemidesmosomal antigen seen in BP and is coded for by a different cDNA on a different chromosome.
Abnormal expression of class II MHC occurs in the placental villi of those with HG, suggesting ongoing immunologic stimulation. This has led some investigators to believe that the primary immunologic event is taking place within the placenta and that the skin is an immunologic bystander.
- 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.
Powell AM, Sakuma-Oyama Y, Oyama N, Albert S, Bhogal B, Kaneko F, Nishikawa T, Black MM.
Department of Dermatological Immunopathology, St John's Institute of Dermatology, St Thomas' Hospital, London, England.
Arch Dermatol. 2005 Jun;141(6):705-10. Abstract quote
BACKGROUND: Pemphigoid gestationis (PG) is a rare pregnancy-associated subepidermal immunobullous disease that targets hemidesmosomal proteins, particularly BP180. Clinically, PG can resemble the eruption known as polymorphic urticarial papules and plaques of pregnancy (PUPPP), and accurate differentiation between these 2 pruritic pregnancy dermatoses has important implications for fetal and maternal prognoses. Results of epitope mapping studies show that IgG autoantibodies in up to 90% of PG serum samples target the well-defined membrane-proximal NC16a domain of BP180.
OBJECTIVE: To examine the usefulness of a commercially available NC16a domain enzyme-linked immunosorbent assay in the serodiagnosis of PG and in the differentiation of PG from PUPPP.
PARTICIPANTS: A total of 412 women consisting of pretreatment patients with PG (n = 82), patients with PUPPP (n = 164), and age- and sex-matched controls (n = 166).
METHODS: All serum samples were assayed in duplicate. Receiver operating characteristic analyses were performed to determine a cutoff value for the diagnosis of PG and for differentiation from PUPPP and controls.
RESULTS: A cutoff value of 10 enzyme-linked immunosorbent assay units was associated with specificity and sensitivity of 96%.
CONCLUSIONS: The NC16a enzyme-linked immunosorbent assay is highly sensitive and highly specific in differentiating PG from PUPPP, and it is potentially a valuable tool in the serodiagnosis of PG.
- A highly sensitive enzyme-linked immunosorbent assay for the detection of circulating anti-BP180 autoantibodies in patients with bullous pemphigoid.
Department of Dermatology, Medical College of Wisconsin, Milwaukee 53226, USA.
- J Invest Dermatol. 1997 Nov;109(5):679-83. Abstract quote
The BP180 antigen, a component of the epidermal anchoring complex, has been identified as one of the major antigenic targets of autoantibodies associated with the blistering skin disease, bullous pemphigoid.
Our research group has recently demonstrated that reactivity of bullous pemphigoid autoantibodies to the BP180 ectodomain is almost entirely restricted to a set of four antigenic sites clustered within the membrane-proximal noncollagenous stretch (NC16A). Using a passive transfer mouse model, antibodies to the corresponding noncollagenous region of murine BP180 were shown to trigger an inflammatory subepidermal blistering disease that closely mimics bullous pemphigoid.
We now report the development of an enzyme-linked immunoabsorbent assay system that is extremely sensitive in detecting disease-specific autoantibodies in the sera of bullous pemphigoid patients. The target antigen in this assay is a recombinant form of the BP180 NC16A domain that contains all four of the well-defined bullous pemphigoid-associated antigenic sites. Of 50 randomly selected bullous pemphigoid sera tested, 47 (94%) were positive in this assay, whereas no specific reactivity was detected in any of the 107 controls. Interestingly, all three of the bullous pemphigoid sera that were negative in this assay had been obtained from patients who were already undergoing treatment.
The NC16A enzyme-linked immunosorbent assay is more sensitive than any of the standard techniques for detecting circulating bullous pemphigoid autoantibodies, including other enzyme-linked immunosorbent assays, immunoblotting, and indirect immunofluorescence.
Finally, the NC16A enzyme-linked immunosorbent assay provides immunologic information that cannot be obtained from direct immunofluorescence studies of skin biopsies, and that may well be relevant in the diagnosis and treatment of bullous pemphigoid.
CLINICAL VARIANTS CHARACTERIZATION
- J Am Acad Dermatol. 2006 Nov;55(5):823-8. Epub 2006 Sep 14. Abstract quote
BACKGROUND: Pemphigoid gestationis is a rare autoimmune blistering disease that occurs during pregnancy.
OBJECTIVE: This study reviewed our clinical experience with pemphigoid gestationis.
METHODS: We reviewed medical records of 10 patients with pemphigoid gestationis seen at Mayo Clinic, Rochester, Minnesota, between 1976 and 2004.
RESULTS: Urticarial papules were the most frequent clinical presentation followed by blisters and rash. Pruritus was the cardinal symptom. Lesions presented initially on the legs, thighs, back, and chest. Direct immunofluorescence had the highest diagnostic test sensitivity. Systemic corticosteroids were the mainstay of treatment. Fetal and maternal outcome was good in all cases.
LIMITATIONS: This was a retrospective, single-institution study.
CONCLUSIONS: This condition can be easily confused with other dermatoses of pregnancy, for example, pruritic urticarial papules of pregnancy. Biopsy for direct immunofluorescence is the preferred test for confirmation of diagnosis. On the basis of good patient outcomes, conservative treatment seems warranted.
Herpes gestationis: clinical and histologic features of twenty-eight cases.
Shornick JK, Bangert JL, Freeman RG, Gilliam JN.
J Am Acad Dermatol 1983 Feb;8(2):214-24 Abstract quote
We have studied 28 patients with well-documented herpes gestationis (HG) to determine the frequency of complications and to review the histopathology, immunopathology, and clinical parameters of disease. T
he frequency of miscarriages and other maternal complications in our series was not extraordinary. Fetal complications were similarly limited. Less than 5% of infants had cutaneous lesions, and no other untoward fetal complications were apparent. Although the clinical features of our patients largely paralleled those typically reported for patients with HG, several variants of disease were noted.
We report one woman with immunofluorescence-confirmed HG who had no clinical disease during a subsequent pregnancy. We also identified cases in which the characteristic vesiculobullous lesions of HG never developed. Instead, four women had urticarial papules or plaques throughout their clinical courses. HG was verified in these four women by typical immunofluorescent findings and by recurrent, classical disease during subsequent pregnancies in two. In addition, two women were identified with recurrent HG during pregnancies by different husbands.
Pemphigoid gestationis with predominant involvement of oral mucous membranes and IgA autoantibodies targeting the C-terminus of BP180.
Shimanovich I, Skrobek C, Rose C, Nie Z, Hashimoto T, Brocker EB, Zillikens D.
Department of Dermatology, University of Wurzburg, and the Department of Dermatology, Kurume University School of Medicine, Fukuoka.
J Am Acad Dermatol 2002 Nov;47(5):780-4 Abstract quote
Pemphigoid gestationis (PG) is an autoimmune pregnancy-associated subepidermal blistering disease. It usually affects skin and, rarely, mucous membranes.
In the vast majority of patients with PG, the autoimmune response is directed to the membrane-proximal NC16A domain of the 180-kd bullous pemphigoid (BP) antigen (BP180) and is mediated by IgG1 and IgG3 autoantibodies.
We report the case of a patient with PG associated with extensive lesions on oral mucous membranes. Immunoblotting studies demonstrated the presence of circulating IgA autoantibodies in the patient's serum that were exclusively directed to a 49 amino acid stretch on the C-terminal portion of the BP180 ectodomain located 800 amino acids downstream from NC16A. This C-terminal stretch of BP180 has previously been demonstrated to localize to the lamina lucida/lamina densa interface and to be recognized by IgG and IgA antibodies in a subgroup of patients with cicatricial pemphigoid as well as by IgG autoantibodies in some BP sera.
Our patient's lesions healed without scarring within 6 weeks after delivery of a healthy child. The findings in this patient extend the clinical and immunopathologic spectrum of PG.
Herpes gestationis. A clinicopathologic study.
Hertz KC, Katz SI, Maize J, Ackerman AB.
Arch Dermatol 1976 Nov;112(11):1543-8 Abstract quote
Herpes gestationis is a pruritic, blistering eruption of pregnancy and the puerperium. In three patients with immunologically verified disease, the clinical presentation consisted of widespread erythematous, edematous papules and plaques, grouped vesicles on erythematous bases, and tense bullae.
Histologically, these lesions showed a moderately dense, mixed-inflammatory cell infiltrate around superficial and deep dermal blood vessels, and focal necrosis of epidermal basal cells. Papillary dermal edema, subepidermal bullae, and spongiosis were prominent. Eosinophils were frequently present in the subepidermal and intrepidermal vesicles.
Differentiation of herpes gestationis from other blistering diseases and other dermatitides of pregnancy may be difficult.
CHARACTERIZATION DIRECT IMMUNO-FLUORESCENCE
J Cutan Pathol. 2006 Apr;33(4):299-302. Abstract quote
Background: Pemphigoides gestationis (PG) is a blistering disorder of pregnancy caused by antibodies against basement membrane proteins. They are directed against the 180 kD bullous pemphigoid antigen (BPAg2), towards the epitopes within the NC 16A domain. There are many similarities between pemphigoid gestationis and bullous pemphigoid (BP), but the literature so far indicated different immunofluorescence results in regards with C3 and IgG, and IgG subclasses (IgG4 vs. IgG1).
Methods: We evaluated staining patterns and IgG subclasses, as well as C5b-9 membrane attack complex (MAC) in 10 pregnant patients with PG, using sandwich double antibody immunofluorescence (SDAI) and direct immunofluorescence (DIF).
Results: All ten specimens stained with C3 by DIF, but only five had trace amount of IgG reactants by this method. By SDAI, 100% were positive for the IgG4 and C5b-9 MAC, 70% for IgG2, 50% for IgG1, and 40% for IgG3.
Conclusion: IgG4 was the predominant IgG subtype identified. This finding has not been reported for PG, but it mimics results reported for BP. One explanation is prolonged disease course, as well as blocking of antigenic domains by IgG4. Understanding this completely will help develop therapies and prevention strategies for immunobullous and other autoimmune diseases, and perhaps aid in an exact classification.
Immunopathological studies in herpes gestationis.
Carruthers JA, Black MM, Ramnarain N.
Br J Dermatol 1977 Jan;96(1):35-43 Abstract quote
Four cases of herpes gestationis are reported and the immunopathological findings in these patients described.
Complement deposition at the basement membrane zone of the patients' peri-bullous skin was seen in all patients, immunoglobulin deposition in two. A circulating factor capable of fixing complement on the basement membrane zone of normal human skin was present in three patients.
These findings are discussed and compared with the immunopathological findings in bullous pemphigoid.
Morrison LH, Anhalt GJ.
Oregon Health Sciences University, Department of Dermatology, Portland 97201-3098.
J Autoimmun 1991 Feb;4(1):37-45 Abstract quote
Herpes gestationis is a rare, self limited bullous disease of pregnancy and the post-partum period with a presumed autoimmune basis. It is characterized clinically by pruritic, urticarial and vesiculobullous lesions, histologically by subepidermal vesicle formation, and immunopathologically by deposition of immunoreactants along the basement membrane zone.
These features are shared by bullous pemphigoid which suggests that herpes gestationis may be a related entity. Immunoblotting studies have shown that herpes gestationis sera recognize a 180 kD epidermal antigen; in comparison, bullous pemphigoid sera most often detect a 220-240 kD antigen, but a significant number also recognize a 180 kD epidermal antigen, suggesting immunological similarities between these two diseases.
Etiology and pathophysiology are not established, but an immunological basis is implicated by the frequent finding of C3 along the basement membrane zone of perilesional skin, the presence of herpes gestationis factor, increased incidence of HLA-DR3 and HLA-DR4, and association with other putative autoimmune diseases. Treatment usually consists of systemic corticosteroids.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES TOXIC ERYTHEMA OF PREGNANCY
A comparative study of toxic erythema of pregnancy and herpes gestationis.
Holmes RC, Black MM, Dann J, James DC, Bhogal B.
Br J Dermatol 1982 May;106(5):499-510 Abstract quote
We compared the clinical features, histopathology, immunopathology and immunogenetics of 30 patients with toxic erythema of pregnancy and 24 patients with herpes gestationis. Although we found some clinical and histopathological overlap we highlighted several important differences.
In toxic erythema of pregnancy prominent striae were frequently present. Herpes gestationis was suggested by the occurrence of periumbilical lesions, acute exacerbations immediately after delivery, and persistence of the eruption for more than 3 weeks post-partum. In herpes gestationis, immunofluorescence studies were consistently positive, there was a high frequency of HLA-B8 and an association with autoimmune thyrotoxicosis. Toxic erythema of pregnancy did not share these immunological features.
Therefore we feel that toxic erythema of pregnancy and herpes gestationis should continue to be classified as separate disorders.
PROGNOSIS AND TREATMENT CHARACTERIZATION GENERAL
Fetal and maternal risk factors in herpes gestationis.
Lawley TJ, Stingl G, Katz SI.
Arch Dermatol 1978 Apr;114(4):552-5 Abstract quote
Forty-one cases of immunologically proved herpes gestationis (HG) are reviewed and there appears to be an increased risk of fetal morbidity and mortality. The onset of HG is most frequent in the second and third trimesters of pregnancy although postpartum onset or exacerbation is common.
The presence of high-titer, antibasement membrane zone antibody seems to correlate with a severe clinical disease. Systemic treatment with corticosteroids is frequently necessary in order to control maternal signs and symtpoms of HG.
Immunopathological and clinical studies in herpes gestationis.
Foidart JM, Yaar M, Hall R, Gaspard U, Katz SI.
Br J Obstet Gynaecol 1981 Feb;88(2):153-9 Abstract quote
Herpes gestationis is a recurring pruritic, vesiculobullous disease of pregnancy and puerperium. Recently, Lawley et al (1979) reported a high frequency (38 per cent) of fetal morbidity and mortality in 40 cases of immunologically proven herpes gestationis. This study was undertaken to determine whether the antibody to skin basement membrane (found in most patients with herpes gestationis) is able to bind to the placenta basement membranes and thereby to threaten the pregnancy.
We were unable to detect this antibody in the placental basement membranes of a patient with herpes gestationis, nor could we demonstrate that the anti-basement membrane antibody, found in the sera of herpes gestationis patients, binds to homologous or autologous placentas and fetal membranes. The importance of an accurate diagnosis and appropriate treatment of this condition is discussed.
The fetal prognosis in pemphigoid gestationis (herpes gestationis).
Holmes RC, Black MM.
Br J Dermatol 1984 Jan;110(1):67-72 Abstract quote
We have studied the infants in fifty pregnancies affected by pemphigoid gestationis (herpes gestationis). There was a significant increase in the frequency of infants that were 'small for dates'. As such infants have a raised mortality and morbidity it follows that in pemphigoid gestationis the fetal prognosis is impaired.
In view of this it is essential that patients with pemphigoid gestationis are delivered in maternity units which have facilities for intensive care of the newborn.
Herpes gestationis. Persistent disease activity 11 years post partum.
Fine JD, Omura EF.
Arch Dermatol 1985 Jul;121(7):924-6 Abstract quote
A patient had herpes gestationis that had persisted for over 11 years post partum despite aggressive therapy with corticosteroids, dapsone, and various immunosuppressants.
Postpartum exacerbation is a characteristic feature of herpes gestationis. However, it usually is of short duration and is responsive to conventional therapy.
Recurrent herpes gestationis with postpartum flare: a case report.
Baxi LV, Kovilam OP, Collins MH, Walther RR.
Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Am J Obstet Gynecol 1991 Mar;164(3):778-80 Abstract quote
A case of herpes gestationis recurring in each pregnancy, with a postpartum flare-up in the last pregnancy, is described. The diagnosis was confirmed by skin biopsy. The first pregnancy ended in a term stillbirth, but there were favorable outcomes in four subsequent pregnancies.
Histopathologic examination of the placentas of the last three pregnancies revealed varying grades of villositis. Symptoms improved with oral corticosteroids.
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Salt split skin assay-Normal skin incubated with 1M NaCl which separates the epidermis from dermis. The epidermal half contains the upper lamina lucida, hemidesmosomes, and BP antigen. The dermal half contains laminin 5, lamina densa, and anchoring fibrils.
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