Journal of Autoimmunity (1991) 4,3745
Herpes Gestationis
Lynne H. Morrison* and Grant J. Anhalt?_ *Oregon Health
Sciences
University,
University,
Department
Department
of Dermatology,
of Dermatology, Portland,
Oregon,
T’johns Hopkins USA
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 lcD epidermal antigen; in comparison, bullous pemphigoid sera most often detect a 220-24OhD 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 C, 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.
Definition
Herpes gestationis (HG) is a pruritic subepidermal, bullous dermatosis of pregnancy and the post-partum period. Despite its name, it is not related to viral infection, but rather is presumed to be an autoimmune disease. It is self-limited, usually beginning in the second trimester and often resolving within 3 months of delivery. Its incidence is estimated to be anywhere from 1:3,00C~1:50,000 pregnancies, with the latter figure probably being more accurate [l.] Definitive diagnosis of HG rests on immunofluorescent (IF) studies.
Reprint requests to: Lynne H. Morrison, MD, Oregon Health Sciences University, Department of Dermatology, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97201-3098 USA. 37 0896-8411/91/010037+09$03.00/0
0 1991 Academic Press Limited
38
L. H. Morrison and G. J. Anhalt
Figure 1. Clinical features of herpes gestationis include urticarial papules and plaques and tense bullae.
Clinical
Features
Intense pruritus is a characteristic feature of HG, which may precede onset of lesions by days to weeks. The eruption of HG, is polymorphic, consisting of urticarial papules, plaques, vesicles, bullae, and targetoid lesions, resembling those seen in erythema multiforme [2, 31. Classically, HG begins as urticarial papules and plaques in and around the umbilicus, however, lesions may initially present on the extremities in up to 50% of patients [4]. Subsequently, vesicles and bullae then appear superimposed on the urticarial plaques and on normal skin (Figure 1). The lesions spread to involve trunk and extremities and palm and sole involvement is common. The face is usually spared and mucosal lesions are rare [ 1,4]. The onset of the eruption is most often during the fourth to seventh month of pregnancy, but it may occur at any time from the first trimester to the immediate post-partum period [2,3]. Post-partum onset usually occurs within 3 days of delivery and may be explosive. Seventy-five to eighty percent of patients experience a postpartum flare of their disease usually beginning within 12-48 hours of delivery [ 1,3]. The eruption usually resolves within 3 months after delivery but rare cases have been reported to last up to 12 years post-partum [S, 61. HG has also been noted to flare with menses for months to years after parturition. Exacerbations associated with use of oral contraceptives have also been reported in 20-50% of patients [ 1,2].
Herpes gestationis
39
Once HG occurs in association with one pregnancy, it is generally expected to recur with subsequent pregnancies, and when it does, the disease usually begins earlier and lasts longer. Studies on fetal prognosis in HG have revealed inconsistent findings. An early review of cases documented by IF studies indicated that there is an increased incidence of stillbirths and premature infants born to affected mothers [7]. In contrast, Shornick et al. reported 28 patients with HG whose diagnosis was also confirmed by IF and found no increase in fetal morbidity or mortality [4]. In a study of 50 pregnancies affected by HG, Holmes and Black found a significant increase in ‘small for dates’ infants. Since such infants have an increase in morbidity and mortality, they concluded that HG is associated with an altered fetal prognosis [8]. Infants born to mothers with HG only infrequently have cutaneous lesions typical of HG. The lesions are transient, resolving spontaneously within a few weeks. Direct immunofluorescent (IF) studies done on perilesional skin from both affected and unaffected infants has shown linear deposition of C, along the basement membrane zone [9, lo]. No long-term sequelae of disease has been noted in offspring of affected mothers. Histology and Ultrastructure The characteristic histopathology of bullous lesions of HG shows a subepidermal blister with a pronounced mixed dermal inflammatory infiltrate, consisting of lymphocytes, histiocytes and eosinophils [l, 2, 111. The epidermis may show spongiosis and spongiotic vesicle formation, with eosinophils scattered singly within the epidermis or found within the spongiotic vesicles. Vacuolar degeneration along the dermal-epidermal junction is a frequent finding lateral to the blister [2]. Biopsies taken from non-bullous edematous plaques show the characteristic dermal infiltrate mixed with eosinophils and papillary edema. Vacuolar degeneration of basal cells is usually present in the absence of overt blister formation. Electron microscopic (EM) studies have shown that early ultrastructnral changes in normal perilesional skin consist of damage to the dermal side of the basal cell plasma membrane accompanied by mild intracellular degeneration [12]. Nonbullous erythematous lesions show pronounced degeneration or loss of basal cells but good preservation of the basal lamina [12]. In bullous lesions, similar basal cell changes were present, with the basal lamina either absent or forming the base of the blister. Thus, the blister formation in HG seems to result from destruction of basal cells [ 12, 131. This is in contrast to what has been observed ultrastructurally in bullous pemphigoid (BP), which is separation occurring between the basal cell plasma membrane and basal lamina with less destruction of basal cells [ 12,141. Immunopathology Biopsies taken from normal perilesional skin or from urticarial lesions for direct IF studies characteristically show linear deposition of C, along the basement membrane zone (BMZ) [l-3] (Figure 2). Thirty to forty percent also show weak linear deposition of IgG, but the intensity is generally much less than that of the C, [l, 2, 151. The characteristic direct IF features of HG have been found in skin of infants born to affected mothers. This has been reported in neonates both with and without
40
L. H. Morrison and G. J. Anhalt
Figure 2. Skin biopsy processed for direct immtmofiuorescent along the basement membrane zone.
studies showing linear deposition of C,
cutaneous lesions [2, 4, 9, IO]. Routine indirect IF studies in HG are most often negative because the levels of circulating anti-BMZ antibodies are present in low enough quantity to fall below the level of sensitivity of this technique. Only 20% of HG sera show anti-BMZ antibodies detectable by this technique. However, using the indirect complement fixation IF technique, the majority of patient sera demonstrate the presence of a factor capable of fixing complement along the BMZ [2,3, l+lSJ. In this technique, normal human skin is first incubated with HG sera, then with a source of complement and finally with fluorescein isothiocyanate (FITC) conjugated anti-human C,. The resulting linear band of fluorescence along the BMZ indicates the presence of complement-fixing IgG class anti-BMZ antibodies present in the patients’ sera. Although normal human skin is routinely used for such IF studies, it has recently been shown that HG factor activity is also demonstrable using human amnion as a substrate [ 19,201. Initial studies suggested that this complement-fixing substance in the serum of HG patients was not an immunoglobulin and it was termed the ‘HG Factor’ [21]. It has since been identified as an avidly complement-fixing IgG class antibody by sucrose density ultracentrifugation, sedimentation characteristics, ion-exchange and gel filtration chromatography [15, 18, 221. Immunofluorescent studies using monoclonal antibodies have shown IgG 1 to be the major IgG subclass present in
Herpes gestationis
41
both serum and tissue [23]. HG factor activity has been demonstrated in cord blood of infants born to affected mothers reflecting the fact that IgG is capable of crossing placental barriers [ 15, 171. Direct immuno-EM studies have demonstrated deposition of IgG and C, in the lamina lucida [24-261. Some investigators have noted that the immunoreactants are closely associated with the dermal aspect of the basal cell membrane, and deposition is accentuated in the areas of hemidesmosomes, similar to that seen in BP [25]. Indirect immuno-EM studies have been performed by only a single investigator who has shown deposition of C, in the lamina lucida of human skin. Relationship to BP The fact that herpes gestationis and bullous pemphigoid share a number of similarities has led to much speculation regarding the exact relationship between the two diseases. Similarities include the morphology of the eruption, histological findings of subepidermal blister formation with a dermal inflammatory infiltrate mixed with eosinophils and the linear deposition of immunoreactants along the BMZ on direct IF examination. Despite these similarities, a number of distinct differences do exist. The population affected in the two syndromes is markedly different; BP is largely a disease of the elderly, affecting males and females equally, while HG is limited to pregnant or post-partum females or those with choriocarcinomas or hydatidiform moles and is exacerbated by estrogens or progestins. Ultrastructurally, more basal cell necrosis is seen in HG than BP, and by IF studies HG shows linear deposition of C, along the BMZ, usually in the absence of IgG deposition. However, in BP the two immunoreactants are usually noted to have approximately equal intensity [2]. This reflects the high avidity with which small quantities of tissue bound and circulating HG autoantibodies fix complement. Further studies have been directed at characterizing the antigens in the two diseases to help delineate the relationship between HG and BP. Immunoblotting studies have been used to determine the specificity of the HG autoantibodies and to compare the antigens recognized by HG autoantibodies to those detected by BP autoantibodies. Immunoblotting performed using sera of 17 HG patients showed that 89% of HG factor-positive sera detected a 180 kD epiderma1 protein, while only one serum recognized both the 180 and 240 kD epidermal antigen [27]. Using similar techniques, it has been shown that BP autoantibodies most frequently recognized a high molecular weight (MW) epidermal antigen of 220-240 kD (28,291, but nearly half of BP sera detect a 180 kD epidermal antigen, either alone or in association with the high MW antigen [27]. These findings suggest immunological similarities between the two diseases and strengthen the proposal that the two entities are closely related. Recent reports suggest that the 180 and 220-240 kD antigens are epidermal hemidesmosomal proteins or are proteins closely associated with these structures [30]. Using purified antibodies to both the high (220-240) and low (180) MW epidermal proteins, Anhalt et al. have found that these two antigens may be immunologically related or may form a complex in the hemidesmosome [3 11. Further characterization of these antigens is being carried out by molecular cloning and sequencing [32,33].
42
L. H. Morrison and G. J. Anhalt
Blocking studies have also been used to investigate similarities between HG and BP antigens and antibodies. Jordon et al. showed that incubation of normal human skin with HG factor-positive sera almost entirely blocked deposition of BP antibodies along the BMZ [18]. Carruthers et aE. in contrast, found no blocking of BP antibody deposition by HG sera, but did show that preincubation of skin with BP sera blocked HG factor deposition in five of seven HG sera [22]. These results suggest heterogeneity of BP antigen/antibody system with some partial similarity of antigens in HG and BP. Pathophysiology
Although the etiology of HG is unknown, the consistent finding of C, deposited along the BMZ of perilesional skin and the frequent presence of the HG factor in patient serum suggest an autoimmune basis for the disease. Another feature which supports this concept is the increased incidence of HLA-DR3 and also the combination of HLA-DR3 and DR4 antigens in patients with HG, findings observed in patients with autoimmune-mediated diseases [34,35]. HLA-DR3 antigen has been reported with increased frequency in patients with dermatitis herpetiformis, Graves’ disease, myasthenia gravis, scleroderma, Addison’s disease, Sjogrens Syndrome and subacute cutaneous lupus erythematosus; the DR4 antigen has been associated with pemphigus vulgaris, Type I diabetes mellitus, multiple sclerosis and rheumatoid arthritis [36]. HG has been reported in association with other putative autoimmune diseases such as Graves’ disease, alopecia areata and ulcerative colitis, but these cases are largely sporadic and the association may be coincidental [3]. One study has found that 21 y0 of HG patients also had Graves’ disease at some time in their life, suggesting more than a coincidental association [37]. This has not been verified by other studies. Although the immunopathological findings support the idea that anti-BMZ autoantibodies mediate the disease, there is currently no proof of their pathogenic role. Because HG sera have been shown to fur complement along the BMZ of normal amnion, it is intriguing to speculate that autoantibodies may initially be formed against an amniotic antigen and then cross-react with skin, mediating lesion formation, but this is purely hypothetical at this point. Because the anti-BMZ antibody is an IgG and is therefore, capable of crossing the placenta, it is presumed that this antibody also mediates development of skin lesions in neonates. Because the infant can catabolize the maternal IgG, its immunologic effect diminishes without intervention, as do the infant’s cutaneous lesions. Several components of both the classic and alternate complement pathways including Clq, C,, C,, C,, properdin and factor B have been identified along the BMZ in Rerilesional skin of HG patients [3, 15, IS]. It was originally proposed that the complement cascade was activated via the alternate pathway because of the presence of properdin and factor B along the BMZ, but subsequent studies implicate the classical pathway as the main route of complement activation [ 15,181. The presence of properdin and factor B along the BMZ probably reflect involvement of the alternate pathway by the C, feedback loop. Because of its strict association with pregnancy, hydatidiform moles and choriocarcinoma [l, 38, 391 and exacerbation with menses, oral contraceptives,
Herpes gestationis
43
progestational agents [40] and estrogens [17] it is likely that hormonal balance plays a role in pathogenesis of HG, but this has not been clearly elucidated. Plasma and urinary estriol levels have been measured in only a few patients and have been generally within normal limits [41]. Foidart reported that serum human placental lactogen and serum human chorionic gonadotropin levels were low in several HG patients, but the significance of these findings is not clear [41]. Further work is needed to clarify the contribution of hormones to disease expression in HG. Treatment Systemic corticosteroids are the mainstay of therapy in HG, with prednisone being the most widely used agent. In most cases, 2040 mg of prednisone daily is adequate to control the pruritus and suppress new lesion formation, which are the primary goals of treatment [ 1,3,4]. Rarely, higher doses may be needed for control. Because the disease frequently flares after delivery, it may be necessary to increase the dose of prednisone at this time, and then gradually taper it during the post-par-turn period. Exacerbations with menses may again require dosage increases or may be controlled with addition of topical steroids. Topical steroids may be helpful in mild cases of HG, but are generally not adequate to control moderate to severely affected patients. Antihistamines are useful adjunctive therapy to topical steroids. Patients very infrequently manifest an unusually severe or long-lasting eruption, not responsive to high doses of corticosteroids and require addition of an immunosuppressive agent [2,5]. This is clearly contraindicated during pregnancy and breast feeding. Cutaneous lesions in infants are transient and require no specific treatment. If an infant’s mother has been treated with systemic corticosteroids, the infant should be evaluated for adrenal suppression, although this is a rare occurrence. Acknowledgements This work was supported in part by U. S. Public Health Service Grant R29 AR39761 (LM), and RO 1 AR32490 and K04 AR0 1686 (G JA) from the National Institutes of Health. References 1. Shornick, J. K. 1987. Herpes Gestationis. J. Am. Acad. Dermatol. 17: 539-556 2. Provost, T. T. and S. I. Katz. 1987. Herpes Gestationis. In Dermatology in GeneraI Medicine, 3rd edn. T. B. Fitzpatrick, A. Z. Eisen, K. Wolff, I. M. Freedberg and
K.F. Austen, eds. McGraw-Hill, Inc., New York, pp. 586-589
3. Eaglestein, N. F., G. J. Anhalt, H. J. Patel, and L. A. Diaz. Herpes Gestationis. In Zmmunopathology of the Skin. E. H. Beutner, T. D. Chorzelski and V. Kuman, eds.
John Wiley, New York. pp. 371-379
4. Shornick, J. K., J. L. Bangert, R. G. Freeman, and J. N. Gilliam. 1983. Herpes gestationis: Clinical and histologic features of twenty-eight cases. J. Am. Acad. Dermatol. 8: 214-224 5. Holmes, R. C., D. M. Williamson, and M. M. Black. 1986. Herpes gestationis persisting for 12 years post parrum. Arch. Dermatol. 122: 375-376 6. Fine, J.-D. and E. F. Omura. 1985. Herpes gestationis. Persistent disease activity 11 years postpartum. Arch. Dermatol. 121: 924-927
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L. H. Morrison and G. J. Anhalt
7. Lawley T. J., G. Sting1 and S. I. Katz. 1978. Fetal and maternal risk factors in herpes gestationis. Arch. Dermatol. 114:552-555 8. Holmes, R. C. and M. M. Black. 1984. The fetal prognosis in pemphigoid gestationis (herpes gestationis). Br. J. Dermatol. 110:67-72 9. Chorzelski, T. I’., S. Jablonska, E. H. Beutner, E. Maciejowska, and M. JarzabekChorzelska. 1976. Herpes gestationis with identical lesions in the newborn. Arch. Dermatol. 112: 1129-1131 10. Katz, A., J. 0. Minta, J. W. P. Toole, and W. Medwidsky. 1977. Immunopathologic study of herpes gestationis in mother and infant. Arch. Dermatol. 113: 1069-1072 11. Lever W. F. and G. Schaumburg-Lever. 1983. Noninfectious vesicular and bullous diseases: Herpes Gestationis. In Histopathology of the Skin. 6th edn, W. F. Lever and G. Schaumburg-Lever, eds. J. B. Lippincott, Philadelphia. pp. 118 12. Yaoita H., M. Gullino, and S. I. Katz. 1976. Herpes gestationis. Ultrastructure and ultrastructural localization of in vivo-bound complement. J. Invest. Dermatol. 66: 383-388 G., 0. E. Saffold, C. E. Orfanos, and W. F. Lever. 1973. Herpes 13. Schaumburg-Lever, gestationis: Histology and ultrastructure. Arch. DermatoZ. 107: 888-892 14. Schaumburg-Lever G., C. E. Orfanos and W. F. Lever. 1972. Electronmicroscopic study of bullous pemphigoid. Arch. Dermatol. 106: 662-667 15. Katz, S. I., K. C. Hertz, and H. Yaoita. 1976. Herpes gestationis: Immunopathology and characterization of the HG factor. J. Cl&. Invest. 57: 1434-1441 16. Carruthers J. A. 1978. Herpes gestationis: Clinical features of immunologically proved cases. Am.J. Obstet. Gynecol. 131: 865-867 17. Carruthers J. A., M. M. Black, and N. Ramnarain. 1977. Immunopathological studies in herpes gestationis. Br. J. Dermatol. 96: 35-43 18. Jordon, R. E., K. G. Heine, G. Tappeiner, L. L. Bushkell and T. T. Provost. 1976. The immunopathology of herpes gestationis: Immunofluorescence studies and characterization of ‘HG Factor’.J. CZin. Invest. 57: 1426-1433 19. Ortonne, J.-P., B.-L. Hsi, P. Verrando, F. Bernerd, G. Pautrat, A. Pisani, and C.-J. G. Yeh. 1987. Herpes gestationis factor reacts with the amniotic epithelial basement membrane. Br.J. Dermatol. 117: 147-154 20. Kelly S. E., B. S. Bhogal, F. Wohnarowska, and M. M. Black. 1988. Expression of a pemphigoid gestationis-related antigen by human placenta. Br.J. Dermatol. 118:605-611 21. Provost, T. T. and T. B. Tomasi, Jr. 1973. Evidence for complement activation via the alternate pathway in skin diseases I. J. CZin. Invest. 52: 1779-1787 22. Carruthers, J. A. and A. R. Ewins. 1978. Herpes gestationis: studies on the binding characteristics, activity and pathogenetic significance of the complement-fixing factor. CZin. Exp. Immunol. 31: 38-44 23. Kelly, S. E., R. Cerio, B. S. Bhogal, and M. M. Black. 1989. The distribution of IgG subclasses in pemphigoid gestationis: PG Factor is an IgGl autoantibody. J. Invest. Dermatol. 92: 695-698 24. Holubar, K., K. Konrad, and G. Stingl. Detection by immunoelectron microscopy of immunoglobulin G deposits in skin of immunofluorescence negative herpes gestationis. BP-.J. Dermatol. 96: 569-571 25. Harrington, C. I. and S. S. Bleehen. 1979. Herpes gestationis: immunopathological ultrastructural studies. Br. J. Dermatol. 100:389-399 26. Honigsmann, H, G. Stingl, K. Holubar, and K. Wolff. 1976. Herpes gestationis: Fine structural pattern of immunoglobulin deposits in the skin in vivo. 3. invest. DermatoZ. 66: 389-392 27. Morrison, L. H., R. S. Labib, J. J. Zone, L. A. Diaz, and G. J. Anhalt. 1988. Herpes gestationis autoantibodies recognize a 180 kD human epidermal antigen. 3. CZin. Invest. 81: 2023-2026 28. Stanley, J. R., D. T. Woodley, and S. I. Katz. 1984. Identification and partial characterization of pemphigoid antigen extracted from normal human skin. J. Invest. DermatoZ. 82: 108-111
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29. Stanley, J. R., P. Hawley-Nelson, S. H. Yuspa, E. M. Shevah, and S. I. Katz. 1981. Characterization of bullous pemphigoid antigen: A unique basement membrane protein of stratified squamous epithelia. Cell 24: 897-903 30. Mutasim, D. F., L. H. Morrison, Y. Takahashi, et al. 1989. Definition of bullous pemphigoid antibody binding to intracellular and extracellular antigen associated with hemidesmosomes. J. Invest. Dermatol. 92: 225-230 31. Robledo, M., R. S. Labib, N. Korman, et al. 1989. The 230 and 18OkD bullous pemphigoid antigens are immunologically related. Clin. Res. 37: 626 32. Stanley, J. R., T. Tanaka, S. Mueller, et al. 1988. Isolation of complementary DNA for bullous pemphigoid antigen by use of patient’s autoantibodies. J. Clin. Invest. 82: 1864-1870 33. Diaz, L. A., S. Futamura, and H. L. Squiquera. 1989. Generation of an E. coli lysogen that synthesizes an epitope of the 180 kD epidermal protein recognized by bullous pemphigoid autantibodies. G&r. Res. 37: 623 34. Holmes, R. C., M. M. Black, W. Jurecka, J. Dann, D. C. 0. James, D. Timlin, and B. Bhogal. 1983. Clues to the aetiology and pathogenesis of herpes gestationis. Br. J. Dermatol. 109: 131-139 35. Shornick, J. K., I’. Stastny, and J. N. Gilliam. 1981. High frequency ofhistocompatibility antigens HLA-DR3 and DR4 in herpes gestationis. J. Gin. Invest. 68: 553-555 36. Svejgaard, A., U. Morling, P. Platz, et al. 1981. HLA and disease associations with special references to mechanisms. Transpl. Proc. 13: 193 37. Holmes, R. C., M. M. Black, J. Dann, D. C. 0. James, and B. Bhogal. 1982. A comparative study of toxic erythema of pregnancy and herpes gestationis. Br. J. Dermatol. 106: 499-510 38. Slazinski, L. and S. Degefu. 1982. Herpes gestationis associated with choriocarcinoma. Arch. Dermatol. 118: 425-428 39. Tindall, J. G., T. H. Rea, I. Shulman, and F. P. Quismorio, Jr. 1981. Herpes gestationis in association with a hydatidiform mole. Arch. Dermatol. 117: 510-512 40. Lynch, F. W. and R. J. Albrecht. 1966. Hormonal factors in herpes gestationis. Arch. Derm. 93: 446-447 41. Foidart, J. M., M. Yarr, R. Hall, U. Garpard and S. I. Katz. 1981. Immunopathological and clinical studies in herpes gestationis. Br. 3. Dermatol. 88: 153-159
Herpes Gestationis
Lynne H. Morrison* and Grant J. Anhalt?_ *Oregon Health
Sciences
University,
University,
Department
Department
of Dermatology,
of Dermatology, Portland,
Oregon,
T’johns Hopkins USA
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 lcD epidermal antigen; in comparison, bullous pemphigoid sera most often detect a 220-24OhD 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 C, 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.
Definition
Herpes gestationis (HG) is a pruritic subepidermal, bullous dermatosis of pregnancy and the post-partum period. Despite its name, it is not related to viral infection, but rather is presumed to be an autoimmune disease. It is self-limited, usually beginning in the second trimester and often resolving within 3 months of delivery. Its incidence is estimated to be anywhere from 1:3,00C~1:50,000 pregnancies, with the latter figure probably being more accurate [l.] Definitive diagnosis of HG rests on immunofluorescent (IF) studies.
Reprint requests to: Lynne H. Morrison, MD, Oregon Health Sciences University, Department of Dermatology, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97201-3098 USA. 37 0896-8411/91/010037+09$03.00/0
0 1991 Academic Press Limited
38
L. H. Morrison and G. J. Anhalt
Figure 1. Clinical features of herpes gestationis include urticarial papules and plaques and tense bullae.
Clinical
Features
Intense pruritus is a characteristic feature of HG, which may precede onset of lesions by days to weeks. The eruption of HG, is polymorphic, consisting of urticarial papules, plaques, vesicles, bullae, and targetoid lesions, resembling those seen in erythema multiforme [2, 31. Classically, HG begins as urticarial papules and plaques in and around the umbilicus, however, lesions may initially present on the extremities in up to 50% of patients [4]. Subsequently, vesicles and bullae then appear superimposed on the urticarial plaques and on normal skin (Figure 1). The lesions spread to involve trunk and extremities and palm and sole involvement is common. The face is usually spared and mucosal lesions are rare [ 1,4]. The onset of the eruption is most often during the fourth to seventh month of pregnancy, but it may occur at any time from the first trimester to the immediate post-partum period [2,3]. Post-partum onset usually occurs within 3 days of delivery and may be explosive. Seventy-five to eighty percent of patients experience a postpartum flare of their disease usually beginning within 12-48 hours of delivery [ 1,3]. The eruption usually resolves within 3 months after delivery but rare cases have been reported to last up to 12 years post-partum [S, 61. HG has also been noted to flare with menses for months to years after parturition. Exacerbations associated with use of oral contraceptives have also been reported in 20-50% of patients [ 1,2].
Herpes gestationis
39
Once HG occurs in association with one pregnancy, it is generally expected to recur with subsequent pregnancies, and when it does, the disease usually begins earlier and lasts longer. Studies on fetal prognosis in HG have revealed inconsistent findings. An early review of cases documented by IF studies indicated that there is an increased incidence of stillbirths and premature infants born to affected mothers [7]. In contrast, Shornick et al. reported 28 patients with HG whose diagnosis was also confirmed by IF and found no increase in fetal morbidity or mortality [4]. In a study of 50 pregnancies affected by HG, Holmes and Black found a significant increase in ‘small for dates’ infants. Since such infants have an increase in morbidity and mortality, they concluded that HG is associated with an altered fetal prognosis [8]. Infants born to mothers with HG only infrequently have cutaneous lesions typical of HG. The lesions are transient, resolving spontaneously within a few weeks. Direct immunofluorescent (IF) studies done on perilesional skin from both affected and unaffected infants has shown linear deposition of C, along the basement membrane zone [9, lo]. No long-term sequelae of disease has been noted in offspring of affected mothers. Histology and Ultrastructure The characteristic histopathology of bullous lesions of HG shows a subepidermal blister with a pronounced mixed dermal inflammatory infiltrate, consisting of lymphocytes, histiocytes and eosinophils [l, 2, 111. The epidermis may show spongiosis and spongiotic vesicle formation, with eosinophils scattered singly within the epidermis or found within the spongiotic vesicles. Vacuolar degeneration along the dermal-epidermal junction is a frequent finding lateral to the blister [2]. Biopsies taken from non-bullous edematous plaques show the characteristic dermal infiltrate mixed with eosinophils and papillary edema. Vacuolar degeneration of basal cells is usually present in the absence of overt blister formation. Electron microscopic (EM) studies have shown that early ultrastructnral changes in normal perilesional skin consist of damage to the dermal side of the basal cell plasma membrane accompanied by mild intracellular degeneration [12]. Nonbullous erythematous lesions show pronounced degeneration or loss of basal cells but good preservation of the basal lamina [12]. In bullous lesions, similar basal cell changes were present, with the basal lamina either absent or forming the base of the blister. Thus, the blister formation in HG seems to result from destruction of basal cells [ 12, 131. This is in contrast to what has been observed ultrastructurally in bullous pemphigoid (BP), which is separation occurring between the basal cell plasma membrane and basal lamina with less destruction of basal cells [ 12,141. Immunopathology Biopsies taken from normal perilesional skin or from urticarial lesions for direct IF studies characteristically show linear deposition of C, along the basement membrane zone (BMZ) [l-3] (Figure 2). Thirty to forty percent also show weak linear deposition of IgG, but the intensity is generally much less than that of the C, [l, 2, 151. The characteristic direct IF features of HG have been found in skin of infants born to affected mothers. This has been reported in neonates both with and without
40
L. H. Morrison and G. J. Anhalt
Figure 2. Skin biopsy processed for direct immtmofiuorescent along the basement membrane zone.
studies showing linear deposition of C,
cutaneous lesions [2, 4, 9, IO]. Routine indirect IF studies in HG are most often negative because the levels of circulating anti-BMZ antibodies are present in low enough quantity to fall below the level of sensitivity of this technique. Only 20% of HG sera show anti-BMZ antibodies detectable by this technique. However, using the indirect complement fixation IF technique, the majority of patient sera demonstrate the presence of a factor capable of fixing complement along the BMZ [2,3, l+lSJ. In this technique, normal human skin is first incubated with HG sera, then with a source of complement and finally with fluorescein isothiocyanate (FITC) conjugated anti-human C,. The resulting linear band of fluorescence along the BMZ indicates the presence of complement-fixing IgG class anti-BMZ antibodies present in the patients’ sera. Although normal human skin is routinely used for such IF studies, it has recently been shown that HG factor activity is also demonstrable using human amnion as a substrate [ 19,201. Initial studies suggested that this complement-fixing substance in the serum of HG patients was not an immunoglobulin and it was termed the ‘HG Factor’ [21]. It has since been identified as an avidly complement-fixing IgG class antibody by sucrose density ultracentrifugation, sedimentation characteristics, ion-exchange and gel filtration chromatography [15, 18, 221. Immunofluorescent studies using monoclonal antibodies have shown IgG 1 to be the major IgG subclass present in
Herpes gestationis
41
both serum and tissue [23]. HG factor activity has been demonstrated in cord blood of infants born to affected mothers reflecting the fact that IgG is capable of crossing placental barriers [ 15, 171. Direct immuno-EM studies have demonstrated deposition of IgG and C, in the lamina lucida [24-261. Some investigators have noted that the immunoreactants are closely associated with the dermal aspect of the basal cell membrane, and deposition is accentuated in the areas of hemidesmosomes, similar to that seen in BP [25]. Indirect immuno-EM studies have been performed by only a single investigator who has shown deposition of C, in the lamina lucida of human skin. Relationship to BP The fact that herpes gestationis and bullous pemphigoid share a number of similarities has led to much speculation regarding the exact relationship between the two diseases. Similarities include the morphology of the eruption, histological findings of subepidermal blister formation with a dermal inflammatory infiltrate mixed with eosinophils and the linear deposition of immunoreactants along the BMZ on direct IF examination. Despite these similarities, a number of distinct differences do exist. The population affected in the two syndromes is markedly different; BP is largely a disease of the elderly, affecting males and females equally, while HG is limited to pregnant or post-partum females or those with choriocarcinomas or hydatidiform moles and is exacerbated by estrogens or progestins. Ultrastructurally, more basal cell necrosis is seen in HG than BP, and by IF studies HG shows linear deposition of C, along the BMZ, usually in the absence of IgG deposition. However, in BP the two immunoreactants are usually noted to have approximately equal intensity [2]. This reflects the high avidity with which small quantities of tissue bound and circulating HG autoantibodies fix complement. Further studies have been directed at characterizing the antigens in the two diseases to help delineate the relationship between HG and BP. Immunoblotting studies have been used to determine the specificity of the HG autoantibodies and to compare the antigens recognized by HG autoantibodies to those detected by BP autoantibodies. Immunoblotting performed using sera of 17 HG patients showed that 89% of HG factor-positive sera detected a 180 kD epiderma1 protein, while only one serum recognized both the 180 and 240 kD epidermal antigen [27]. Using similar techniques, it has been shown that BP autoantibodies most frequently recognized a high molecular weight (MW) epidermal antigen of 220-240 kD (28,291, but nearly half of BP sera detect a 180 kD epidermal antigen, either alone or in association with the high MW antigen [27]. These findings suggest immunological similarities between the two diseases and strengthen the proposal that the two entities are closely related. Recent reports suggest that the 180 and 220-240 kD antigens are epidermal hemidesmosomal proteins or are proteins closely associated with these structures [30]. Using purified antibodies to both the high (220-240) and low (180) MW epidermal proteins, Anhalt et al. have found that these two antigens may be immunologically related or may form a complex in the hemidesmosome [3 11. Further characterization of these antigens is being carried out by molecular cloning and sequencing [32,33].
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L. H. Morrison and G. J. Anhalt
Blocking studies have also been used to investigate similarities between HG and BP antigens and antibodies. Jordon et al. showed that incubation of normal human skin with HG factor-positive sera almost entirely blocked deposition of BP antibodies along the BMZ [18]. Carruthers et aE. in contrast, found no blocking of BP antibody deposition by HG sera, but did show that preincubation of skin with BP sera blocked HG factor deposition in five of seven HG sera [22]. These results suggest heterogeneity of BP antigen/antibody system with some partial similarity of antigens in HG and BP. Pathophysiology
Although the etiology of HG is unknown, the consistent finding of C, deposited along the BMZ of perilesional skin and the frequent presence of the HG factor in patient serum suggest an autoimmune basis for the disease. Another feature which supports this concept is the increased incidence of HLA-DR3 and also the combination of HLA-DR3 and DR4 antigens in patients with HG, findings observed in patients with autoimmune-mediated diseases [34,35]. HLA-DR3 antigen has been reported with increased frequency in patients with dermatitis herpetiformis, Graves’ disease, myasthenia gravis, scleroderma, Addison’s disease, Sjogrens Syndrome and subacute cutaneous lupus erythematosus; the DR4 antigen has been associated with pemphigus vulgaris, Type I diabetes mellitus, multiple sclerosis and rheumatoid arthritis [36]. HG has been reported in association with other putative autoimmune diseases such as Graves’ disease, alopecia areata and ulcerative colitis, but these cases are largely sporadic and the association may be coincidental [3]. One study has found that 21 y0 of HG patients also had Graves’ disease at some time in their life, suggesting more than a coincidental association [37]. This has not been verified by other studies. Although the immunopathological findings support the idea that anti-BMZ autoantibodies mediate the disease, there is currently no proof of their pathogenic role. Because HG sera have been shown to fur complement along the BMZ of normal amnion, it is intriguing to speculate that autoantibodies may initially be formed against an amniotic antigen and then cross-react with skin, mediating lesion formation, but this is purely hypothetical at this point. Because the anti-BMZ antibody is an IgG and is therefore, capable of crossing the placenta, it is presumed that this antibody also mediates development of skin lesions in neonates. Because the infant can catabolize the maternal IgG, its immunologic effect diminishes without intervention, as do the infant’s cutaneous lesions. Several components of both the classic and alternate complement pathways including Clq, C,, C,, C,, properdin and factor B have been identified along the BMZ in Rerilesional skin of HG patients [3, 15, IS]. It was originally proposed that the complement cascade was activated via the alternate pathway because of the presence of properdin and factor B along the BMZ, but subsequent studies implicate the classical pathway as the main route of complement activation [ 15,181. The presence of properdin and factor B along the BMZ probably reflect involvement of the alternate pathway by the C, feedback loop. Because of its strict association with pregnancy, hydatidiform moles and choriocarcinoma [l, 38, 391 and exacerbation with menses, oral contraceptives,
Herpes gestationis
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progestational agents [40] and estrogens [17] it is likely that hormonal balance plays a role in pathogenesis of HG, but this has not been clearly elucidated. Plasma and urinary estriol levels have been measured in only a few patients and have been generally within normal limits [41]. Foidart reported that serum human placental lactogen and serum human chorionic gonadotropin levels were low in several HG patients, but the significance of these findings is not clear [41]. Further work is needed to clarify the contribution of hormones to disease expression in HG. Treatment Systemic corticosteroids are the mainstay of therapy in HG, with prednisone being the most widely used agent. In most cases, 2040 mg of prednisone daily is adequate to control the pruritus and suppress new lesion formation, which are the primary goals of treatment [ 1,3,4]. Rarely, higher doses may be needed for control. Because the disease frequently flares after delivery, it may be necessary to increase the dose of prednisone at this time, and then gradually taper it during the post-par-turn period. Exacerbations with menses may again require dosage increases or may be controlled with addition of topical steroids. Topical steroids may be helpful in mild cases of HG, but are generally not adequate to control moderate to severely affected patients. Antihistamines are useful adjunctive therapy to topical steroids. Patients very infrequently manifest an unusually severe or long-lasting eruption, not responsive to high doses of corticosteroids and require addition of an immunosuppressive agent [2,5]. This is clearly contraindicated during pregnancy and breast feeding. Cutaneous lesions in infants are transient and require no specific treatment. If an infant’s mother has been treated with systemic corticosteroids, the infant should be evaluated for adrenal suppression, although this is a rare occurrence. Acknowledgements This work was supported in part by U. S. Public Health Service Grant R29 AR39761 (LM), and RO 1 AR32490 and K04 AR0 1686 (G JA) from the National Institutes of Health. References 1. Shornick, J. K. 1987. Herpes Gestationis. J. Am. Acad. Dermatol. 17: 539-556 2. Provost, T. T. and S. I. Katz. 1987. Herpes Gestationis. In Dermatology in GeneraI Medicine, 3rd edn. T. B. Fitzpatrick, A. Z. Eisen, K. Wolff, I. M. Freedberg and
K.F. Austen, eds. McGraw-Hill, Inc., New York, pp. 586-589
3. Eaglestein, N. F., G. J. Anhalt, H. J. Patel, and L. A. Diaz. Herpes Gestationis. In Zmmunopathology of the Skin. E. H. Beutner, T. D. Chorzelski and V. Kuman, eds.
John Wiley, New York. pp. 371-379
4. Shornick, J. K., J. L. Bangert, R. G. Freeman, and J. N. Gilliam. 1983. Herpes gestationis: Clinical and histologic features of twenty-eight cases. J. Am. Acad. Dermatol. 8: 214-224 5. Holmes, R. C., D. M. Williamson, and M. M. Black. 1986. Herpes gestationis persisting for 12 years post parrum. Arch. Dermatol. 122: 375-376 6. Fine, J.-D. and E. F. Omura. 1985. Herpes gestationis. Persistent disease activity 11 years postpartum. Arch. Dermatol. 121: 924-927
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7. Lawley T. J., G. Sting1 and S. I. Katz. 1978. Fetal and maternal risk factors in herpes gestationis. Arch. Dermatol. 114:552-555 8. Holmes, R. C. and M. M. Black. 1984. The fetal prognosis in pemphigoid gestationis (herpes gestationis). Br. J. Dermatol. 110:67-72 9. Chorzelski, T. I’., S. Jablonska, E. H. Beutner, E. Maciejowska, and M. JarzabekChorzelska. 1976. Herpes gestationis with identical lesions in the newborn. Arch. Dermatol. 112: 1129-1131 10. Katz, A., J. 0. Minta, J. W. P. Toole, and W. Medwidsky. 1977. Immunopathologic study of herpes gestationis in mother and infant. Arch. Dermatol. 113: 1069-1072 11. Lever W. F. and G. Schaumburg-Lever. 1983. Noninfectious vesicular and bullous diseases: Herpes Gestationis. In Histopathology of the Skin. 6th edn, W. F. Lever and G. Schaumburg-Lever, eds. J. B. Lippincott, Philadelphia. pp. 118 12. Yaoita H., M. Gullino, and S. I. Katz. 1976. Herpes gestationis. Ultrastructure and ultrastructural localization of in vivo-bound complement. J. Invest. Dermatol. 66: 383-388 G., 0. E. Saffold, C. E. Orfanos, and W. F. Lever. 1973. Herpes 13. Schaumburg-Lever, gestationis: Histology and ultrastructure. Arch. DermatoZ. 107: 888-892 14. Schaumburg-Lever G., C. E. Orfanos and W. F. Lever. 1972. Electronmicroscopic study of bullous pemphigoid. Arch. Dermatol. 106: 662-667 15. Katz, S. I., K. C. Hertz, and H. Yaoita. 1976. Herpes gestationis: Immunopathology and characterization of the HG factor. J. Cl&. Invest. 57: 1434-1441 16. Carruthers J. A. 1978. Herpes gestationis: Clinical features of immunologically proved cases. Am.J. Obstet. Gynecol. 131: 865-867 17. Carruthers J. A., M. M. Black, and N. Ramnarain. 1977. Immunopathological studies in herpes gestationis. Br. J. Dermatol. 96: 35-43 18. Jordon, R. E., K. G. Heine, G. Tappeiner, L. L. Bushkell and T. T. Provost. 1976. The immunopathology of herpes gestationis: Immunofluorescence studies and characterization of ‘HG Factor’.J. CZin. Invest. 57: 1426-1433 19. Ortonne, J.-P., B.-L. Hsi, P. Verrando, F. Bernerd, G. Pautrat, A. Pisani, and C.-J. G. Yeh. 1987. Herpes gestationis factor reacts with the amniotic epithelial basement membrane. Br.J. Dermatol. 117: 147-154 20. Kelly S. E., B. S. Bhogal, F. Wohnarowska, and M. M. Black. 1988. Expression of a pemphigoid gestationis-related antigen by human placenta. Br.J. Dermatol. 118:605-611 21. Provost, T. T. and T. B. Tomasi, Jr. 1973. Evidence for complement activation via the alternate pathway in skin diseases I. J. CZin. Invest. 52: 1779-1787 22. Carruthers, J. A. and A. R. Ewins. 1978. Herpes gestationis: studies on the binding characteristics, activity and pathogenetic significance of the complement-fixing factor. CZin. Exp. Immunol. 31: 38-44 23. Kelly, S. E., R. Cerio, B. S. Bhogal, and M. M. Black. 1989. The distribution of IgG subclasses in pemphigoid gestationis: PG Factor is an IgGl autoantibody. J. Invest. Dermatol. 92: 695-698 24. Holubar, K., K. Konrad, and G. Stingl. Detection by immunoelectron microscopy of immunoglobulin G deposits in skin of immunofluorescence negative herpes gestationis. BP-.J. Dermatol. 96: 569-571 25. Harrington, C. I. and S. S. Bleehen. 1979. Herpes gestationis: immunopathological ultrastructural studies. Br. J. Dermatol. 100:389-399 26. Honigsmann, H, G. Stingl, K. Holubar, and K. Wolff. 1976. Herpes gestationis: Fine structural pattern of immunoglobulin deposits in the skin in vivo. 3. invest. DermatoZ. 66: 389-392 27. Morrison, L. H., R. S. Labib, J. J. Zone, L. A. Diaz, and G. J. Anhalt. 1988. Herpes gestationis autoantibodies recognize a 180 kD human epidermal antigen. 3. CZin. Invest. 81: 2023-2026 28. Stanley, J. R., D. T. Woodley, and S. I. Katz. 1984. Identification and partial characterization of pemphigoid antigen extracted from normal human skin. J. Invest. DermatoZ. 82: 108-111
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29. Stanley, J. R., P. Hawley-Nelson, S. H. Yuspa, E. M. Shevah, and S. I. Katz. 1981. Characterization of bullous pemphigoid antigen: A unique basement membrane protein of stratified squamous epithelia. Cell 24: 897-903 30. Mutasim, D. F., L. H. Morrison, Y. Takahashi, et al. 1989. Definition of bullous pemphigoid antibody binding to intracellular and extracellular antigen associated with hemidesmosomes. J. Invest. Dermatol. 92: 225-230 31. Robledo, M., R. S. Labib, N. Korman, et al. 1989. The 230 and 18OkD bullous pemphigoid antigens are immunologically related. Clin. Res. 37: 626 32. Stanley, J. R., T. Tanaka, S. Mueller, et al. 1988. Isolation of complementary DNA for bullous pemphigoid antigen by use of patient’s autoantibodies. J. Clin. Invest. 82: 1864-1870 33. Diaz, L. A., S. Futamura, and H. L. Squiquera. 1989. Generation of an E. coli lysogen that synthesizes an epitope of the 180 kD epidermal protein recognized by bullous pemphigoid autantibodies. G&r. Res. 37: 623 34. Holmes, R. C., M. M. Black, W. Jurecka, J. Dann, D. C. 0. James, D. Timlin, and B. Bhogal. 1983. Clues to the aetiology and pathogenesis of herpes gestationis. Br. J. Dermatol. 109: 131-139 35. Shornick, J. K., I’. Stastny, and J. N. Gilliam. 1981. High frequency ofhistocompatibility antigens HLA-DR3 and DR4 in herpes gestationis. J. Gin. Invest. 68: 553-555 36. Svejgaard, A., U. Morling, P. Platz, et al. 1981. HLA and disease associations with special references to mechanisms. Transpl. Proc. 13: 193 37. Holmes, R. C., M. M. Black, J. Dann, D. C. 0. James, and B. Bhogal. 1982. A comparative study of toxic erythema of pregnancy and herpes gestationis. Br. J. Dermatol. 106: 499-510 38. Slazinski, L. and S. Degefu. 1982. Herpes gestationis associated with choriocarcinoma. Arch. Dermatol. 118: 425-428 39. Tindall, J. G., T. H. Rea, I. Shulman, and F. P. Quismorio, Jr. 1981. Herpes gestationis in association with a hydatidiform mole. Arch. Dermatol. 117: 510-512 40. Lynch, F. W. and R. J. Albrecht. 1966. Hormonal factors in herpes gestationis. Arch. Derm. 93: 446-447 41. Foidart, J. M., M. Yarr, R. Hall, U. Garpard and S. I. Katz. 1981. Immunopathological and clinical studies in herpes gestationis. Br. 3. Dermatol. 88: 153-159
