A comparative study of toxic erythema of pregnancy and herpes gestationis

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.     

A comparative histopathological study of polymorphic eruption of pregnancy and herpes gestationis

We have compared the histopathological findings in twenty-five patients with polymorphic eruption of pregnancy and eighteen patients with herpes gestationis. The histopathology of polymorphic eruption of pregnancy varied with the clinical stage of the eruption. In the early lesions there was epidermal and upper dermal oedema with a perivascular lymphohistiocytic infiltrate. The fully developed lesions demonstrated vesicular spongiosis, and, in one case, suhepidermal vesicle formation. Eosinophils were frequently present in the perivascular infiltrate and in two cases there was eosinophilic spongiosis. In the resolving stage of the eruption there was acanthosis and foci of parakeratosis. These histopathological features were indistinguishable from those of the urticarial lesions of herpes gestationis. It was only in the presence of large bullac that the two disorders could he differentiated histopathologically. This finding emphasizes the importance of immunonuorescence studies in the investigation of urticarial eruptions occurring during pregnancy.     

The specific dermatoses of pregnancy

The terminology of the specific dermatoses of pregnancy has become increasingly confusing, with several names in use for identical clinical disorders. On the basis of our own study of sixty-four patients and a review of the literature, we propose a simplified classification: (1) herpes gestationis (pemphigoid gestationis); (2) polymorphic eruption of pregnancy; (3) prurigo of pregnancy; and (4) pruritic folliculitis of pregnancy.     

Polymorphic eruption of pregnancy: histopathologic study

The microscopic findings in 31 biopsies of patients with polymorphic eruption of pregnancy are reported with a literature review. Cutaneous changes include edema, dermal lympho-histiocytic infiltrate and epidermal lesions. We have found a correlation between the intensity of the inflammatory response and the presence of epidermal involvement. In our opinion, the histopathological changes may allow an accurate diagnosis with the adequate clinical information. Direct immunofluorescence did not reveal immunoglobulin or complement deposits in the ten cases studied. It may help in the differential diagnosis with nonbullous herpes gestationis.     

Dermatoses of Pregnancy - Clues to Diagnosis, Fetal Risk and Therapy

The specific dermatoses of pregnancy represent a heterogeneous group of pruritic skin diseases that have been recently reclassified and include pemphigoid (herpes) gestationis, polymorphic eruption of pregnancy (syn. pruritic urticarial papules and plaques of pregnancy), intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. They are associated with severe pruritus that should never be neglected in pregnancy but always lead to an exact work-up of the patient. Clinical characteristics, in particular timing of onset, morphology and localization of skin lesions are crucial for diagnosis which, in case of pemphigoid gestationis and intrahepatic cholestasis of pregnancy, will be confirmed by specific immunofluorescence and laboratory findings. While polymorphic and atopic eruptions of pregnancy are distressing only to the mother because of pruritus, pemphigoid gestationis may be associated with prematurity and small-for-date babies and intrahepatic cholestasis of pregnancy poses an increased risk for fetal distress, prematurity, and stillbirth. Corticosteroids and antihistamines control pemphigoid gestationis, polymorphic and atopic eruptions of pregnancy; intrahepatic cholestasis of pregnancy, in contrast, should be treated with ursodeoxycholic acid. This review will focus on the new classification of pregnancy dermatoses, discuss them in detail, and present a practical algorithm to facilitate the management of the pregnant patient with skin lesions.     

Pregnancy Dermatoses

Some aspects regarding the etiology and the nosologic classification of various pregnancy dermatoses are highly controversial. While some authors highlight the existence of premises allowing several skin disorders to be re-grouped within broader disease concepts, others underline the absence of clear, undisputed etiopathogenetic data that could support such classifications. This review exhaustively analyzes the various pregnancy dermatoses (pemphigoid gestationis, intrahepatic cholestasis of pregnancy, impetigo herpetiformis, polymorphic eruption of pregnancy, and the papular dermatoses of pregnancy [prurigo of pregnancy, pruritic folliculitis of pregnancy, and the new classification, atopic eruption of pregnancy]) in an attempt to shed light over this confusing and disputed domain, while subsequently offering an algorithmic approach to their diagnosis and management. While for pemphigus gestationis, intrahepatic cholestasis of pregnancy, and impetigo herpetiformis, specific diagnostic tests such as histopathology, immunofluorescence, or laboratory investigations will confirm the diagnosis, the identification of the other types of pregnancy dermatoses is based only on clinical criteria. In this context, the review argues for the inclusion of the whole group represented by the papular dermatoses of pregnancy within the broad spectrum of polymorphic eruption of pregnancy, separating each of these entities by focusing on their onset: early-onset polymorphic eruption of pregnancy (comprising prurigo of pregnancy, pruritic folliculitis of pregnancy, and atopic eruption of pregnancy) and late-onset polymorphic eruption of pregnancy. In light of the same practical approach guiding it, the review provides updated treatment strategies for each of these conditions.     

Clues to the aetiology and pathogenesis of herpes gestationis

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.     

Immunity in herpes gestationis: inhibition of mixed lymphocyte culture by patients'sera

The families of four patients with herpes gestationis (HG) (pemphigoid gestationis) and five patients with polymorphic eruption of pregnancy (PEP) were HLA typed. Anti-HLA-D antibodies in the maternal sera were sought using mixed lymphocyte culture (MLC) inhibition test. Two of the four patients with HG had Dw3, one of which was combined with Dw4. One of the fathers had Dw2. The sera of the four patients with HG strongly inhibited (48–100%) the MLC reaction of maternal cells against cells of the father or the child. This kind of inhibition could not be shown in the patients with PEP. We conclude that patients with HG often seem to have MLC inhibiting factors which obviously are antibodies directed against HLA-D region determinants. Their pathogenic role is still obscure.     

Herpes gestationis factor reacts with the amniotic epithelial basement membrane

Sera from five patients with clinically and immunopathologically proven herpes gestationis were studied by complement fixing immunofluorescence and complement fixing immuno-electron microscopy using specimens of skin, amniochorion and placenta. The results demonstrated that the complement fixation antibody (herpes gestationis factor) could bind to the basement membrane zone of skin, amnion and chorion laeve but not to that of the placental syncytiotrophoblast. These data suggest that the herpes gestationis factor may be induced by the basement membrane zone antigens of extra-villous cytotrophoblasts.     

THE DERMATOSES OF PREGNANCY

The skin changes in pregnancy can be either physiological (hormonal), changes in pre-existing skin diseases or development of new pregnancy specific dermatoses. Pregnancy-specific skin dermatoses include an ill-defined heterogeneous group of pruritic skin eruptions which are seen only in pregnancy. These include atopic eruption of pregnancy, polymorphic eruption of pregnancy, pemphigoid gestationis and intrahepatic cholestasis of pregnancy. Atopic eruption of pregnancy is the most common of these disorders. Most skin eruptions resolve postpartum and require only symptomatic treatment. Antepartum surveillance is recommended for patients with pemphigoid gestationis and intrahepatic cholestasis of pregnancy as they carry fetal risk. This article deals with the classification, clinical features and treatment of the specific dermatoses of pregnancy.     

Specific detection of anti-cell surface antibodies in herpes gestationis sera

Abstract We examined 42 herpes gestationis sera with immunofluorescence of normal human skin sections, and found that anti-keratinocyte cell surface antibodies were detected specifically in 10 herpes gestationis sera. The diagnosis of these herpes gestationis cases was confirmed by detecting antibodies against the 180 kD bullous pemphigoid antigen with immunoblotting of its fusion protein. The results of immunoadsorption assay using baculoproteins of both pemphigus vulgaris and pemphigus foliaceus antigens indicated that the herpes gestalionis sera did not recognize common pemphigus antigens. Immunoblotting of human epidermal extracts and immunofluorescence of various tissues also suggested that the sera did not recognize any other desmosomal components or paraneoplastic pemphigus antigens. The significance of this reactivity is unclear. However, because no control bullous pemphigoid sera showed this reactivity, it may suggest a different pathophysiology between herpes gestationis and bullous pemphigoid.     

Pregnancy dermatoses

Dermatoses of pregnancy are relatively rare. The terminology becomes increasingly confusing, as only few of these skin eruptions are proved entities. Apart from pruritus gravidarum and herpes gestationis (pemphigoid gestationis), the symptoms of dermatoses of pregnancy should be classified according to polymorphic exanthema, which are characterized by urticarial lesions, or according to prurigo gravidarum, predominantly characterized by excoriated papules.     

Indirect complement immunofluorescence in the immunopathological assessment of bullous pemphigoid, cicatricial pemphigoid, and herpes gestationis

Sera from 50 untreated patients with bullous pemphigoid were examined by both the customary method of indirect immunofluorescence using anti IgG conjugate and by indirect complement immunofluorescence using anti C₃ conjugate to detect circulating antibasement membrane zone antibodies. A circulating antibasement membrane zone antibody could be detected by the IgG method in 58% and by the C₃ method in 76%. Sera from six patients with cicatricial pemphigoid examined in the same way showed a circulating antibasement membrane zone antibody in one by the IgG method but in three by the C₃ method of indirect immunofluorescence. Sera from ten patients with active herpes gestationis contained anti-basement membrane zone antibody demonstrable by the C₃ method in every case and by the IgG method of indirect immunofluorescence in one of these. Basement membrane zone bound IgG, or more commonly C₃ in a linear pattern, was shown by direct immunofluorescence in all patients with bullous or cicatricial pemphigoid from whom adequate biopsy material was obtained. The immunopathological similarities of bullous pemphigoid, cicatricial pemphigoid and herpes gestationis are stressed, and the usefulness of indirect complement immunofluorescence in their diagnosis is emphasized.     

Differentiating anti-lamina lucida and anti-sublamina densa anti-BMZ antibodies by indirect immunofluorescence on 1.0 M sodium chloride-separated skin

Sixty-one bullous disease sera containing IgG anti-BMZ antibodies were examined by indirect immunofluorescence on intact skin and skin separated through the lamina lucida by incubation in 1.0 M NaCl. All sera produced an indistinguishable pattern of linear immunofluorescence on intact skin at dilutions of 1:10 or higher. On separated skin, antibodies bound to either the epidermal (epidermal pattern), dermal (dermal pattern), or epidermal and dermal (combined pattern) sides of the separation. The binding patterns were consistent on separated skin from several donors and titers of anti-basement membrane zone antibodies on separated skin were comparable to those on intact skin. Sera from 3 patients with herpes gestationis (HG), 36 patients with bullous pemphigoid (BP), and 1 patient with clinical and histologic features of epidermolysis bullosa acquisita (EBA) showed an epidermal pattern. Sera from 9 patients with BP showed a combined pattern and sera from 6 patients with EBA and 6 patients with clinical and histologic features of BP showed a dermal pattern. Indirect immunoelectron microscopy of selected sera showed antibodies producing the epidermal and combined patterns were anti-lamina lucida antibodies and those producing the dermal pattern were anti-sublamina densa antibodies. These results show indirect immunofluorescence on separated skin is a dependable method for differentiating bullous disease anti-lamina lucida and anti-sublamina densa antibodies and that differentiating between the antibodies is essential for accurate diagnosis in some patients. The results also suggest BP anti-lamina lucida antibodies may have more than one antigenic specificity.     

Chronic pemphigoid gestationis: comparative clinical and immunopathological study of 10 patients

BACKGROUND: Pemphigoid gestationis (PG) is a rare autoimmune bullous disorder occurring during the last trimester of pregnancy and usually regressive within 3 months after delivery. Prolonged forms of the disease lasting more than 6 months after delivery have been reported as chronic PG. OBJECTIVE: The aim of the present study was to compare the clinical and immunopathological findings between 4 patients presenting a normal regression of the disease after delivery and 6 patients with a chronic course. METHODS: All patients were evaluated and studied by clinical patterns (age, mucosal and cutaneous involvement, obstetrical history, duration of the blistering disease and response to treatment), by direct and indirect immunofluorescence and Western blot. Eight patients were studied by immunoelectron microscopy (IEM) and 3 patients had an indirect IEM. RESULTS: Patients with chronic PG were older, had multigravidity, a history of PG during previous pregnancies, widespread cutaneous eruption and mucosal involvement. Subclass analysis of circulating autoantibodies showed an IgG1 anti-BP180 response in all patients except 1 with disease of 7 years' duration. Direct IEM was positive in 6/8 patients showing a labeling of the lamina lucida, and indirect IEM using colloidal gold probes confirmed the localization of the target antigens to the proximal part of the anchoring filaments in the lamina lucida. CONCLUSION: This study suggests that, even in chronic long-lasting PG, IgG1 remains the predominant subtype of IgG. Therefore no biological and predictable marker of chronicity can be ascertained from this series.     

Evidence for eosinophil degranulation in the pathogenesis of herpes gestationis

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.     

A prospective immunofluorescence study of 111 cases of pruritic dermatoses of pregnancy: IgM anti-basement membrane zone antibodies as a novel finding

Since 1981, all pregnant women presenting to our department with a pruritic dermatosis have been investigated by histological and immunopathological techniques. We recruited 111 patients and performed skin histology in 77, 109 direct immunofluorescence tests (DIF), 74 indirect immunofluorescence tests (IIF) and 15 Western blots (WB). We identified: (i) five typical cases of pemphigoid gestationis (PG) (4.5%), corresponding to an incidence of 1/7000 pregnancies. (ii) Five cases without PG but showing circulating anti-BMZ antibodies of IgM type. With the exception of one case, clinical features were homogeneous--occurrence of erythematous papular and/or urticarial lesions on the trunk, and less often, on the limbs between the 32nd and 38th week of pregnancy. Rapid clearance of lesions within a few days was the rule. Whenever performed, DIF was negative and IIF showed circulating anti-BMZ antibodies of IgM type. Western blot studies were negative in these five cases. (iii) One hundred and one cases with negative immunofluorescence tests, considered to be suffering from polymorphic eruption of pregnancy. Our results show the value of systematic immunopathological investigations in pregnant women presenting with a pruritic dermatosis, and raise the possibility of a new entity, as defined by circulating anti-BMZ antibodies of IgM type.     

Pruritus in der Schwangerschaft

Pruritus is the leading dermatological symptom during pregnancy. Besides preexisting or acquired dermatoses, there are a number of pregnancy-specific dermatological diseases such as PEP (polymorphic eruption of pregnancy, previously named PUPPP), pemphigoid (herpes) gestationis, and pruritus gravidarum that are accompanied by severe itching and scratching. Because of potential effects on the fetus, the treatment of pruritus in pregnancy requires prudent consideration. The use of topical and systemic treatments depends on the underlying aetiology of pruritus and the stage and status of the skin. In general, emollients, topical anti-pruritics and topical corticosteroids appear to be the safest options for localised forms of pruritus in pregnancy whereas systemic treatments and/or UV phototherapy are adequate for generalized pruritus. Systemic corticosteroids and a restricted number of antihistamines may be administered in severe cases. This paper highlights the major aetiologies of pruritus during pregnancy and points out the cornerstones of antipruritic therapy in recognition of our own clinical experiences and the current literature.     

The distribution of IgG subclasses in pemphigoid gestationis: PG factor is an IgG1 autoantibody

Using monoclonal antibodies in immunofluorescence techniques, the subclass distribution of anti-basement membrane zone IgG antibodies was studied in the skin, placenta, and serum of patients with pemphigoid (herpes) gestationis. IgG1 was found to be the major IgG subclass in both serum and tissue, being detected in the sera of all pemphigoid gestationis patients studied. In pemphigoid and pemphigus, however, the distribution of IgG subclasses was heterogeneous, with IgG4 being the dominant autoantibody. Pemphigoid (herpes) gestationis factor, the circulating anti-basement membrane zone autoantibody thought to be pathogenic in pemphigoid gestationis, is therefore, an IgG1 antibody, with inferred complement binding capacity. Tissue damage in pemphigoid gestationis is apparently mediated by complement fixation which is detected via the classical complement cascade.