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Pemphigoid gestationis

  • Author(s): Lu, Phoebe D
  • Ralston, Jonathan
  • Kamino, Hideko
  • Stein, Jennifer A
  • et al.
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Pemphigoid gestationis
Phoebe D Lu MD PhD, Jonathan Ralston MD, Hideko Kamino MD, Jennifer A Stein MD PhD
Dermatology Online Journal 16 (11): 10

Department of Dermatology, New York University, New York, New York

Abstract

Pemphigoid gestationis is a rare autoimmune blistering disease of pregnancy. It is characterized by pruritic, urticarial plaques with the development of tense vesicles and bullae within the lesions. Pemphigoid gestationis has been associated with premature delivery, small-for-gestational-age infants. Recurrences with subsequent pregnancies are often more severe. Oral glucocorticoids are the mainstay of therapy. Differentiation of pemphigoid gestationis from pruritic urticarial papules and plaques of pregnancy is essential because management and outcomes differ. In instances in which clinical diagnosis is difficult, direct immunofluorescence tests, immunoblots, or ELISA studies of anti-basement-membrane zone antibodies are useful in establishing the diagnosis.



History


Figure 1Figure 2

A 36-year-old woman at 24-weeks gestation presented to New York University Dermatologic Associates in July, 2009, with a widespread, pruritic eruption. The lesions initially presented at eight weeks of gestation on the legs and spread to the abdomen, arms, and back. The patient previously had been treated with triamcinolone cream and oral diphenhydramine with persistence of the skin lesions. Prednisone was initiated during the pregnancy with gradual clinical improvement. The pregnancy was complicated by the development of diabetes mellitus secondary to systemic glucocorticoids and she delivered prematurely at 34 weeks. A healthy, asymptomatic male infant was born, who weighed 5 pounds and 2 ounces; the patient did not suffer a postpartum flare of the skin lesions. Although the eruption has improved, the patient continues to have active lesions eight months post-partum, even while on prednisone. Past medical history included two prior deliveries in 2004 and 2006. With her second pregnancy in 2006, the patient reported a similar but milder pruritic eruption that began mid-pregnancy and ended after she delivered a healthy, asymptomatic female infant, who weighed 5 pounds and 12 ounces at 37 weeks of gestation. She does not use oral contraceptives and did not report a flare with her menses. Past dermatologic history included possible polymorphous light eruption, which started at age ten and was previously treated with PUVA photochemotherapy.


Physical examination

Widespread, edematous, erythematous plaques with vesicles were present on the trunk, umbilicus, proximal aspects of the arms, thighs, hands, and feet.


Laboratory data

A complete blood count and comprehensive metabolic profile were normal.


Histopathology

There is a perivascular infiltrate of lymphocytes and eosinophils. Eosinophils are present at the dermoepidermal junction with associated early subepidermal vesiculation.


Immunopathology

Direct immunoflorescence studies show deposists of C3 and trace, focal IgG at the basement-membrane zone, deposists of fibrin in the reticular dermis but not in or near blood vessels, and deposits of fibrin in the tips of two dermal papillae.


Comment

Pemphigoid gestationis (PG) is a rare, autoimmune blistering dermatosis of pregnancy, with an incidence of 1 in 50,000 pregnancies [1]. In a retrospective study of 505 pregnant patients presenting to two university-based dermatologic hospitals with skin complaints between 1994 and 2004, PG accounted for 4.2 percent of the diagnoses [2].

PG develops in the second or third trimester of pregnancy. Severe pruritus is followed by the appearance of erythematous, urticarial papules and plaques that progress to tense vesicles and bullae. The lesions usually arise on the abdomen, spread centrifugally, and often involve the umbilicus. The face and mucous membranes usually are spared. In 75 percent of the cases, a relative remission may occur in the last weeks of pregnancy, which is followed by a postpartum flare. Flares also have been observed pre-menses and with the use of oral contraceptives. There is a tendency for PG to recur with subsequent pregnancies, during which there may be an earlier onset and a more severe course; however, skip pregnancies have been reported in 5 to 8 percent of cases [1, 3]. In a retrospective cohort study of 87 patients with PG, 47 percent developed PG during their first pregnancy, and, of the multiparous patients, 65.7 percent were spared during their first pregnancy but went on to have one or more episodes of PG [3]. There have been case reports of pemphigoid gestationis that persisted for years after delivery, in which the diagnoses of chronic pemphigoid gestationis or conversion to bullous pemphigoid must be considered [4].

PG has been associated with neonatal disease and complications of affected pregnancies. Neonatal skin involvement may be observed in up to 10 percent of infants secondary to passive transfer of immunoglobulins. Premature delivery may occur in 20 percent of patients and infants may be small-for-gestational-age at birth [1]. In a retrospective cohort study of 61 pregnancies complicated by pemphigoid gestationis, decreased gestational age at delivery was associated with the presence of bullae and onset of disease during the second trimester. In addition, low birth weight was found to be associated with the onset of disease in the first and second trimesters. An association of adverse pregnancy outcomes with systemic glucocorticoid use was not found [5].

Pemphigoid gestationis has been reported to develop in association with other autoimmune diseases as well as with trophoblastic tumors, hydatiform moles, and choriocarcinoma [6]. Grave disease also has been reported in 10 percent of patients with PG [1, 3].

The pathogenic mechanism is unclear but is thought to result from a breakdown of the protective immunity of the fetoplacental unit from maternal recognition. As in bullous pemphigoid, the main target of the autoantibodies in PG is collagen VII, which is a constituent of the skin and placenta. In particular, the non-collagenous 16A (NC16A) domain of collagen VII is the major antigenic epitope targeted by the autoantibodies. PG also has been associated with the presence of MHC class II HLA antigens DR3 and DR4 [1].

Histopathologically, PG is characterized by eosinophilic spongiosis, papillary dermal edema, and subepidermal blister formation. Direct immunofluorescence study shows linear deposition of C3 and sometimes IgG along the basement-membrane zone in perilesional skin [3].

It is important to distinguish PG from pruritic urticarial papules and plaques of pregnancy (PUPPP), which can resemble non-bullous PG clinically and histopathologically. In contrast to PG, PUPPP affects women in their first pregnancy during the third trimester as urticarial papules and plaques that arise within the striae distensae and spare the periumbilical area. Unlike PG, PUPPP does not tend to recur in subsequent pregnancies, nor is there a risk for adverse fetal effects with PUPPP. Differentiation between the PG and PUPPP may be confirmed by the presence of anti-basement-membrane zone antibodies by immunofluorescence study, immunoblots, or ELISA study [1]. A commercially available ELISA to the NC16a domain of BP180 has been shown to have a sensitivity of 96 percent and a specificity of 96 percent in differentiating PG from PUPPP [7].

Potent topical glucocorticoids, oral glucocorticoids, and oral antihistamines are the standard medications that are used to treat PG during pregnancy. However, plasmapheresis [8] and immunopheresis [9] also have been used during pregnancy. In the postpartum period, topical and oral glucocorticoids continue to be the treatments of choice. However, other treatments that have been tried in isolated cases include tetracyclines with or without nicotinamide, cyclophosphamide, plasmapheresis, intravenous immunoglobulin, rituximab, and goserelin [1].

References

1. Semkova K, M Black. Pemphigoid gestationis: current insights into pathogenesis and treatment. Eur J Obstet Gynecol Reprod Biol 2009; 145: 138 [PubMed]

2. Ambros-Rudolph CM, et al. The specific dermatoses of pregnancy revisited and reclassified: results of a retrospective two-center study on 505 pregnant patients. J Am Acad Dermatol 2006; 54: 395 [PubMed]

3. Jenkins RE, et al. Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol 1999; 24: 255 [PubMed]

4. Amato L, et al. A case of chronic herpes gestationis: persistent disease or conversion to bullous pemphigoid? J Am Acad Dermatol 2003; 49: 302

5. Chi CC, et al. Pemphigoid gestationis: early onset and blister formation are associated with adverse pregnancy outcomes. Br J Dermatol 2009; 160: 1222 [PubMed]

6. Shornick JK, MM Black. Secondary autoimmune diseases in herpes gestationis (pemphigoid gestationis). J Am Acad Dermatol, 1992; 26: 563 [PubMed]

7. Powell AM, et al. 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. Arch Dermatol 2005; 141: 705 [PubMed]

8. Van de Wiel A, et al. Plasma exchange in herpes gestationis. Br Med J 1980; 281: 1041 [PubMed]

9. Wohrl S, et al. Pemphigoid gestationis: treatment with immunoapheresis. J Dtsch Dermatol Ges 2003; 1: 126 [PubMed]

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