Pemphigoid Gestationis

Article Author:
William Gossman
Article Author (Archived):
Grishma Gandhi
Article Editor:
Wissem Hafsi
Updated:
7/11/2019 9:55:57 PM
PubMed Link:
Pemphigoid Gestationis

Introduction

Pemphigoid gestationis (PG) (previously called herpes gestationis) is a rare, specific dermatosis of pregnancy. It is a bullous autoimmune, sub-epidermal dermatosis clinically and pathogenetically similar to bullous pemphigoid. It occurs during the third trimester and less commonly in the second trimester or even after delivery, but it can manifest in principle during all three trimesters. It manifests with inflammatory skin lesions and severe pruritus. It recurs in subsequent pregnancies earlier and as a more serious course.

Etiology

In PG, the skin lesions are caused by an autoimmune process implicated anti-basement membrane zone auto-antibodies. The target autoantigen is BP 180 also designated BPAG2 and collagen XVII. PG is strongly associated with the maternal HLA-DRs DRB1*0301 (HLA-DR3) and DRB1*0401/040X (HLA-DR4). This strong association indicates the important role of MHC class II in the pathogenesis of the disease.

Epidemiology

The incidence of PG has been variably estimated, one case per 2000 up to 60,000 pregnancies. It is more frequent in persons with fair skin than dark skin. PG mainly occurs late in pregnancy with 60% of cases occurring between the 28th and the 32nd week of amenorrhea. Multigravidae are more susceptible to develop PG than primigravidae with an earlier onset of symptoms.

PG usually resolves within 2 months after delivery. Nonetheless, it may persist or exacerbate after pregnancy due to a sudden increase in the level of antibodies. Recurrence may occur with subsequent pregnancies, menstruations or treatment with estrogens and progesterone-containing oral contraceptives. Fetal risks observed in PG are low birth weight baby, prematurity, and temporary skin lesions which resolve several weeks after the birth, but there is no increased risk of stillbirth and abortion. This risk may be correlated with disease severity. A postpartum flare-up has been observed.

The association of this disease with hydatidiform mole and choriocarcinoma must not be forgotten.

Pathophysiology

PG is associated with the presence of IgG autoantibodies against BP180, which predominantly recognize the NC16A domain of BP180. BP180 is not only expressed in the skin, but also in the first trimester of pregnancy in the placental cytotrophoblastic and syncytiotrophoblastic cells as well as in the epithelial cells of the amniotic membrane. Autoimmunization may occur due to loss of tolerance to this 180 kDa placental antigen, resulting in a local allogeneic reaction against the fetoplacental unit. This process, which is promoted by abnormal expression of placental HLA class II antigens, is accompanied by alterations in the placental basement membrane. After that, there is an immune response in the skin.[1][2][3][4]

Histopathology

Routine histopathologic studies are helpful; the findings during examination depend on the phase of the disease. While it shows in the pre-bullous stage a papillary edema with an infiltration of the dermis, consisting of lymphocytes and histiocytes and a variable number of eosinophils, it reveals in the bullous stage subepidermal blistering, however, histology is not sufficient in the diagnosis of PG.

History and Physical

The eruption of PG is polymorphic. Pruritus is the main symptom, and it may precede the manifestation of skin lesions in some cases. It may be very severe and have a significant emotional impact on the patient. The eruption can include eczematous or erythema multiforme-like lesions, erythematous urticarial plaques and papules which progress to vesicles, tense blisters and bullae in over 65% of cases. At first, the lesions erupt in the periumbilical area and subsequently spread to the abdominal region and the extremities, involving exceptionally the face or mucous membranes. The lesions may extend to the entire body. There is no mucosal involvement. The clinical aspect and the distribution of skin lesions or histological examinations (almost constantly unspecific) in the initial phase cannot distinguish pemphigoid gestationis from other pruriginous dermatoses of pregnancy especially the multi-morphe eruption of pregnancy (previously nommed Polymorphic Urticarial Papules and Plaques of Pregnancy (PUPPP)) which is the main differential diagnosis. This latter also develops in the third trimester of pregnancy and exhibit similar clinical features. In pre-bullous stage, the differentiation between the two diseases is impossible, both histopathologically and clinically. However, the direct immunofluorescence is negative in this case.

Evaluation

Direct immunofluorescence (DIF) staining on skin biopsy specimen should be realized because it is considered the most sensitive and specific examination used for confirming the diagnosis. It confirms the diagnosis by showing positive linear C in 100% of the cases, and occasionally IgG in 30%, depositions along the dermal-epidermal junction of lesional, perilesional and clinically normal skin. DIF sometimes remains positive even for six months to 4 years after clinical remission.

Indirect immunofluorescence microscopy (indirect IF) allows the detection of circulating IgG antibodies in the patient's serum in 30% to approximately 100% of cases.[5][6][7][8]

ELISA-BP180 is very sensitive and specific (approximately 95%) for the diagnosis of pemphigoid gestationis. His positivity would allow to differentiate GP from other pruriginous dermatoses of pregnancy reliably and to potentially render obsolete the practice of a direct immunofluorescence test, which nevertheless remains the reference standard.

Its positivity would make it possible to reliably distinguish pemphigoid gravidarum from other pruriginous dermatoses of the pregnancy, and potentially make obsolete the practice of a direct immunofluorescence examination, which nevertheless remains still the reference standard. The result of the ELISA-BP180 is semi-quantitative, and its evolution correlates with the activity of the disease. 

Treatment / Management

Treatment of PG depends on the severity and the stage of the skin lesions. The main goal is to relieve itching and to avoid the formation of new blisters.

  • PG is often treated with topical corticosteroids and oral antihistaminics especially in localized disease with minimal blistering. Patients that are resistant to topical treatment or have a severe form exceeding 10% of the body surface area require systemic corticosteroids. Treatment includes 0.3 mg/kg to 0.5 mg/kg (20 mg to 40 mg/day) of prednisolone, and in some cases, the addition of immunosuppressant agents such as cyclosporine or azathioprine for disease control.
  • Intravenous immunoglobulins (IVIG) have been utilized successfully in some cases. In one case of chronic gestational pemphigoid resistant to numerous treatments (corticosteroids, dapsone, azathioprine, IVIG), the disease has been controlled successfully with rituximab-anti-CD20 antibodies.
  • Isolated cases of PG have been treated successfully with dapsone or sulfapyridine.

Enhancing Healthcare Team Outcomes

PG is a rare disease and does not pose a major health burden. When suspected clinically, the diagnosis must be established, and treatment should be started early as the disease responds well to steroids. A multidisciplinary approach between gynecologist and dermatologist is required to ensure coordinated monitoring (search for signs of prematurity, abnormalities of fetal growth, detect possible systemic and local side effects of topical and systemic corticosteroid). The association with hydatiform mole, trophoblastic tumors, or choriocarcinoma must not be forgotten. The pharmacist should encourage medication compliance to help ease the intense pruritus.


References

[1] Daniel BS,Murrell DF, Review of Autoimmune Blistering Diseases: the Pemphigoid diseases. Journal of the European Academy of Dermatology and Venereology : JEADV. 2019 May 13;     [PubMed PMID: 31087464]
[2] Kukkamalla RM,Bayless P, Pemphigoid Gestationis. Clinical practice and cases in emergency medicine. 2019 Feb;     [PubMed PMID: 30775676]
[3] Lobato-Berezo A,Fernández Figueras MT,Moreno Romero JA,Pujol RM, Pemphigoid Gestationis Mimicking Erythema Multiforme With Mucosal Involvement. Actas dermo-sifiliograficas. 2019 Feb 4;     [PubMed PMID: 30732852]
[4] Maglie R,Quintarelli L,Verdelli A,Fabbri P,Antiga E,Caproni M, Specific dermatoses of pregnancy other than pemphigoid gestationis. Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia. 2019 Jun;     [PubMed PMID: 30375214]
[5] Feliciani C,Genovese G,D'astolto R,Pontini P,Marzano AV, Autoimmune bullous diseases during pregnancy: insight into pathogenetic mechanisms and clinical features. Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia. 2019 Jun;     [PubMed PMID: 30375213]
[6] Papapanagiotou IK,Tsagouri S,Liakou CG,Besharat A,Vogiatzis N,Ntzeros K,Petrakis E,Koutroumanis P,Thomakos N,Loutradis D, Pemphigoid gestationis. Clinical case reports. 2018 Jul;     [PubMed PMID: 29988643]
[7] Pruritus in Pregnancy and Its Management., Bechtel MA,, Dermatologic clinics, 2018 Jul     [PubMed PMID: 29929597]
[8] Yang A,Uhlenhake E,Murrell DF, Pemphigoid gestationis and intravenous immunoglobulin therapy. International journal of women's dermatology. 2018 Sep;     [PubMed PMID: 30175219]