Pemphigoid gestationis: a rare pregnancy dermatosis treated with a combination of IVIg and rituximab

Abstract

Pemphigoid gestationis is a rare autoimmune subepidermal bullous dermatosis occurring during pregnancy and post partum. A 32-year-old woman developed itchy urticarial wheals over the trunk and extremities at 6 months of gestation. This was not controlled with antihistamines, and 2 months later, the patient developed multiple vesiculobullous lesions. The patient had an exacerbation 3 weeks post-delivery. She did not go into remission for 6 months post partum despite treatment with prednisolone 40 mg/day, doxycycline 100 mg two times per day and dapsone 100 mg/day. The patient went into remission following treatment with three courses of intravenous immunoglobulin 2 mg/kg/course and 2 doses of rituximab 1 g at a 2-week interval.

Background

Pemphigoid gestationis (PG) is a rare autoimmune subepidermal bullous dermatosis occurring during pregnancy and post partum. The rarity of the disease and paucity of treatment options make the treatment of this disease difficult.

Case presentation

A 32-year-old woman started developing itchy urticarial wheals over the dorsum of the left ankle when she was 6 months pregnant. This was followed by the development of wheals over the periumbilical area, thighs, palms and soles. She was treated with levocetirizine 10 mg daily for 10 days without any improvement. Two months after the onset of wheals, she started developing vesiculobullous lesions all over the body, which was treated with oral prednisolone in tapering doses by a physician with minimal improvement. She had a good improvement 2 weeks prior to delivery but the disease relapsed 3 weeks post-delivery in the form of multiple itchy wheals and vesiculobullous lesions over the trunk and extremities. This episode was also treated with oral prednisolone 40 mg daily with good response, though, the disease recurred when prednisolone was tapered to 25 mg. She presented to us with 70% body surface area involvement. Physical examination revealed multiple, clear fluid-filled, tense bullae clustered together on the trunk, especially around the umbilicus, and the extremities with multiple haemorrhagic crusts (figure 1). Face and mucous membranes were spared.

Figure 1.

Tense vesicles and bullae over periumbilical area (A) and over urticarial plaques on the nape of neck (B).

Investigations

A clinical diagnosis of PG was made. On histopathological examination, a full thickness subepidermal cleft was seen with mild papillary dermal inflammatory infiltrate of lymphocytes and occasional neutrophils (figure 2). Direct immunofluorescence had linear positivity for C3 along the dermoepidermal junction. Ultrasonography of the abdomen and pelvis and ß-hCG levels did not show any abnormality.

Figure 2.

Subepidermal cleft with papillary dermis showing mild infiltrate of lymphocytes and occasional neutrophils (H&E, ×100).

Treatment

The patient continued developing new lesions while on treatment with prednisolone 40 mg, doxycycline 100 mg two times per day and dapsone 100 mg/day. Given inadequate control, she was treated with a combination of intravenous immunoglobulin (IVIg) 30 g/day for 5 days (three courses, 2 weeks apart) and injection rituximab (1 g, 2 doses, 2 weeks apart). She was also started on azathioprine 50 mg two times per day after her second course of IVIg.

Outcome and follow-up

One month after the third course of IVIg, all the old lesions had resolved, and the patient stopped developing new lesions. Subsequently, oral steroids and azathioprine were tapered and stopped. The patient has been in complete remission for another 6 months without any treatment.

Discussion

PG, also known as herpes gestationis, gestational pemphigoid or dermatitis multiformis gestationis, occurs in 1 in 3000 to 1:35 000 pregnancies.¹ PG is one of the most clearly characterised dermatoses of pregnancy. The pathogenesis of PG has not been fully understood. It is hypothesised that the breakdown of protective immunity of the fetoplacental unit from maternal allogenic recognition may result in the disease. The patient develops autoantibodies against BP180 antigen in the skin and a few against BP230. Normally, major histocompatibility complex (MHC) class II antigens are not expressed on the trophoblast and this silencing protects the fetus from recognition of the maternal immune system. However, when there is an aberrant expression of the MHC class II molecule in the amniochorionic stromal cells, BP180 gets exposed to the maternal immune system. The presentation of self-antigen triggers the production of antibodies, which cross-react with the skin antigens and cause blister formation. Furthermore, progesterone is elevated during the last few weeks of pregnancy, which depresses antibody production. This may explain why the disease improves just before delivery.

The patient initially presents with pruritic urticarial papules, annular plaques and targetoid lesions. Few days to 4 weeks later, the patient starts developing vesicles and tense bullae in a clustered or herpetiform arrangement. The patient develops lesions usually in the second or third trimester of pregnancy and sometimes in the second week of gestation or the early postpartum period. PG usually recurs in subsequent pregnancies with early onset and increased severity; only in 5%–8% of cases, it skips a pregnancy.²

The treatment of PG is a challenge as most immunosuppressive treatments are contraindicated in pregnancy. Potent topical corticosteroids and emollients with or without antihistamines are often sufficient in the mild pre-blistering form of the disease. After blisters start to appear, treatment often is cautious use of prednisolone.³ Dapsone, ciclosporin and cyclophosphamide have been used during the postpartum period. Immunopheresis is a helpful option for severe cases during pregnancy.

Many case reports have demonstrated the efficacy of IVIg^4–6 and one report⁷ has demonstrated the efficacy of rituximab in the treatment of PG. Cianchini et al⁷ reported a 31-year-old woman with PG having partial response to treatment with prednisolone 100 mg daily, azathioprine 150 mg daily and dapsone 125 mg daily. Even IVIg therapy could provide only temporary improvement. Hence, 2 months after her IVIg therapy, the patient was treated with rituximab 375 mg/m² for 4 consecutive weeks with complete resolution in the subsequent 4 months. Tourte et al⁸ described a case where they had successfully used rituximab prophylactically to prevent PG. This is of importance especially in cases where each subsequent pregnancy is associated with exacerbation of the disease. Genovese et al recommended IVIg or rituximab as the second-line treatment after dapsone or azathioprine in the postpartum period.⁹ However, an exhaustive literature search did not reveal any documented use of the combination of IVIg and rituximab.

This demonstrates a severe and recalcitrant case of PG resistant to conventional treatment with good improvement with a combination of IVIg and rituximab.

Patient’s perspective.

This was my 1st child and when it started in the 2nd trimester of pregnancy, there was unbearable pain and stress. With the help of medication, there was some relief initially. Everyone told that after delivery, it will be cured. However, after deliver as well, there was no relief. Then I was admitted in the hospital. Initially my condition was unbearable with my entire body being covered with boils. My treatment started and that helped me get over the illness. I was not able to hold my baby before. However, the medication helped my recover from this illness and now I am able to take care of my baby. I am happy to be finally rid of this disease and have a new life.

Learning points.

• Pemphigoid gestationis, a pregnancy-related vesiculobullous disease, has a risk of recurrence in subsequent pregnancies and with oral contraceptive use.

• Patients should be made aware of the same.

• Rituximab and intravenous immunoglobulin combination is effective in controlling disease activity in patients refractory to other treatment modalities.

• In a subset of patients, the disease activity may persist beyond 6-month postpartum period.