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Pregnant with possibility: Rituximab prophylaxis for pemphigoid gestationis

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By Warren R. Heymann, MD
April 26, 2018

Pemphigoid gestationis in 34-year-old primigravida at 28 weeks gestation. A, Urticated erythema with multiple tense blisters on both thighs. B, Histopathologic findings reveal subepidermal blister formation with abundant eosinophils, accompanied by superficial and middermal perivascular lymphohistiocytic infiltrate. (Hematoxylin-eosin stain; original magnification: ×10.) C, Direct immunofluorescence examination of perilesional skin shows bright linear staining with C3 at basement membrane.
Credit: JAAD

I was taken aback by the report of anhydramnios in two women with pemphigoid gestationis (PG) resulting in the death of the newborn babies within days of birth. Each child died of sepsis. (1)

The most common complications of PG are preterm delivery and children who are small for gestational age. Associated risks correlate with disease severity in the mother. Neonatal PG occurs in up to 10% of cases. Skin lesions may develop in newborns due to antibody transfer from mother to fetus, but lesions resolve spontaneously. (2)

Fortunately, fetal demise in PG is rare. Pérez et al reported a case of dyshidrosiform PG that developed 48 hours after a Caesarian section that was performed because of intrauterine fetal death. (3) Powell et al detailed the case of a woman with a prior history of PG who developed intensely pruritic vesicles on her fingers and toes that rapidly deteriorated into florid PG starting at week 14 gestation. At 22 weeks, fetal death was noted; that was found to be due to cerebral hemorrhage on post-mortem examination. The thrombophilia screen was normal; the placenta showed signs of mild acute chorioamnionitis, which may be found in many “normal” placentae. (4). I find it curious that both cases had dyshidrosiform features of PG — this finding warrants further exploration.

PG is a rare disorder, with an estimated incidence of 1 in 20,000 to 50,000 pregnancies. In a small number of cases, the disease can be a paraneoplastic manifestation of trophoblastic tumors, hydatidiform mole, or choriocarcinoma. It sometimes relapses with the onset of menses or use of oral contraceptives postpartum but quickly remits after their discontinuation.

In PG, an immune response against the hemidesmosomal protein BP180, also designated as type XVII collagen or BPAG2, is executed. The disease starts between the second trimester and the puerperium, manifesting as severely pruritic erythematous papules, plaques, vesicles, and bullae, that first erupt around the umbilicus. The lesions then appear on the abdomen and extremities, only rarely involving the face or mucous membranes.

According to Sadik et al, the pathogenesis of PG remains elusive. The disorder is associated with maternal HLA-DRs DRB1*0301 (HLA-DR3) and DRB1*0401/040 X (HLA-DR4). These MHC class II molecules are aberrantly expressed on amniochorionic stromal cells and on the trophoblast. This aberrant expression is presumably involved in a loss of immunoprivilege of the fetoplacental unit. As a consequence, BP180, which is expressed in the amniotic epithelium of the placenta and the umbilical cord, is presented to maternal MHC class II in the presence of paternal MHC class II; it is then recognized as a foreign antigen, resulting in the formation of IgG autoantibodies, predominantly of the IgG 1 and IgG 3 subclasses. An aberrant complement system may also be involved, with 90% of PG patients carrying the C4 null allele. Hormonal modulation is also at play, correlating with elevated estrogen to progesterone ratios, which would explain the decline of activity toward the end of pregnancy when progesterone levels are high, and the potential post-partum flare when progesterone declines. The skin lesions themselves develop from proteases elaborated from eosinophils and neutrophils that have been recruited to the involved sites. (5)

The diagnosis of PG can be confirmed by direct immunofluorescence (DIF) demonstrating linear C3 +/- IgG and ELISA for BP 180 NC16a. Recently, immunoperoxidase stains for linear C4d on formalin-fixed paraffin-embedded tissue has been demonstrated in all 8 PG cases, compared to none of 11 cases of polymorphic eruption of pregnancy (aka PUPPP). (6) If confirmed by other studies, this could obviate the need for DIF for diagnosing PG.

Therapeutically, topical and systemic steroid are used initially. In severe cases, other immunosuppressants, such as azathioprine may be necessary (remember mycophenolate mofetil should not be used during pregnancy). Fortunately, for most patients, PG has a self-limited course without complications. PG usually recurs is subsequent pregnancies with earlier onset an increased severity.(2) Understandably, some patients might opt not to get pregnant again. Is there any reasonable approach for PG prophylaxis? Tourte et al describe the case of a 35-year-old woman whose miscarried her first pregnancy; was preterm at 30 weeks in her second, with the baby dying inexplicably at day 9 of life; developed documented PG in her third gestation, which was complicated by gestational diabetes from steroid therapy and; had recurrent PG in the first trimester of her fourth pregnancy, followed by fetal death one week later. She sought consultation in the second month of her fifth gestation. She was found to have elevated anti-BP-180 titers. Because of her prior history, rituximab was administered (1g infusions), off label, at weeks 9 and 11. Her ELISA titers diminished, no PG developed, and she gave birth to a full-term, healthy baby. (7)

There are occasional sequelae of disease that can never be predicted. Twenty-five year ago, a 36-year-old woman presented post-partum with new onset PG. I examined her in the morning; she called me in the afternoon saying how much worse she had become. I asked her to return, and the progression of her disease was frightfully dramatic. She required several months of steroids and azathioprine before she would go into remission. Her son Greg is now graduating Georgetown Law School. Most importantly, Judy Malloy became our nurse, and subsequently, our long-term superlative practice manager. Our dermatology practice is indebted to her, and by extension, to PG.

Point to remember: Rituximab may be effective agent to prevent recurrent pemphigoid gestationis.

1 Dabas G, et al. Anhydramnios in patients with pemphigoid gestationis. JAMA Dermatol 2018; 154: 484-6.
2. Cohen S, et al. Pemphigoid gestationis: A case series and review of the literature. J Dermatolog Treat 2018; Apr 5: 1-17 [Epub ahead of print].
3. Pérez J, et al. Dyshidrosiform presentation (pompholyx-like) of pemphigoid gestationis with intrauterine fetal death. Int J Dermatol 2013; 53: 1383-5.
4. Powell J, et al. Pemphigoid gestationis with intra-uterine death associated with foetal cerebral hemorrhage in the mid-trimester. Clin Exp Dermatol 2000; 25: 452-3.
5. Sadik CD, et al. Pemphigoid gesationis: Toward a better understanding of the etiopathogenesis. Clin Dermatol 2016; 34: 378-82.
6. Kwon EJ, et al. The utility of C4d immunohistochemistry on formalin-fixed paraffin-embedded tissue in the distinction of polymorphic eruption of pregnancy from pemphigoid gestationis. Am J Dermatopathol 2013; 35: 787-91.
7. Tourte M, et al. Pemphigoid gestationis: A successful preventive treatment by rituximab. J Eur Acad Dermatol Venereol 2017; 31: e206-7.

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