Pruritic urticarial papules and plaques of
Pregnancy
Contact dermatitis
Drug eruption
Urticaria
Erythema multiforme
Varicella
Other autoimmune blistering diseases
32.6 Associated Conditions
PG has been associated with patients diagnosed with trophoblastic tumors, hydatidiform mole, or choriocarcinoma [5]. It has also been reported to be associated with Graves’ disease, thyroiditis, vitiligo, and pernicious anemia, explained by the presence of HLA-DR3 and DR4 in these other autoimmune conditions [25].
32.7 Laboratory Tests
32.7.1 Histology
32.7.2 Immunofluorescence
The typical pattern of direct immunofluorescence (DIF) on a perilesional skin is linear deposition of C3 ± IgG along the basement membrane zone (BMZ). C3 is reported in 100 % of cases, while IgG is seen in 25–50 % of cases. These bind to the epidermal side of salt-split skin. On indirect immunofluorescence (IIF), there is circulating IgG targeting the BMZ [3, 6, 26].
32.7.3 ELISA
This test will reveal circulating IgG against collagen XVII (BP180), particularly the NC16A domain [25]. Antibodies against some adjacent epitopes have also been reported [10]. Using ELISA, sensitivity has been reported at 93 % and specificity at 96 % (P < 0.001) compared with a sensitivity of 74 % and a specificity of 96 % (P < 0.001) for IIF [27].
32.8 Diagnosis
Diagnosis is made by a high clinical suspicion on presentation and confirmed by histology, DIF. If required, IIF, ELISA, and immunoblotting may be done. An HLA profile may be performed as well [2].
32.9 Possible Complications to the Fetus and the Newborn
An earlier study of 74 PG cases reported an increased risk for prematurity and small-for-gestational-age babies. There were no reports of fetal loss, nor was there any report on the adverse effects of the use of systemic corticosteroids [29].
A more recent study of 39 PG compared with 22 normal controls observed that an early onset of disease (during the first or second trimester) and the presence of blisters may lead to adverse pregnancy outcomes, such as decreased gestational age, preterm birth, and low-birth-weight babies [6, 24].
There have also been reports of the neonate born to a mother with PG being affected, but the incidence is rare (one case per 100,000 affected PG mothers) [30]. These affected newborns have mild and transient blistering, resolving in days to weeks with no long-term complications [22]. A case report on a 33-year-old mother diagnosed with PG and her affected neonate reported that they had the same level of pathogenic antibodies transferred from the mother to fetus, but the blisters of the newborn resolved without treatment, long before the antibody disappeared [30].
32.10 Current Management
Most of the literature on the management of PG are small case series and retrospective reviews. This is primarily because pregnancy is usually an exclusion criterion for most clinical trials and the usual medications used for the treatment are contraindicated during pregnancy. We also have to consider that breastfeeding sets limitations on the recommended treatments. It is very important that the risk of therapy be balanced against the severity of symptoms [31].
It is accepted that the mainstay treatments for PG are potent topical corticosteroids (CS) for milder and localized diseases and systemic CS for more extensive cases. For chronic, relapsing, and recalcitrant cases, immunosuppressive treatment has been reported to be successful [3, 5, 6, 22, 32–34] (see Table 32.2).
Table 32.2
Treatment options for pemphigoid gestationis and their pregnancy categories
Pregnancy categorya | |
|---|---|
First line | |
Topical corticosteroids | C |
Systemic corticosteroids | C |
Others | |
Tetracyclines | D |
Nicotinamide | D |
Cyclophosphamide | C |
Cyclosporine | D |
Azathioprine | C |
Dapsone | C |
IVIg | C |
Rituximab | Unclassified |
Plasmapheresis | X |
Goserelin | |
There are reports suggesting that early onset of the disease is associated with more severe adverse outcomes in pregnancy indicating a need for more aggressive early management [31].
32.10.1 General Measures
The main goal of treatment for PG is to alleviate discomfort and relieve the pruritus, thereby addressing the psychological anxiety of the disease. Systemic treatment should only be started when symptom severity outweighs the possible risks to the fetus [6]. Prior to starting, baseline blood tests must be done. These include full blood count, liver and renal function tests, as well as specific enzyme levels related to specific systemic drugs (i.e., glucose-6-phosphate-dehydrogenase [G6PD] for dapsone and thiopurine methyltransferase [TPMT] for azathioprine). These tests are ideally done every 2–4 weeks while on treatment [31].
The pruritus may be controlled with category A antihistamines (i.e., chlorpheniramine). First-generation H1 blockers are not associated with any risk of major adverse fetal effects [35]. There are less evidence on second-generation H1 blockers and no established link to adverse pregnancy outcomes [36, 37]. None of the antihistamines are excreted in the breast milk [38]. Cool compresses may also help alleviate the pruritus. Intact blisters may be drained with a sterile, large-bore needle and avoid unroofing the blister. Silicone dressings or nonstick Vaseline gauze may be applied to the blisters until they heal. Antibiotics may be given for secondary bacterial infections [31].
32.10.2 Corticosteroids
Potent topical CS (i.e., betamethasone dipropionate) are used to control limited forms of the disease [31]. In a large systematic review on the safety profile of topical CS in pregnancy, there were no significant associations with congenital anomalies, stillbirths, or premature delivery. However, they did report a link with low neonatal birth weights [39, 40].
Prednisolone is the preferred systemic CS as it bypasses the metabolism in the liver and therefore is safer in pregnancy compared to its prodrug, prednisone [41]. Dose may be started at 0.5–1 mg/kg/day, which may be increased or decreased slowly, depending on the response of the patient. This drug is generally safe during pregnancy, but the long-term complications of taking it must be kept in mind, such as Cushing’s syndrome, hypertension, impaired glucose metabolism, osteoporosis, as well as susceptibility to infection. Bone mineral density scan monitoring as well as calcium and vitamin D supplementation must be implemented for patients requiring long-term use of systemic CS [31]. A study comparing 39 PG patients with 22 normal controls advised that the systemic use of CS is the ideal treatment as it did not have any adverse effects on pregnancy outcomes [6, 24].
32.10.3 Anti-inflammatory Antibiotics
32.10.3.1 Doxycycline/Minocycline and Nicotinamide
There are two small case series published reporting the success of doxycycline 200 mg/day and nicotinamide 500 mg/day or Minomycin 100 mg/day and nicotinamide 1,000 mg/day for 6 months in postpartum PG patients with persistent disease. Tetracycline is however listed as pregnancy category D because of potential permanent teeth discoloration, enamel hypoplasia, as well as harm to the bone formation in the fetus. No long-term follow-up was given in these reports [42, 43].
32.10.3.2 Dapsone
Dapsone is used for its anti-inflammatory properties. With proper monitoring of G6PD levels, dapsone may be given in addition to systemic CS at doses ranging from 50 to 150 mg/day for severe persistent PG [44–47]. Used as treatment for leprosy and malaria, there are no reports of adverse pregnancy outcomes while on dapsone [48]. There are however rare reports on neonatal hemolysis and neonatal jaundice which should be monitored [49].
32.10.4 Immunosuppressives
32.10.4.1 Azathioprine
With proper monitoring of TPMT levels, azathioprine has been used as an adjunct to systemic CS for severe persistent PG in the postpartum period, at a dose of 50–150 mg/day [5, 32, 45, 46, 50, 51]. In animal studies, it has been shown to have various teratogenic effects at high doses but not at therapeutic doses. Data from inflammatory bowel disease patients treated with azathioprine showed that it is safe and well tolerated during pregnancy [52, 53].
32.10.4.2 Cyclosporine
Cyclosporine is another alternative immunosuppressant that seems to be safe in pregnancy. It crosses the placenta in high quantities but is rapidly cleared from the newborn and has not been shown to be teratogenic or myelotoxic in animal studies except in very high doses. These data are from transplant recipients. It did not increase the rate of malformation frequency, low birth weight, or prematurity [54–56]. A severe persistent case of PG was treated with cyclosporine at a dose of 100 mg/day in conjunction with low-dose prednisolone and intravenous immunoglobulin at a dose of 0.4 g/kg/day for 5 days starting at 7 months postpartum. However, this patient continued to have blisters up to 1.5 years postpartum [44].
32.10.4.3 Cyclophosphamide
There is a case report on a patient with severe persistent PG in the postpartum period who also had antiphospholipid antibody syndrome and responded well to pulsed-dose intravenous cyclophosphamide at 0.75 g/m2 for two doses in an 8-week period, followed by another dose 5 months later. This resulted in complete remission and had been off treatment up to 18 months after birth [57].
32.10.4.4 Intravenous Immunoglobulin
IVIg has been reported to be safe both during pregnancy and postpartum period. It has been used as an off-label drug in addition to systemic CS and immunosuppressants at a dose of 0.4–0.5 g/kg/day for 2–5 days in monthly cycles [44–47]. There was a case report published reporting a PG patient who was successfully treated with IVIg (2 g/kg each infusion cycle) during both antepartum and postpartum periods. There were no reported complications for either the baby or the mother [58].
32.10.4.5 Rituximab
Rituximab has been used as an off-label drug for PG. A case of severe persistent PG was successfully treated with rituximab at a dose of 375 mg/m2 for four weekly infusions and went into remission for 6 months. The patient had a flare-up of the disease and was treated with four more infusions at 2-month intervals and resulted in complete remission [50].
32.10.4.6 Plasmapheresis
Plasmapheresis has been used for severe PG that are persistent up to 2 years postpartum. It was reported to be successful in a 40-year-old PG patient in the 20th week of her fifth pregnancy. She received plasma exchanges on her 26th week, during her delivery, and postpartum resulting in rapid resolution of her condition [51, 59]. Immunoapheresis (IA) is a subtype of plasmapheresis that has been successful in the treatment of a patient with severe PG, receiving 15 IA sessions (14 prepartum and 1 postpartum) in conjunction with methylprednisolone [60].
32.10.5 Others
Goserelin has been reported to be effective for a 6-month course in addition to systemic CS during the postpartum period for persistent PG. This was used as chemical oophorectomy [61].
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