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Pemphigoid Gestationis

- Other pruritic conditions of pregnancy - Besnier prurigo gestationis: excoriated papules and no vesicles; usually limited to extensor surface of extremities - Papular urticarial papules and plaques of pregnancy (PUPPP): urticarial plaques and small papules with a narrow, pale halo, and no vesicles; usually in primigravidas near term - PUPPP usually in fundal striae; PG is periumbilical. - Differentiate with immunofluorescent studies

- Impetigo herpetiformis: sterile pustules, not vesicles. May involve mucous membranes, groin, and inner thighs - Papular dermatitis of pregnancy/allergic dermatitis of pregnancy

- Nonpregnancy related conditions - Dermatitis herpetiformis (chronic; more common in middle-aged males) - Bullous pemphigoid, drug-induced - Toxic drug eruption, including erythema multiforme - Contact dermatitis

- Routine histology specimen (2) - Eosinophilic spongiosis - Papillary dermal edema - Subepidermal blister with necrosis of basal cell layer - Dermal perivascular infiltrate of lymphocytes and eosinophils

para>Association with prematurity (20%) and growth restriction; less commonly associated with stillbirth

~5 " 10% of infants born to mothers with PG have cutaneous lesions that are usually self-limited and likely the result of transplacental transference of maternal IgG antibasement membrane zone autoantibodies.

Children born to mothers with PG are not at increased risk of autoimmune diseases.

Pregnancy Considerations

  • By definition, PG is a condition of pregnancy and puerperium; rarely seen in conjunction with hydatidiform mole and choriocarcinoma.
  • Fetuses in mothers with PG are at risk for growth restriction and prematurity due to potential for placental insufficiency from immune response to placental antigens. Antenatal testing is indicated.
  • Onset in 1st or 2nd trimester and presence of blisters may lead to adverse pregnancy outcomes including preterm birth and low birth weight. Treatment with systemic corticosteroids does not adversely affect pregnancy outcomes (1).

ETIOLOGY AND PATHOPHYSIOLOGY

During pregnancy, patients develop IgG antibodies against placental basement membrane proteins that cross-react with skin and result in an immune response.

  • Placental proteins/antigens are recognized as foreign and result in the production of antiplacental antibodies.
  • Main antigen = BP180 (type XVII collagen or BPAG2; a transmembrane protein required for dermal-epidermal adhesion), less frequently involves antigen BP230
  • Antibodies to placental proteins cross-react with same proteins in skin of mother (and potentially fetus)
  • Maternal autoantibodies to BP180 in basement membranes initiate C3 fixation, complement and leukocyte activation which release proteolytic enzymes that separate the dermis and epidermis forming vesicles and bullae.
  • Higher association with HLA-DR3 and/or HLA-DR4
  • Not caused by herpes virus

Genetics

Genetic predisposition is possible-HLA-DR3 and HLA-DR4 association.

RISK FACTORS

  • Episode in prior pregnancy
  • Herpes simplex does not increase risk.

GENERAL PREVENTION

  • Avoid secondary infection of open skin lesions.
  • Estrogens may trigger future flare-up (e.g., oral contraceptives and menses).

COMMONLY ASSOCIATED CONDITIONS

  • Pregnancy
  • Rarely, trophoblastic tumors, hydatidiform mole, and choriocarcinoma
  • Other associated diseases: Graves disease and other autoimmune thyroid disorders, pernicious anemia

DIAGNOSIS

HISTORY

History of current pregnancy or recent delivery in patient with pruritic papules and/or plaques with or without periumbilical blisters

PHYSICAL EXAM

  • Pruritus followed by periumbilical papules and plaques on pregnant female that, over days to weeks, progress to vesicles and bullae.
  • Lesions also may be present on trunk, buttocks, limbs, palms, and soles.
  • Face, scalp, and mucous membranes involved rarely.

DIFFERENTIAL DIAGNOSIS

  • Other pruritic conditions of pregnancyBesnier prurigo gestationis: excoriated papules and no vesicles; usually limited to extensor surface of extremitiesPapular urticarial papules and plaques of pregnancy (PUPPP): urticarial plaques and small papules with a narrow, pale halo, and no vesicles; usually in primigravidas near termPUPPP usually in fundal striae; PG is periumbilical.Differentiate with immunofluorescent studiesImpetigo herpetiformis: sterile pustules, not vesicles. May involve mucous membranes, groin, and inner thighsPapular dermatitis of pregnancy/allergic dermatitis of pregnancy
  • Nonpregnancy related conditionsDermatitis herpetiformis (chronic; more common in middle-aged males)Bullous pemphigoid, drug-inducedToxic drug eruption, including erythema multiformeContact dermatitis

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

  • May have elevated ESR and/or antithyroid antibodies
  • Peripheral eosinophilia may be present and correlates with severity.
  • Indirect immunofluorescence (IIF): circulating serum C3 (90%), herpes gestationis factor (IgG1 antibody) (20 " 25%) (2)
  • ELISA: circulating IgG antibodies against BP180 (collagen XVII) (2,3)
  • Immunoblotting: circulating IgG antibodies to 180 kDa and/or 230 kDa protein bands (2)
  • HLA-profile: DR3, DR4, or both (2)
  • Tzanck smear negative
  • Herpes simplex virus culture negative
  • Imaging is not indicated.
  • Antenatal testing for fetal well-being is indicated. Evaluate for adequate amniotic fluid volume, potential preterm labor, and fetal growth.
  • Skin biopsy of blister margin

Diagnostic Procedures/Other

Two skin biopsies

  • One for routine histology
  • One for direct immunofluorescence (place in Michel medium)

Test Interpretation

  • Routine histology specimen (2)Eosinophilic spongiosisPapillary dermal edemaSubepidermal blister with necrosis of basal cell layerDermal perivascular infiltrate of lymphocytes and eosinophils
  • Immunofluorescence biopsy specimenDirect IF: heavy linear deposition of C3 (100%, pathognomonic) and IgG (25 " 50%) along BMZ; C3 and IgG at epidermal site on salt-split skin

TREATMENT

  • Primary target for treatment is discomfort from lesions and patient anxiety.
  • Treat mild disease with oral antihistamines and topical steroids.
  • Treat more involved cases primarily with systemic corticosteroids.
  • Severe cases can require plasmapheresis.

GENERAL MEASURES

  • Exclude herpes virus infection
  • Relieve pruritus.
  • Prevent secondary infection.
  • Soothing compresses, such as with aluminum acetate (Burow solution, Domeboro), may help to relieve itching as may tepid baths, compresses, and emollients.

MEDICATION

Medications directed at relieving pruritus and preventing new blister formation. In addition, may need treatment for secondary infection of skin lesions.

First Line

  • Mild disease: topical steroids and second generation oral antihistamines for mild pruritus; topical corticosteroids for early lesions (2)[A]: side effects of topical steroids: spread and worsening of untreated infections, telangiectasia, striae, hypertrichosis, skin atrophy
  • Severe disease: systemic corticosteroids. Caution in pregnancy.Starting dose prednisolone 20 to 40 mg/day (2)[A]3 days and, if no new lesions, maintain dose for 1 to 2 weeks and then taper to maintenance dose or discontinue. If new lesions, consider increasing dose.Natural course of disease often allows for tapering/discontinuing steroid before delivery, and then increasing/restarting after delivery.Maternal risk of systemic steroids includes hypertension, osteoporosis, diabetes, adrenal suppression, peptic ulceration, weight gain, Cushing syndrome, and cataracts (2)[A].Avoid betamethasone and dexamethasone, as they cross the placenta. Placental enzyme inactivates 88% of prednisolone. Increased risk of intrauterine growth restriction and adrenal suppression in neonates with long-term corticosteroid exposure. Concern for fetal risks with systemic corticosteroids, although generally considered safeNo clinical trials yet performed to identify most optimal treatment for disease.
  • Weigh risk of aggravating hyperglycemia, potential effects on maternal and fetal bone, increased susceptibility to infections versus benefit of relieving pruritus and resolving the lesions.
  • PrecautionsUse prednisone cautiously in immunosuppressed patients and those with diabetes or thrombophlebitis.If prednisone has been used for more than several weeks, taper when discontinuing to prevent cortisol deficiency and provide with stress-dose steroids at appropriate times (e.g., at delivery).

Second Line

Only for refractory cases

  • Plasmapheresis
  • IVIG
  • Immunophoresis

ISSUES FOR REFERRAL

  • Consider dermatology referral.
  • Pediatric referral for neonate (if mother receiving systemic steroids) to monitor for adrenal suppression

INPATIENT CONSIDERATIONS

Apply and change soothing compresses.

ONGOING CARE

PATIENT EDUCATION

  • Benign disease; no permanent adverse sequelae (e.g., scarring) in the absence of secondary infection; usually resolves after delivery. Post inflammatory hyperpigmentation is common.
  • PG may recur with subsequent pregnancies, resumption of menses, or oral contraceptive agents.
  • Goals of therapy include control of itch, suppression of blistering, and avoidance of secondary infection.
  • Discuss the benefits and potential risks of all prescribed medications.
  • PG alone is not a contraindication for breastfeeding; need to consider medications, including systemic corticosteroids.

PROGNOSIS

  • Typically excellent
  • Regresses prior to, but more commonly after, delivery " usually within weeks to months
  • Often flares in postpartum (75%), especially with oral contraceptives or menses.
  • Cutaneous involvement in infants is rare (5 " 10%) and regresses with clearance of maternal antibodies.
  • PG often recurs in subsequent pregnancies.
  • Systemic steroids may suppress new lesions, relieve pruritus, and dampen course, but maternal/fetal risks need to be considered.
  • Duration of PG lesions is less in breastfeeding women.

COMPLICATIONS

  • Secondary bacterial infection
  • Risks of systemic medications in pregnancy for mother and baby
  • Premature birth
  • Fetal growth restriction
  • Transient herpes gestationis in the neonate

REFERENCES

11 Chi CC, Wang SH, Charles-Holmes R, et al. Pemphigoid gestationis: early onset and blister formation are associated with adverse pregnancy outcomes. Br J Dermatol. 2009;160(6):1222 " 1228.22 Semkova K, Black M. Pemphigoid gestationis: current insights into pathogenesis and treatment. Eur J Obstet Gynecol Reprod Biol. 2009;145(2):138 " 144.33 Lipozen i J, Ljubojevic S, Bukvi -Mokos Z. Pemphigoid gestationis. Clin Dermatol. 2012;30(1):51 " 55.

ADDITIONAL READING

  • Aoyama Y, Asai K, Hioki K, et al. Herpes gestationis in a mother and newborn: immunoclinical perspectives based on a weekly follow-up of the enzyme-linked immunosorbent assay index of a bullous pemphigoid antigen noncollagenous domain. Arch Dermatol. 2007;143(9):1168 " 1172.
  • Huilaja L, M €kikallio K, Tasanen K. Gestational pemphigoid. Orphanet J Rare Dis. 2014;9:136.
  • Ingen-Housz-Oro S, Bedane C, Prost C, et al. Pemphigoid gestationis. Guidelines for the diagnosis and treatment. Centres de reference des maladies bulleuses auto-immunes. Societe Fran §aise de Dermatologie [in French]. Ann Dermatol Venereol. 2011;138(3):264 " 266.
  • Lu PD, Ralston J, Kamino H, et al. Pemphigoid gestationis. Dermatol Online J. 2010;16(11):10.
  • Westermann L, H Όgel R, Meier M, et al. Glucocorticosteroid-resistant pemphigoid gestationis: successful treatment with adjuvant immunoadsorption. J Dermatol. 2012;39(2):168 " 171.
  • Yakasai IA, Thomson AJ, Fitzsimons C. Specific dermatoses of pregnancy: a review [in English, French]. West Afr J Med. 2011;30(4):239 " 244.

SEE ALSO

Algorithm: Genital Ulcers

CODES

ICD10

  • O26.40 Herpes gestationis, unspecified trimester
  • O26.42 Herpes gestationis, second trimester
  • O26.43 Herpes gestationis, third trimester
  • O26.41 Herpes gestationis, first trimester

ICD9

  • 646.83 Other specified complications of pregnancy, antepartum condition or complication
  • 646.80 Other specified complications of pregnancy, unspecified as to episode of care or not applicable

SNOMED

  • Herpes gestationis (disorder)
  • Herpes gestationis - not delivered
  • Transplacental herpes gestationis (disorder)
  • Herpes gestationis - delivered

CLINICAL PEARLS

  • Rare autoimmune bullous dermatosis of pregnancy and the puerperium.
  • Originally named herpes gestationis on the basis of the morphologic herpetiform features. PG is not associated with herpes virus infection.
  • Treatment focuses on controlling itch, suppressing lesions with corticosteroids, and monitoring fetal well-being.