A 32-year-old woman at 27 weeks 6 days gestation was seen by a dermatologist on July 25, 2018 for a rash on the lower extremities, extensor elbows, and buttocks. The rash began 1 to 1.5 months ago on the legs and was initially associated with erythema and an itchy and burning sensation. The rash developed pustules and had a brown discoloration upon fading. No constitutional symptoms were present. The patient denied family history of autoimmune disease and was only taking vitamin and iron supplements. The patient was seen in 2010 for a rash during her first pregnancy, which was thought to be psoriasiform dermatitis or erythema annulare centrifugum and resolved with triamcinolone acetonide 0.1% cream.
Figure 1. Dermatologic examination reveals erythematous annular plaques of varying sizes with trailing scale on the lower extremities.
Clinical examination demonstrated erythematous annular plaques of varying sizes with trailing scale and small pustules at the border (Figure 1). There were several plaques with raised red borders. The largest plaques were on the lower extremities bilaterally and smaller plaques were on the buttocks and extensor elbows. Dark brown patches were located centrally above the abdomen and abdominal striae were noted.
The patient underwent a punch biopsy of the right posterior calf and the rash improved with clobetasol proprionate 0.05% cream.
Laboratory tests showed an absolute neutrophil count of 6.7 × 103/uL and a C-reactive protein level of 1.0 mg/dL (both within the reference ranges), an increased erythrocyte sedimentation rate of 54 mm/hr, and hypoalbuminemia (albumin = 2.9 g/dL).
Light Microscopic Findings
The biopsy specimen (Figures 2A-D) showed a mild psoriasiform epidermal hyperplasia with an absent granular cell layer. The epidermis was surmounted by a parakeratotic scale that was focally imbued with neutrophils. There were also intraepidermal collections of neutrophils. Within the superficial dermis, there was an interstitial and perivascular neutrophilic infiltration and conspicuous red cell extravasation to the point where this superficial dermal neutrophilic process almost had features reminiscent of an incipient urticarial vasculitic picture. There was attendant vacuous edematous alteration of the dermal papillae. The periodic acid–Schiff stain did not disclose any fungus.
Figure 2. The punch biopsy specimen showed mild psoriasiform epidermal hyperplasia (A) with intraepidermal collections of neutrophils (B), and parakeratotic scale containing neutrophils (C). An interstitial and perivascular neutrophilic infiltrate was present within the dermis and was associated with significant red cell extravasation (D).
The patient’s biopsy demonstrated a sterile pustular psoriasiform dermatitis with a concomitant neutrophil-rich urticarial tissue reaction in the dermis. Along with the clinical presentation of an annular skin rash during the patient’s last trimester of pregnancy, these findings are consistent with a rare dermatosis of pregnancy called pustular psoriasis of pregnancy (PPP), or impetigo herpetiformis (IH).
Historically, PPP has been included within the same classification scheme as other dermatoses of pregnancy, such as polymorphic eruption of pregnancy, atopic eruption of pregnancy, pemphigoid gestationis, and intrahepatic cholestasis of pregnancy (ie, prurigo gravidarum).1 However, most experts agree that PPP is not pregnancy-specific but rather a variant of generalized pustular psoriasis (GPP) due to the similar clinical presentation and histologic features between the 2 conditions.1-4 The relationship between PPP and GPP is not without controversy, and some researchers argue that PPP is a distinct entity because some patients are not affected by the disease outside of pregnancy.4,5 Currently, PPP is still classified as a dermatosis of pregnancy due to the importance of early treatment.1,4 IH itself is a misnomer, as there is no association with either bacterial impetigo or with the herpes simplex virus.1
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GPP is a subtype of psoriasis and can occur in both genders and at any age, with the median age of onset in the fifth decade.2 The etiology of GPP is unknown, but flares have been linked to medications, infections, UV sunlight, stem cell transplantation, emotional stress, and menstruation. GPP has been linked to homozygous or compound heterozygous mutations in IL36RN, which encodes IL-36-receptor antagonist to 3 cytokines in the IL-1 family. The disinhibition of IL-1 and IL-36 has been implicated in pustular disease, as these interleukins sustain neutrophil chemotaxis and further activate pro-inflammatory pathways.4
A 2014 case report of 2 patients from Japan with PPP also showed mutations in IL36RN, further strengthening the link between PPP and GPP.5 IL-36 is not found in normal skin and is induced by cytokines such as tumor necrosis factor-α (TNF-α), which is elevated during pregnancy. This case report suggested that women with an IL36RN mutation are unable to antagonize the excessive amount of IL-36, resulting in PPP. Otherwise, like GPP, the pathogenesis of PPP is not well elucidated, but has been associated with the same triggers as GPP.4
As seen in this patient, PPP commonly occurs in the third trimester and resolves after parturition but is likely to recur in following pregnancies. Some patients have a positive family history of psoriasis, but there are also many cases where there is no such antecedent history. PPP presents as symmetric erythematous plaques with pustules at the periphery and scaling or crusting at the center, beginning in intertriginous areas and spreading centrifugally to the extremities.2-4 The face, palms, and soles are typically unaffected.4 There are many other conditions on the differential diagnosis for pustular psoriasis, but PPP must be differentiated from acute generalized exanthematous pustulosis (AGEP).2 AGEP is drug-induced and commonly associated with antibiotic use, with symptoms resolving a lot quicker than in PPP.4 The patient was not taking any medication at this time.
PPP is strongly associated with hypocalcemia which may be responsible for systemic symptoms such as delirium, diarrhea, vomiting, and tetany along with fever and malaise.2,4 Laboratory values typically reveal leukocytosis, elevated erythrocyte sedimentation rate, hypoalbuminemia, hypoparathyroidism, and low vitamin D levels.3 Histologically, pustular psoriasis is characterized by spongiform pustules of Kogoj located in the epidermis, an absent granular layer, parakeratosis, and psoriasform hyperplasia.2 The dermis typically contains dilated blood vessels.
PPP must be recognized and treated early to avoid complications which may endanger both the mother and the fetus, such as intrauterine growth restriction due to placental insufficiency, electrolyte imbalances, premature rupture of membrane, and stillbirth.3 However, treatment remains difficult due to the teratogenicity of the drugs commonly used to treat GPP, and no specific guidelines exist. Initial first-line treatment typically consists of small dosages of systemic corticosteroids, but topical corticosteroids may be used for less severe cases.2-4 This patient did not have leukocytosis or any systemic symptoms, which may explain why her rashes during both pregnancies resolved with topical corticosteroids. Cyclosporine has been used for severe cases not responsive to corticosteroids, and biologic agents (such as infliximab [Remicade], a TNF-α inhibitor) have been used successfully in a few reports.3,4 If there are further flares in the postpartum period, retinoids or methotrexate may be used if the mother is not breastfeeding.2
With the clinical presentation and histologic findings, this patient had the typical characteristics of PPP, which has recurred in her second pregnancy. Although she has seen improvement with topical corticosteroids during both pregnancies, subsequent pregnancies should be monitored closely along with laboratory values.
Ms Leung is a medical student in the department of dermatopathology at Weill Cornell Medicine in New York, NY.
Dr Saab is a pathology fellow at Memorial Sloan Kettering Cancer Center in New York, NY.
Dr Wildman is an associate professor of clinical dermatology at Weill Cornell Medicine in New York, NY.
Dr Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY. For more information, please visit www.weillcornelldermpath.com.
Disclosure: The authors report no relevant financial relationships.
1. Danesh M, Pomeranz MK, McMeniman E, Murase JE. Dermatoses of pregnancy: Nomenclature, misnomers, and myths. Clin Dermatol. 2016;34(3):314-319.
2. Hoegler KM, John AM, Handler MZ, Schwartz RA. Generalized pustular psoriasis: a review and update on treatment [published online March 24, 2018]. J Eur Acad Dermatol Venereol. doi:10.1111/jdv.1494
3. Namazi N, Dadkhahfar S. Impetigo herpetiformis: review of pathogenesis, complication, and treatment. Dermatol Res Pract. 2018;2018:5801280.
4. Trivedi MK, Vaughn AR, Murase JE. Pustular psoriasis of pregnancy: current perspectives. Int J Women’s Health. 2018;10:109-115.
5. Sugiura K, Oiso N, Iinuma S, et al. IL36RN Mutations underlie impetigo herpetiformis. J Invest Dermatol. 2014;134(9):2472-2474.