A Case of New-Onset Pemphigus Erythematosus after Topical Application of Ingenol Mebutate.

Sir,

Several reports on pemphigus induced by agents for actinic keratosis, including topical 5-fluorouracil and imiquimod, have been published. Ingenol mebutate is one of the topical agents used for treating actinic keratosis in some countries.

A 58-year-old woman presented with painful erythema and yellowish crusts on nose and cheeks. Previously, the patient was diagnosed with actinic keratosis and applied ingenol mebutate gel 150 μg/g for three consecutive days. As erythema appeared on the area where gel was applied, considering irritant contact dermatitis, the patient was given 2 weeks of steroid treatment prior to the first visit. In our clinic, we stopped oral steroid and prescribed doxycycline 100 mg daily. Despite months of antibiotics, erythema did not improve. Then, a biopsy was done on left cheek [Figure 1a-d]. Histopathologic examination revealed superficial separation with dyskeratotic acantholytic granular keratinocytes [Figure 2a and b]. The serologic test for antinuclear antibodies was negative. In light of these findings, considering the diagnosis of pemphigus erythematosus, we prescribed topical methylprednisolone but the lesions persisted. After 21 months of wax and wane, second biopsy was done on the rim of lesional and perilesional skin. Histopathologic examination showed intragranular separation with acantholytic granular cells [Figure 2c]. Direct immunofluorescence was weak positive on epidermis and basement membrane [Figure 2d]. The patient refused to check autoantibody titers because there was no agreement for further examination. She is now on mycophenolate mofetil with slight improvement in erythema.

Figure 1

Clinical features of pemphigus erythematosus in the patient. The clinical features of the patient are shown in chronological order from the (a) earliest to (d) latest. (a) Diffuse ill-demarcated erythematous patch on both cheeks mainly on left and yellow crusts on left cheek and nose were present on the first visit. (b) The lesion exacerbated with more prominent erythema and erosions, despite months of treatment with doxycycline 100 mg daily. The first biopsy was done on her left cheek (c) The erosive erythema on malar and nasal areas did not improve while the patient was on topical steroid. (d) The patient underwent second punch biopsy on periphery of erythema on left cheek and perilesional skin

Figure 2

Histological features with direct immunofluorescence of the patient. (a) The first 4-mm-punch biopsy was done on the rim of the lesion on left cheek. Superficial epidermal separation was notable with dyskeratotic acantholytic granular keratinocytes, distinctive of pemphigus foliaceus (hematoxylin-eosin, ×100). (b) Perifollicular inflammation was appreciable with infiltration of mixed cells of lymphocytes, neutrophils, eosinophils, and histiocytes, most of which were lymphocytes (hematoxylin-eosin, ×200). (c) The second 4-mm-punch biopsy was done on the rim of the lesion on left cheek, 21 months after the first one. Intragranular separation and acantholytic granular cells were noted (hematoxylin-eosin, ×100). (d) Direct immunofluorescence of perilesional skin revealed weak positive on cell surface staining of IgG in lace-like pattern and deposition of IgG on basement membrane

Pemphigus erythematosus, a localized form of pemphigus foliaceus, typically presents as crusted lesions on seborrheic areas. Until now, there has been one report of relapsed pemphigus vulgaris after using ingenol mebutate,[1] but none on newly triggered pemphigus. Prior case reported a patient with crusted plaques on nose and erosion on lower lip, which resulted in complete remission after treatment. In this case, however, the patient still presents erythema with crusts that has not completely resolved.[1] As local skin reaction by applying ingenol mebutate gel is known to usually subside within 4 weeks, special consideration should be given if crusted lesions persist for months.

The mechanism of ingenol mebutate triggering pemphigus may be through the stimulation of pro-inflammatory factors. Pro-inflammatory cytokines including TNF-alpha, IL-6, and IL-8 were increased when ingenol mebutate was applied in in vitro study on human cells.[2] They are postulated to mediate blistering process of pemphigus with significant difference in their expression between lesional and nonlesional biopsies of pemphigus patients.[3] Another mechanism may be through the generation of autoantibodies. Ingenol mebutate produces antibodies that lead neutrophils to target dysplastic epidermal cells.[4] In this process of inducing antibodies, anti-desmoglein autoantibodies may be produced accidentally.

Moreover, several herbal supplements were associated with pemphigus, suggesting a possibility of the agents' role in immune-modulation.[5] Of note, ingenol mebutate is an ester of diterpene ingenol and angelic acid, an active compound used in herbal medicine for pain-relief. Topical herbal supplements should be monitored for any immune-enhancing effects.

To conclude, this is the first report of pemphigus erythematosus that newly developed after using ingenol mebutate. Dermatologists should be aware of pemphigus associated with its use and consider a biopsy including direct immunofluorescence if crusted lesions last for months.

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Conflicts of interest

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