What Caused These Pustules?

Case Report
In case one, a 62-year-old woman with actinic keratoses on the forehead and nose was prescribed a 3-day course of ingenol mebutate 0.015%. On day two of treatment, she developed a painful erythematous pustular eruption on the forehead and nose associated with periorbital edema. The rash was not associated with pruritus or systemic symptoms such as fever or chills.

In case two, a 62-year-old man was prescribed ingenol mebutate 0.015% for actinic keratoses on the temples, cheeks, nose, and helices. On day three of treatment, he presented with brightly erythematous patches on the malar cheeks and nose with numerous overlying minute superficial pustules (Figures 1A and 1B). He denied pain, pruritus, or systemic symptoms.

What Is The Diagnosis?

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Diagnosis: Pustular Eruption Secondary to Ingenol Mebutate for Actinic Keratoses

Ingenol mebutate is an effective, topical field-directed therapy for actinic keratoses. Two strength formulations are approved for use on the face and scalp (0.015%) and on the trunk and extremities (0.05%).¹ The most commonly reported side effects are erythema and scaling.^1,2 We present two patients who developed acute pustular reactions after treatment of the face with ingenol mebutate. 

Clinical Presentation 
In the two cases presented, pustular reactions to ingenol mebutate occurred as early as two to three days after initiation of treatment. The reaction consists of erythematous patches with overlying pustules in the areas of topical application. The reaction does not appear to extend beyond the boundaries of treatment.

Pathogenesis
Ingenol mebutate is known to have two sequential mechanisms of action. The first is induction of primary necrosis by direct disruption and swelling of the plasma membrane and mitochondria of dysplastic keratinocytes.³ The second mechanism of action involves the recruitment of neutrophils by inflammatory cytokines produced by keratinocytes that survived the initial insult.⁴ These neutrophils produce reactive oxygen species that kill keratinocytes directly and attract cytotoxic T cells to the treated area.⁴ In the study that elucidated the second mechanism of action, recruitment of neutrophils was found to be necessary for prevention of relapse of squamous cell carcinomas in mice treated with ingenol mebutate.⁴ A pustular eruption after the use of ingenol mebutate represents a pronounced neutrophilic response to treatment with ingenol mebutate.

Histology
Histologic examination of murine skin treated with ingenol mebutate shows a dense neutrophilic infiltrate starting 24 hours after topical treatment.⁴ The histopathological features of the sterile pustular eruption secondary to ingenol mebutate have not been characterized in the literature.

Differential Diagnosis 
Differential diagnoses for pustular eruptions on the face include impetigo, demodicosis, acne vulgaris, and papulopustular rosacea. The temporal relationship between the use of ingenol mebutate and the development of erythema and pustules suggests the diagnosis of a sterile pustular eruption secondary to this medication. Furthermore, demodicosis, acne vulgaris, and rosacea tend to have a more chronic time course and will not resolve with supportive care alone.

Management
Patients can be managed with supportive care such as gentle cleansing and application of petrolatum and cool compresses. Bacterial cultures and potassium hydroxide (KOH) preparations can be done to rule out infection; however, it is also acceptable to observe the pustular eruption for resolution instead.

Prognosis
Pustular reactions to ingenol mebutate have previously been reported only with the use of the 0.05% concentration, and the prognosis for this reaction was not noted.¹ However, the eruption appears to be short-lived and harmless, resolving within 1 to 2 weeks without long-term sequelae such as scarring.

Our Patients
Treatment was discontinued in our first patient. She was instructed to apply petrolatum and cool compresses to the affected areas. The patient was prescribed cephalexin empirically, although bacterial culture of the pustular content later came back negative. KOH preparation of a pustule revealed no fungal elements or Demodex mites. Follow-up at 2 weeks showed resolution of the pustular eruption and complete clearance of the actinic keratoses on the forehead and nose. 

Our second patient (Figure 1), who presented on day three after completion of the three-day course of ingenol mebutate, was reassured and told to return if any new concerns arose. No treatment was prescribed to alleviate the pustules. Three months later, he presented with three actinic keratoses, but none in the areas of pustular eruption. The pustules had resolved without residual scarring, erythema, or pigmentary changes. The new actinic keratoses were treated with cryotherapy. 

Conclusion
These cases highlight pustular eruptions as a side effect of ingenol mebutate treatment. While pustular reactions have been reported in trials of this medication, this peculiar reaction may be underrecognized in clinical practice.

The most common side effects of ingenol mebutate are erythema and scaling.^1,2 The incidence of pustular eruptions with the 0.015% concentration of ingenol mebutate has not been characterized. Moreover, a trial comparing concentrations of 0.0025%, 0.01%, and 0.05% did not note any pustular reactions.² A pooled study of four randomized clinical trials reported a rate of vesiculation or pustulation of 43.6% in patients treated with 0.05% ingenol mebutate on the trunk or extremities.¹ Rates of vesiculation or pustulation in patients treated with the lower 0.015% concentration on the face and scalp were not reported as that adverse event was noted to be minimal.¹

The pustular eruption noted in the two patients presented likely represented a pronounced neutrophil response to treatment with ingenol mebutate. Interestingly, both patients had remarkable clearance of actinic keratoses at the sites that developed pustular reactions. The first patient had a pustular reaction at all treated areas and experienced complete clearance, despite discontinuing treatment after two applications. The second patient had recurrence of actinic keratoses at the temples and helices where pustules had not developed, but experienced complete clearance at the sites of pustular eruption on the nose and cheeks. Pustular reactions may herald a favorable response to ingenol mebutate treatment, but further investigation is necessary. Patients and their providers should be aware of the possibility of a pustular reaction to ingenol mebutate, and reassurance of resolution should be provided.

Dr Anderson is a graduate of Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, PA, and will start her dermatology residency there in July 2020. Dr Wilson is an associate professor of dermatology at department of dermatology, University of Virginia Health System, in Charlottesville, VA. Dr Flowers is an assistant professor of dermatology at department of dermatology, University of Virginia Health System.

Disclosure: The author reports no relevant financial relationships.  

References
1. Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366(11):1010-1019. doi:10.1056/NEJMoa1111170

2. Siller G, Gebauer K, Welburn P, Katsamas J, Ogbourne SM. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study. Australas J Dermatol. 2009;50(1):16-22. doi:10.1111/j.1440-0960.2008.00497.x

3. Ogbourne SM, Suhrbier A, Jones B, et al. Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. 2004;64(8):2833-2839. doi:10.1158/0008-5472.can-03-2837

4. Challacombe JM, Suhrbier A, Parsons PG, et al. Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J Immunol. 2006;177(11):8123-8132. doi:10.4049/jimmunol.177.11.8123