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Vasodilatory adverse events associated with topical imiquimod 5 percent cream

  • Author(s): Jacobs, Aleda A
  • Snavely, Nick
  • Markus, Jodi
  • Rosen, Ted
  • et al.
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Vasodilatory adverse events associated with topical imiquimod 5 percent cream
Aleda A Jacobs MD, Nick Snavely MD, Jodi Markus MD, Ted Rosen MD
Dermatology Online Journal 14 (4): 4

Department of Dermatology, Baylor College of Medicine, Houston, TX. ajmd14@yahoo.com

Abstract

The immune response modulator, imiquimod, has a wide ranging utility in dermatology. Some rare adverse events are easily explained based upon its mechanism of action (such as induction of vitiligo and worsening of psoriasis). We report the occurrence of cutaneous vasodilatory side effects, angioedema and urticaria, which accompanied the treatment of basal cell carcinomas in two patients. These phenomena must be quite rare considering a paucity of similar reports in the literature.



Introduction

Imiquimod cream, the first topical immune upregulator, has become established as an FDA approved agent in the management of actinic keratoses, superficial basal cell carcinomas, and external genital warts. Aside from very marked inflammatory reactions, which typically resolve with excellent cosmetic outcomes, and the rare induction of localized vitiligo, cutaneous side effects of imiquimod have not been noted. Vasodilatory adverse events have not been previously reported and thus can be assumed to be rare events. We report herein two such cases that occurred in patients during imiquimod treatment of superficial basal cell carcinoma (sBCC). Although both cases demonstrated an expected brisk reaction at the application site, both patients also developed an unexpected immune-mediated response in a body area distant from the site of application. A brief discussion of potential mechanisms for this type immune system activation follows.


CASE 1

A 56-year-old female presented with a 1.0 cm2 erythematous, scaling plaque on her abdomen; biopsy demonstrated superficial basal cell carcinoma. Imiquimod 5 percent cream was to be applied once daily, Monday through Friday, for a total duration of therapy of 6 weeks. Following 4 weeks of strict adherence to the regimen, she was noted to have moderate erythema at the application site as well as a new abdominal lesion—identical in appearance to the first—outside the original treatment area. The patient was advised to complete her 6-week course at the original application site, as well as to begin the same treatment to the new area. Some 6 weeks later she developed intense pruritus at the second application site. This area had become ulcerated with several centimeters of surrounding erythema and edema. She noted also the concomitant appearance of diffuse, pruritic, non-erythematous swelling of the superior and inferior eyelids bilaterally. The diagnosis of angioedema was made clinically. Signs and symptoms promptly resolved after the discontinuation of imiquimod. The patient denied a prior history of urticaria or angioedema, and further denied any known exposures to potential antigens. Symptoms have not recurred after cessation of imiquimod. Both sBCC lesions were successfully treated with imiquimod.


CASE 2


Figure 1
Figure 1. Brisk ulcerative reaction at sBCC treatment site

A 50-year-old man presented with a 2cm x 2cm scaly and erythematous plaque on his right antero-lateral arm. Biopsy identified the lesion to be sBCC, and a treatment course identical to that utilized in the foregoing case was initiated with imiquimod 5-percent cream. After 3 weeks of imiquimod application, the patient developed an intensely pruritic, widespread eruption involving the buttocks and both lower extremities. The targeted neoplasm had developed a superficial ulceration with a moderate amount of surrounding erythema. The patient consulted his primary care physician who administered an intramuscular triamcinolone acetonide injection and asked him to discontinue the topical imiquimod. Signs and symptoms quickly resolved.


Figure 2Figure 3
Figure 2. Urticarial plaques distant from treatment site
Figure 3. Annular urticarial plaques distant from treatment site

In an effort to resume treatment of the upper extremity sBCC as originally prescribed, the patient re-instituted imiquimod application 1 week after resolution of the aforementioned eruption. Less than 48 hours after restarting imiquimod therapy, the eruption on lower extremities and buttocks returned; the patient then presented to dermatology 1 week later. At this time, he was still applying imiquimod only to the arm. The right upper-outer arm (Fig. 1) was noted to have a superficial ulceration surrounded by erythema. In addition, the patient demonstrated rather striking bilateral, symmetric, often annular urticarial papules and plaques located on the buttocks and lower extremities (Figs. 2 & 3). On biopsy, the wheals were found to have mild perivascular inflammation and edema consistent with urticaria. He was instructed to discontinue the imiquimod and his symptoms resolved completely within 48 hours, exactly as they had after the previous interruption of therapy. He had no prior history of urticaria or angioedema, nor has he developed these symptoms subsequently. The ulceration on his arm ultimately healed without scarring and the basal cell carcinoma has not recurred to date.


Discussion

Urticaria and angioedema are distinct diagnoses, but each belongs on a continuum of vasodilatory responses, the morphology ultimately determined by the depth of swelling within the skin. They are both cutaneous manifestations of various specific immunologic and inflammatory mechanisms, but both share the final common pathway of venular dilation [1]. When this process occurs in the superficial dermis, urticaria develops; when the same process occurs in the deep dermis, angioedema ensues. This dilation can be attributed to both basophil and mast cell release and subsequent degranulation of venodilators (either by IgE independent or IgE receptor-dependent pathways), by inappropriate activation of the complement system as seen in hereditary angioedema, or by idiopathic mechanisms [1, 2].

Imiquimod, a topical immune response modulator, is frequently employed in the treatment of basal cell carcinoma, HPV-related genital warts, verruca vulgaris, Bowen disease, and actinic keratoses [3-7]. Its proposed mechanism of action is through induction of various cytokines and chemokines and the resultant immune reaction to the chemical messengers released at the site of application. Lymphocytes, keratinocytes, Langerhans cells, and tissue macrophages are all influenced by the cytokine network [8]. Multiple cytokines work in concert to affect individual cells. Thus, the ultimate end-point is best thought of as a cellular response dependent on the general environment of local cytokines, rather than as a one-to-one cytokine-to-cell interaction. The imiquimod mechanism of action has been proposed to be mediated primarily via interferon (IFN) alpha, along with TNF- alpha, Interleukin (IL)-6, IL-12, and suppression of IL-4, and IL-5 [9-12]. Imiquimod's effect on other cytokines remains unknown. It is important to consider that imiquimod may have other effects as yet undetermined.

In our cases, imiquimod appears to be responsible for eliciting a response of urticaria or angioedema distant from the site of original application. There are several potential mechanisms by which imiquimod may produce this type of clinical response. As seen in specific antigen sensitization, imiquimod may be acting as a direct mast cell degranulator through IgE-linked mechanisms. Another possible theory is that imiquimod may also activate mast cells by IgE-independent mechanisms, as is seen in reactions to radiocontrast material. Lastly, given what is known about imiquimod interaction with the immune system, it is most probable that imiquimod produces urticaria and angioedema because its direct action on cytokines. Since this is uncommon, it may well be that selected individuals have a preferentially enhanced susceptibility to imiquimod-related cytokine production.

Interferon-alpha and tumor necrosis factor-alpha, two cytokines induced by imiquimod, have both been shown related to mast cell degranulation and the development of urticaria [1, 13, 14]. In addition, IL-3, a cytokine whose relationship to imiquimod has not been reported, has also been described as a contributing factor to an urticarial eruption [15].

In addition to the direct associations between cytokines induced by imiquimod and those involved in the development of urticaria or angioedema, the cytokine profiles seen in a chronic viral state are also similar to that induced by imiquimod. For example, infections such as hepatitis B and C have both been reported to cause urticaria and angioedema [16]. In a 1995 study by Megyeri et al., imiquimod was found to induce a cytokine profile similar to that found in a state of viral activation [17].

Finally, imiquimod induces a cytokine profile similar to that observed in a non-immediate, delayed cutaneous drug reaction [18]. Interferon-gamma levels are elevated in drug-induced urticaria and angioedema, implicating IFN as a possible mediator of these cutaneous responses [19]. Imiquimod is known to be associated with the ultimate upregulation of IFN-gamma production and release.

In conclusion, imiquimod is an immune modulator that exerts its effects on many cytokines, most of which drive the immune response profile within the body toward a predominantly TH1 cellular immunity promoting state. Angioedema and urticaria are clinical responses to immune system activation with multiple possible mechanisms of induction. Although no one clear-cut, specific mechanism can be shown to link imiquimod to angioedema or urticaria, the association between imiquimod mechanisms of action, and the similarities in the mediators involved in the skin disorders of angioedema and urticaria, highlight the likely link in susceptible persons. Perhaps most importantly, physicians should remain aware of the potential systemic responses to imiquimod, including the development of urticaria or angioedema at sites distant to the treatment area.

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