Published Web Locationhttps://doi.org/10.5070/D32kr0d81x
Imiquimod-induced vitiligo1. Tulane Medical School, New Orleans, Louisiana2. Department of Dermatology, Baylor College of Medicine, Houston, Texas
Zeena Al-Dujaili MD1, Sylvia Hsu, MD2
Dermatology Online Journal 13 (2): 10
|Figure 1. Depigmented patches on penile shaft and scrotum|
A 21-year-old man presented with multiple genital warts on his penis, scrotum, and suprapubic area. He was prescribed imiquimod three times weekly. After using the medication for 4 months, the patient complained of erythema at the sites of application without improvement of the warts. The patient stopped using imiquimod and returned to see us 2 months later. On examination, there were depigmented patches in the areas of application (Fig. 1).
Imiquimod, available commercially as Aldara™, is an immune response modifier approved in the United States for the topical treatment of external genital and perianal warts . Imiquimod treatment associated pigmentary changes have been reported and are listed as possible side effects on the package insert. Of the 1257 adverse reports made from 1997 to November 2003 in association with imiquimod use, 68 (5.4%) were reports of pigmentary changes: 43 reported occurrences of depigmentation, 7 of vitiligo, 1 of hypopigmentation, and 17 of hyperpigmentation .
Imiquimod does not directly kill the human papilloma virus (HPV), but rather causes regression by enhancing the host's innate immune response and by promoting a local response via the induction of cytokines . Application of imiquimod activates the cell-mediated arm of the immune system via the stimulation of multiple pro-inflammatory cytokines, most notably interferon alpha (IFN-α), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). IFN-α is the primary natural defense mechanism against viral infections within cells .
In wart infections, the HPV is protected in keratinocytes from the cellular-mediated immune response. However, with the application of imiquimod there is an induction of the production of IFN-α, which inhibits viral reproduction via the induction of 2'-5' oligoadenylate synthetase and upregulates natural killer cells in infected keratinocytes, and protects adjacent keratinocytes from viral infection. Presumably because of its potent immunomodulatory activity, the use of INF-α has been associated with various autoimmune diseases such as vitiligo. It is postulated that INF-α upregulates a Type-1 cell response (Th1) that unmasks an innate predilection for the development of vitiligo [4, 5, 6].
Imiquimod inhibits the production, partially mediated by the activation of INF-α, of the Type-2 cell response (Th2) cytokines IL-4 and IL-5 [7, 8]. Thus, as imiquimod-induced IFN-α inhibits Th2 responses, IFN-α and TNF-α induced by imiquimod promote the Th1 response. A Th1 cytokine secretion profile has also been found to predominate in vitiligo. Furthermore, the degree of type 1 polarization has been demonstrated to parallel the depigmentation process observed locally .
In vitro treatment of keratinocytes with imiquimod results in production of IL-6 and IL-8 . Along with IFN-α, these cytokines can stimulate natural killer cells and cytotoxic T cells and act as chemokines for polymorphonuclear leukocytes and macrophages. Thus, if imiquimod activates epidermal cytokines and induces a cytotoxic T-cell response and vitiligo is a cytotoxic T-lymphocyte-mediated autoimmune disease, then the application of imiquimod could have contributed to the development of vitiligo in our patient. In addition, the depigmentation did not extend beyond the treatment area, suggesting a local factor was responsible. Furthermore, it has been found that the some of the same cytokines induced by Imiquimod, IL-6, IL-1, and TNF-α, are paracrine inhibitors of melanocytes and exhibit significantly higher expression in vitiligo skin compared to healthy skin [11, 12, 13, 14]. All three cytokines were found to elicit a dose-dependent decrease in the activity of the enzyme tyrosinase . IL-6 can, also, enhance melanocyte ICAM-1 expression, resulting in increased leukocyte-melanocyte attachment and melanocyte damage . Moreover, TNF-α and IFN-α have been found to induce the expression of a nitric oxide synthase isoform associated with the production of nitric oxide and the resulting autodestruction of melanocytes . Thus, indirectly via the activation of numerous cytokines, the use of imiquimod can be linked to skin depigmentation.
Langerhans cell functional maturation and migration to regional lymph nodes is enhanced by imiquimod. Thus, imiquimod stimulates a Th1 response resulting in the activation of cells, lysing of virus-infected cells, and induction of the maturation of Langerhans cells leading to enhancement of antigen presentation [16, 17, 18]. Similarly, it is theorized that vitiligo may be mediated through antigen presentation by activated Langerhans cells with resultant destruction of melanocytes by cytotoxic T lymphocytes directed to melanocyte surface antigens .
The abnormalities in both the humoral and cell-mediated immunity associated with vitiligo has led to the use of immunomodulating agents in the treatment of vitiligo. Currently, topical macrolide immunomodulators, such as tacrolimus and pimecrolimus, which inhibit the action of calcineurin, and consequently inhibit T-cell activation and the production of various cytokines, have been shown in several case reports to effectively treat vitilligo [20, 21]. In our patient, 4 months after discontinuing imiquimod, the condyloma had resolved clinically; however, the depigmented areas remained unchanged. Furthermore, a previous case report found similar results with no change in hypopigmentation at 6 months follow-up ; thus, it appears that even with the discontinuation of the cytokine stimulus there is no repigmentation. No studies have been conducted on the effectiveness of the use of topical macrolide immunomodulators in imiquimod associated vitiligo. Perhaps, the macrolide immunomodulators may be able to inhibit the stimulation of cytokines associated with imiquimod use and reverse the depigmentation.
Imiquimod has shown significant benefit in the treatment of HPV via its immune enhancing capabilities. It induces antiviral and antitumor effects through the induction of cytokines and the enhancement of cell-mediated cytolytic antiviral activity in vivo. The initial indication for imiquimod was genital warts; however, because of its effect on immune function, it has wide applicability in the treatment of neoplastic, infectious, or immune-mediated diseases. Thus, as the use of imiquimod expands, clinicians should be made aware of the possible pigmentary changes associated with its use, particularly when used in visible areas. Furthermore, clinicians should keep in mind that not all individuals treated with imiquimod will result in pigmentary change. Each case should be individually examined, the course of action determined, and the patient monitored while receiving imiquimod therapy.
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