- Author(s): Al-Dujaili, Zeena
- Hsu, Sylvia
- et al.
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.
References1. Sauder DN. Immunomodulatory and pharmacologic properties of imiquimod. J Am Acad Dermatol 2000; 43: S6-S11.
2. Brown T, Zirvi M, Cotsarelis G, Gelfand J. Vitiligo-like hypopigmentation associated with imiquimod treatment of genital warts. J Am Acad Dermatol 2005; 52
3. Dahl MV. An immune response modifier. J Am Acad Dermatol 2000; 43: S1-5.
4. Simsek H, Savas C, Akkiz H et al. Interferon-induced vitiligo in a patient with chronic viral hepatitis C infection. Dermatology 1996; 193: 65-66.
5. Nouri K, Busso M, Machler BC. Vitiligo associated with alpha-interferon in a patient with active hepatitis C. Cutis 1997; 60: 289-290.
6. Bernstein D, Reddy K, Jeffers L, et al. Canities and vitiligo complicating interferon therapy for hepatitis C. Am J Gastroenterol. 1995; 90:1176-1177.
7. Wagner TL, Ahonen CL, Couture AM, et al. Modulation of TH1 and TH2 cytokine production with the immune response modifiers, R848 and imiquimod. Cell Immunol 1999;191:10-9.
8. Skinner R.B., Jr.,Imiquimod. Dermatol Clin 2003; 21: pp 291-300.
9. Wankowicz-Kalinska A, Van den Wijngaard RM, Tigges BJ et al. Immunopolarization of CD4+ and CD8+ to type 1like is associated with melanocyte loss in human vitiligo. Lab Invest 2003; 83: 683-695.
10. Miller R, Birmachu W, Gerster J, et al. Imiquimod cytokine induction and antiviral activity. Int Antiviral News 1995;3:111-3.
11. Moretti S, Spallanzani A, Amato L et al. New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 2002; 15: 87-92.
12. Swope VB, Abdel-Malek Z, Kassem LM, Nordlund JJ. Interleukins 1 alpha and 6 and tumor necrosis factor-alpha are paracrine inhibitors of human melanocyte proliferation and melanogenesis. J Invest Dermatol. 1991 Feb;96(2):180-5.
13. Yu HS, Chang KL, Yu CL et al. Alterations in IL-6, IL-8, GMCSF, TNF-a, and INF- α release by peripheral mononuclear cells in patients with active vitiligo. J Invest Dermatol 1997; 108: 527-29.
14. Tu CX, Gu JS, Lin XR. Increased interleukin-6 and granulocyte macrophage clony stimulating factor levels in the sera of patients with non-segmental vitiligo. J Dermatol Sci 2003; 31: 73-78.
15. Rocha IM, Guillo LA. Lipopolysacharide and cytokines induce nitric oxide synthesis and produce nitric oxide in cultured normal human melanocytes. Arch Dermatol Res 2001; 293: 245-248.
16. Burns Jr. RP, Ferbel B, Tomai M, et al. The imidazoquinolones, imiquimod and R-848 induce functional, but not phenotypic, maturation of human Langerhans' cells. Clin Immunol 2000;94:13-23.
17. Suzuki H, Wang B, Shivji GM, et al. Imiquimod, a topical immune response modifier, induces migration of Langerhans' cells. J Invest Dermatol 2000;114:135-41.
18. Suzuki H., Wang B., Shivji G.M., Toto P., Amerio P., Tomai M.A., Imiquimod, a topical immune response modifier, induces migration of Langerhans cells. J Invest Dermatol 2000; 114: 135-141.
19. Ongenae K., Van Geel N., Naeyaert J.M., Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res 2003; 16: 90-100.
20. Kostovic K., Pasic A., New Treatment modalities for vitiligo: focus on topical immunomodulators. Drugs. 2005; 65: 447-459.
21. Tjioe M., Vissers W. H., Gerritsen M. J., Topical macrolide immunomodulators: a role in the treatment of vitiligo. Am J Clin Dermatol. 2006; 7: 7-12.
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