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Home , Actinic keratosis, Imiquimod, Vitiligo

Permanent -induced

Anne Donato, MD,* J. Kate Jackson, PA-C,** Laura Sandoval, DO,*** Jonathan S. Crane, DO, FAOCD****

*Internal Medicine Resident, 1st year, New Hanover Regional Medical Center, Wilmington, NC ** Physician Assistant, Dermone, Wilmington, NC ***Dermatology Resident, 1st year, Campbell University School of Osteopathic Medicine, Buies Creek, NC; Sampson Regional Medical Center, Clinton, NC ****Dermatologist, Dermone, Wilmington, NC; Campbell University School of Osteopathic Medicine, Buies Creek, NC; Dermatology Residency Program Director, Sampson Regional Medical Center, Clinton, NC

Abstract Imiquimod may be used as a topical therapy for actinic .1 We report on a patient treated with imiquimod for actinic keratoses who developed an inflammatory reaction, which subsequently resulted in depigmentation of the at the sites of imiquimod application. At nine-year follow-up, the patient still had skin depigmentation. We hope to increase awareness amongst dermatologists of this rare but potentially permanent adverse effect of imiquimod and discuss the possible mechanisms by which depigmentation may occur. Introduction Imiquimod is a topical immune-response modifier commonly used in dermatology. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of condyloma acuminata; non-hyperkeratotic, non-hypertrophic ; and superficial basal- less than 2 cm in diameter located on the trunk (excluding anogenital area), neck, or extremities (excluding hands and feet).1 The most frequently reported dermatologic adverse reactions include localized , , and crusted skin.1 Pigmentary changes secondary to imiquimod use have been previously reported and are therefore mentioned as a possible side effect on the package.2 However, there are relatively few clinical cases available in the literature, and there is a lack of multi- year follow-up to determine the duration of depigmentation. The FDA lists 68 reports of pigmentary changes out of a total of 1,257 reports related to imiquimod from 1997 to 2003.3 In this case, we report an unusual presentation of imiquimod-induced depigmentation with nine years of follow-up, supporting the possibility that this adverse effect may be permanent. depigmentation on the chest from the imiquimod. (-alpha, interferon-gamma, and Nine years after use of imiquimod cream, the interleukin-12), thereby leading to cell-mediated Case Report patient continues to have areas of depigmentation immunity including anti-viral and anti-tumor A 57-year-old woman presented with multiple 16,17 actinic keratoses at various locations including on her chest (Figure 1). activity. This creates an inflammatory the nose, right upper lip, and chest. She was reaction, such as the erythema that our patient prescribed imiquimod 5% cream to apply to Discussion initially experienced where she applied the the Monday, Wednesday, and Friday Imiquimod-induced depigmentation is a imiquimod cream. Thus, the depigmentation nights. After one month, this was increased to rare side effect. In our case, depigmentation may be analogous to post-inflammatory application every night for three weeks. Five days continued at nine years post imiquimod therapy, . after starting the nightly application, the patient providing valuable insight suggesting that the Additional mechanisms may also play a role. called complaining of swelling and blistering depigmentation can be permanent. A literature Imiquimod may further cause depigmentation around her lips, swelling around her eyes, and review revealed the development of imiquimod- via a mechanism similar to the pathogenesis of erythema where she had applied the imiquimod. induced depigmentation in a limited number of . Imiquimod promotes release, She was instructed to stop the imiquimod and previously published case reports.3-15 The nine- which results in the activation of cytotoxic T cells return to office for evaluation. On evaluation, the year follow-up in our case supports that this effect and antigen presentation by Langerhans cells.17 patient was noted to have erythema, edema, and may be long-lasting and of cosmetic significance Depigmentation in vitiligo occurs with the crusting on facial and chest application sites. The to patients. presentation of autoantigens by Langerhans cells patient was instructed to use petroleum jelly three The possible mechanism of the pigmentary leading to activation of cytotoxic T cells to destroy times a day and continue the discontinuation changes secondary to imiquimod use relates to . Melanocytes also have increased of topical imiquimod. At the follow-up two its properties as an immune-response modifier. sensitivity to the that may be months later, the patient had developed areas of 18 Imiquimod stimulates cytokine production mediated by imiquimod. Depigmentation may

DONATO, JACKSON, SANDOVAL, CRANE Page 45 be a result of direct effects on melanocytes. One imiquimod cream. Clin Exp Dermatol. 2006 study demonstrated that imiquimod induces Sep;31(5):721-2. apoptosis of melanocytes.19 Therefore, the 9. Senel E, Seckin D. Imiquimod-induced desirable therapeutic anti-viral and anti-tumor vitiligo-like depigmentation. Indian J Dermatol effects of imiquimod, through a mechanism Venereol Leprol. 2007 Nov-Dec;73(6):423. involving and Langerhans cells antigen presentation, may also lead to the 10. Serrao VV, Paris FR, Feio AB. Genital undesirable side effect of depigmentation. vitiligo-like depigmentation following use of imiquimod 5% cream. Eur J Dermatol. 2008 Imiquimod may also lead to depigmentation via May-Jun;18(3):342-3. its signaling of the innate through toll-like receptor 7 (TLR7).20 Melanocytes treated 11. Stefanaki C, Nicolaidou E, Hadjivassiliou M, with imiquimod led to reduced pigmentation, Antoniou C, Katsambas A. Imiquimod-induced suggesting TLRs in melanocytes play a role in vitiligo in a patient with genital . J Eur Acad inflammation-related pigmentary changes. Dermatol. 2006 Jul;20(6):755-6. 12. Urbina F. Giant basal cell . Conclusion Improvement and vitiligo-like hypopigmentation Given that imiquimod is a commonly used after intermittent treatment with 5% imiquimod. therapy, dermatologists should be aware of the Acta Dermatol Croatica. 2012 Dec;20(4):275-8. potential side effect of depigmentation that may 13. Sriprakah K, Godbolt A. Vitiligo-like be permanent. Patients should be educated about depigmentation induced by imiquimod treatment their treatment options and informed about of superficial basal cell carcinoma. Aust J this possible side effect before deciding whether Dermatol. 2009 Aug;50(3):211-13. or not to use imiquimod therapy. Alternative treatments such as may also result 14. Li W, Xin H, Ge L, Song H, Cao W. in depigmentation; in fact, in a small study Induction of vitiligo after imiquimod treatment comparing to imiquimod therapy of condylomata acuminata. BMC Infectious for actinic keratosis, the cosmetic outcome was Diseases. 2014 Jun; 14: 329. better with imiquimod, with significantly fewer 15. Kwon HH, Cho KH. Induction of Vitiligo- 21 patients experiencing hypopigmentation. The Like Hypopigmentation after Imiquimod mechanism leading to imiquimod-induced Treatment of Extramammary Paget’s Disease. depigmentation likely involves post-inflammatory Ann Dermatol. 2012 Nov; 24(4):482-84. hypopigmentation as well as immune-mediated 16. Sauder DN. Immunomodulatory and effects on melanocytes. pharmacologic properties of imiquimod. J Am Acad Dermatol. 2000 Jul;43(1 Pt 2):S6-11. References 17. Suzuki H, Wang B, Shivji GM, Toto P, 1. Imiquimod: Drug Information [Internet]. Amerio P, Tomai MA, et al. Imiquimod, a topical Waltham, MA: UpToDate. [Cited 2014 Aug immune response modifier, induces migration 24]. Available from http://www.uptodate.com/ of Langerhans cells. J Invest Dermatol. 2000 contents/imiquimod-drug-information. Jan;114(1):135-41. 2. ALDARATM (imiquimod) cream, 5% 18. Mashiah J, Brenner S. Possible mechanisms in [Internet]. FDA. [Cited 2014 Aug 24]. Available the induction of vitiligo-like hypopigmentation from http://www.accessdata.fda.gov/drugsatfda_ by topical imiquimod. Clin Exp Dermatol. 2008 docs/label/2002/20723s11s12lbl.pdf. Jan;33(1):74-6. 3. Brown T, Zirvi M, Cotsarelis G, Gelfand JM. 19. Kim CH, Ahn JH, Kang SU, Hwang HS, Vitiligo-like hypopigmentation associated with Lee MH, Pyun JH, et al. Imiquimod induces imiquimod treatment of genital warts. J Am Acad apoptosis of human melanocytes. Arch Dermatol Dermatol. 2005 Apr;52(4):715-6. Res. 2010 May;302(4):301-6. 4. Al-Dujaili Z, Hsu S. Imiquimod-induced 20. Jin SH, Kang HY. Activation of toll-like vitiligo. Dermatol Online J. 2007;13(2):10. receptors 1, 2, 4, 5, and 7 on human melanocytes 5. Burnett CT, Kouba DJ. Imiquimod-induced modulate pigmentation. Ann Dermatol. 2010 depigmentation: report of two cases and Nov;22(4):486-9. review of the literature. Dermatol Surg. 2012 21. Foley P, Merlin K, Cumming S, Campbell Nov;38(11):1872-5. J, Crouch R, Harrison S, et al. A comparison 6. Gowda S, Tillman DK, Fitzpatrick JE, Gaspari of cryotherapy and imiquimod for treatment AA, Goldenberg G. Imiquimod-induced vitiligo of actinic keratosis: clearance, safety, and after treatment of nodular basal cell carcinoma. J skin quality outcomes. J Drugs Dermatol. 2011 Cutan Pathol. 2009 Aug;36(8):878-81. Dec;10(12):1432-8. 7. Jacob SE, Blyumin M. Vitiligo-like hypopigmentation with following Correspondence: Jonathan S. Crane, DO, treatment of superficial basal cell carcinoma with FAOCD; [email protected] imiquimod. Dermatol Surg. 2008 Jun;34(6):844- 5. 8. Mendonca CO, Yates VM. Permanent facial hypopigmentation following treatment with

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