Imiquimod-Induced Hypopigmentation Following Treatment of Periungual Verruca Vulgaris

Comment

Imiquimod therapy is commonly used to treat conditions for which an antiviral or antitumor immune response is necessary for treatment and full resolution of skin conditions. It can yield positive results in conditions that are difficult to treat, such as periungual verruca vulgaris.⁴ The most common adverse effects of imiquimod include localized inflammation and application-site reactions. Pigment changes, though less common, also have been reported. From 1997 to 2003, 1257 cases of imiquimod adverse effects were reported to the FDA. There were 68 reported cases of pigmentary change, of which 51 documented vitiligo, hypopigmentation, or depigmentation. The others reported hyperpigmentation following imiquimod use.⁴ The imiquimod package insert lists application-site hypopigmentation as a possible adverse effect.⁵ Imiquimod-induced hypopigmentation and depigmentation have been reported in the peer-reviewed literature.^4,6-14 Pigment loss has been reported in imiquimod treatment of condyloma acuminata, superficial BCC, nodular BCC, and extramammary Paget disease.^6-8 Duration of therapy to onset of pigment loss ranged from 7 to 28 weeks.⁹ Imiquimod dosing varied among reported cases, ranging from 3 times weekly to daily application. Interestingly, hypopigmentation or depigmentation are not commonly associated with imiquimod use for the treatment of AKs, which Burnett and Kouba⁹ proposed may be due to the twice weekly imiquimod dosing regimen recommended by the FDA for the treatment of AK (below the minimum threshold for pigment loss). Our patient applied imiquimod cream 5% to periungual verruca vulgaris 3 times weekly for 3 months and may have developed vitiligolike depigmentation because he met this theoretical dosage threshold. Further research is necessary to confirm a dosage-related threshold for the development of depigmentation. Imiquimod-induced pigment loss has mainly been limited to the site of application.

Depigmentation was limited to the application site the majority of the time; however, depigmentation at adjacent sites has been reported.¹⁰ This finding was consistent with the proposed notion that cytokines induced by imiquimod have localized paracrine activity.¹¹ Our patient was unique in that his depigmentation was present at the site of application, adjacent to the site of application, and at distant sites. He applied imiquimod only to the periungual area of the right fifth digit and left thumb but experienced depigmentation at several other sites. Although it is possible that our patient unintentionally spread imiquimod on the distant sites, it is less likely that the application would have been sufficient to cause depigmentation. Although systemic absorption of topical medications varies depending on multiple factors, the systemic absorption of imiquimod is minimal with mild systemic side effects reported, including headache, myalgia, and influenzalike symptoms.⁵ Thus, it is possible that our patient developed distant vitiligolike depigmentation as a systemic side effect of imiquimod therapy. Although our patient declined to have a biopsy performed, Gowda et al¹⁵ reported biopsy-proven vitiligo, demonstrating the absence of melanin and melanocytes following the use of imiquimod.

Several mechanisms have been proposed for imiquimod-induced depigmentation. For example, imiquimod may induce melanocyte apoptosis by increasing the levels of several proinflammatory and proapoptotic cytokines.¹⁶ Imiquimod-induced melanocyte apoptosis appears to involve elevated caspase-3, decreased B-cell lymphoma 2, altered mitogen-activated protein kinase expression, and ubiquitin-mediated proteolysis.^13,17 Additionally, increased levels of IL-6 appear to increase melanocyte-binding molecules and increase melanocyte-leukocyte interactions. Another proposed theory targets toll-like receptor 7 on melanocytes that are acted on directly by imiquimod.^11,17 In contrast, development of vitiligo following trauma (Koebner phenomenon) is not uncommon, and the immune effects induced by imiquimod may mimic those seen with trauma.¹⁴ Further research is needed to elucidate the mechanism by which imiquimod causes vitiligolike depigmentation.

Unfortunately, the depigmentation seen with imiquimod generally is permanent. Stefanaki et al¹⁰ showed repigmentation on cessation of imiquimod use. Our patient’s depigmentation remains unchanged despite treatment with tacrolimus ointment. Although it is possible for vitiligo to occur de novo without obvious inciting event or laboratory abnormality, the timeline and number of other cases in the literature make ours highly suspect for imiquimod-induced depigmentation.

Conclusion

Imiquimod is a commonly used immune-enhancing medication with an increasing list of off-label uses. Prior to prescribing imiquimod for a benign skin condition, clinicians should be cognizant of the potential for localized or possibly even distant depigmentation. We report a case of distant depigmentation following the use of imiquimod for periungual verruca vulgaris.