Repigmentation in Vitiligo with Imiquimod Immunopeel: A Therapeutic Paradox

Dear Editor, Vitiligo, the most common acquired pigmentary disorder, is marked by the loss of functional melanocytes and affects approximately 1%–2% of the global population.[1] In individuals with extensive disease who have not responded to medical treatments, and who experience significant cosmetic concern due to patchy residual pigmentation, depigmentation therapy may be considered. Although an ideal depigmenting agent is lacking, monobenzyl ether of hydroquinone remains the only US FDA-approved option, requiring several months to achieve depigmentation. However, its limited availability and potential for local side effects and repigmentation present challenges.[2] In view of these limitations and the potential depigmenting side effects of imiquimod,[3,4] we explored the use of topical imiquimod cream as an alternative depigmenting agent. A 34-year-old female presented to the dermatology outpatient department with extensive, rapidly progressive vitiligo for 6 years. On examination, diffuse depigmented macules were found on the trunk and extremities. On the other hand, islands of depigmented macules were noted in the background of variegated residual pigmented macules on the face [Figure 1a–c]. With the diagnosis of vitiligo vulgaris, the patient had received oral betamethasone pulse therapy for 6 months and tofacitinib for 1 year, with no stability. With the failed medical management, after 6 months off therapy, the patient requested depigmentation therapy for facial pigmented macules.Figure 1: Clinical image depicts pretreatment vitiligo vulgaris on face (a-c) and at 3 months after imiquimod peel (d-f)We initiated immunopeeling therapy using imiquimod 5% cream for 3 months. The patient was instructed to apply the contents of a single 250 mg sachet, containing 12.5 mg of imiquimod, to the entire face (approximately 600 cm²) on alternate days, along with strict adherence to physical photoprotection and the use of a sunscreen with sun protection factor 30. At 3-month follow-up, uniform pigmentation was noted, areas of depigmentation showed repigmentation, and variegated residual pigmented macules developed a light, homogeneous color [Figure 1d–f]. Three months after discontinuation of imiquimod therapy, the achieved pigmentation remained stable. Imiquimod is a topical immunomodulator that is commercially available in 2.5%, 3.75%, and 5% concentrations and is US FDA approved for the treatment of actinic keratosis, superficial basal cell carcinoma (less than 2 cm in diameter on the face and trunk), and genital warts. It exerts its immunomodulatory effects by activating toll-like receptors (TLRs) 7 and 8 on antigen-presenting cells, thereby regulating both innate and adaptive immune responses.[5] Interestingly, various TLRs, including TLR 2, 3, 4, 7, 9, 19, and 20, are expressed by human melanocytes, and their functional activity is influenced by the expression levels of these receptors.[6] Studies have shown that imiquimod may directly impact melanocyte biology through TLR activation. Specifically, Kim et al.[6] demonstrated that imiquimod induces apoptosis in human melanocytes, implicating its potential to cause melanocyte dysfunction or destruction. Furthermore, emerging evidence suggests that autophagy plays a key role in melanocyte function and melanin aggregation. In vitro studies assessing imiquimod’s effects on melanocytes have examined its influence on melanogenesis, autophagy, apoptosis, and the expression of TLR7 and TLR9, along with the production of inflammatory cytokines such as IL (interleukin)-8, IL-6, and soluble ICAM (intercellular adhesion molecule)-1.[7] While some reports paradoxically suggest that imiquimod may stimulate melanogenesis, the exact pathomechanisms remain unclear and are likely to be dose-dependent. The concept of ’immunopeeling’, originally described in the treatment of premalignant and malignant lesions in xeroderma pigmentosum, was adopted in our case to target islands of residual pigmentation.[8] Additionally, given the documented depigmenting effects of imiquimod reported in multiple case studies, its use was considered a rational therapeutic option in our patient.[3,4] However, we noted uniformity of skin tone at follow-up, that may be attributed to the relatively low-dose application of imiquimod, which may have been insufficient to exert its full depigmenting potential. Future studies are warranted to better understand the dose-dependent effects of imiquimod on melanocyte biology and its precise mechanism of action in vitiligo. In conclusion, we highlight the effectiveness of imiquimod immunopeel in promoting repigmentation and restoring uniform skin tone in islands of hyperpigmented macules, without any side effects. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.