LAUSR

Oral alitretinoin (9-cis-retinoic acid) is a useful treatment option for chronic hand eczema [1]. The most common adverse events include headache and nausea, which are usually managed by dose reduction or a symptomatic treatment [2]. In this study, we report a case of aggravation of pre-existing melasma due to alitretinoin intake. In vitro studies suggest that the melanogeneic action of alitretinoin is involved in the aggravation of pigmentation. A 43-year-old woman with Fitzpatrick skin type IV received alitretinoin (Alitoc®; GlaxoSmithKline, UK), 10 mg once daily for three weeks, due to chronic hand eczema, which was later increased to 30 mg. She noticed that her existing melasma had darkened three weeks after starting therapy. Ten weeks later, subsequent photographs confirmed that the existing melasma had worsened with continuous alitretinoin intake. The patient stopped taking alitretinoin, and the melasma improved seven months after discontinuation (figure 1A). All other causes of melasma aggravation, such as sun exposure or medications, were excluded. The melasma worsened in the autumn (September) and the improvement after discontinuation was maintained even during the summer. The patient did not take oral contraceptive as she has no plans for pregnancy and her husband had a vasectomy. As the case was unexpected considering that retinoid is known to improve hyperpigmentation of photoaged skin [3], we investigated the effects of alitretinoin on skin pigmentation. Normal human melanocytes (Gibco, HEMn-MP, C1025C) were treated with different dosages (20-500 nM) of alitretinoin and cell viability was examined (figure 1B); the concentration was determined considering plasma alitretinoin levels (50 ∼ 150 ng/mL) of patients [4]. As reported previously [5], we confirmed that alitretinoin significantly increased melanin content and tyrosinase activity (figure 1C). Consistently, the mRNA and protein levels of both tyrosinase and MITF were significantly upregulated (figure 1D). The stimulatory action of alitretinoin on pigmentation was further confirmed in a reconstituted skin equivalent (MelanoDermTM, MatTek Corp, Ashland, MA). As the skin was continuously exposed to alitretinoin for two weeks, the total melanin content significantly increased in the alitretinoin-treated skin compared to control skin (figure 1E). To address the effect of alitretinoin on human skin pigmentation further, ex vivo human skin obtained during surgical procedures (IRB No. AJIRB-BMR-SMP-17-438) was maintained with alitretinoin for three days. In the presence of alitretinoin, the skin showed significantly increased epidermal pigmentation, as shown by Fontana-Masson staining (figure 1F). Taken together, these results indicate that alitretinoin induces skin pigmentation and also support the clinical finding of melasma aggravation by alitretinoin intake. Topical tretinoin is widely recognized to improve mottled hyperpigmentation of photoaged skin [3]. However, there is controversy with regards to whether retinoic acid inhibits or stimulates melanogenesis in vitro [6, 7]. The mechanism of melanocyte activation by alitretinoin remains unknown, however, the MITF promoter region has been shown to contain a highly conserved retinoic acid receptor (RAR)-retinoid X receptor (RXR) binding site, located proximal to the transcription start site [8, 9]. Also, agents stimulating both RAR and RXR, such as alitretinoin, can induce melanogenesis more effectively than the RAR agonist, tretinoin, alone [5]. Moreover, one study identified a novel regulator of MITF and tyrosinase expression, aldehyde dehydrogenase 1A1 (ALDH1A1), which catalyses the oxidation of 9-cis retinal to 9-cis retinoic acid [5]. It is also speculated that the effect of induction or inhibition of pigmentation in response to retinoid depends on whether it is administered topically or systemically. In the above case, it is unclear why pigmentation occurred only on melasma, and not elsewhere. It is possible that the melanocytes of melasma lesional skin differ from those of non-lesional skin that actively respond to melanogenic stimuli [10]. Considering that patients taking oral retinoid have increased photosensitivity, hyperpigmentation may occur when sun protection is not provided or is suboptimal. Our study has limitations; this is a single case and these experiments do not establish a cause and effect relationship, given the lack of in vivo data. In summary, this study confirms that alitretinoin functions as a melanogenic stimulator and may also play a role in the aggravation of pre-existing hyperpigmentory disorders on sun-exposed skin.