Multi-center retrospective review of vitiligo-like lesions in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors.

PURPOSE: Cutaneous adverse effects from cyclin-dependent 4 and 6 kinase inhibitors (CDK4/6i) used in metastatic breast cancer are prevalent and well described. Vitiligo-like lesions have been reported and are rare. They can negatively impact patients' quality of life and may be associated with survival benefits. We describe the clinical characteristics of vitiligo-like lesions in an international cohort of patients treated with CDK4/6i to help improve recognition and management. METHODS: Retrospective review of patients diagnosed with vitiligo-like lesions from CDK4/6i from five academic institutions in the USA and Europe was performed. Ten patients were included in the study. RESULTS: Median age of our patients was 55 (range 37-86). Median progression-free survival was 24 months in 5 patients. The median time to rash was 10 months. Sun-exposed areas such as the arms and face were the most affected areas. Multiple skin-directed therapies such as topicals, laser, and phototherapy were trialed with minor success. Mild repigmentation was seen in one patient treated with ruxolitinib cream. CDK4/6 treatment was discontinued due to the vitiligo-like lesions in one patient. CONCLUSION: Clinical characteristics are similar to previously reported findings in case reports and series. We add topical ruxolitinib as a potential treatment option for these patients and include data regarding progression-free survival that should continue to be collected. No definitive conclusions can be made regarding survival benefits from our cohort. Clinicians should refer these patients to dermatologists to aid with management.

Immune checkpoint inhibitor-induced vitiligo in cancer patients: characterization and management.

This study highlights the range of non-melanoma cancers where ICI-induced vitiligo can be present and challenges the exclusivity of this phenomenon to melanoma. We believe our manuscript will encourage awareness in our colleagues and stimulate interest in further studies to elucidate the mechanisms of ICI-induced vitiligo in both melanoma and non-melanoma cancers, and to understand whether this phenomenon holds the same positive prognostic value in both cancer groups. This is a retrospective cohort study from a single-institution's electronic medical record for cancer patients treated with ICIs who subsequently developed vitiligo. We identified 151 patients with ICI-induced vitiligo, 19 (12.6%) non-melanoma and 132 (77.4%) melanoma patients. Time to onset of vitiligo was nearly doubled in the non-melanoma cohort, however, this is confounded by possible delayed diagnosis or under reporting of this asymptomatic condition in patients who do not regularly receive skin exams. The majority of patients had a stable course of vitiligo with 91.4% receiving no treatment in this largely Caucasian cohort. Two patients with non-melanoma cancers and Fitzpatrick type IV or above skin received treatment with narrowband ultraviolet B light therapy and topical steroids with near-complete response. This study highlights the occurrence of ICI-induced vitiligo in a variety of non-melanoma cancers, where skin of color patients will be more prevalent and the need for treatment will potentially be more urgent. Further study is needed to elucidate the mechanism of ICI-induced vitiligo and determine if non-melanoma cancers have the same association between vitiligo and increased tumor response.

Mechanisms of action of Lycium barbarum polysaccharide in protecting against vitiligo mice through modulation of the STAT3-Hsp70-CXCL9/CXCL10 pathway.

CONTEXT: Vitiligo is a common skin disease with a complex pathogenesis, and so far, no effective treatment is available. Lycium barbarum L. (Solanaceae) polysaccharide (LBP), the main active ingredient of goji berries, has been demonstrated to protect keratinocytes and fibroblasts against oxidative stress. OBJECTIVE: This study explored the effects and mechanism of LBP on monobenzone-induced vitiligo in mice. MATERIALS AND METHODS: C57BL/6 mice were randomly divided into five groups (n = 6): negative control that received vaseline, vitiligo model group induced by monobenzone that treated with vaseline, positive control that received tacrolimus (TAC), LBP groups that received 0.3 and 0.6 g/kg LBP, respectively. We quantified the depigmentation by visual examination and scores, detected the expression of CD8+ T cells, pro-inflammatory cytokines and analysed the STAT3-Hsp70-CXCL9/CXCL10 pathway. RESULTS: LBP 0.3 and 0.6 g/kg groups can significantly reduce depigmentation scores and the infiltration of local inflammatory cells in the skin lesions. Moreover, the expression of CXCL9, CXCL3, CXCL10 and HSP70 decreased by 54.3, 20.3, 48.5 and 27.2% in 0.3 g/kg LBP group, which decreased by 62.1, 26.6, 58.2 and 34.5% in 0.6 g/kg LBP group. In addition, 0.3 and 0.6 g/kg LBP decreased the release of IL-8 (9.7%, 22.8%), IL-6 (40.8%, 42.5%), TNF-α (25.7%, 35%), IFN-γ (25.1%, 27.6%) and IL-1ß (23.7%, 33.7%) and inhibited the phosphorylation expression of STAT3 by 63.2 and 67.9%, respectively. CONCLUSION: These findings indicated LBP might be recommended as a new approach for vitiligo which provide a theoretical basis for the clinical application of LBP in treating vitiligo patients.

Anti-IL-17A antibody-associated de novo vitiligo: Case report and review of literature.

Interleukin (IL)-17 inhibitor is a biological therapy approved for moderate to severe psoriasis and psoriatic arthritis. The common adverse events of IL-17 inhibitor include injection site reaction, infections, nasopharyngitis, and headache. However, vitiligo associated with the use of IL-17 inhibitors was rarely reported in the previous literature. Here we described a woman who developed de novo vitiligo after 4 months of IL-17A inhibitor treatment for psoriasis and psoriatic arthritis. Upon discontinuation of IL-17A inhibitor and shifting to a broader T cell inhibitor-cyclosporine, our patient had control of both psoriasis and vitiligo and achieved 75% repigmentation after 3 months of oral cyclosporine without phototherapy. Due to the increasing use of anti-IL-17 biologics in psoriasis patients, clinicians should inquire about vitiligo's history before treatment and inform patients of the possible adverse effects.

The Effect of Butin on the Vitiligo Mouse Model Induced by Hydroquinone.

Vernonia anthelmintica (L.) Willd has been traditionally used in the treatment of vitiligo in Uyghur medicine. This study used butin, the main component of V. anthelmintica, to study the influence on hydroquinone-induced vitiligo in mice. The animals were randomly divided into six groups: control, model, 8-methoxypsoralen (8-MOP, 4.25 mg/kg), and butin (0.425, 4.25, and 42.5 mg/kg) groups. The number of melanin-containing hair follicles, basal layer melanocytes, melanin-containing epidermal cells, the expression of tyrosinase (TYR) and tyrosinase-related protein-1 (TRP-1), the malondialdehyde (MDA), and cholinesterase (CHE) activity in serum were measured. Our results indicated that compared with the model group, the melanin-containing hair follicles, the expression of TYR and TRP-1 increased, the activity of CHE decreased after treatment with 8-MOP and all doses of butin (p < 0.05, p < 0.01), the basal layer melanocytes and melanin-containing epidermal cells increased significantly after treatment with butin 4.25 and 42.5 mg/kg (p < 0.05, p < 0.01), and the MDA activity decreased after using butin 4.25 and 42.5 mg/kg and 8-MOP (p < 0.05, p < 0.01). Our results support the use of butin on vitiligo, and its possible mechanisms may be related to increase the TYR and TRP-1 protein expression and decrease the activity of MDA and CHE in hydroquinone-induced vitiligo model in mice. Copyright © 2017 John Wiley & Sons, Ltd.

Nivolumab-induced vitiligo in a metastatic melanoma patient: A case report.

The programmed-death-1 inhibitors selectively block programmed-death-1 interaction with its receptor, which restores active T-cell response directed at tumor cells, inducing an anti-tumor effect. This nonspecific activation of the immune system can also lead to a wide spectrum of side effects. Nivolumab has been used effectively to prolong survival in patients with metastatic melanoma and is recommended as a category 1 agent for systemic therapy in metastatic or unresectable melanoma per the National Comprehensive Cancer Network guidelines. We present a case of a 64-year-old woman who began nivolumab therapy for metastatic melanoma. After six doses of nivolumab therapy, the patient experienced generalized hypopigmentation on her face, chest, back, arms, and lower extremities. Although vitiligo has been reported in as many as 10.7% of patients undergoing nivolumab therapy in some clinical trials, we believe this is the first case to describe the progression of nivolumab-induced vitiligo in a metastatic melanoma patient. This case provides significant insight into the onset, symptoms, development, and treatment options for patients experiencing vitiligo as a result of nivolumab therapy.

Vitiligo induced by specific immunotherapy with grass pollen: the Koebner phenomenon

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Pre-clinical evidences of Pyrostegia venusta in the treatment of vitiligo.

ETHNOPHARMACOLOGICAL RELEVANCE: Leaves of Pyrostegia venusta are popularly used to treat vitiligo; however, none in vivo study showed its ability. AIM OF THE STUDY: The overall objective of the present study was to evaluate the antiinflammatory and hyperpigmentant activities of hydroethanolic (HE) extract of leaves from P. venusta in animal models of vitiligo induced by croton oil and monobenzone. MATERIALS AND METHODS: The antiinflamatory and antioxidative effects of topical and oral administration of HE extract of P. venusta were evaluated in Swiss mice on edema model induced by croton oil, and further the N-acetyl-b-d-glucosaminidase (NAG) activity, cell infiltration, and cytokine and reactive species oxygen (ROS) levels. The involvement on mice pigmentation, cell infiltration and cytokine levels were evaluated on vitiligo model induced by monobenzone in C56BL/6 mice. RESULTS: HE of P. venusta by gavage (300 mg/kg) reduced NAG activity in 32.5 ± 5% on mouse ear edema induced by croton oil. Similarly, cell infiltration was lower (42.3 ± 5.9%) when compared to control group, as well as interleukin-1ß (IL-1ß), interleukin (IL-6) and tumor necrosis factor-α (TNF-α) levels, in 44.1 ± 9.7%, 71.9 ± 22.2% and to basal levels, respectively. Topical treatment with HE of P. venusta (10%) diminished cell infiltration (67.7 ± 7.1%) and ROS levels (total reduction). P. venusta either by gavage (300 mg/Kg) or topically (10%) increased epidermal melanin level (116.5 ± 13% and 100 ± 16.9%, respectively), diminished dermal depigmentation (36.0 ± 6.7% and 38.2 ± 6.2%, respectively), as well as tissue TNF-α levels (68.2 ± 11.6% and 99.2 ± 12.1%, respectively) and cell infiltration (basal levels and 94.3 ± 9.17%, respectively). However, only topical treatment with HE of P. venusta altered melanin specific marker in hair follicles. CONCLUSIONS: For the first time these data show that topical and oral administrations of P. venusta have significant antiinflammatory and hyperpigmentant effects, demonstrating different topical and systemic effects through two animal models. Together these models are capable to mimic several features founded in vitiligo, and the results support the ethnopharmacological use of P. venusta.

The therapeutic effects of EGCG on vitiligo.

Epigallocatechin-3-gallate (EGCG) is one of the main chemical constituents of green tea, which has been used as an important traditional Chinese medicine. Green tea has anti-inflammatory, anti-oxidant, and immunomodulatory properties. However, the effects of EGCG on vitiligo are not known. We assessed the role of EGCG in vitiligo induced by monobenzone in mice. We demonstrated that EGCG: delayed the time of depigmentation; reduced the prevalence of depigmentation; and decreased the area of depigmentation. Examination of depigmented skin treated with EGCG by reflectance confocal microscopy suggested increased numbers of epidermal melanocytes and histologic examination showed decreased perilesional accumulation of CD8(+) T cells. To further investigate the mechanism of the anti-inflammatory effects of EGCG, levels of inflammatory mediator tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6 were tested by enzyme-linked immunosorbent assay. Serum cytokine levels were significantly decreased after administration of EGCG compared with the model group. These results suggested that EGCG may have protective effects against vitiligo, and that it could contribute to suppression of activation of CD8(+) T cells and inflammatory mediators. Based on these results, 5% EGCG was considered to be the most suitable concentration for treating vitiligo, and was used for further study. In addition, we investigated the gene-expression profile of this model in relation to EGCG. Using a 4×44K whole genome oligo microarray assay, 1264 down-regulated genes and 1332 up-regulated genes were recorded in the 5% EGCG group compared with the model group, and selected genes were validated by real-time polymerase chain reaction. Our study demonstrated that EGCG administration was significantly associated with a decreased risk of vitiligo. EGCG could be a new preventive agent against vitiligo in the clinical setting.

The effects of galangin on a mouse model of vitiligo induced by hydroquinone.

Galangin, the main active component of Alpinia officinarum Hance, was tested in a mouse model of vitiligo induced in C57BL/6 mice by the topical application of 2 mL of 2.5% hydroquinone daily to shaved areas (2 × 2 cm) of dorsal skin for 60 days. Thirty days after the final application of hydroquinone, galangin (0.425, and 4.25 mg/kg) was administered orally for 30 days. The hair colour darkened when it grew back after treatment, and histological analysis showed that the number of melanin-containing hair follicles had increased after treatment with all doses of galangin groups and 8-methoxypsoralen (8-MOP, the positive control) compared with the untreated vitiligo group (p < 0.05). The number of skin basal layer melanocytes and melanin-containing epidermal cells had also increased significantly with the application of 4.25 mg/kg of galangin. The concentration of tyrosinase (TYR) in serum was found to have increased, whereas the content of malondialdehyde and the activity of cholinesterase had decreased after treatment with all doses of galangin and 8-MOP, compared with control (p < 0.05). The expression of TYR protein in treated areas of skin also increased with the application of 4.25 mg/kg galangin and 8-MOP. In conclusion, the results showed that galangin was able to improve vitiligo induced by hydroquinone in mice, with the activity related to concentrations of TYR, expression of TYR protein, activity of malondialdehyde and content of cholinesterase. Galangin may therefore be a potential candidate for the treatment of vitiligo, subject to further investigation.

Imiquimod induces apoptosis of human melanocytes.

Development of vitiligo-like hypopigmentary lesions associated with topical imiquimod has been reported. We hypothesized that mode of action of imiquimod in melanocytes may include triggering of apoptosis resulted in loss of cells, which may be a possible mechanism of imiquimod-induced hypopigmentary lesions. Therefore, we investigated whether imiquimod induces apoptosis of human melanocytes and also whether it modulates expression of apoptosis-related molecules in human melanocytes. Imiquimod treatment induced apoptosis of melanocytes, which was observed by TUNEL assay and Hoechst 33258 staining. Imiquimod-induced apoptosis was further shown by measuring mitochondrial membrane potential in melanocytes. The apoptotic activity of imiquimod was associated with caspase-3, Bcl-2 and mitogen-activated protein kinase expression in melanocytes. These results indicated that imiquimod induces apoptosis of melanocytes. These findings may provide a clue to understand pathogenesis of imiquimod-induced vitiligo-like hypopigmentary lesions.

Chemical leucoderma: a clinico-aetiological study of 864 cases in the perspective of a developing country.

BACKGROUND: Chemical leucoderma, often clinically mimicking idiopathic vitiligo and other congenital and acquired hypopigmentation, has been increasing rapidly in incidence in developing countries such as India. OBJECTIVES: This study attempts to detect clinical and epidemiological patterns of chemical leucoderma. METHODS: Detailed history-taking, especially of exposure to contributory chemicals, clinical examination, relevant investigations, data recording and analysis were done. RESULTS: In a total of 864 cases of chemical leucoderma, 65.6% cases started de novo and vitiligo patches were pre-existing in the remaining cases. Patches were limited to the contact area in 73.7% but had spread to remote areas in 26.3% cases. The face (41.1%) and scalp (5.9%) were the commonest and least involved sites. Confetti macules were seen in 89% and pruritus was complained of in 21.8%. Aetiological agents identified were hair dye 27.4% (21% self-use; 6.4% not self-use), deodorant and spray perfume 21.6%, detergent and cleansers 15.4%, adhesive bindi 12%, rubber chappal 9.4%, black socks and shoes 9.1%, eyeliner 8.2%, lipliner 4.8%, rubber condoms 3.5%, lipstick 3.3%, fur toys 3.1%, toothpaste 1.9%, insecticides 1.7%, 'alta' 1.2%, amulet string colour 0.9%. Therapeutic response was much better in 'pure' chemical leucoderma (73.4%) than in those with co-existing vitiligo (20.9%). CONCLUSIONS: Chemical leucoderma, a disease of mostly industrial origin in developed countries, may be induced by common domestic products in developing countries. Diagnosis and differentiation from other causes of hypopigmentation can be done confidently by following the clinical criteria as proposed. The therapeutic response of chemical leucoderma is better than that of vitiligo.

Mycosis fungoides with depigmentation secondary to treatment.

A 51-year-old man presented with itchy, erythematous patches and plaques on his trunk, arms, and legs. A skin biopsy specimen showed mycosis fungoides. Initially the patient did not respond to PUVA photochemotherapy but later improved on NB-UVB phototherapy combined with bexarotene and interferon-alpha. The lesions progressed from erythematous patches and plaques to hyperpigmented patches with central depigmentation and localized areas of follicular repigmentation. The development of depigmentation after PUVA photochemotherapy for mycosis fungoides has been described in the literature and does not have associated prognostic implications. It is important to be cognizant of phototoxicity associated with PUVA photochemotherapy or NB-UVB phototherapy in patients with mycosis fungoides, who may be taking photosensitizing medications or have depigmented patches which renders them more sensitive to lower doses of ultraviolet light.