Vitiligo-like Depigmentation Research Articles

Early poliosis- and vitiligo-like depigmentation as an indicator of treatment response in patients with uveal melanoma under tebentafusp therapy.

We report novel findings of early vitiligo- and poliosis-like depigmentation of skin and hair in three patients with uveal melanoma under tebentafusp therapy, which are associated with a good treatment response to tebentafusp.

Exploring the Genetic Landscape of Vitiligo in the Pura Raza Español Horse: A Genomic Perspective.

Vitiligo is a depigmentation autoimmune disorder characterized by the progressive loss of melanocytes leading to the appearance of patchy depigmentation of the skin. The presence of vitiligo in horses is greater in those with grey coats. The aim of this study was therefore to perform a genome-wide association study (GWAS) to identify genomic regions and putative candidate loci associated with vitiligo depigmentation and susceptibility in the Pura Raza Español population. For this purpose, we performed a wssGBLUP (weighted single step genomic best linear unbiased prediction) using data from a total of 2359 animals genotyped with Affymetrix Axiom™ Equine 670 K and 1346 with Equine GeneSeek Genomic Profiler™ (GGP) Array V5. A total of 60,136 SNPs (single nucleotide polymorphisms) present on the 32 chromosomes from the consensus dataset after quality control were employed for the analysis. Vitiligo-like depigmentation was phenotyped by visual inspection of the different affected areas (eyes, mouth, nostrils) and was classified into nine categories with three degrees of severity (absent, slight, and severe). We identified one significant genomic region for vitiligo around the eyes, eight significant genomic regions for vitiligo around the mouth, and seven significant genomic regions for vitiligo around the nostrils, which explained the highest percentage of variance. These significant genomic regions contained candidate genes related to melanocytes, skin, immune system, tumour suppression, metastasis, and cutaneous carcinoma. These findings enable us to implement selective breeding strategies to decrease the incidence of vitiligo and to elucidate the genetic architecture underlying vitiligo in horses as well as the molecular mechanisms involved in the disease's development. However, further studies are needed to better understand this skin disorder in horses.

Cutaneous type IV hypersensitivity reaction following tebentafusp treatment for uveal melanoma.

Tebentafusp is a bispecific protein that recently underwent FDA approval for the treatment of metastatic uveal melanoma that functions by redirecting cytotoxic T cells to glycoprotein-100, a protein highly expressed in melanoma. Although clinical trials have demonstrated that rashes are common in the first few days of treatment, little is known about skin reactions that develop later in the treatment course. Herein, we describe a type IV hypersensitivity reaction and vitiligo-like depigmentation that developed six weeks into treatment and discuss the possible mechanisms underlying these reactions. The type IV hypersensitivity reaction resolved without intervention within seven weeks of onset, suggesting that tebentafusp can be safely continued in select patients who develop this cutaneous reaction.

A case of allergic contact dermatitis presented with acquired vitiligo-like depigmentation developed persistent light reactivity: Unforeseen entity

Abstract Chemical leukoderma is an acquired depigmentary skin disorder, caused by repeated exposure to specific chemical compounds or secondarily to allergic contact dermatitis or through direct toxic effects, sharing similar clinical and histological features with vitiligo. We report a case of widespread allergic contact dermatitis with chemical leukoderma which later became a persistent light reactor.

222 New perspectives on immune checkpoint inhibitor-induced vitiligo-like depigmentation in melanoma: a comparative study with classical vitiligo and healthy skin

222 New perspectives on immune checkpoint inhibitor-induced vitiligo-like depigmentation in melanoma: a comparative study with classical vitiligo and healthy skin

LB1643 Novel insights into vitiligo-like depigmentation under immune checkpoint inhibitors in melanoma compared to classical vitiligo and healthy skin biopsies

LB1643 Novel insights into vitiligo-like depigmentation under immune checkpoint inhibitors in melanoma compared to classical vitiligo and healthy skin biopsies

Cutaneous adverse events under new clinical therapies: drug-induced vitiligo-like depigmentation

Various types of drug-induced vitiligo-like depigmentation have been reported in recent years. Commonly implicated drugs include immune checkpoint inhibitors, targeted drugs, monoclonal antibodies, immunomodulators, chemotherapy drugs, and imiquimod. Unlike the mechanism of vitiligo, the mechanism of drug-induced vitiligo-like depigmentation is not clear, and it has some different characteristics. We herein summarize the vitiligo-like depigmentation induced by different drugs, which will help dermatologists to further understand its pathogenesis and clinical features.

Cutaneous manifestations associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block key mediators of tumor-mediated immune evasion. The frequency of its use has increased rapidly and has extended to numerous cancers. ICIs target immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1), and T cell activation, including cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). However, ICI-driven alterations in the immune system can induce various immune-related adverse events (irAEs) that affect multiple organs. Among these, cutaneous irAEs are the most common and often the first to develop. Skin manifestations are characterized by a wide range of phenotypes, including maculopapular rash, psoriasiform eruption, lichen planus-like eruption, pruritus, vitiligo-like depigmentation, bullous diseases, alopecia, and Stevens-Johnson syndrome/toxic epidermal necrolysis. In terms of pathogenesis, the mechanism of cutaneous irAEs remains unclear. Still, several hypotheses have been proposed, including activation of T cells against common antigens in normal tissues and tumor cells, increased release of proinflammatory cytokines associated with immune-related effects in specific tissues/organs, association with specific human leukocyte antigen variants and organ-specific irAEs, and acceleration of concurrent medication-induced drug eruptions. Based on recent literature, this review provides an overview of each ICI-induced skin manifestation and epidemiology and focuses on the mechanisms underlying cutaneous irAEs.

Clinical Presentation and Prognostic Features in Patients with Immunotherapy-Induced Vitiligo-like Depigmentation: A Monocentric Prospective Observational Study.

Simple SummaryIn this study, we thoroughly explore the clinical and biological features of immunotherapy-induced vitiligo-like depigmentation (VLD) in patients with stage III-IV melanoma receiving immunotherapy. Key findings include a distinct immune signature with an upregulation of ITGA in the VLD group, an upregulation of EDAR and downregulation of LAG3 in VLD-responders group, a longer time to VLD onset in patients pre-treated with targeted therapy, the distribution of VLD lesions primarily in sun-exposed areas as opposed to mechanically stressed areas in non-immunotherapy-related vitiligo, the predominance of a symmetrical, small-freckle lesional pattern and a prolonged progression-free survival (PFS) and overall survival (OS) in VLD patients without LDH elevation as opposed to those with LDH elevation.Vitiligo-like depigmentation (VLD) is an immune-related adverse event (irAE) of checkpoint-inhibitor (CPI) treatment, which has previously been associated with a favourable outcome. The aim of this study was to explore clinical, biological and prognostic features of melanoma patients with VLD under CPI-treatment and to explore whether they exhibit a characteristic immune response profile in peripheral blood. Melanoma patients developing VLD under CPI were included in a prospective observational single-center cohort study. We collected and analysed clinical parameters, photographs and serum from 28 VLD patients. They received pembrolizumab (36%), nivolumab (11%), ipilimumab/nivolumab (32%) or clinical trial medications (21%). We performed a high-throughput proteomics assay (Olink), in which we identified a distinct proteomic signature in VLD patients in comparison to non-VLD CPI patients. Our clinical assessments revealed that VLD lesions had a predominantly symmetrical distribution pattern, with mostly smaller “freckle-like” macules and a preferential distribution in UV-exposed areas. Patients with previous targeted therapy showed a significantly longer time lapse between CPI initiation and VLD onset compared to non-pre-treated patients (12.5 vs. 6.25 months). Therapy responders exhibited a distinct proteomic profile when compared with non-responders in VLD such as upregulation of EDAR and downregulation of LAG3. ITGA11 was elevated in the VLD-group when compared to non-VLD-CPI-treated melanoma patients. Our findings demonstrate that on a proteomic level, VLD is characterized by a distinct immune signature when compared to CPI-treated patients without VLD and that therapy responsiveness is reflected by a characteristic immune profile. The pathomechanisms underlying these findings and how they could relate to the antitumoral response in melanoma remain to be elucidated.

Vitiligo-Like Depigmentation Induced by Anti-Programmed Death 1 Antibody.

Vitiligo-Like Depigmentation Induced by Anti-Programmed Death 1 Antibody.

Vitiligo-specific soluble biomarkers as early indicators of response to immune checkpoint inhibitors in metastatic melanoma patients

Immunotherapy with checkpoint inhibitors (CPIs) strongly improved the outcome of metastatic melanoma patients. However, not all the patients respond to treatment and identification of prognostic biomarkers able to select responding patients is currently of outmost importance. Considering that development of vitiligo-like depigmentation in melanoma patients represents both an adverse event of CPIs and a favorable prognostic factor, we analyzed soluble biomarkers of vitiligo to validate them as early indicators of response to CPIs. Fifty-seven metastatic melanoma patients receiving CPIs were enrolled and divided according to the best overall response to treatment. Patient sera were evaluated at pre-treatment and after 1 and 3 months of therapy. We found that basal CD25 serum levels were higher in stable and responding patients and remained higher during the first 3 months of CPI therapy compared to non-responders. CXCL9 was absent in non-responding patients before therapy beginning. Moreover, an increase of CXCL9 levels was observed at 1 and 3 months of therapy for all patients, although higher CXCL9 amounts were present in stable and responding compared to non-responding patients. Variations in circulating immune cell subsets was also analyzed, revealing a reduced number of regulatory T lymphocytes in responding patients. Altogether, our data indicate that a pre-existing and maintained activation of the immune system could be an indication of response to CPI treatment in melanoma patients.

Tislelizumab Induced Vitiligo-Like Depigmentation in a Chinese Patient with Oesophageal Squamous Cell Carcinoma.

Tislelizumab Induced Vitiligo-Like Depigmentation in a Chinese Patient with Oesophageal Squamous Cell Carcinoma.

Equine vitiligo-like depigmentation in grey horses is related to genes involved in immune response and tumor metastasis

BackgroundIn horses, the autoimmune disease vitiligo is characterized by the loss of melanocytes and results in patchy depigmentation of the skin around the eyes, muzzle and the perianal region. Vitiligo-like depigmentation occurs predominantly in horses displaying the grey coat colour and is observed at a prevalence level of 26.0–67.0% in grey horses compared with only 0.8–3.5% in non-grey horses. While the polygenetic background of this complex disease is well documented in humans, the underlying candidate genes for this skin disorder in horses remain unknown. In this study we aim to perform a genome-wide association study (GWAS) for identifying putative candidate loci for vitiligo-like depigmentation in horses.MethodsIn the current study, we performed a GWAS analysis using high-density 670 k single nucleotide polymorphism (SNP) data from 152 Lipizzan and 104 Noriker horses, which were phenotyped for vitiligo-like depigmentation by visual inspection. After quality control 376,219 SNPs remained for analyses, the genome-wide Bonferroni corrected significance level was p < 1.33e-7.ResultsWe identified seven candidate genes on four chromosomes (ECA1, ECA13, ECA17, ECA20) putatively involved in vitiligo pathogenesis in grey horses. The highlighted genes PHF11, SETDB2, CARHSP1 and LITAFD, are associated with the innate immune system, while the genes RCBTB1, LITAFD, NUBPL, PTP4A1, play a role in tumor suppression and metastasis. The antagonistic pathogenesis of vitiligo in relation to cancer specific enhanced cell motility and/or metastasis on typical melanoma predilection sites underlines a plausible involvement of RCBTB1, LITAFD, NUBPL, and PTP4A1.ConclusionsThe proposed candidate genes for equine vitiligo-like depigmentation, indicate an antagonistic relation between vitiligo and tumor metastasis in a horse population with higher incidence of melanoma. Further replication and expression studies should lead to a better understanding of this skin disorder in horses.

Immune checkpoint inhibitor associated vitiligo and its impact on survival in patients with metastatic melanoma: an Italian Melanoma Intergroup study

BackgroundCheckpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes.MethodsTo assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors.ResultsA total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients.ConclusionsAmong VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration.

Cutaneous immune-related adverse events in patients with melanoma treated with checkpoint inhibitors.

Checkpoint inhibitor (CPI) therapy has vastly improved long-term outcomes in metastatic malignant melanoma (MMM). Therapy takes the form of monoclonal antibody infusions that target immune cell checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed death 1/programmed death ligand 1 (PD1/PDL1). Cutaneous immune-related adverse effects (IrAEs) are frequent in patients with MMM treated with CPIs. Our aim was to review the clinical presentations of cutaneous IrAEs associated with CPI therapy in adult patients with MMM. We carried out a literature review of clinical trials, case series and case reports of patients with melanoma and those with other cancers treated with anti-CTLA4, anti-PD1/PDL1, or a combination of these therapies. Diverse clinical presentations of cutaneous IrAEs are recognized. Anti-CTLA4 therapy has a higher associated rate of cutaneous IrAEs than anti-PD1/PDL1 therapies. Low-grade cutaneous IrAEs are common and are usually managed supportively while continuing CPI therapy. Delayed presentations arising after established use of CPIs can make therapy-associated cutaneous IrAEs difficult to distinguish from coincidental dermatological disease. Vitiligo-like depigmentation is a good prognostic indicator of outcome in patients with melanoma. Life-threatening adverse events including toxic epidermal necrolysis are rare. The identification of predictive biomarkers that highlight patients at risk of life-threatening IrAEs remains an unmet need. The involvement of dermatologists in the multidisciplinary assessment of cutaneous IrAEs is increasingly pertinent in the management and care of CPI-treated patients with melanoma.

Targeting the PD-1/PD-L1 Axis in Human Vitiligo.

Autoreactive CD8+ T cells play a pivotal role in melanocyte destruction in autoimmune vitiligo. Immunotherapy for melanoma often leads to autoimmune side-effects, among which vitiligo-like depigmentation, indicating that targeting immune checkpoints can break peripheral tolerance against self-antigens in the skin. Therapeutically enhancing immune checkpoint signaling by immune cells or skin cells, making self-reactive T cells anergic, seems a promising therapeutic option for vitiligo. Here, we review the current knowledge on the PD-1/PD-L1 pathway in vitiligo as new therapeutic target for vitiligo therapy.

Melanoma Inhibitory Activity (MIA) Is Able to Induce Vitiligo-Like Depigmentation in an in vivo Mouse Model by Direct Injection in the Tail.

In the complex pathogenesis of vitiligo, the exact mechanism of the dermatosis is still to be clarified. We previously demonstrated that a protein called melanoma inhibitory activity (MIA) is present in non-segmental vitiligo skin and seems to cause the detachment of melanocytes, consequently creating the depigmented macules. In this study, we present an animal model of vitiligo on the basis of the ability of the MIA protein to induce vitiligo-like lesions. Twenty pigmented mice were chosen for the experiments and received injections in the tail with saline (control group) or with saline + MIA protein (treated group). The control group did not show any sign of depigmentation. The treated group showed, instead, clear zones of complete depigmentation in the injected areas in each mouse, with the appearance of white patches with whitening of the hair and a clear-cut edge. Histological examination of the tail in the treated zone showed the absence of melanocytes, without the presence of any inflammatory cell or any sign of skin inflammation patterns, confirming the detachment of the melanocyte operated by the MIA protein. These data seem to confirm a possible role played by the MIA protein in the pathogenesis of vitiligo and may support the development of treatments able to inhibit its action as an alternative therapeutic strategy for this disorder.

Vitiligo and Melanoma-Associated Vitiligo: Understanding Their Similarities and Differences.

There has been a significant increase in the number and efficacy of therapies for advanced melanoma. Immunotherapies, such as anti-cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 inhibitors, have improved the prognosis for patients with advanced melanoma. While spontaneous melanoma-associated vitiligo is a known phenomenon, the occurrence of melanoma-associated vitiligo following melanoma therapy is now recognized to associate with favorable outcomes. The objective of this article is to provide a comprehensive literature review of melanoma-associated vitiligo and explore the insights these findings provide about the pathobiology of vitiligo and mechanisms underlying melanoma therapies. PubMed and Science Direct databases were searched for studies pertaining to melanoma-associated vitiligo. The 36 studies reviewed included meta-analyses (n = 2), prospective cohort studies (n = 4), prospective observational studies (n = 3), retrospective studies (n = 12), case series (n = 2), and case reports (n = 13). The basic mechanisms underlying melanoma-associated vitiligo and vitiligo may be shared. Characterization of these mechanisms will identify new biomarkers and therapeutic targets for both melanoma and vitiligo. Co-opting the immune system to target tumor antigens highlights the potential overlap between anti-tumor immunity and autoimmunity. The development of vitiligo-like depigmentation in association with immunotherapy for melanoma may provide insights into both the immune response against melanoma as well as the pathogenesis of vitiligo.

Second primary melanoma in advanced melanoma patients treated with anti-PD-1 monoclonal antibodies.

e22025 Background: Development of a second primary melanoma (SCPM) has not been reported in melanoma patients treated with anti-PD-1 monoclonal antibodies (mAb), in contrast with those reported in BRAF-inhibitor-treated patients. Our aim was to report arising SCPM in patients with advanced melanoma treated with anti-PD-1 therapy. Methods: Retrospective study, conducted in 2 referral centres, including advanced melanoma patients who developed a SCPM after anti-PD-1 mAb initiation, between September 2010 and May 2019. BRAF or NRAS mutational status was assessed by targeted NGS panels, real-time PCR, and immunohistochemistry. Results: Among a total of 509 patients treated with anti-PD-1 mAb, 4 had a SCPM (incidence: 0.8%; 95%CI: 0.02-1.57%). All patients were treated with nivolumab, in first (N = 3) or second line after progression with BRAF + MEK inhibitors (N = 1). No immune-related adverse event greater than grade 2 according to Common Terminology Criteria for Adverse Events version 5.0. was observed in these 4 cases; a vitiligo-like depigmentation (grade 1) was observed in two patients. The median time from the first nivolumab infusion to the SCPM diagnosis was 17.5 months (range: 5-21). All patients developed the SCPM after achieving a complete response. Nivolumab administration had been discontinued (4 months prior) in one patient. Histology revealed 4 superficial spreading melanomas (SSM): one invasive (without BRAFV600 mutation) and 3 intraepidermal melanomas (2 with a BRAFV600E mutation and one with a NRASQ61H mutation). 3 patients had risk factors for developing multiple melanomas: a dysplastic nevus syndrome, a high number of nevi (≥100 nevi), and a family history of melanoma in first-degree relatives and constitutional heterozygous mutation of exon 2 of the CDKN2A gene. Occurrence of SPCM did not alter advanced melanoma treatment. With a median follow-up of 29 months [range: 18-41] from the first anti-PD-1 mAb infusion, all patients had prolonged CR, and treatment was discontinued in all patients, without relapse after a median 11.5 months [0-18] off therapy. The median duration of nivolumab treatment was 15.5 months [10-24]. Conclusions: Although anti-PD-1 mAb could theoretically decrease the risk of developing another melanoma in metastatic melanoma patients, we found 4 such cases, highlighting the importance of regular clinical screenings for new primary melanoma in patients with metastatic melanoma even when responsive to anti-PD-1 therapy. Immune checkpoint inhibitors do not totally prevent the risk of occurrence a SCPM.

Vitiligo-like depigmentation in a patient with advanced melanoma

Vitiligo-like depigmentation in a patient with advanced melanoma