| Abstract|| |
Melanocytes are highly specialized dendritic cells that synthesize and store melanin in subcellular organelles called melanosomes, before transfer to keratinocytes. Melanin is a complex pigment that provides colour and photoprotection to the skin, hair and eyes. The process of synthesis of melanin is called melanogenesis and is regulated by various mechanisms and factors such as genetic, environmental and endocrine factors. The knowledge of the pigmentation process is important to understand hypopigmentation disorders such as vitiligo and also to design adequate treatments. In the present work, we review the signalling pathways involved in vitiligo. Finally, current therapies and treatments including topical, oral and phototherapies are discussed and described, emphasizing future therapies based on different pigmentation mechanisms.
Keywords: Hypopigmentation, melanin synthesis, melanocyte, treatment, vitiligo
|How to cite this article:|
Vinardell M P, Maddaleno AS, Mitjans M. Melanogenesis and hypopigmentation: The case of vitiligo. Indian J Dermatol 2022;67:524-30
|How to cite this URL:|
Vinardell M P, Maddaleno AS, Mitjans M. Melanogenesis and hypopigmentation: The case of vitiligo. Indian J Dermatol [serial online] 2022 [cited 2023 Jan 30];67:524-30. Available from: https://www.e-ijd.org/text.asp?2022/67/5/524/366095
| Introduction|| |
Melanin is a complex pigment that provides colour and photoprotection to the skin, hair and eyes of mammals. Melanogenesis is the process through which melanocytes synthesise melanin and can be altered by decreasing the production of the pigment such as in the case of vitiligo.
Melanogenesis can be regulated by genetic, environmental (ultraviolet [UV] radiation) and endocrine factors. Knowledge of the pigmentation process is important for designing tanning products to treat hypopigmentation disorders such as vitiligo.
Vitiligo is an autoimmune acquired chronic skin disorder that is characterised by white macules resulting from the damage and loss of melanocytes. Although many disorders induce hypopigmentation, vitiligo is the most frequent cause of depigmentation worldwide affecting about 1% in the population., Vitiligo can be segmental, non-segmental or mixed. Segmental vitiligo presents one or more areas of depigmented skin usually only on one side of the body such as on the face, neck, trunks, arms or legs during childhood and usually stabilises in a few years. Non-segmental vitiligo is a chronic and progressive loss of melanin with well-defined white patches in the middle of normally pigmented skin, increasing in size over time and located on the hands, underarms, eyelids, ears, knees and ankles and whose progression is unpredictable. Vitiligo is usually associated with different autoimmune disorders such as thyroid diseases, diabetes mellitus, lupus, inflammatory bowel disease, psoriasis and atopic dermatitis among others. Other authors have observed also metabolic comorbidities and psychological and psychiatric disorders.
| Signalling Pathways in Vitiligo|| |
Vitiligo is a complex disease and different hypotheses have been proposed for the multifactorial feature of vitiligo pathogenesis involving immunological, genetic, biochemical and environmental factors [Figure 1].
Oxidative stress has been suggested to be the first step in the loss of melanocytes in vitiligo, but it is not the unique initiating mechanism involved in the disease.,
High levels of reactive oxygen species (ROS) are found in lesioned and non-lesioned skin, damaging melanocytes by generating autoantigens whose presentation by Langerhans cells and dendritic cells initiate an autoimmune response, bridging the gap between oxidative stress and adaptive immunity.[8.9] Disruptions in metabolic processes such as melanogenesis and immune reactions can lead to the accumulation of ROS, although several studies suggest that mitochondrial damage altering the mitochondria structure of melanocytes is the main cause of ROS accumulation., A recent study has observed that molecular hydrogen revers hydrogen peroxide-induced apoptosis in melanocytes, protecting mitochondrial morphology and function in melanocytes under stress and promoting the activation of Nrf2 signalling.
ROS generation can also be induced by exogenous factors such as the environment, medical applications and other diseases., Studies have reported that melanocytes from vitiligo patients die upon exposure to exogenous stress in vitro, such as peroxide exposure, whereas melanocytes from healthy controls do not. Intracellular ROS include hydrogen peroxide (H2O2), superoxide anions and hydroxyl radicals. H2O2 can disrupt melanin synthesis and can deactivate and deregulate acetylcholinesterase in the epidermis, providing more evidence of the role of oxidative stress in vitiligo. Zhang et al. showed that H2O2-induced apoptosis increases the level of calreticulin, which induces the expression of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α).
The activity of superoxide dismutase (SOD), a metalloprotein that scavenges O2- and converts it into H2O2, is increased in the erythrocytes of vitiligo patients. H2O2 is converted into O2 by catalase, whose expression is down regulated in vitiligo. The imbalance in the oxidative/antioxidative equilibrium is another cause of ROS accumulation. Several studies have reported an increase in malondialdehyde (MDA) levels in vitiligo patients, which is a product of lipid peroxidation reactions induced by oxidative stress.
The immune-mediated destruction of melanocytes is the main factor causing vitiligo. Stressed melanocytes activate the innate immune system through cytokines secreted within the skin, that is, induced by the generation and release of damage-associated molecular patterns (DAMPs). This has been demonstrated through the recruitment of innate immune cells, such as natural killer cells, as well as the production and release of highly pro-inflammatory proteins and cytokines including heat shock proteins, IL-1β, IL-6 and IL-8. Moreover, it has been reported that CD8+ T cells induce the destruction of melanocytes.,
Autoreactive T cells locate stressed melanocytes using the cytokines secreted within the skin. Studies have shown that IFN-γ and the IFN-γ-induced chemokines CXCL9 and CXCL10, which act as chemoattractants to guide T cell migration, are highly expressed in the skin and blood of vitiligo patients. The CXCL10/CXCR3 axis mediates T cell recruitment in progressive vitiligo, suggesting that the blocking of this mechanism could be a new form of therapy.
El-Gayyar et al. suggested that anti-melanocyte antibodies have an important role in the pathogenesis of non-segmental vitiligo, correlating with the severity of the disease. Furthermore, a higher prevalence of anti-thyroperoxidase, anti-thyroglobulin, antinuclear, anti-gastric parietal cell and anti-adrenal antibodies has been reported in vitiligo patients compared to healthy controls. Indeed, autoantibodies have an important role in disease pathology, confirming the important role of humoral immunity in vitiligo. Major melanocytic antigens include the proteins tyrosinase, TRP-1, TRP-2, Pmel17, SOX9, SOX10 and the type 1 membrane receptor for melanin-concentrating hormone (MCH-R1). SOX9 and SOX10, key transcription factors for melanocyte differentiation, have been reported many years ago to be autoantigens in vitiligo.
One of the proposed mechanisms for melanocyte destruction in vitiligo is the autoimmune intolerance via CD8+ and T helper 17 (Th17), which have an important role in exosomes in melanogenesis serving as mediators in the communication between keratinocytes and melanocytes.
Pro-inflammatory cytokines, such as IL-6, TNF-α, IL-1β, IFN-γ and IL-8 and some anti-inflammatory/immunoregulatory cytokines such as IL-5 and IL-10 are increased in vitiligo patients. Mitra et al. suggested that the high level of IL-10 is due to the attempt to avoid the loss of melanocytes by the organism. However, other studies have shown a low level of IL-10. Zhou et al. indicated that IL-17 induces a stressful microenvironment for melanocytes, promoting autophagic cell apoptosis in vitiligo.
Different studies have demonstrated the relationship between alterations in the skin microbiome and some skin diseases such as psoriasis and atopic dermatitis., The first study correlating microbiota and vitiligo demonstrated a dysbiosis in the diversity of the bacterial community of the areas with vitiligo hypopigmentation compared to normal skin. The authors observed distinctive distribution of bacterial populations with more Actinobacterial species, such as Actinomycetes, in areas of the skin without lesions and Firmicutes in areas with lesions.
More recent studies observed similar alterations in microbiota and associated the dysbiosis with mitochondrial damage. Moreover, the loss of protective bacteria in patients can be associated with an increase in immune responses.
Moreover, the role of the gut microbiome is known in the development of other skin diseases such as psoriasis autoimmune diseases. In the case of vitiligo, authors have found alterations in the gut microbiome composition and serum metabolites usually used as biomarkers of vitiligo. These findings can implicate the gut–skin axis in vitiligo pathogenesis.
Among vitiligo patients, 15–20% have at least one first-degree relative with this disease. Furthermore, the risk of a patient's sibling developing vitiligo is 6%, whereas that of a monozygotic twin is 23%, illustrating the genetic basis of vitiligo.
At least 50 susceptibility loci for vitiligo have been identified by genome-wide association studies (GWAS), with 90% of these loci associated with innate and adaptive immunity and 10% associated with melanocytic antigens and stress response pathways, further demonstrating that immune mechanisms are the key in vitiligo.
The most significant genetic risk for vitiligo involves HLA-A polymorphisms, followed by HLA-DRB1/DQA1 and CPVL, which are related to antigen presentation. Moreover, genes associated with immune target cell lysis (GZMB and FASLG), adaptive immunity (FOXP3, CTLA4, IL2RA, BACH2, CD80, CCR6, PTPN22 and α-GZMB), innate immunity (TICAMI, IFIH1, CD80, NLRP1, CASP7, C1QTNF6 and TRIF), and melanocytes (TYR, PMEL, MC1R, OCA2-HERC2 and IRF4) have been identified as risk factors for vitiligo.
Previous studies have demonstrated that the polymorphisms of superoxide dismutase (SOD), a crucial mitochondrial reactive oxygen species (ROS) scavenger, are genetic risk factors for the susceptibility and progression of vitiligo.
Different chemicals have been observed to induce skin depigmentation, that is, indistinguishable from idiopathic vitiligo. The mechanism of chemical-induced vitiligo is complex and still not clear., It has been observed that some chemicals such as monobenzyl ether of hydroquinone (MBEH) and 4-tertiary butyl phenol can downregulate microphthalmia-associated transcription factor (MITF) leading to decreased melanin synthesis and thereby initiation of vitiligo. MBEH was the first chemical known as causing depigmentation and nowadays, MBEH is approved by the US Food and Drug Administration (FDA) and is used therapeutically to complete and accelerate depigmentation to make the skin tone of patients with severe vitiligo uniform.
Several studies have confirmed that exposure to chemical agents, specifically phenolic and catechol derivatives found in dyes (including hair dyes), resins/adhesives and leather is associated with vitiligo. Phenols can act as tyrosinase analogues, affecting melanin synthesis and causing high levels of stress in melanocytes. Cell stress leads to ROS accumulation and the unfolded protein response, triggering immune reactions that destroy melanocytes and result in skin depigmentation.
| Treatments and Future Perspectives|| |
Finding the best treatment for vitiligo has become a challenge due to the complexity of the pathology of the condition. Therefore, vitiligo therapy must be personalised depending on each case and the degree of depigmentation. Safer and more effective treatments with long-lasting benefits are being studied because current treatments do not provide a long-lasting effect [Table 1].
Phototherapy is the first-line treatment of choice for vitiligo. Narrowband UVB (NB-UVB) phototherapy induces re-pigmentation and is an effective treatment of vitiligo. This therapy provides good results on the face, trunk and limbs but topical treatment must be applied after phototherapy to prevent skin depigmentation. NB-UVB phototherapy can decrease the rate of new vitiligo lesions in non-segmental vitiligo patients, with earlier re-pigmentation in non-progressive vitiligo. Progressive patients required more doses of NB-UVB than non-progressive patients. The action of NB-UVB in the re-pigmentation of the skin can be attributed to an increase in the expression of the genes involved in pigmentation such as the TYR gene family constituted by tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1) and tyrosinase-related protein 2 (TYRP2).
However, there are patients who do not respond to conventional phototherapies and in these cases, some studies have demonstrated that UVA1 laser can be an applicable therapeutic option.,
Topical corticosteroids are the most commonly used drug to treat vitiligo but there are concerns over side effects. Topical corticosteroids have been observed as effective in recent and facial lesions; however, to reduce the risk of side effects the administration should be limited to small areas, avoiding prolonged use and introducing another topical therapy after some weeks of continuous administration.,
Topical corticosteroids exert anti-inflammatory responses, but re-pigmentation is more likely to occur on the face and neck than in the other areas. Moreover, topical corticosteroids can increase the efficacy of UVB and are indicated for small-localised patches. A combination of NB-UVB and topical corticosteroids has been demonstrated to be more effective than topical corticosteroids alone, presenting good tolerability both in adults and children.,
Topical immunomodulators such as corticosteroids reduce the production of proinflammatory cytokines by inhibiting T-cell activity, thereby increasing pigmentation. Other immunomodulators can be used such as the macrolide antibiotic tacrolimus, which inhibits calcineurin action, thus preventing T-cell activation and the production of various inflammatory cytokines. Tacrolimus has been demonstrated to increase the proliferation of melanocytes. The topical application of tacrolimus is effective in the treatment of vitiligo and does not present the adverse effects observed with corticosteroids.
Surgery is used when medical therapies are not effective and consists of pigment cell transplantation. The melanocyte–keratinocyte transplantation procedure (MKTP) is the most popular option for the management of select patients with vitiligo. MKTP consists of cellular grafting in which cells from a donor are grafted to a treated area as a cellular suspension covering a larger area. The combination of surgery and other therapies as topical administration of immunomodulators is used to reduce immune response. Other adjuvant therapies include narrowband UVB phototherapy with a proliferative and stimulatory effect on transplanted melanocytes. The use of epidermal cell suspension is usually performed in patients with clinical stability of a minimum of 12 months. The combination of epidermal suspension and dermal cell suspension gives a better response in patients with vitiligo and can be used early in the course of stable vitiligo without waiting for 12 months or more.
The best option to treat extensive vitiligo is the depigmentation of the pigmented areas by chemical or laser therapy. However, the efficacy of this treatment and the duration of its benefits are not enough.
Skin camouflage is the traditional application of pigmented creams that are designed to mask skin discolouration and can be useful where dermatological or surgical treatments may be considered invasive. Camouflaging the depigmented areas with cosmetic products can improve the social life of patients with vitiligo despite potential risks. Cosmetics can have a transient, semi-permanent or permanent (tattoos) effect. The most commonly used self-tanning product is dihydroxyacetone, whose effects increase with concentration. It is noticeable that 10% is the highest concentration allowed in the European Union for the purpose of tanning, and from 2022, all cosmetics containing more than 10% of dihydroxyacetone will be banned in Europe.
| Future Perspectives|| |
Emerging treatments will focus on the re-pigmentation of the skin through regulating autoimmunity, controlling melanocyte stress, and regenerating or depigmenting the remaining small-pigmented areas of the skin.
Targeted immunotherapy is one of the most important ways of treating vitiligo. Examples of this type of emerging therapy include the interference of IFN-γ-CXCL10 signalling, and the use of JAK inhibitors, STAT inhibitors and immune checkpoint inhibitors.
The regeneration of melanocytes can be stimulated with α-MSH analogues such as afamelanotide, which can improve the efficacy of phototherapy, and with Wnt activators.
ROS generation in patients with vitiligo can be resolved by reducing melanocyte stress through the use of antioxidants such as oral or topical natural health products.
As mentioned above, in vitiligo patients with small areas of pigmentation, depigmenting products can be used to achieve a uniform skin tone. For this reason, compounds with low toxicity and no side effects are currently being investigated for depigmenting skin.
As reviewed, several factors account for the pathophysiology of vitiligo but still open questions remain. However, a better knowledge of the pathogenesis of hypopigmentation epigenetic regulation by genomic imprinting can reveal the specific functional genes and their regulatory elements and pathways. In this sense, omics analysis, by Cai et al. performed for vitiligo, can open a new perspective to understanding the causes, mechanisms and specific treatments for different skin pigmentation disorders.
| Conclusions|| |
In vitiligo, the destruction of melanocytes by the immune system is the major cause of this disease. Although the main signalling pathways are known, new therapies should be developed to treat vitiligo due to the low efficacy or side effects of current treatments. Therapies that can modulate the immune system, which is the main driver of hypopigmentation, are the best option to repigment the skin. Other agents that stimulate melanocytes can also be useful in inducing pigmentation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ezzedine K, Eleftheriadou V, Whitton M, Van Geel N. Vitiligo. Lancet 2015;386:74-84.
Brown AE, Qiu CC, Drozd B, Sklover LR, Vickers CM, Hsu S. The color of skin: White diseases of the skin, nails, and mucosa. Clin Dermatol 2019;37:561-79.
Dahir AM, Thomsen SF. Comorbidities in vitiligo: Comprehensive review. Int J Dermatol 2018;57:1157-64.
D'Arino A, Picardo M, Truglio M, Pacifico A, Iacovelli P. Metabolic comorbidities in vitiligo: A brief review and report of new data from a single-center experience. Int J Mol Sci 2021;22:8820. doi: 10.3390/ijms22168820.
Simons RE, Zevy DL, Jafferany M. Psychodermatology of vitiligo: Psychological impact and consequences. Dermatol Ther 2020;33:e13418.
Bergqvist C, Ezzedine K. Vitiligo: A focus on pathogenesis and its therapeutic implications. J Dermatol 2021;48:252-70.
Speeckaert R, Dugardin J, Lambert J, Lapeere H, Verhaeghe E, Speeckaert MM, et al
. Critical appraisal of the oxidative stress pathway in vitiligo: A systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2018;32:1089-98.
Chiarella P. Vitiligo susceptibility at workplace and in daily life: The contribution of oxidative stress gene polymorphisms. Biomedical Dermatol 2019;3:1-12.
Wang Y, Li S, Li C. 2019. Perspectives of new advances in the pathogenesis of vitiligo: From oxidative stress to autoimmunity. Med Sci Monitor 2019;25:1017-23.
Dell'Anna ML, Ottaviani M, Kovacs D, Mirabilii S, Brown DA, Cota C, et al
. Energetic mitochondrial failing in vitiligo and possible rescue by cardiolipin. Sci Rep 2017;7:13663.
Sahoo A, Lee B, Boniface K, Seneschal J, Sahoo SK, Seki T, et al
. MicroRNA-211 regulates oxidative phosphorylation and energy metabolism in human vitiligo. J Invest Dermatol 2017;137:1965-74.
Fang W, Tang L, Wang G, Lin J, Liao W, Pan W, et al
. Molecular hydrogen protects human melanocytes from oxidative stress by activating Nrf2 signaling. J Invest Dermatol 2020;140:2230-41.
Richmond JM, Frisoli ML, Harris JE. Innate immune mechanisms in vitiligo: Danger from within. Curr Opini Immunol 2013;25:676-82.
Xie H, Zhou F, Liu L, Zhu G, Li Q, Li C, et al
.Vitiligo: How do oxidative stress-induced autoantigens trigger autoimmunity? J Dermatol Sci 2016:81:3-9.
Ahn Y, Seo J, Lee EJ, Kim JY, Park MY, Hwang S, et al
. ATP-P2X7-induced inflammasome activation contributes to melanocyte death and CD8+ T-cell trafficking to the skin in vitiligo. J Invest Dermatol 2020;140:1794-804.
Said ER, Nagui NAER, Rashed LA, Mostafa WZ. Oxidative stress and the cholinergic system in non-segmental vitiligo: Effect of narrow band ultraviolet b. Photodermatol Photoimmunol Photomed 2021;37:306-12.
Zhang Y, Liu L, Jin L, Yi X, Dang E, Yang Y, et al
. Oxidative stress-induced calreticulin expression and translocation: New insights into the destruction of melanocytes. J Invest Dermatol 2014;134:183-91.
Wu J, Zhou M, Wan Y, Xu A. CD8+ T cells from vitiligo perilesional margins induce autologous melanocyte apoptosis. Mol Med Rep 2013;7:237-41.
Riding RL, Harris JE. The role of memory CD8(+) T cells in vitiligo. J. Immunol 2019;203:11-9.
Wang XX, Wang QQ, Wu JQ, Jiang M, Chen L, Zhang CF, et al
. Increased expression of CXCR3 and its ligands in patients with vitiligo and CXCL10 as a potential clinical marker for vitiligo. Br J Dermatol 2016;174:1318-26.
El-Gayyar M, Helmy M, Amer E, Elsaied MA, Gaballah MA. Antimelanocyte antibodies: A possible role in patients with vitiligo. Indian J Dermatol 2020;65:33-7.
] [Full text]
Liu CW, Huang YC. Vitiligo and autoantibodies: A systematic review and meta-analysis. J Dtsch Dermatol Ges 2018;16: 845-53.
Unal A, Ozkol HU, Bayram Y, Akdeniz N. Comparison of tyrosinase antibody, tyrosinase-related protein-1 and -2 antibodies, melanin-concentrating hormone receptor antibody levels with autologous serum skin test and autologous plasma skin test results in patients with vitiligo. Postepy Dermatol Alergol 2021;38:473-9.
Hedstrand H, Ekwall O, Olsson MJ, Landgren E, Kemp EH, Weetman AP, et al
. The transcription factors SOX9 and SOX10 are vitiligo autoantigens in autoimmune polyendocrine syndrome type I. J Biol Chem 2001;76:35390-5.
Wong PM, Yang L, Yang L, Wu H, Li W, Ma X, Katayama I, Zhang H. New insight into the role of exosomes in vitiligo. Autoimmun Rev 2020;19:102664. doi: 10.1016/j.autrev. 2020.102664.
Mitra S, De Sarkar S, Pradhan A, Pati AK, Pradhan R, Mondal D, et al
. Levels of oxidative damage and proinflammatory cytokines are enhanced in patients with active vitiligo. Free Radic Res 2017;51 (11-12):986-94.
Gomes IA, de Carvalho FO, de Menezes AF, Almeida FM, Shanmugam S, de Souza SiqueiraQuintans J, et al
. The role of interleukins in vitiligo: A systematic review. J Eur Acad Dermatol Venereol 2018;32:2097-111.
Zhou J, An X, Dong J, Wang Y, Zhong H, Duan L, et al
. IL-17 induces cellular stress microenvironment of melanocytes to promote autophagic cell apoptosis in vitiligo. FASEB J 2018;32:4899-916.
Zeeuwen PL, Kleerebezem M, Timmerman HM, Schalkwijk J. Microbiome and skin diseases. CurrOpin Allergy Clin Immunol 2013;13:514-20.
Hidalgo-Cantabrana C, Gomez J, Delgado S, et al
. Gut microbiota dysbiosis in a cohort of patients with psoriasis. Br J Dermatol 2019;181:1287-95.
Ganju P, Nagpal S, Mohammed MH, Requena-López S, Queiro-Silva R, Margolles A, Coto E, et al
. Microbial community profiling shows dysbiosis in the lesional skin of Vitiligo subjects. Sci Rep 2016;6:18761.
Bzioueche H, SimonytéSjödin K, West CE, Khemis A, Rocchi S, Passeron T, et al
. Analysis of matched skin and gut microbiome of patients with vitiligo reveals deep skin dysbiosis: Link with mitochondrial and immune changes. J Invest Dermatol 2021;141:2280-90.
Ni Q, Ye Z, Wang Y, Chen J, Zhang W, Ma C, et al
. Gut microbial dysbiosis and plasma metabolic profile in individuals with vitiligo. Front Microbiol 2020;11:592248. doi: 10.3389/fmicb. 2020.592248.
Spritz RA. Modern vitiligo genetics sheds new light on an ancient disease. J Dermatol 2013;40:310-8.
Rahman R, Hasija Y. Exploring vitiligo susceptibility and management: A brief review. Biomedical Dermatol 2018;2:1-13.
Frisoli ML, Essien K, Harris JE. Vitiligo: Mechanisms of pathogenesis and treatment. Annu Rev Immunol 2020;38:621-48.
Laddha NC, Dwivedi M, Gani AR. Shajil EM, Begum R. Involvement of superoxide dismutase isoenzymes and their genetic variants in progression of and higher susceptibility to vitiligo. Free Radic Biol Med 2013;65:1110-25.
Alam M, Ghosh S. Effect of chemical exposure in induction and evolution of vitiligo: Correlation between duration of exposure and disease, site of exposure and onset, and impact upon avoidance. Clin Epidemiol Glob Health 2015;3:S91-95.
Kammeyer A, Willemsen KJ, Ouwerkerk W, Bakker WJ, Ratsma D, Pronk SD, et al
. Mechanism of action of 4-substituted phenols to induce vitiligo and antimelanoma immunity. Pigment Cell Melanoma Res 2019;32:540-52.
Kaushik H, Kaul D, Kumaran MS, Parsad D. Chemical induced pathognomonic features observed in human vitiligo are mediated through miR-2909 R Nomics pathway. J Dermatol Sci 2020;100:92-8.
Harris JE. Chemical-induced vitiligo. Dermatol Clin 2017;35:151-61.
Toosi S, Orlow SJ, Manga P. Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8. J Invest Dermatol 2012;132:2601-9.
Bhatia S, Khaitan BK, Gupta V, Khandpur S, Sahni K, Sreenivas V. Efficacy of NB-UVB in progressive versus non-progressive non-segmental vitiligo: A prospective comparative study. Indian Dermatol Online J 2021;12:701-5. [Full text]
Awad SS, Moftah NH, Rashed LA, Touni AA, Telep RAA. Evaluation of the effect of narrow band-ultraviolet B on the expression of tyrosinase, TYRP-1, and TYRP-2 mRNA in vitiligo skin and their correlations with clinical improvement: A retrospective study. Dermatol Ther 2021;34:e14649.
Lotti T, Tchernev G, Wollina U, França K, Lotti J, Satolli F, et al
. Successful treatment with UVA 1 laser of non-responder vitiligo patients. Open Access Maced J Med Sci 2018;6:43-5.
Babino G, Giunta A, Esposito M, Saraceno R, Pavlidis A, Del Duca E, et al
. UVA1 laser in the treatment of vitiligo. Photomed Laser Surg 2016;34:200-4.
de la Fuente-Garcia A, Gomez-Flores M, Mancillas-Adame L, Ocampo-Candiani J, Welsh-Lozano O, Pérez JZ, et al
. Role of the ACTH test and estimation of a safe dose for high potency steroids in vitiligo: A prospective randomized study. Indian Dermatol Online J 2014;5:117-21.
Dellatorre G, Antelo DAP, Bedrikow RB, Cestari TF, Follador I, Ramos DG, et al
. Consensus on the treatment of vitiligo-Brazilian Society of Dermatology. An Bras Dermatol 2020;95(Suppl 1):70-82.
Batchelor JM, Thomas KS, Akram P, Azad J, Bewley A, Chalmers JR, et al
. Home-based narrowband UVB, topical corticosteroid or combination for children and adults with vitiligo: HI-Light Vitiligo three-arm RCT. Health Technol Assess 2020;24:1-128. doi: 10.3310/hta24640.
Thomas KS, Batchelor JM, Akram P, Chalmers JR, Haines RH, Meakin GD, et al
. Randomized controlled trial of topical corticosteroid and home-based narrowband ultraviolet B for active and limited vitiligo: Results of the hi-light vitiligo Trial. Br J Dermatol 2021;184:828-39.
Sisti A, Sisti G, Oranges CM. Effectiveness and safety of topical tacrolimus monotherapy for repigmentation in vitiligo: A comprehensive literature review. An Bras Dermatol 2016;91:187-95.
Rokni GR, Golpour M, Gorji AH, Khalilian A, Ghasemi H. Effectiveness and safety of topical tacrolimus in treatment of vitiligo. J Adv Pharm Technol Res 2017;8:29-33.
] [Full text]
Nahhas AF, Mohammad TF, Hamzavi IH. Vitiligo surgery: Shuffling melanocytes. J Investig Dermatol Symp Proc 2017;18:S34-7.
Majid I., Imran S. Ultrathin split-thickness skin grafting followed by narrowband UVB therapy for stable vitiligo: An effective and cosmetically satisfying treatment option. Indian J Dermatol Venereol Leprol 2012;78:159-64.
] [Full text]
Thakur V, Kumar S, Kumaran MS, Kaushik H, Srivastava N, Parsad D. Efficacy of transplantation of combination of noncultured dermal and epidermal cell suspension vs epidermal cell suspension alone in vitiligo: A randomized clinical trial. JAMA Dermatol 2019;155:204-10.
Derbyshire E. Innovations in skin camouflaging techniques: Where are we scientifically? Int J Cosmet Sci 2019;41:526-33.
Levy LL, Emer JJ. Emotional benefit of cosmetic camouflage in the treatment of facial skin conditions: Personal experience and review. Clin CosmetInvestig Dermatol 2012;5:173-82.
Rajatanavin N, Suwanachote S, Kulkollakarn S. Dihydroxyacetone: A safe camouflaging option in vitiligo. Int J Dermatol 2008;47:402-6.
Rashighi M, Harris JE. Interfering with the IFN-γ/CXCL10 pathway to develop new targeted treatments for vitiligo. Ann Transl Med 2015;3:343.
Speeckaert R, van Geel N. Targeting CTLA-4, PD-L1 and IDO to modulate immune responses in vitiligo. Exp Dermatol 2017;26:630-4.
Grimes PE, Hamzavi I, Lebwohl M, Ortonne JP, Lim HW. The efficacy of afamelanotide and narrowband UV-B phototherapy for repigmentation of vitiligo. JAMA Dermatol 2013;149:68-73.
Harris JE. Melanocyte regeneration in vitiligo requires WNT beneath their wings. J Invest Dermatol 2015;135:2921-3.
Konstantinova VA, Olisova OY, Gladko VV, Burova EP. Vitiligo-new treatment approach. Clin CosmetInvestig Dermatol 2019;12:911-7.
Cai M, Yuan T, Huang H, Gui L, Zhang L, Meng Z, Wu W, Sheng Y, Zhang X. Integrative analysis of omics data reveals regulatory network of CDK10 in vitiligo risk. Front Genet 2021;12;634553. doi: 10.3389/fgene. 2021.634553.