Introduction

Vitiligo is a common dermatological disorder of the epidermis and hair follicles, manifesting clinically as expanding hypopigmented lesions of the skin. It affects 0.5–1% of the world population, and its incidence ranges from 0.1 to 8.8% in India 1, 2. Absence of melanocytes in the skin lesion due to their destruction has been suggested to be the key event in the pathogenesis of vitiligo 3. The aetiology of vitiligo remains obscure despite being in focused debate for the last six decades 3–6, and hence, it is important to unravel the underlying pathomechanisms of vitiligo.

A single dominant pathway appears unlikely to account for all cases of melanocyte loss in vitiligo, and apparently, a complex interaction between genetic, environmental, biochemical and immunological events is likely to generate a permissive milieu (Fig. 1). Loss of melanocytes in vitiligo appears to occur through a combination of several mechanisms that act in concert. Here, we discuss the possible interconnections of oxidative stress and immune system that are involved in melanocyte loss. There might be alteration in melanocyte-specific proteins by the action of reactive oxygen species (ROS), which results in the generation of neoantigens, autoimmunity and melanocytorrhagy leading to defective apoptosis.

Oxidative stress and vitiligo

Oxidative stress is considered to be one of the possible pathogenic events in melanocyte loss 7, 8. Defective recycling of tetrahydrobiopterin in whole epidermis of patients with vitiligo is related to the intracellular production of H₂O₂ 9, 10. In addition, an increased intracellular production of ROS due to mitochondrial impairment 11 and a compromised antioxidant status 8, 12, 13 supports the concept of a possible systemic oxidative stress in vitiligo. This accumulated oxidative stress causes DNA damage, lipid and protein peroxidation 14, 15 (Fig. S1). Many proteins are altered and show partial or complete loss of functionality due to H₂O₂-mediated oxidation. H₂O₂ can also function as an inhibitor of tyrosinase, or in the presence of H₂O₂, DOPA (dihydroxyphenylalanine) substrate can generate a secondary complex that can bind and inhibit tyrosinase 16.

Elevated extracellular calcium levels and inhibition of thioredoxin reductase also contribute to the generation of oxidative stress in the vitiligo epidermis 17, 18. Several sources have been documented for the unusual production/accumulation of epidermal H₂O₂ [Table 1: 8–12, 19–29]. Our studies also showed systemic oxidative stress in patients with vitiligo due to an imbalance in enzymatic and non-enzymatic antioxidant systems 20, 25 and significant decrease in acetylcholine esterase (AChE) activity 30, which could be due to H₂O₂-mediated oxidation of AchE 31, thus emphasizing the role of oxidative stress in precipitation of vitiligo. Moreover, our recent study suggests oxidative stress as the initial triggering factor in precipitating vitiligo. Patients with early onset (<3 months) of vitiligo showed significant decrease (P = 0.005) in the levels of antimelanocyte antibodies compared to patients with long duration (>3 months), and moreover, erythrocyte lipid peroxidation levels were significantly increased (P = 0.0085) in patients with early-onset vitiligo compared to patients with long-standing vitiligo.

Table 1. Sources for epidermal/systemic H₂O₂ generation/accumulation in vitiligo

Source	References	H2O2 generation/accumulation	Increase/decrease
Monoamine oxidase A	Schallreuter et al. 19	Epidermal	Increase
Superoxide dismutase	Agrawal et al. 20; Hazneci et al. 21	Blood	Increase
Glucose 6 phosphate dehydrogenase	Agrawal et al. 20	Blood	Decrease
NADPH oxidase	Schallreuter et al. 10	Epidermal	Increase
Photooxidation of pterins	Rokos et al. 22	Epidermal	Increase
Nitric oxide synthases	Gibson and Liley 23	Epidermal	Increase
Short circuit in 6BH4 recycling	Schallreuter et al. 9; Kaufman et al. 24	Epidermal	Increase
Catalase	Dell’Anna et al. 11; Schallreuter et al. 12; Maresca et al. 8; Shajil and Begum 25	Blood and epidermal	Decrease
Glutathione peroxidase/reduced glutathione	Beazley et al. 26; Dell’Anna et al. 11; Agrawal et al. 20; Yildirim et al. 27	Blood	Decrease
Tyrosinase-related protein 1	Jimbow et al. 28	Epidermal	Decrease
Xanthine oxidase	Koca et al. 29	Blood	Increase

Further, increased levels of ROS in melanocytes may cause defective apoptosis resulting in release of aberrated proteins, which can serve as autoantigens leading to autoimmunity 32. The intracellular levels of H₂O₂ and other ROS also increase in response to cytokines such as TNFα (tumor necrosis factor α) and TGFβ1 (transforming growth factor β1), which are potent inhibitors of melanogenesis 33–36. High ROS also increase the levels of cytokines, including IL-2 (interleukin-2), which upregulate the expression of anti-apoptotic protein, Bcl-2 (B-cell lymphoma-2), thereby making T cells resistant to apoptosis (Fig. 2; pathway 2) 37. Moreover, transepidermal loss of melanocytes under stress conditions (adrenaline and H₂O₂) supports the hypothesis that non-segmental vitiligo (NSV) melanocytes have an intrinsic defect, which limits their adhesion in a reconstructed epidermis 38, thus leading to melanocytorrhagy 39–41.

Autoimmunity and vitiligo

Vitiligo lesions are characterized by an infiltration of inflammatory cells, particularly cytotoxic, helper T cells and macrophages. This infiltration is most prominent in the perilesional skin just prior to clinical appearance of vitiligo. Only early-stage lesions show non-specific infiltrate of lymphocytes in the epidermis and the dermis suggesting involvement of T cells in active vitiligo lesions 42. Elevated antibody levels against melanocyte antigens in 2624 patients showed increased frequency of autoimmune disorders such as hypothyroidism, pernicious anaemia, Addison’s disease, systemic lupus erythematosus and inflammatory bowel disease in vitiligo probands and their first-degree relatives suggesting a common genetic aetiological link between vitiligo and other autoimmune diseases 43, 44. Further, Michelsen 45 has proposed antibody-based and T-cell-based dominant mechanisms in generalized and localized vitiligo, respectively, as the contributory factors for autoimmune vitiligo. Thus, humoral and cell-mediated immune mechanisms are likely to be involved in the melanocyte destruction.

Humoral immune response in vitiligo

Antibodies against melanocyte antigens are detected in the sera of patients with vitiligo, and a correlation exists between melanocyte antibody levels and disease activity 46–49. Tyrosinase is the principal antigen recognized by these antibodies 49, 50. Our recent study has also suggested that 75% of patients with vitiligo had antimelanocyte antibodies in their circulation. Kemp et al. 51 found that 23% of the patients with non-segmental vitiligo were positive for tyrosine hydroxylase antibodies.

The other melanocyte antigens recognized by autoantibodies are gp100/Pmel 17 (a melanosomal matrix glycoprotein) and tyrosinase-related proteins 1 and 2 (TRP 1 and TRP 2) 52, 53 (Table S1). These cell differentiation antigens are localized primarily to melanosomes 54. A summary of the autoantigens implicated in vitiligo is given in Table S1 41, 52, 53, 55–61. In vitro studies showed that vitiligo antibodies are able to destroy melanocytes by complement-mediated damage and antibody-dependent cellular cytotoxicity 62. The selective loss of melanocytes might result from antibody reactivity directed to the antigens preferentially expressed on pigment cells, which might result from a genetic predisposition to immune dysregulation at the T-cell level 50, 63. Moreover, B-cell infiltration in juxtaposition to depigmented zones supports the idea that the autoimmune phenomenon is mediated by a humoral mediator or is local to some areas of skin 64.

Cell-mediated immunity

The high frequencies of melanocyte-reactive cytotoxic T cells in the peripheral blood of patients with vitiligo, perilesional T-cell infiltration and melanocyte loss in situ suggest the involvement of cellular autoimmunity in vitiligo pathogenesis 65–69. In particular, active cases of vitiligo were demonstrated to have higher levels of cytotoxic T cells 70. Histopathological and immunohistochemical studies have confirmed the presence of infiltrating CD8⁺ T cells in generalized vitiligo 71–76. In vitro studies demonstrated an increased production of pro-inflammatory cytokines IL-6 and IL-8 by monocytes of active patients with vitiligo, which will affect effector cell migration, effector target attachment and also cause B-cell activation 77. In most patients with vitiligo, the balance of cytotoxic/suppressor and helper/inducer T cells in peripheral blood is disturbed 64, 78. Moreover, in progressive disease, the CD4⁺⁄CD8⁺ ratio is decreased among skin-infiltrating T cells 79.

Recent studies have demonstrated that the number and suppressive effects of peripheral T regulatory cells in progressive generalized patients with vitiligo were significantly reduced, suggesting an impairment in their ability to inhibit the proliferation 76, 80, 81. Nevertheless, Abdallah and Saad 82 also showed a dysfunction of Tregs by the elevation of Tregs and Teffs in generalized patients with vitiligo suggesting that Tregs were unable to control the immunological attack and destruction of melanocytes by cytotoxic T cells. In addition, our findings demonstrated decreased levels of both sCTLA4 and flCTLA4 transcripts in patients, suggesting the disturbance in the suppressive capacity of Tregs and thus emphasize the role of cellular immunity in vitiligo 83.

Recently, the role of Th17 cells has gained more attention in vitiligo, as immunohistochemical analysis showed Th17 cell infiltration in vitiligo skin samples in addition to CD8⁺ T cells 84, 85. Moreover, the studies provide evidence for the influence of a Th17 cell-related cytokine environment (IL-17A, IL-1β, IL-6 and TNFα) in local depigmentation in autoimmune vitiligo 84, 85. IL-17 has also been reported to be involved in augmented production of ROS 86, thereby implicating its role in oxidative stress-mediated cell damage. In addition, studies have also found increased levels of IL-17 in serum, lesional skin 87 and in neutrophils of patients with vitiligo 88, thus suggesting an important role of Th17 cytokine in the pathogenesis of vitiligo.

Genetics of vitiligo

Vitiligo is characterized by multiple susceptibility loci, incomplete penetrance and genetic heterogeneity and may involve genes associated with the biosynthesis of melanin, antioxidant system and regulation of autoimmunity 89, 90. Recent studies suggest that genetic factors may play a major role in the pathogenesis of vitiligo. Our study also suggests that 21.93% of Gujarat patients with vitiligo exhibited positive family history and 13.68% patients had at least one affected first-degree relative 91. Because vitiligo is a polygenic disease, several candidate genes including MHC, ACE, CAT, CTLA4, COMT, ESR, MBL2, PTPN22, HLA, NALP1, XBP1, FOXP1 and IL-2RA that are involved in regulation of immunity have been tested for genetic association with generalized vitiligo 89, 92, 93.

Recently, we have shown positive association between HLA-A*33:01, HLA-B*44:03 and HLA-DRB1*07:01 with patients with vitiligo from North India and Gujarat suggesting an autoimmune link of vitiligo in these cohorts 94. We have also shown that the three most significant class II region SNPs: rs3096691 (just upstream of NOTCH4), rs3129859 (just upstream of HLA-DRA) and rs482044 (between HLA-DRB1 and HLA-DQA1) are associated with generalized vitiligo 95. The genotype–phenotype correlation between CTLA-4, IL-4 and TNFA gene polymorphisms supported the autoimmune pathogenesis of vitiligo in Gujarat population 83, 96, 97, whereas our earlier studies on CAT, GPX, MBL-2, ACE and PTPN22 polymorphisms did not show significant association 98–101.

Cytokines and apoptosis

The exact pathway for loss of melanocytes is not yet known; however, apoptotic death has been suggested in vitiligo 102, 103. Cytokines such as IL-1, IFNγ or TNFα are paracrine inhibitors of melanocytes and can initiate apoptosis 102. Our recent study has shown increased TNFα protein and transcript levels in patients with vitiligo, suggesting an early apoptosis of melanocytes 97. In addition, TNFα induces IL-1α, thereby promoting B-cell differentiation, immunoglobulin production and also cause maturation of dendritic cells, thus results in development of autoimmunity 65. Apoptosis of melanocytes in vitiligo may also be due to melanocyte-specific antibodies 73.

Kotobuki et al. 84 showed that IL-17A dramatically induced IL-1β, IL-6 and TNFα production in keratinocytes and fibroblasts, which can affect apoptosis of melanocytes. IL-6 and IL-13 secreting CD8⁺ T cells from vitiligo perilesional margins may induce autologous melanocyte apoptosis 104. Also, an imbalance of keratinocyte-derived cytokines such as GM-CSF, bFGF, SCF, IL-6, IL-1α and TNFα in the lesional skin has been demonstrated, which could impair the normal life and function of melanocytes 105, 106. Moreover, alteration in mRNA expression pattern of IL-20RB, IL-22RA2, IL-28A, IL-28B, IL-28RA, IFNA1, IFNB1 and IFNG genes involved in regulation of survival/apoptosis of melanocytes has been observed in vitiligo skin and/or peripheral blood mononuclear cells (PBMC) 107.

Defective apoptosis and generation of autoimmunity

Melanocytes from patients with vitiligo demonstrate various abnormalities, including incompetent synthesis, processing of melanocytes, abnormal rough endoplasmic reticulum, homing-receptor dysregulation and early apoptosis 5, 103. Oxidative stress, which can induce apoptosis by cytochrome C–mediated pathway of caspase activation, may contribute to melanocyte loss in vitiligo lesions 108. During apoptosis, modification of melanocytic antigens through proteolysis, changes in the phosphorylation state and citrullination may give rise to potentially immunostimulatory forms of intracellular or membrane-associated autoantigens. These modified autoantigens, which may also expose cryptic epitopes, may be processed by mature Langerhans cells and presented to T cells 109. Subsequently, the autoreactive CD4⁺ T cells may stimulate autoreactive B cells to produce autoantibodies, whereas CD8⁺ T cells may attack melanocytes directly 109. It is worth noting that efficient clearance of apoptotic cells is crucial for the avoidance of autoimmune responses to intracellular antigens.

Interplay of oxidative stress and immune system

The two major theories of vitiligo pathogenesis include autoimmune aetiology for the disease and oxidative stress-mediated toxicity in the melanocyte. Although these two theories are often presented as mutually exclusive entities, it is likely that vitiligo pathogenesis may involve both oxidative stress and autoimmune events, for which there is variability within a patient. The synergistic interaction of oxidative stress with immune system may lead to either direct or indirect loss of melanocytes, as it has been previously suggested in melanocytorrhagic hypothesis 38. In addition, oxidative stress produced through increased catecholamine release or from other sources such as toxic intermediates of melanin precursors can also initiate or at least amplify the autoimmune loss of melanocytes (Fig. 2).

In autoimmune disorders, the immune system creates a chronic or relapsing inflammatory milieu in which ROS can accumulate with a toxic effect on surrounding cells. This can explain the pathogenesis of inflammatory vitiligo 110. The bottom line question that remains unanswered is what causes this aberrant inflammatory response in autoimmunity and whether these ROS are a result of the chronic inflammation and autoimmunity or part of the cause of the autoimmune response?

ROS are produced as by-products of melanogenesis in melanocytes and controlled by several redundant antioxidant enzymes. Given the role of oxidative stress in both melanogenesis and in the immune system, it can be hypothesized that biochemical defects in the melanin biosynthesis pathway, as well as possible defects in patient’s antioxidant enzymes, are responsible for the generation of ROS in the epidermis of patients with vitiligo 111. Moreover, there are several ways by which ROS, besides having a direct melanocytotoxicity, can induce an autoimmune attack against melanocytes. In fact, ROS are involved in specific early events in T-cell activation and antioxidants are involved in reducing T-cell proliferation, IL-2R expression and IL-2 production 112. The build-up of ROS along with possible immune system defects allows for the inappropriate autoimmune response against melanocytes (Fig. 2).

The melanogenic pathway involves the formation and polymerization of L-tyrosine, which is converted into L-dopaquinone with O-quinone as an intermediate product. Exposure to UV radiation for longer time causes the spontaneous production of O-quinone leading to the formation of H₂O₂ as a by-product 60 (Fig. 2, pathway 4). The structures of melanocytic macromolecules and small molecules, such as Melan-A and tyrosinase, may be changed by acute or chronic oxidative stress and can act as antigens (neoantigens). Neoantigens with sufficient homology or identity to host antigenic proteins induce autoreactivity. This phenomenon is referred to as ‘molecular mimicry’ 113. The presence of rheumatoid factors in the sera and lesions of patients with vitiligo can be explained by this mechanism 114. Over time, chronic oxidative stress could generate several adducted and⁄or non-adducted molecules that would essentially act as a neoantigens 115. More than one neoantigens/autoantigens are involved in amplifying the autoaggressive lymphocytes by a process referred to as ‘antigen spreading’. This is an autoimmune reaction initially directed against a single autoantigen that spreads to other autoantigens, causing the T helper cells to recognize them 113.

Further, increased phenols⁄catechols, in vitiliginous skin areas, may serve as surrogate substrates of tyrosinase, converting into reactive quinones 16. Such reactive quinones, whose production is enhanced by increased H₂O₂ in the vitiligo lesions, can covalently bind to tyrosinase (haptenation). This could give rise to a neoantigen, carried by Langerhans cells to the regional lymph nodes and stimulate the proliferation of cytotoxic T cells 116. Moreover, Kroll et al. 117 showed that 4-tertiary butyl phenol (4-TBP) exposure sensitizes human melanocytes to dendritic cell (DC)-mediated killing through release of HSP70 and DC effector functions. Recently, Elassiuty et al. 118 have demonstrated that stress-induced (UV, 4-TBP) melanocyte cell death is protected by haem oxygenase-1 (HO-1) overexpression, thereby contributing to beneficial effects of UV treatment for patients with vitiligo.

During chronic oxidative stress and other noxious processes, neoantigens potentially cause tissue damage and release a plethora of sequestered autoantigens. This process is referred to as the ‘bystander effect’. Such an outburst of autoantigens from the target tissue would potentially amplify the effect of the neoantigens, leading to the breakdown of self-tolerance 113. These reports have yielded some interesting clues linking oxidative stress and immune system and provide an insight into the generation of autoimmunity due to oxidative stress. However, the conjunction of oxidative stress and autoimmune hypotheses is unable to explain the potential triggering factors and different depigmentation patterns observed in different types of vitiligo.

Major open questions

Based on the available data, melanocyte loss in vitiligo is still an enigma and the triggering factors are still being debated. Also, the proposed hypotheses have not been tried on animal models to support their validity. Moreover, the bilateral symmetrical distribution of vitiligo patches on skin demands more scrutiny. Further, in generalized vitiligo, the involvement of autoimmunity should vanquish all melanocytes in the skin but it is not so, why? However, it has been suggested that many external triggering factors (such as mechanical traumas) could play a crucial role in the final clinical expression of vitiligo and it is well known that vitiligo lesions are predominantly located on skin areas chronically submitted to repeated frictions and continuous pressures 119, 120. Thus, the interconnections of the different hypotheses and their role in vitiligo pathogenesis are yet to be understood.

Conclusion

The pathogenesis of vitiligo, though, partially understood still remains complex and enigmatic to a greater extent. However, the presented scientific approaches in recent years have yielded some interesting clues giving credence to both oxidative stress and autoimmune hypotheses with potential clinical relevance. Although the condition may be precipitated by multiple aetiologies, the interaction of oxidative stress with immune system clearly appears to be the key convergent pathway that initiates and/or amplifies the enigmatic loss of melanocytes. Better understanding of triggering factors for generation of autoimmunity in patients with vitiligo could pave the way towards the development of preventive/ameliorative therapies. Dissecting out this mode of skin depigmentation in vitiligo animal model/in vitro reconstructed epidermis [as previously reported; 38] will be helpful in unravelling the vitiligo puzzle.

Acknowledgements

RB thanks DBT, New Delhi {‘BT/PR9024/MED/12/332/2007’} and GSBTM, Gujarat {‘GSBTM/MD/PROJECTS/SSA/453/2010-2011’} for financial support. NCL thanks the Council of Scientific and Industrial Research (New Delhi) for awarding SRF. RB carefully revised and edited the manuscript. NCL and MD wrote the article. All authors including MSM, ARG, Ansarullah, AVR and SD critically revised the text and approved the submitted version.

Image Credit: Ron Lach

Source: 

Question  What is the current point prevalence of vitiligo among adults in the US?

Findings  This cross-sectional, population-based online survey study of more than 40 000 adults in the US was conducted between December 2019 and March 2020. Participant self-report, and adjudication of vitiligo by 3 dermatologists through participant submission of photographs of their skin lesions, resulted in an estimated point prevalence for diagnosed and undiagnosed vitiligo combined of 1.38% (self-reported) and 0.76% (clinician adjudicated).

Meaning  This study provides current US population-based point prevalence estimates of all vitiligo, beyond just the diagnosed population, including estimates for undiagnosed, segmental, and nonsegmental vitiligo.

Importance  Vitiligo can have profound effects on patients and is often associated with other autoimmune comorbid conditions. It is important to understand the current prevalence of vitiligo, including diagnosed, undiagnosed, and subtypes (nonsegmental and segmental).

Objective  To estimate the point prevalence of vitiligo in the US.

Design, Setting, and Participants  For this population-based study of adults in the US, a cross-sectional online survey was administered between December 2019 and March 2020 to obtain participant self-reported vitiligo status. A representative sample of the US adult general population, aged 18 to 85 years, was recruited using a stratified proportional, sampling design from general population research panels. Additionally, 3 expert dermatologists adjudicated participants’ self-reported vitiligo diagnosis by reviewing photographs uploaded by the participants using a teledermatology app designed and tested specifically for this study.

Main Outcomes and Measures  The main outcomes were the point prevalence estimates of overall vitiligo, as well as diagnosed, undiagnosed, nonsegmental, and segmental vitiligo.

Results  Among the 40 888 eligible adult participants, the mean (SD) age was 44.9 (17.4) years, 23 170 (56.7%) were female, 30 428 (74.4%) were White, and 4225 (10.3%) were of Hispanic, Latino, or Spanish origin. Self-reported vitiligo prevalence was 1.38% (95% CI, 1.26%-1.49%), with 0.77% (95% CI, 0.68%-0.85%) for diagnosed and 0.61% (95% CI, 0.54%-0.69%) for undiagnosed. Based on expert dermatologist review of 113 photographs of participants with self-reported vitiligo, clinician-adjudicated vitiligo prevalence (sensitivity bounds) was 0.76% (0.76%-1.11%), with 0.46% (0.46%-0.61%) for diagnosed and 0.29% (0.29%-0.50%) for undiagnosed. Self-reported nonsegmental vitiligo prevalence was 0.77% (95% CI, 0.68%-0.85%), with 0.48% (95% CI, 0.41%-0.55%) for diagnosed and 0.29% (95% CI, 0.23%-0.34%) for undiagnosed. Clinician-adjudicated nonsegmental vitiligo prevalence (sensitivity bounds) was 0.58% (0.57%-0.84%), with 0.37% (0.37%-0.49%) for diagnosed and 0.21% (0.20%-0.36%) for undiagnosed. Self-reported segmental vitiligo prevalence was 0.61% (95% CI, 0.53%-0.69%), with 0.28% (95% CI, 0.23%-0.33%) for diagnosed and 0.33% (95% CI, 0.27%-0.38%) for undiagnosed. Clinician-adjudicated segmental vitiligo prevalence (sensitivity bounds) was 0.18% (0.18%-0.27%), with 0.09% (0.09%-0.12%) for diagnosed and 0.08% (0.08%-0.15%) for undiagnosed.

Conclusions and Relevance  Results of this survey study demonstrated that the current US population-based prevalence estimate of overall (diagnosed and undiagnosed combined) vitiligo in adults is between 0.76% (1.9 million cases in 2020) and 1.11% (2.8 million cases in 2020). Additionally, this study suggests that approximately 40% of adult vitiligo in the US may be undiagnosed. Future studies should be performed to confirm these findings.

Vitiligo is an autoimmune disorder in which the immune system causes patchy loss of skin pigmentation.¹ Two forms of the disease, segmental and nonsegmental vitiligo, are well recognized. Segmental vitiligo, characterized by unilateral, localized distribution of vitiligo lesions, more often has rapid onset and stabilization with early hair follicle involvement. Nonsegmental vitiligo, characterized by bilateral distribution of vitiligo lesions on the body, more frequently has progressive onset with multiple flare-ups, later hair follicle involvement, and an unpredictable course.^2,3 Segmental vitiligo is a less common form of the disease occurring in 5% to 16% of patients with vitiligo while nonsegmental vitiligo is the more common form.² The average age of onset follows a bimodal pattern of early onset at 7.3 years and late onset at 40.5 years.⁴ However, segmental vitiligo tends to occur more commonly than nonsegmental vitiligo in younger children.²

Worldwide prevalence estimates of vitiligo vary widely with prevalence estimates ranging from 0.004% to 2.28%.^5,6 In the United States, there is a paucity of population-based studies; however, based on the few studies that have been conducted in specific subpopulations, the prevalence estimates vary from 0.05% to 1.55%. Furthermore, these estimates are either outdated, do not include patients with undiagnosed vitiligo, or are sampled from specific subgroups of the general population.^7–12

Vitiligo can have profound effects on a patient’s well-being and is often associated with other autoimmune comorbid conditions. Furthermore, because the disease course, prognosis, and treatment modalities are different between segmental and nonsegmental vitiligo, it is important to distinguish between these vitiligo forms at diagnosis.¹³ Therefore, it is important to gain a better understanding of the current prevalence of vitiligo among adults, particularly the prevalence of nonsegmental vitiligo compared with segmental vitiligo, along with the prevalence of diagnosed and undiagnosed vitiligo. This information can help inform timely diagnosis and clinical management with new and emerging therapies, inform patient access to health care, improve patient education efforts, and inform efforts to increase disease awareness. The objectives of this large, general population survey study were to estimate the point prevalence of vitiligo in the US, including diagnosed and undiagnosed vitiligo, as well as segmental and nonsegmental vitiligo, and to describe the demographic and clinical characteristics of this patient population.

A cross-sectional population-based survey was conducted between December 30, 2019, and March 11, 2020. Participants who reported being diagnosed with vitiligo by a clinician (self-reported diagnosed) or reported having vitiligo by screening positive for undiagnosed vitiligo in the survey (self-reported undiagnosed) were invited to submit photographs for clinician evaluation using a teledermatology mobile health application (teledermatology app) designed and tested specifically for this study. Clinician evaluation of the photographs was conducted by vitiligo experts between February 21 and March 30, 2020. This study was approved by the New England Institutional Review Board, and participants provided online consent.

A representative sample of the US adult general population, 18 to 85 years of age, was recruited by email invitation using a stratified proportional, sampling design from a proprietary US general population research panel provided by Schlesinger Group. Stratified quotas were set to be representative of the 2017 US Census estimates with respect to age (4-85 years), gender, race, household income level, and geographic region.^14,15 To be eligible for the general population research panel, participants must have had an email address and valid photograph identification, provided key demographic information, and validated email through a confirmation email link.

Based on response rates within the various census quotas, subsequent invitations were sent by email to randomly selected participants to achieve a census-balanced sample of the targeted 50 000 participants. The survey link was provided in the email. Participant compensation ranged from $2.50 for participants who did not report having vitiligo to $60 for participants who reported having vitiligo and uploaded photographs. Information for the pediatric population (4-17 years of age) was obtained through parent and/or legal guardian proxy in accordance with the Federal Trade Commission’s Children’s Online Privacy Protection Act. The results among adults in the US are reported herein. The results of the pediatric population will be published elsewhere.

The participant survey included demographics, clinical characteristics, comorbidities, and vitiligo screening questions for all participants. Vitiligo screening questions were adapted from published screening tools, the patient-administered Vitiligo Screening Tool,¹⁶ and a self-reported questionnaire. The screening questions included an atlas of photographs developed by Phan et al¹⁷ and by expert clinicians in the field to enable identification of participants with diagnosed or undiagnosed vitiligo. A representation of the consecutive screening questions and vitiligo images that participants saw in the online survey are shown in the eAppendix in the Supplement.

Both self-reported diagnosed participants and self-reported undiagnosed participants (Figure) were asked to complete additional questions on the laterality (bilateral or unilateral) of their lesions and vitiligo characteristics (eg, age of onset and extent of body surface area [BSA] involvement). The Self Assessment Vitiligo Extent Score was used to determine BSA involvement for participants reporting bilateral vitiligo (proxy for nonsegmental vitiligo),¹⁸ and hand or index finger units were used to measure the extent of BSA involvement for participants reporting unilateral vitiligo (proxy for segmental vitiligo).^19,20

Participants with self-reported diagnosed or undiagnosed vitiligo were invited to upload photographs of their lesions for clinician evaluation. Participants who consented to upload photographs were asked to download the study’s teledermatology app to their personal device (eg, smartphone). Participants were provided instructions in the app, including logging in with a unique, deidentified code; granting access to the mobile device camera; selecting a body part location for each photograph; and submitting up to 3 photographs. The teledermatology app was designed with facial recognition and blur detection to ensure clear and anonymized images by prompting participants to retake photographs when needed.

Three board-certified dermatologists with expertise in vitiligo (including K.E. and A.G.P.) served as adjudicators and evaluated the uploaded photographs from participants who self-reported having diagnosed or undiagnosed vitiligo. The clinicians were provided with participants’ self-reported information on age, gender, race, age of vitiligo onset, laterality, Fitzpatrick skin type (FST), and other skin conditions to assist with their evaluation. They were blinded to the participant’s report of being diagnosed or undiagnosed and independently classified each participant into 1 of 6 classifications: (1) definitely has vitiligo, (2) probably has vitiligo, (3) definitely does not have vitiligo, (4) probably does not have vitiligo, (5) unable to determine due to poor quality photographs, or (6) unable to determine due to any other reason (eg, need more photographs, need more clinical history). The 6 classifications were subsequently collapsed into 3 categories for analysis: (1) vitiligo (included classifications 1 and 2), (2) nonvitiligo (included classifications 3 and 4), and (3) indeterminate (included classifications 5 and 6).

Final vitiligo adjudication was made by clinician majority, defined by at least 2 of the 3 clinicians agreeing on the categorization of vitiligo, nonvitiligo, or indeterminate. If there was no majority, the case was categorized as indeterminate. Clinicians further evaluated the self-reported laterality (ie, lesions on 1 or both sides of the body) of the vitiligo lesions and provided their own assessment of nonsegmental vitiligo or segmental vitiligo based on photographs and following the consensus classification from the 2011 Vitiligo European Taskforce consensus conference for segmental vitiligo.²¹ Agreement between the clinicians was assessed using the Fleiss (unweighted) κ coefficient.^22–24

All analyses were performed using SAS software, version 9.4 (SAS Institute). Descriptive statistics were calculated for participant demographic and clinical characteristics and reported overall and for the participants with self-reported diagnosed and self-reported undiagnosed vitiligo. Comparisons between the participants with self-reported diagnosed and self-reported undiagnosed vitiligo were assessed using t test for continuous variables and χ² test for categorical variables. The level of significance was 2-sided P = .05 and is presented for descriptive purposes. The sample size for this study was chosen to provide reasonable precision around the estimate of prevalence and not to examine differences in these characteristics between the diagnosed and undiagnosed vitiligo participants.

Self-reported point prevalence estimates of vitiligo were calculated as the percentage of participants who self-reported vitiligo. Clinician-adjudicated point prevalence estimates of vitiligo were calculated as the prevalence of self-reported vitiligo weighted by the proportion of participants with self-reported vitiligo that was in agreement with the clinician adjudication. Indeterminate cases were not included in either the numerator nor denominator for the clinician-adjudicated prevalence (base case scenario). Two sensitivity analyses were conducted in which indeterminate diagnoses were recategorized as: (1) vitiligo diagnoses (upper-bound scenario) and (2) nonvitiligo diagnoses (lower-bound scenario).

Additionally, self-reported and clinician-adjudicated point prevalence estimates were calculated separately for participants reporting bilateral (nonsegmental proxy) and unilateral (segmental proxy) vitiligo lesions. To improve the representativeness of the estimates, all point prevalence estimates were weighted using raked weights to adjust the census-based sample to 2020 US Census estimates and mitigate differential representation across key subgroups (eg, age groups, gender, race) by using an iterative proportional fitting process.^25,26

A total of 322 240 individuals were invited to take part in the survey, of which 60 524 (18.8%) responded (Table 1). Approximately one-third (n = 19 636 [32.4%]) of those who responded were not eligible, with the most common reason (n = 10 630 [54.1%]) being that the US Census quota (ie, age, gender, race, geographic region, income level) was already met.

The 40 888 eligible adult participants aged 18 to 85 years were generally representative of the estimated 2017 US Census population (Table 2). The mean (SD) age was 44.9 (17.4) years, and 23 170 (56.7%) were female. The majority (n = 30 428 [74.4%]) identified themselves as White, and 4225 (10.3%) participants identified themselves of Hispanic, Latino, or Spanish origin. The greatest number of participants (n = 16 265 [39.8%]) resided in the US South geographic region.

Prior diagnosis with vitiligo by a clinician (self-reported diagnosed vitiligo) was reported by 314 adults. An additional 249 adults screened positive for vitiligo in the survey (self-reported undiagnosed vitiligo) (Table 2). Compared with participants with self-reported undiagnosed vitiligo, participants with self-reported diagnosed vitiligo were older on average (42.8 vs 39.3 years; P = 0.01 [all adult participants, 44.9 years]), had a greater percentage of female (191 [60.8%] vs 135 [54.2%]; P = .12 [all adult participants, 23 170 (56.7%)]) and White participants (215 [68.5%] vs 149 [59.8%]; P = .03 [all adult participants, 30 428 (74.4%)]), and a lower percentage of participants of Hispanic, Latino, or Spanish origin (48 [15.3%] vs 53 [21.3%]; P = .07 [all adult participants, 4225 (10.3%)]) (Table 2).

The mean age at vitiligo onset was 27.6 years for participants with self-reported diagnosed vitiligo compared with 25.0 years for participants with self-reported undiagnosed vitiligo (P = 0.06; Table 2). More participants with self-reported diagnosed vitiligo reported bilateral presentation compared with participants with self-reported undiagnosed vitiligo (197 [62.7%] vs 114 [45.8%]; P < .001). Among participants with self-reported diagnosed vitiligo, more reported facial involvement compared with participants with self-reported undiagnosed vitiligo (140 [71.1%] vs 75 [65.8%]; P = .33) (Table 2). Participants with self-reported diagnosed vitiligo also reported greater mean BSA percentage compared with participants with self-reported undiagnosed vitiligo for both unilateral presentation (0.62% [95% CI, 0.45%-0.78%] vs 0.55% [0.38%-0.71%]; P = .55) and bilateral presentation (11.46% [95% CI, 9.05%-13.87%] vs 7.68% [95% CI, 5.59%-9.77%]; P = 0.04). Lastly, FST distribution was similar among participants with self-reported diagnosed and self-reported undiagnosed vitiligo, with the most common being FST III (self-reported diagnosed, 123 [39.2%] vs self-reported undiagnosed, 96 [38.6%]), followed by FST IV (self-reported diagnosed, 91 [29.0%] vs self-reported undiagnosed, 74 [29.7%]) and FST II (self-reported diagnosed, 73 [23.2%] vs self-reported undiagnosed, 60 [24.1%]) (P = .44; Table 2).

The self-reported point prevalence of vitiligo was 1.38% (95% CI, 1.26%-1.49%), of which 0.77% (95% CI, 0.68%-0.85%) was for nonsegmental vitiligo (self-reported as bilateral) and 0.61% (95% CI, 0.53%-0.69%) was for segmental vitiligo (self-reported as unilateral) (Table 3). Following clinician adjudication of the 113 participants who agreed to participate in the expert dermatologist review of their lesions and uploaded photographs (71 self-reported diagnosed vitiligo and 42 self-reported undiagnosed vitiligo), the base case scenario point prevalence of vitiligo was 0.76% (95% CI, 0.68%-0.84%), of which 0.58% (95% CI, 0.49%-0.66%) was for nonsegmental vitiligo and 0.18% (95% CI, 0.15%-0.21%) was for segmental vitiligo. There was moderate agreement among the 3 expert dermatologists (κ = 0.52; P < .001).

Among diagnosed vitiligo, the self-reported point prevalence was 0.77% (95% CI, 0.68%-0.85%), of which 0.48% (95% CI, 0.41%-0.55%) was for nonsegmental vitiligo (self-reported as bilateral) and 0.28% (95% CI, 0.23%-0.33%) was for segmental vitiligo (self-reported as unilateral). Following clinician adjudication, the point prevalence was 0.46% (95% CI, 0.39%-0.52%), of which 0.37% (95% CI, 0.30%-0.43%) was for nonsegmental vitiligo and 0.09% (95% CI, 0.07%-0.11%) was for segmental vitiligo (Table 3).

Lastly, among undiagnosed vitiligo, the self-reported point prevalence was 0.61% (95% CI, 0.54%-0.69%), of which 0.29% (95% CI, 0.23%-0.34%) was for nonsegmental vitiligo (self-reported as bilateral) and 0.33% (95% CI, 0.27%-0.38%) was for segmental vitiligo (self-reported as unilateral). Following clinician adjudication, the point prevalence was 0.29% (95% CI, 0.24%-0.34%), of which 0.21% (95% CI, 0.15%-0.26%) was for nonsegmental vitiligo and 0.08% (95% CI, 0.06%-0.11%) was for segmental vitiligo (Table 3).

After the sensitivity analyses, the clinician-adjudicated prevalence remained unchanged when indeterminate diagnoses were reclassified as nonvitiligo diagnoses (lower-bound scenario) and increased when indeterminate diagnoses were reclassified as vitiligo diagnoses (upper-bound scenario) to 1.11% (from 0.76%) overall, 0.61% (from 0.46%) for diagnosed vitiligo, and 0.50% (from 0.29%) for undiagnosed vitiligo (Table 3).

In this large population-based study of more than 40 000 adults, representative of the 2017 US general population national estimates, we found that the estimated point prevalence of vitiligo was 0.76% based on clinician adjudication and 1.38% based on self-report. These results support generalizability because we performed targeted sampling of participants that represents the 2017 US population estimates by age, gender, race, region, and household income level. Additionally, the use of raking analytic methods to further weight the sample to 2020 US population estimates when determining the point prevalence supports the generalizability of the prevalence estimates.

The estimates of point prevalence of diagnosed vitiligo were 0.46% (clinician-adjudicated base case) and 0.77% (self-reported) and fell within the range of previously published estimates of diagnosed vitiligo in the US. Specifically, 1 large, general population study in the US, conducted 4 decades ago, estimated the prevalence of diagnosed vitiligo at 0.49%.^6,8 Additionally, a large database study estimated the prevalence of diagnosed vitiligo at 0.50%.⁷ Other studies on the prevalence in the US only focused on regional US communities (eg, control patients from a case-control study of juvenile rheumatoid arthritis [prevalence estimate of 0.40%] and Arab Americans [prevalence estimate of 1.55%]).^10,11 Lastly, a large administrative claims database study reported a prevalence estimate of 0.05%, which is inherently reliant on the clinician recording the diagnosis in a claim for reimbursement and, thus, is likely to underestimate the true prevalence.¹²

The estimates of point prevalence of undiagnosed vitiligo were 0.29% (clinician-adjudicated) and 0.61% (self-reported). These findings suggest that up to 40% of adults with vitiligo in the US may be undiagnosed. We found that among participants with undiagnosed vitiligo compared with participants with diagnosed vitiligo, there was a higher proportion who were non-White (40.2% vs 31.5%) or of Hispanic, Latino, or Spanish origin (21.3% vs 15.3%). Additionally, unilateral presentation of lesions was more common among those with self-reported undiagnosed vitiligo than among participants with diagnosed vitiligo (54.2% vs 37.3%). The estimates of unilateral presentation (ie, segmental vitiligo) among those with diagnosed vitiligo is higher than the 5% to 16% previously reported in those with vitiligo.² To our knowledge, this is the first study to identify these trends in the undiagnosed population.

The present study also estimated the prevalence of segmental and nonsegmental vitiligo for both diagnosed and undiagnosed vitiligo. The distinction between segmental and nonsegmental vitiligo is of prime importance for both patients and physicians when reporting on the prevalence of vitiligo. Indeed, patients are usually concerned by the spreading of the disease and its unpredictable course, which is the hallmark of nonsegmental vitiligo. In fact, these vitiligo forms do not behave in the same manner, and the unpredictable nature of vitiligo is associated with negative emotions in patients.^27,28 Besides, this unpredictable characteristic of nonsegmental vitiligo is of most importance in the therapeutic algorithm of vitiligo.

While this study closely represents the distribution of the US general population with respect to demographic characteristics, there is a potential for selection bias owing to internet accessibility. However, it was estimated by the American Community Survey that the percentage of households in the US with internet access was nearly 90% in 2016.²⁹ Additionally, because the survey data were self-reported by participants and a low percentage of participants with vitiligo uploaded photographs (20.1%), the data may be subject to reporting bias. To mitigate some reporting bias, the survey questions included nonclinical terminology next to any clinical terminology, where appropriate.

Furthermore, vitiligo status was self-reported by participants and not confirmed with in-person evaluation or diagnostic testing. However, vitiligo screening questions were developed based on adaptations of published screening tools and feedback from expert dermatologists in the field. Clinician adjudication of self-reported vitiligo was also undertaken using a teledermatology app. The use of telehealth solutions is evolving in epidemiology research, and while user error and photograph quality cannot be closely controlled, advantages include the ability to scale to a large population study, retain a large sample size owing to ease of use, and standardize data collection and submission.

Clinician adjudication was performed for only 20.1% of participants who uploaded photographs, and assumptions of missing at random cannot be confirmed. Nevertheless, the clinician-adjudicated prevalence estimates of vitiligo in this study, with the inclusion of sensitivity analyses, provide a conservative and reliable estimate of the prevalence of vitiligo in the US population with lower prevalence of clinician-adjudicated vitiligo potentially accounting for bias owing to higher self-reporting. In light of the remarkably high number of participants with undiagnosed vitiligo observed in this study, future studies could potentially explore the development and validation of teledermatology apps that allow for potential diagnosis of vitiligo and encourage undiagnosed patients to seek diagnosis and treatment.

This survey study provides current US population-based prevalence estimates of overall (diagnosed and undiagnosed combined) vitiligo in adults between 0.76% (1.9 million cases in 2020) and 1.11% (2.8 million cases in 2020) and estimates that approximately 40% of adults with vitiligo may be undiagnosed in the US. Importantly, it also provides prevalence estimates for segmental and nonsegmental vitiligo. The high percentage of participants with undiagnosed vitiligo coupled with different rates across racial and ethnic demographic subpopulations should be studied further.

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Article written by Charity Nyawira

Medically reviewed by Amit G. Pandya, M.D., President of the Global Vitiligo Foundation

Vitiligo is a skin condition in which people lose skin pigment and develop patches of lighter skin, called macules. These patches, which can be white, pink, red, or brownish in color, can be widespread or may only affect a small area of the body. Vitiligo is not contagious — no one can get vitiligo through physical contact, sexual activity, or sharing utensils with a person who has the condition.

The effects of vitiligo can have a direct impact on the self-esteem of people who are living with the condition, and can lead to anxiety, depression, and relationship issues. Fortunately, there are ways of coping with the effects of vitiligo on self-esteem.

The Impact of Vitiligo on Self-Esteem

A study on the correlation between vitiligo and self-esteem found that the majority of people with vitiligo deal with low confidence and reduced self-esteem. According to the study, 70 percent of women and 54 percent of men who participated experienced self-esteem issues as a result of their vitiligo. The study also showed that self-esteem was significantly impacted among people who had vitiligo on exposed areas of their bodies. Those with darker complexions have also been shown to struggle more with their vitiligo, as the loss of pigment (depigmentation) is more visible on darker skin.

It can be frustrating to feel different because of vitiligo. As one MyVitiligoTeam member said, “Having vitiligo is a daily mind battlefield/rollercoaster. It can tear you into pieces emotionally. There are times when I feel I’m not normal, especially if the flaws are exposed. This disease can consume a person mentally. I also don’t wear shorts. I love the fall/winter season where you can cover up.”

While coping with these feelings can be challenging, there is hope for people who face emotional distress due to vitiligo. One study found that people with vitiligo were better able to cope with their feelings by participating in cognitive behavioral therapy (CBT), a type of therapy that focuses on addressing thoughts and behaviors that have a negative impact on a person’s well-being. This can significantly affect emotional health, because people with higher self-esteem have been shown to cope better with their vitiligo than those with lower self-esteem.

How Vitiligo Contributes To Low Self-Image

People with vitiligo may deal with poor body image and low self-esteem for a number of reasons. One cause involves the unpredictability of the condition. People with vitiligo may worry about their depigmentation worsening because the progression can be hard to predict. Patches of depigmented skin may remain the same for years, or could progress quickly to cover the entire body. As one member of MyVitiligoTeam said, “I don’t think I can live with myself if this becomes worse. I’m in the very early stages, and I don’t see myself being able to live like this!”

In addition, people with vitiligo may try to hide depigmentation using clothing or makeup to avoid comments or unwanted attention. This may cause stress and impact self-esteem. One study found that some people with vitiligo report having strong feelings of dissatisfaction with their appearance, even when patches of lighter skin are covered.

Feeling a sense of disempowerment — having no control over the progression of your depigmentation — is another way vitiligo may contribute to a reduction in self-esteem. Vitiligo is one of many chronic skin diseases that currently has no cure. While some drugs and treatment options, such as phototherapy, can help reduce depigmentation, these treatments do not prevent vitiligo from progressing.

Emotional Impact of Vitiligo on Children and Adults

Both children and adults can face emotional distress as a result of vitiligo. In particular, teenagers between the ages of 15 and 17 were reported to be the most self-conscious about their vitiligo among all pediatric age groups.

Children may face unique challenges, including strained peer relationships, reduced socialization, and social issues that may carry into adulthood. One of the biggest contributors to reduced self-esteem can be a misunderstanding of the condition.

Dr. Lisa Schuster, a licensed pediatric psychologist with the REACH Clinic at Children’s Medical Center in Dallas, Texas, explained that providing basic information about vitiligo will help children and others understand and dispel misunderstandings about the condition. “I think it is important for other children to understand the fact that this is not an infectious disease, because we want them to know that they can have close physical proximity with a child who has vitiligo and it won’t rub off on them,” she said.

Mood Disorders, Low Self-Esteem, and Vitiligo

People with vitiligo may experience psychological stress related to their condition, including depression and social anxiety. One member of MyVitiligoTeam wrote, “Having vitiligo can be very depressing. It has affected me a lot. Mostly when going out, people just look at you or don’t want any skin contact with you. It’s hard being in public.”

Another member described challenges involving covering up their vitiligo: “I have to use lots of makeup on my face to go to work. I start at 11:30 am. I have to start getting ready two hours early just to do my makeup. I’m 49 years old. I never used makeup. Sometimes I feel OK. Other times I feel like I’m wearing a mask.”

Depression and Vitiligo in Children and Adults

Depression affects both children and adults. Even parents and relatives of children with vitiligo may experience anxiety and depression.

Recognizing the signs of depression and other mental health issues is the first step to finding the right treatment and support. Dr. Schuster pointed out some patterns that may suggest a child is depressed:

• Significant changes in mood, including a depressed or irritable mood
• Sudden withdrawal from family and social activities
• Poor sleeping habits
• Changes in appetite
• Self-deprecating comments, such as “I’m worthless”
• Saying they are depressed

Signs of depression in adults may also include hopelessness, suicidal thoughts, losing interest, sadness, self-accusation, and suicidal ideation, among others. Signs of anxiety may include irritability, fear, stress, inability to relax, restlessness, and worry.

Treatment for Depression and Anxiety in Vitiligo

While depression and anxiety can be challenging to live with, these conditions may be treated in a number of ways. Some approaches to improving depression and anxiety in both children and adults with vitiligo include:

• Therapy — Psychotherapy can be an effective way to manage depression and anxiety. Specific types of therapy include CBT and acceptance and commitment therapy (ACT).
• Medication — Several medication options can be used to treat depression and anxiety, including antidepressants and anxiolytics, respectively.
• Proactive management — Working with a mental health professional can help you detect the early signs of anxiety and depression, and prevent progression.

How Parents Can Support Children and Teens With Vitiligo

There are many ways for parents of children with vitiligo to provide support, Dr. Schuster said. Parents must first deal with their own reactions so they don’t pass on stress to their children. “For example, if you are worried or upset, your children will feel upset too,” she said.

Parents should also explain vitiligo to children in such a way that it doesn’t frighten them or cause unnecessary anxiety, she noted. Parents should aim to “increase their comfort with what is going on,” Dr. Schuster advised. Rather than just telling children not to feel embarrassed, parents should allow children to talk about their feelings — if they want to.

When children with vitiligo are entering new environments or interacting with new people, parents should proactively educate the people who will be around their children. Educating others about vitiligo can help avoid social stigmatization and allow children to fit in more easily, Dr. Schuster explained.

Listening to your child and following their lead is crucial in helping them cope. Some children, for example, are not interested in treatment. Instead of continuing to push or pressure them to seek treatment, Dr. Schuster advised parents to allow their children to have a say in whether or not they would like treatment — and, if so, when.

Finding Self-Worth To Improve Self-Esteem With Vitiligo

There are many ways in which adults, teens, and children with vitiligo can help improve their self-esteem. Please realize that your self-worth is not tied to what your skin looks like. Try to find someone or something that brings you joy. Stay in the positive zone.

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The 2023 Pigmentary Disorders Exchange Symposium held in Chicago, Illinois, from May 5th to May 6th, covered numerous hot topics in managing pigmentary disorders. Hosted by conference co-chairs Pearl Grimes, MD, and Jill Waibel, MD, faculty members met for the 2-day conference to discuss the pathogenesis of vitiligo, hyperpigmentation, medical and surgical treatments for vitiligo, cosmeceuticals for photodamage, and more.

Iltefat Hamzavi, MD, spoke with Dermatology Times® to review key highlights of his session, “Vitiligo Surgical Treatment Advances,” including punch graft techniques and non-cultured epidermis suspension.

Hamzavi: I’m Iltefat Hamzavi from Henry Ford Hospital, Hamzavi Dermatology, and Dermatology Specialists, and a dermatologist in the Detroit area. And we’ll get jump into some of the points of the talk today. So, I had the good fortune of joining as inaugural faculty with Pearl Grimes and the rest of the group to look at vitiligo surgery. So, we had a session on hypo and depigmentation, and I was charged with the responsibility of talking about vitiligo surgery. So, at the meeting, we talked about the role of the immune system on causing vitiligo. But the melanocytes also are an area of destruction and dysfunction. And so in order to really repigment individuals, you have to manage the immune system, but then you have to create the milieu for the melanocytes to come back into the skin. Sometimes melanocytes just don’t want to come back in there.So there’s a role for vitiligo surgery. Vitiligo surgery can provide rates of repigmentation you can almost never get with phototherapy, topical agents or systemic agents. But if you don’t manage the immune system, the transplant procedure will not work. And we covered a variety of different transplant options. There is the traditional punch grafting where you take a larger punch, then you take another punch of the recipient site that’s smaller, and you place a larger punch in that area. That can give you good results for smaller areas. Talked about blister grafting where you create a blister and transplant the blister on the recipient side. We talked about split-thickness skin grafting, which is basically what sounds like, when you take a split-thickness graft, you dermabrade the vitiligo area and place it on top.

We spent most of our time talking about non cultured epidermal suspension technique also known as MKTP, melanocyte keratinocyte transplant procedure. These non-cultured epidermal suspension techniques have become the preferred technique for many of us. It allows you to treat a larger area with a smaller donor area. And so if you’ve managed the immune system, or you have segmental vitiligo, you can often use that. So as many of the attendees knew, we categorized the ideal surgical patient as somebody whose immune system is stable, their vitiligo is not progressing. And within that group, there’s 2 subgroups. There’s the segmental vitiligo where it only covers one segment of their body, and there’s nonsegmental, vitiligo. Nonsegmental vitiligo often has an immune activity, it’s active, but it goes through active and quiescent phases, versus segmental often is burnt out. Segmental patients tend to have a better response than nonsegmental, partly because the immunomodulation that’s occurring in the skin. And so with both of these types of subgroups, if you pick the right patient and location, you can have some dramatic results. And we talked about the rates of the repigmentation, they approached anywhere from 71% to 92% repigmentation in segmental vitiligo, and around 54% to 60% for nonsegmental. And that pigmentation tends to hold over 2 years based on some studies that have been presented, and again in this systematic reviews, it showed that split-thickness skin grafts and non-cultured epidermis suspensions were the most successful techniques. But our data is still generating, it doesn’t have the same robust nature as the pharmaceutical trials.

The ideal treatment also involves an awareness of where you can treat. So generally we want to treat 40 to 100 square centimeter locations, we would like to use an appropriate dressing process. And then you also have to have a nursing team. The nursing team’s role is to help you obtain the graft where you often from the hip, you process that tissue with the non-cultured epidermis suspension technique and the MKTP technique by heating it in an incubator and stripping off the collagen and dermal cells. And then you will continue to process that until the point where you are able to scrape the dermal components from the epidermal cells and you end up with a mix of keratinocytes and melanocytes. You spin those cells down and we suspend them in a solution and you convert that solid graft into a liquid solution. And then you dermabrade or laser abrade the recipient site, let’s say in the face, and you spray that solution over there and then place a collagen dressing or a gauze dressing and over 6 to 7 days, we leave that dressing in place. And we showed pictures of the face, the legs, and arms, having significant degrees of repigmentation.

And then we talked a little bit about adjunct techniques to preserve the level of pigmentation. But there is nothing that we have today for vitiligo that repigments to the degree and the speed that the vitiligo surgery can offer. We finished up by talking about some new commercial options, which are going to FDA review, using kits that will allow this technique to be much more accessible. And we presented an FDA-approved trial, where I believe it’s around 56% of patients had greater than 75% pigment. They’re not able to use a VASI score yet for these areas. But we’re working on that. But the VASI is the primary outcome measure for many of the topical systemic trials. But this measure of degree of repigmentation, more than 56% of people achieved that more than 75% pigmentation rate versus 0% in one arm, and about 12% was given to the other arm. So a great degree of improvement that was sustained with very few side effects ever noted. And we showed pictures of that. The patients served as their own control in these trials. And so this was comparing the area that did not receive treatment compared to treatment area that did receive treatment. So we finished the lecture summarizing the appropriate candidates, we talked about the appropriate expectations of the degree response. We talked about what patients to avoid, we talked about the upcoming new research. And we talked about how to continue to maintain the immunostability of the patient so that you don’t get a recurrence of vitiligo after you do the surgery. And hopefully at the end of it, the audience was able to at least have an understanding of vitiligo surgery. And then hopefully, over time, develop the techniques we can apply that to that patient whose immune systems is managed, they just cannot repigment them.

Dermatology Times: What are a few highlights from the 2023 Pigmentary Disorders Exchange Symposium?

Hamzavi: I’m just so excited that we are able to actually have a conference on pigmentation. So there are some excellent talks on dermal pigmentation done by Dr. Heather Woolery Lloyd, and she talked about the different classifications and different agents that we can use. She talked about oral agents that might trigger pigmentation. This is very disfiguring pigmentation that can occur. We had some great talks on melasma options and treatment of hyperpigmentation with Dr. Andrew Alexis. And he gave us an extensive summary of treatment options and other from the therapeutic ladder of photoprotection, topical intervention, systemic interventions and procedural based interventions. And then we also had some great lectures by Dr. Berson, and she spoke about the numerous agents that help manage hyperpigmentation and where they might be useful. And Pearl Grimes also gave a very, very strong overview of these pigmentary options across the different disease states. And those are the portions that I was able to attend. But really an in-depth conference. If you really want to improve your ability to treat hyperpigmentation and depigmentation, I haven’t seen a conference like this.

[Transcript edited for clarity]

Image Credit: Envato Elements

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Pandya gives an in-depth overview of his vitiligo treatment pearls from the 2023 Pigmentary Disorders Exchange Symposium.

Vitiligo is a chronic skin disease that affects millions of people worldwide. It is characterized by the loss of pigment in the skin, resulting in white patches that can appear anywhere on the body. While the cause of vitiligo is not fully understood, it is believed to be an autoimmune disorder in which the body’s immune system attacks and destroys the melanocytes, the cells that produce skin pigment. Vitiligo affects about 1% of the world’s population, and there is currently no cure for the disease. However, there are several treatments available that can help control the spread of vitiligo and improve the appearance of the skin. Vitiligo can cause significant psychological distress and social stigma, especially in people with darker skin tones as it is more visible.

Historical Perspectives on Vitiligo Treatments:

Ancient texts from Egypt, India, and China describe various treatments for vitiligo, including the use of herbal remedies, sunlight exposure, and topical preparations made from animal products.

The earliest recorded treatments for vitiligo date back to ancient times. In ancient Egypt, for example, people with vitiligo were treated with a mixture of tar, honey, and oil. In India, vitiligo was treated with a combination of herbs, including psoralea corylifolia, which was believed to stimulate melanin production in the skin. In Ancient Greece, the physician Hippocrates recommended a mixture of ashes, wine, and honey to treat vitiligo.

However, it was not until the 20th century that more effective treatments for vitiligo were developed. In the early 1900s, doctors began experimenting with various topical treatments, such as corticosteroids and topical immunomodulators. In the 1950s, PUVA therapy was developed, which involves exposing the skin to a combination of psoralen and UVA light. This treatment can stimulate melanin production in the skin and is still used today. Other treatments for vitiligo included topical corticosteroids, topical calcineurin inhibitors, and phototherapy.

In the 1980s, a surgical procedure known as skin grafting was developed, which involves taking healthy skin cells from one part of the body and transplanting them to the affected area. This procedure can be effective but is expensive and can be associated with significant scarring.

In recent years, several new treatments for vitiligo have emerged, including targeted phototherapy, excimer laser therapy, and surgical treatments such as skin grafting and melanocyte transplantation. In 2019, the FDA approved a new treatment for vitiligo called Opzelura (ruxolitinib cream), which is a topical cream that works by inhibiting the Janus kinase (JAK) signalling pathway, a key pathway involved in the development of vitiligo. Opzelura was approved based on the results of two phase 3 clinical trials involving more than 500 patients with vitiligo. Read more about that here.

Opzelura is the first FDA-approved treatment specifically for non-segmental vitiligo, and it is also approved for use in the European Union. In clinical trials, Opzelura was shown to be effective in reducing the size and severity of vitiligo lesions, and it was well-tolerated by patients. However, like all medications, Opzelura may cause side effects, including skin irritation, itching, and redness.

While Opzelura represents a significant advance in the treatment of non-segmental vitiligo, it is not a cure for the disease. Vitiligo is a complex disease, and it is likely that a combination of treatments will be needed to effectively manage the spread of the disease. However, the approval of Opzelura is a promising development for people with vitiligo, and it is likely to be an important treatment option for many years to come.

 

Diverse Perspectives on Vitiligo Treatments:

Many people with vitiligo have tried multiple treatments with varying degrees of success. Some people report significant improvement with topical treatments, while others find them ineffective. PUVA therapy can be effective in some people, but it can also cause side effects, such as skin irritation and increased risk of skin cancer.

Many people with vitiligo also turn to alternative treatments, such as herbal remedies and dietary supplements. While some of these treatments may have anecdotal evidence of effectiveness, there is a lack of scientific evidence to support their use.

Vitiligo is a complex disease that can be challenging to manage. While there have been significant advances in the treatment of vitiligo over the years, there is still no cure for the disease. It is essential to consider diverse perspectives when evaluating the effectiveness of different treatments. What works for one person may not work for another, and it is important to work with a healthcare professional to find the most effective treatment for your individual needs.

Vitiligo is a depigmentation disorder of the skin that occurs secondary to the destruction of melanocytes by an immune-mediated process. Vitiligo can be associated with various autoimmune diseases such as hypothyroidism, pernicious anemia, alopecia areata, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), among others.^1, 2 Vitiligo clinically presents with depigmented macules and patches, most commonly on the face, acral sites, and genitalia. It can be characterized as generalized or localized based on distribution. The localized form can be further divided into segmental (linear, band-like, or Blaschkoid) and non-segmental vitiligo.¹ The diagnosis of vitiligo is made clinically, and examination with Wood’s Lamp shows “milky-white fluorescence” of the depigmented patches.¹ This helps differentiate vitiligo from conditions with hypopigmentation rather than depigmentation such as pityriasis alba. The classical treatment of vitiligo includes topical steroids, pulsed oral steroids in unstable vitiligo, phototherapy, a combination of steroid therapy and phototherapy, surgical grafting, as well as intentional depigmentation therapy in severe cases.^1, 3–8 However, recent advances in understanding the immune mechanisms implicated in the pathogenesis of vitiligo have led to the use of an FDA-approved topical Janus kinase (JAK) inhibitors for vitiligo.⁹ JAK inhibitors are small molecules that disrupt the JAK–STAT (Signal Transducer and Activator of Transcription) signaling pathways, leading to inhibition of immune-mediated inflammatory pathways.^4, 8–10In March of 2022, Opzelura™ (ruxolitinib), a topical JAK inhibitor was approved by the FDA for the treatment of non-segmental vitiligo in patients 12 and older.⁹ In the largest clinical trial for this medication, a total of 674 patients with non-segmental vitiligo were enrolled in phase 3 clinical trials of TRuE-V1 and TRuE-V2, (ClinicalTrials.gov Identifier: NCT04052425 and NCT04057573).⁹ Ruxolitinib therapy showed 75% improvement in Total Vitiligo Area Scoring Index (T-VASI) at 24 weeks posttreatment.⁹ Topical ruxolitinib addresses melanocyte dysfunction through inhibiting cytokines which lead to immune-mediated destruction of melanocytes by T cells.⁹ The safety profile of topical ruxolitinib has been studied in these trials and has been shown to have fewer adverse effects than the systemic route of administration.^8, 9 Patients with oral JAK inhibitors are at risk of developing serious bacterial, fungal, and viral infections that may result in hospitalization or death.⁴Despite this novel therapy advancement, we recommend the addition of narrowband ultraviolet B (NB-UVB) to JAK inhibitors in patients with extensive and progressive lesions, or those not fully responsive to JAK inhibitor monotherapy. In Opzelura clinical trials, 25% of patients did not respond to treatment.¹⁰ Subsequently, in the study by Leu et al, treatment with topical tofacitinib led only to re-pigmentation when there was concomitant light exposure.⁴ Topical JAK inhibitor monotherapy might not be an appropriate choice for extensive (>5%–10% of BSA) progressive non-segmental vitiligo, therefore we recommend the addition of an optimized aggressive NB-UVB regimen to topical ruxolitinib due to its paucity of side effects.³ In NB-UVB devices, the starting safe dose (200 mJ) 2–3 times per week can be increased by a 10%–20% dose increment to achieve light pink erythema or development of skin burning, sensitivity, peeling, or thickening.⁵ Furthermore, the 308-nm excimer laser therapy can be considered for smaller lesions.⁷ There have been several studies that have investigated the use of JAK inhibitors with various adjunctive therapy, including NB-UVB and excimer laser (Table 1).⁸ The maximum dose depends on Fitzpatrick’s skin phototype, photosensitive, and lesion location.⁶ After stabilization of progression and distribution of vitiligo through NB-UVB and topical ruxolitinib combination therapy, maintenance of regimentation may be achieved with JAK inhibitor monotherapy.

TABLE 1. Vitiligo treatment modalities with JAK inhibitors and various adjunctive therapy options in different studies

Investigator	Number Of subjucts	JAK inhibitor dosage and frequency	Study duration	Adjunct therapy	Outcome	Adverse events
Rothstein et al (2017)	11	Ruxolitinib 1.5% cream BID	20 weeks	None	Face: 76% VASI improvement Non-acral upper extremity: 3.6% VASI improvement Lower extremity/trunk (undefined): 0% VASI improvement	Erythema Peripheral hyperpigmentation Transient acne
Rothstein et al (2017)	8	Ruxolitinib 1.5% cream BID	32-week extension (52 weeks total)	NB-UVB	Face: 92% VASI improvement Non-acral upper extremity: 12.6% VASI improvement Trunk: 16.7% VASI improvement	Erythema Transient acne
McKesey et al (2019)	11	Tofacitinib 2% cream BID	8–16 weeks	NB-UVB 3 times weekly	70% VASI improvement	N/A
Rosmarin et al (2020)	1	Tofacitinib 2% cream BID	24 weeks	NB-UVB (3 times weekly, home unit)	Face:100 repigmentation	None
Ferreira et al (2021)	2	Delgocitinib cream BID	36 weeks	NB-UVB (3 times weekly)	Face: Significant repigmentation,	Erythema Transient acne

The psychosocial and cosmetic burden from this chronic autoimmune disease can lead to patients’ isolation. The cost and access of this recent FDA-approved topical JAK inhibitor for non-segmental vitiligo can pose a burden on patients to be compliant and receive appropriate treatment. Adjuvant light exposure treatment can overcome these challenges with effective targeted treatment. Topical JAK inhibitors found their place in the treatment of vitiligo after years of investigation. Prospective clinical trials are needed to further assess adjuvant light therapy and the future formulation of topical JAK inhibitors for the treatment of non-segmental rapidly progressive vitiligo.

References

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