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Disease Burden and Management of Vitiligo

Vitiligo is a skin disease characterized by selective loss of melanocytes followed by depigmentation in the affected areas of the skin.1 The disease, which has a complex pathogenesis, can have a serious psychosocial impact on patients.1 Although management of vitiligo is complex, there are safe, effective treatments available and promising emerging therapies.1,2 In a recent AJMC® Peer Exchange™, experts who specialize in treating patients with vitiligo were joined by professionals from the insurance industry to explore the clinical and economic burden of vitiligo, review treatment paradigms and standard-of-care therapies, and discuss unmet needs and future directions in treatment. The session was moderated by Jeffrey D. Dunn, PharmD, MBA, chief clinical officer at Cooperative Benefits Group in Salt Lake City, Utah.

Disease Burden

Vitiligo is a chronic, acquired disease of the skin and mucous membranes that is characterized by sharply demarcated, milky white, depigmented macules and patches, with neat borders and variable dimensions and distribution.3,4 There are 2 forms of the disease: segmental and nonsegmental.1,5 Segmental vitiligo is characterized by unilateral, localized distribution of lesions. It is more common in younger children, and often has rapid onset and stabilization with early hair follicle involvement. Nonsegmental vitiligo is characterized by bilateral distribution of lesions on the body, with progressive onset and multiple flare-ups, later hair follicle involvement, and an unpredictable course.6

Vitiligo has been dismissed as a cosmetic disease.7 However, patients may experience a severe impact on quality of life because the disorder can be psychologically devastating.3,7-9 Vitiligo lesions, which typically occur in exposed areas of the skin such as the hands and face, are often mistaken for an infectious disease, which contributes to the stigma experienced by patients.1,3,7-9 Furthermore, the lesions may have a strong negative impact on patients’ self-esteem and perception of self,3 and patients may experience psychological problems such as depression, anxiety, and shame, which can result in social isolation.1,7 In fact, recent systematic reviews of the available evidence for the psychosocial burden in vitiligo found that depression and anxiety were the most commonly reported psychological disorders; feelings of stigmatization, adjustment disorders, sleep disturbance, relationship difficulties such as sexual dysfunction, and avoidance or restriction behavior were the most prevalent psychosocial comorbidities; female sex, visible or genital lesions, age younger than 30 years (particularly adolescents), and greater body surface area involvement were factors associated with a significantly higher psychosocial burden; and lesion concealment was the most common coping strategy.9,10 Importantly, most interventions significantly improved quality of life for patients.10 Therefore, it is important to assess quality of life during consultations and refer patients to psychological help, if needed.1,3,9

Finally, vitiligo carries a significant economic burden as management of the disease is associated with high direct and indirect costs.7 Costs include those for prescription and OTC medications, medical office visits, phototherapy, lost workdays, public avoidance, and impaired quality of life.11 Because patients with insurance are more likely to receive treatment, it is important that payers understand that early treatment of vitiligo lesions has better results, as well as benefits via early detection of associated autoimmune diseases.7,12

Epidemiology and Pathogenesis

The average age of onset follows a bimodal pattern, with early onset at a mean of 7.3 years and late onset at a mean of 40.5 years; the overall mean (SD) age of onset is 31.8 (20.2) years.13,14 Although vitiligo can occur in individuals of all genetic backgrounds, the prevalence varies widely across geographic areas, ranging from a low of 0.06% to a high of 2.28%.1,15 In the United States, the prevalence of vitiligo varies between 0.76% based on clinician adjudication and 1.38% based on self-report.16 The incidence and prevalence of segmental vitiligo is not well established1; however, it is less common than nonsegmental vitiligo and affects between 5% and 16% of patients.17,18

Vitiligo has a complex multifactorial pathogenesis.4 However, the exact mechanisms that integrate the genetic susceptibility of each individual with melanocyte auto-aggression and failure of immune tolerance mechanisms are not fully elucidated.19 The most common theory for the pathogenesis of vitiligo is that a convergence of immunological and nonimmunological factors ultimately leads to the development of the disease. Patients with a background of genetic susceptibility and intrinsic skin abnormalities are more susceptible to oxidative stress damage, which triggers the release of various factors that activate the immune system and lead to melanocyte loss.4

There is strong evidence for the importance of genetic factors in the development of vitiligo; however, these influences are complex and the genetic risk is not absolute.1 The disease tends to aggregate in families, as approximately 20% of patients have at least 1 first-degree relative with vitiligo, and the relative risk of vitiligo for first-degree relatives is increased.20 However, monozygotic twins have only a 23% concordance rate, highlighting the importance of additional stochastic or environmental factors in the development of the disease.21 There are nearly 50 different genetic loci that confer a vitiligo risk, with relevant genes involved in the innate and adaptive immune system, melanogenesis, and apoptosis. Furthermore, several of these genes are associated with other pigmentary and autoinflammatory disorders, as well as autoimmune disorders such as thyroid disease, type 1 diabetes, and rheumatoid arthritis.22

Intrinsic alterations in the skin of patients with vitiligo include a thicker epidermis with a reduced number of basal melanocytes and the presence of degenerated keratinocytes with swollen mitochondria, increased levels of reactive oxygen species (ROS), and reduced E-cadherin expression. The melanocytes have a senescent phenotype with high intracellular ROS levels, reduced antioxidant activity, abnormalities in mitochondrial function, and release of senescence-associated proteins. The fibroblasts have a myofibroblast phenotype, increased intracellular ROS, and mediators that contribute to the downregulation of E-cadherin. Finally, there is a decrease in microbial diversity, possibly due to the altered microenvironment of the skin.4

In this background of intrinsic skin alterations together with genetic susceptibility, additional environmental stress causes widespread alterations in the antioxidant system.1 Oxidative stress leads to the secretion of interferon-γ (IFN-γ) by natural killer (NK) cells and innate lymphoid cells (ILCs).4 The increase in IFN-γ levels has several effects, starting with the release of CXCL9 and CXCL10, which recruit CD8+ T cells, and MMP9, which contributes to the detachment of melanocytes from the basal layer, from damaged keratinocytes. Damaged melanocytes release damage-associated molecular patterns, heat shock protein 70, and HMGB1, which further activates NK cells and ILCs, acting as a positive feedback loop, and activates dendritic cells, further potentiating the development of a specific immune response through the activation of autoreactive CD8+ T cells. Following this autoimmune reaction, a portion of T cells remains in the skin as resident memory T cells (TRM), which may be responsible for the recurrence of vitiligo following repigmentation.1,4

Diagnosis and Assessment

The diagnosis of vitiligo is generally straightforward and made clinically based on appearance of the characteristic lesions. It usually does not require confirmatory laboratory tests, and a skin biopsy is only used to exclude other disorders. The diagnosis may be facilitated by use of a handheld UV irradiation device that emits UVA, commonly referred to as a Wood lamp. Under the Wood lamp, the vitiligo lesions emit a bright blue-white fluorescence and appear sharply demarcated, which helps identify focal melanocyte loss and detect areas of depigmentation that may not be visible to the eye.3,6,23

Physicians should reserve enough time for a careful initial assessment of a patient with vitiligo. The evaluation entails a detailed history and complete skin examination to assess disease severity and individual prognostic factors. An assessment form created by the Vitiligo European Task Force summarizes the personal and family history elements of the clinical examination items and may be useful for evaluation. It is important to routinely ask patients about family history of vitiligo and premature hair graying and about personal and family history of thyroid disease or other autoimmune diseases. Aspects that should be assessed include the skin phototype, disease duration, extent, activity, rate of progression or spread of lesions, presence of the Koebner phenomenon, presence of halo nevi, previous treatments (including their type, duration, and effectiveness), previous episodes of repigmentation, and occupational history/exposure to chemicals.6

Finally, the quality of life of patients with vitiligo should be assessed regularly. Assessment tools used in the research setting include the Short Form-12, the Dermatology Life Quality Index, the Vitiligo Impact Scale, the Vitiligo-Specific Health-Related Quality of Life Instrument, and the Vitiligo Impact Patient Scale.1 All patients with vitiligo should be offered psychological support and counseling.23

Stakeholder Insights

More than 1 million individuals in the United States have vitiligo. However, “it is very hard to know the exact incidence and prevalence of vitiligo in the population,” said David Rosmarin, MD, vice chair of education and research at Tufts Medical Center in Boston, Massachusetts. This is because many patients do not seek care for their disease. They may not be aware of it or may have received a misdiagnosis. Therefore, some patients may be missed when the incidence and prevalence are calculated. The reason for the reported differences in incidence is not well understood, as vitiligo can affect any individual. However, “how it affects somebody in terms of their quality of life may vary greatly depending on the culture and some of the subgroups,” Rosmarin said. He underscored that it is the burden on mental health that clinicians are particularly concerned about when it comes to vitiligo. Although some individuals adapt to their disease, perhaps because it is less noticeable on fair skin or because they are older, others find that it has a significant impact on their quality of life.

Brett King, MD, PhD, associate professor of dermatology at Yale School of Medicine in New Haven, Connecticut, emphasized the social impact of the disease. “Imagine having white spots all over [your] face or having white spots just surrounding your eyes, having big raccoon eyes, having white spots all over your arms and your hands,” he said. Other individuals may react negatively to these lesions, thinking they are infectious, and avoid touching them. In other words, vitiligo is associated with stigma. Therefore, patients can find day-to-day life challenging. There are data showing the impact that the disease has on work productivity, life decisions, and quality of life.

In terms of the economic burden of vitiligo, David Epstein, MD, MBA, an independent consultant, shared that from the payer perspective, this is not being tracked because most medications are not expensive. Dunn agreed and said that the challenge, from the payer perspective, will be how to manage the direct costs once new treatments are approved. But from the perspective of the patient, there certainly is an economic impact associated with the treatment, Rosmarin said, especially with phototherapy sessions, which may require patients to miss work.

The fact that vitiligo is an autoimmune disease was emphasized by Rosmarin and King. A further clinical clue about the autoimmune nature of vitiligo is the fact that it is sometimes associated with autoimmune thyroid disease, King said. The autoimmune nature of vitiligo also points to the other causative aspect of the disease, which is the genetic predisposition that is probably present in all patients. This genetic predisposition is likely what explains the well-documented association between autoimmune thyroid disease and vitiligo, which is also seen in patients with other autoimmune skin diseases. Finally, although emerging data suggest there is systemic inflammation in vitiligo, it is not clear whether patients are predisposed to any other internal organ disease, King said.

Although several tools are used in the research setting to assess quality of life of patients with vitiligo, there are no standardized tools used in clinical practice, Rosmarin said. Clinicians typically ask questions, such as whether patients have switched to different clothing or changed their going-out habits or whether they feel people are staring at them, to determine how the disease is affecting patients. Furthermore, Rosmarin wished there were better tools to assess quality of life of patients with vitiligo in the research setting as well.

Management of Vitiligo

Several guidelines have been published for the treatment of patients with vitiligo.23-26 As most of the therapeutic options are time-consuming and require long-term follow-up, management of vitiligo requires a personalized treatment approach that considers the preferences of the patient. The choice of treatment depends on factors including the subtype of vitiligo, as well as the extent, distribution, and activity of the disease. The patient’s age, phototype, effect on quality of life, and motivation for treatment also play a role in the decision-making process.1

The areas that have the best response to treatment are the face, neck, trunk, and midextremities, whereas the lips and distal extremities are more resistant. The repigmentation starts at the periphery of the lesions in a perifollicular pattern, and at least 2 to 3 months of continued treatment is necessary to determine efficacy for the individual patient.1

Commonly used treatments for vitiligo are topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). TCSs can be used for patients with limited lesions that are not on the face. The first choice should be a less potent TCS, and treatment should be no longer than 3 months if administered daily, or 6 months if following a discontinuous scheme. TCIs are as effective as TCSs on facial lesions and have less severe adverse effects.24

UV light–based therapy is associated with an improved outcome when combined with an additional therapy. Phototherapy treatments include narrowband UV-B (NBUVB) and psoralen and UVA (PUVA). NBUVB is indicated for generalized nonsegmental vitiligo, with total body treatments being suggested for lesions involving more than 15% to 20% of the body area, whereas targeted phototherapies are indicated for localized and small lesions.24

The combination of phototherapy and TCS and TCI treatments appears safe and leads to better results. Additionally, phototherapy should be used for 3 to 4 weeks following surgical procedures to enhance repigmentation. There is less evidence for combining phototherapy with antioxidant therapy; however, it might be beneficial. The only therapy for which combination with phototherapy is not recommended is therapy with vitamin D analogues.24

Systemic steroid treatment may also be used in some cases. Patients experiencing rapid disease progression may be treated with systemic oral minipulse steroids, a treatment that consists of twice-a-week corticosteroid administration.24 For patients with more resistant vitiligo, options include surgical grafting as a third-line therapy and depigmenting treatments as a fourth-line therapy.1

Additionally, patients should be offered advice on cosmetic camouflage by a cosmetician or a specialized nurse, as this can be beneficial for patients with vitiligo lesions in exposed areas. Cosmetic camouflage includes foundation-based cosmetics and self-tanning products containing dihydroxyacetone. Patients may also opt to have cosmetic tattoos, especially on the lips and nipples.1,24

Stakeholder Insights

Although there are other agents available, the main 3 therapies used in the front line are TCSs, TCIs, and phototherapy, which can be used alone or in combination, Rosmarin said. Corticosteroids are inexpensive but can be difficult to use for prolonged periods, which are typically needed for repigmentation. Calcineurin inhibitors generally work well for repigmentation of the face. However, as it is a large molecule, it does not work as well on other parts of the body. Phototherapy is also very effective, as it stimulates the melanocytes to migrate back to the lesion and calms the immune system. However, it can be inconvenient for patients to go to the clinic 3 times a week for treatments, especially if they live far away and must miss work.

Treatment goals vary by patient, Rosmarin said. Some patients just want to get a diagnosis and they do not want any treatment. Others experience severe anxiety about spread of the lesions and want to stop progression, which is easier to do than repigmenting. For some patients, the goal is to repigment at least some areas. Finally, the goal can also be repigmentation maintenance, which may be helped by twice-a-week application of a TCI. Vitiligo is a chronic disease with no permanent cure, and new spots may appear at any time. Existing and emerging therapies manage the underlying cause of an overactive immune system but do not cure the disease.

On the other hand, it is possible to achieve remission without continued treatment, King noted, which is not the case for other autoimmune diseases such as psoriasis. Furthermore, once repigmentation has been achieved, it is also likely that patients will be less motivated to continue treatment as diligently, which ends up also being a cost-saving mechanism. King emphasized that it is important for patients, providers, and payers to understand that vitiligo treatment is a monthslong process. There are data indicating that a significant proportion of patients achieves success in 6 months, but others need up to a year.

In terms of insurance coverage, some payers will not cover even the diagnosis of vitiligo, although this is rare. As for treatment, corticosteroids are generally covered and do not require prior authorization, Rosmarin said. However, both Rosmarin and King expressed that coverage for calcineurin inhibitors and phototherapy varies depending on the payer and the plan and is frequently denied.

From the payer perspective, vitiligo is acknowledged as a disease and assessed in a way similar to other diseases, with a focus on the standard of care, Epstein said. Coverage for the management of vitiligo is based on the opinions from experts and key opinion leaders. The main concern of payers at this moment is the potential manipulation of information from the manufacturer side. Dunn concurred with the idea that payers view vitiligo as a disease and not merely a cosmetic problem. Part of the problem, in his view, is that right now most of the therapies used to treat vitiligo are relatively inexpensive, as there are a lot of generic medications available; however, as more expensive options become available, there will be a need to work with providers to determine the best use for these medications. Together, they must determine who are the appropriate patients for the new medications and how to assess whether the new medications are working. Both agreed that there will probably be a need to use payer tools to control costs, such as initial authorization followed by reauthorization after a period, with physician attestation as to progress.

King agreed that it is important to have documentation that patients are getting better with treatment. This is also important from the physician and patient point of view, as neither would normally want to continue a treatment that is not working. He further said that payers and formulary managers will need to be thoughtful about which patients are likely to get better and which are not, and to develop decision trees around those parameters. A key question will be the appropriate amount of time to determine whether a patient is having a meaningful clinical response to treatment; that is, what percentage of skin repigmentation in a set period would be the cutoff for continuing treatment.

Emerging Therapies and Unmet Needs in Vitiligo

There are various agents being tested for the treatment of patients with vitiligo, including calcineurin inhibitors, MC1R agonists, antioxidants, metabolism inhibitors, cytokine inhibitors, and kinase inhibitors.27 The most promising new therapies are the Janus kinase (JAK) inhibitors tofacitinib and ruxolitinib.

Tofacitinib

Oral tofacitinib, a JAK 1/3 inhibitor, demonstrated promising repigmentation results in case studies and a retrospective observational study. The addition of NBUVB therapy seems to improve its efficacy. It is well tolerated in most patients, and adverse events include respiratory tract infections, diarrhea, arthralgia, weight gain, and mild lipid and liver enzyme elevation. In rare cases it can lead to malignancies.2

Ruxolitinib

Ruxolitinib is a JAK 1/2 inhibitor that has been tested in 2 phase 2 clinical trials (NCT02809976 and NCT03099304) and is being evaluated in 3 phase 3 trials (NCT04052425, NCT04057573, and NCT04530344).28 The phase 2 trials’ results showed that ruxolitinib may be a good option for vitiligo management as patients had substantial repigmentation and good dose tolerance.28 Furthermore, results from the phase 3 trials presented at the 2022 American Academy of Dermatology Annual Meeting showed that approximately half the patients treated with ruxolitinib cream achieved at least 75% improvement in the facial lesions at 52 weeks, leading to FDA approval of ruxolitinib cream (Opzelura) in July 2022.29,30

Stakeholder Insights

Dunn explained that, in a setting where there are various options that work, from the payers’ perspective there is a fiduciary responsibility to encourage the use of the most cost-effective therapy first. Therefore, there may be a need for payers to influence the first therapy choice without overstepping their bounds in determining whether a drug works. On the other hand, King said the fact that vitiligo is an autoimmune disease that responds to JAK inhibitors, as do other autoimmune diseases, may also be a factor in the decision algorithm; using the more expensive treatment might lead to less expenditure over the lifetime of the patient. Epstein stressed that payers would be looking at specialists, key opinion leaders, and specialty societies to make these determinations and indicate when these drugs would best be used in the front line. There will need to be collaboration between specialists to determine the best treatment for each patient and minimize burden, King said. On the other hand, Epstein noted that the safety profiles of some of the new agents will also have to be considered.

In terms of managing costs, payers used to focus on disease states. However, that focus has switched dramatically to the drugs, Epstein explained. So, for JAK inhibitors, the focus of payers will not be on the use of this agent in vitiligo but on how to manage the use of JAK inhibitors more broadly. This change is putting pressure on insurance purchasers, which eventually gets passed down to patients through deductibles, coinsurance, and premiums. This is a challenge because patient affordability is likely to become an issue, Dunn said.

Rosmarin and King suggested that the fact that none of these therapies are specifically approved for the treatment of vitiligo is influencing their coverage and that approval of a new agent would change this scenario because they would be significantly less expensive than the new agent. Dunn suggested that a step approach, where patients must try a generic medication before getting approval for a biologic agent, may be a solution. However, Rosmarin cautioned that although a step approach may be reasonable for treatment of facial lesions, which respond well to calcineurin inhibitors, it would not be advisable for other areas such as the hands, which are notoriously challenging to treat. Therefore, the newer agents might be more adequate as first-line therapies for the extremities, genitals, and trunk.

Considering this, it is possible that payers may restrict coverage for the treatment of sensitive areas such as the head, neck, and hands, Epstein said. King agreed that this might make sense; however, he cautioned that these decisions should be driven by data. Physicians will always advocate for the patient to get the treatment, because having vitiligo in any part of the body can be debilitating. However, if the data say a certain treatment works well in one location but not so well in another, then it is reasonable that it should be covered for the locations where it works. Physicians would then have to make the argument if they want to use it for the location where it does not typically work as well.

On the other hand, this approach may be challenging to implement with the introduction of new agents such as ruxolitinib. Ruxolitinib has shown a significant effect in all areas of the body, with a greater effect on the face. This is not surprising, as all therapies work better on the face. If payers cover ruxolitinib treatment only for facial lesions, because that is where it is more effective, then patients would lose access to the best medication available for repigmentation of other areas, Rosmarin explained. However, he agrees that starting with a generic medication before introducing a JAK inhibitor may be the way forward, with the key being that these requirements are data driven.

The greatest unmet need for patients was the lack of an FDA-approved treatment for vitiligo, Rosmarin said. Vitiligo is a difficult disease to treat. Whereas all it takes for the disease to develop is an overactive immune system that destroys the melanocytes, treatment is a 2-step process. The immune system must be regulated so that there is a more hospitable environment for the melanocytes, which then must be coaxed to migrate back to the lesions. Treatment can often facilitate both processes.

JAK inhibitors, especially ruxolitinib, have shown the greatest promise for patients with vitiligo, Rosmarin said. Results from 2 phase 3 trials have shown that after 1 year of treatment with ruxolitinib cream, patients regain 75% or more of pigmentation on the face and 50% or more on the whole body. Furthermore, its safety profile is also promising, and it was approved for the treatment of atopic dermatitis in September 2021. The choice of JAK inhibitors for vitiligo was deliberate, King explained. JAK inhibitors disrupt the signaling pathway that induces the T cells to attack and destroy the melanocytes. Therefore, there are ample data to support the use of JAK inhibitors in vitiligo.

King mentioned the concept behind the REVEAL trial (NCT04338581) that is testing an antibody of IL-15, which is necessary for the survival of TRMs. Targeting IL-15 would dampen or even abolish the survival signal, which could lead to a durable disease remission without ongoing treatment. Although this provocative concept is not ready to be used in practice, it could revolutionize the field if it is safe and effective. Rosmarin added that depending on what the data show, there is a possibility that a combination of therapies including the IL-15 antibody at the end might be the best option for some patients.

In the next 5 years, it is expected that there will be several new agents approved for vitiligo, which will change how the disease is managed and will have implications for all stakeholders. This has already started with the approval of ruxolitinib cream and will probably be followed by oral JAK inhibitors and then other novel agents. Rosmarin concluded by saying, “There is going to be some work to do to decide how these different treatments fit into the paradigm, and we just don’t know that yet, but it’s important to be data driven and follow that pathway so we can make those best decisions for patients.”

Source

Quality of life of adult vitiligo patients using camouflage: A survey in a Chinese vitiligo community

Abstract

 

Background

Vitiligo is an acquired depigmented skin disease resulting in white macules, which may significantly impair the quality of life (QoL) of the patients.

 

Objective

To estimate the QoL in Chinese vitiligo patients using camouflage with a more detailed description, and to identify the possible risk factors related to poor QoL.

 

Methods

An online survey was conducted in vitiligo patients using camouflage from a vitiligo community. Survey questions included demographic, clinical information, dermatology- and vitiligo-specific QoL questionnaires. Multivariate logistic analysis was performed to identify risk factors that related to poor QoL.

 

Results

In total, 884 respondents were included in the analyses, of which 413 (46.7%) were male. The score of DLQI was 5.83±5.75 (mean± SD). Age, gender, marriage status, occupational status, anogenital involvement, patient-perceived severity (presented by VAS score), symptoms as itching, pain, sunburn and koebner phenomenon, total cost of treatment and degree of satisfaction in camouflage therapy were independently associated with DLQI score (p<0.05).

 

Conclusion

Vitiligo has considerable impact on QoL of affected patients in Chinese population even when they were using camouflage. Camouflage might be helpful to improve QoL of the patients.

Introduction

Vitiligo is an acquired chronic depigmenting disorder of the skin, predominantly asymptomatic, manifested by circumscribed depigmented macules and patches due to the disappearance of melanocytes from the epidermis. Vitiligo was recognized in ancient times and is still confused with leprosy in some countries[1]. Numerous studies have revealed that vitiligo has a major effect on the patients’ quality of life (QoL) and negatively affects sexual relations[2].

Cosmetic camouflage is an alternative and complementary option to the traditional standard treatment options, since the effectiveness of the latter are often disappointing with only partial results, and the treatment may last for months or years, before re-pigmentation occur. Preliminary studies have reported that camouflage for patients with vitiligo could improve their quality of life[3,4]. However, all these studies were conducted in small populations, therefore this effect remains to be observed in a larger population. Furthermore, the effect of camouflage on QoL can be significantly influenced by social-psychological factors but has not been studied in Chinese population.

We conducted this study to determine the dermatology-specific QoL in a group of adult vitiligo patients using camouflage in a large Chinese vitiligo community, especially to identify the possible risk factors for poor QoL. We also used a vitiligo-specific QoL questionnaire to illustrate the vitiligo-specific QoL aspects that haven’t been covered by DLQI.

 

Methods

An online survey was conducted from September to December 2016 to assess QoL of adult vitiligo patients using camouflage, and to identify risk factors that related to poor QoL.

 

Recruitment

An online questionnaire was formulated and sent to 8602 consecutive adult patients (age ≥18 years) with vitiligo, in WeChat groups and QQ groups of a vitiligo community, “Leukoplakia Common Home”. Before taking the survey, participants had to sign the online consent form first. Patients who had been using camouflage for more than 1 month were invited. Patients who were younger than 18 years, and who had not been diagnosed by dermatologists were excluded from the study. Information that could identify individual participants was not collected.

The study protocol was approved by the ethics committee of Beijing Tsinghua Changgung Hospital.

 

Measures

 

Demographic and clinical Information.

Demographic and clinical information was collected including gender, age, residential location, marital status, fertility status, educational level, employment status, income, duration of the disease, localizations of vitiligo (e.g. face, neck, scalp, upper arms, forearms, hands, thighs, legs, feet, chest, upper back, waist, axillae, groins, anogenital area), percentage of body surface area (BSA) affected, symptoms, duration of camouflage therapy, degree of satisfaction in camouflage therapy, other previous treatment, and total cost of treatment, as well as visual analogue scale (VAS) to assess the patient-perceived severity.

 

Quality of life.

  We used a dermatology-specific QoL questionnaire, Dermatology Life Quality Index (DLQI) and a vitiligo-specific QoL questionnaire, Vitiligo Impact Scale-22 (VIS-22), to assess the impact of vitiligo. The DLQI contains 10 questions related to patients’ symptoms and feelings, daily activities, leisure, work or school, personal relationships, and treatment over the previous 1 week, and each question has four possible answers scored from 0 to 3. The VIS-22 comprises 22 items covering domains of self-confidence, anxiety, depression, marriage, family worries, social interactions, school/college-related, occupation-related, treatment-related and attitude. Each question has four possible answers scored from 0 to 3. The QoL impairment could be classified into 5 levels according to the total score of DLQI. A DLQI score of 0–1 means no effect at all, 2–5 means a small effect, 6–10 moderate effect, 11–20 large effect, and 21–30 extremely large effect on patient’s life.

 

Statistical analysis

The data was carefully checked for consistency and plausibility to guarantee the quality of data. Normally distributed data were expressed as means±SD, whereas variables with a skewed distribution were reported as median (range). Categorical variables were represented by frequency and percentage. Univariate associations were calculated using Mann-Whitney U test or Kruskal-Wallis test with Bonferroni correction. The outcome variables were the sum score of DLQI. Independent variables were the sociodemographic and clinical characteristics. The independent variables that were univariately associated with the outcome variables (P <0.10) were entered into a stepwise multivariate logistic regression models with dichotomized DLQI (6–30 vs. 0–5) as dependent variable. A value of P < 0.05 was considered significant. All calculations were performed with the statistical package Stata 12.0 (Stata Corp., College Station, Tex.).

 

Results

One thousand nine hundred and twenty four patients had shown a willingness to participate in this study. Of whom 1198 completed the questionnaires. However, 314 were excluded after plausibility checking (Fig 1). Therefore, 884 respondents were included in the final analyses.

Fig 1. Flow diagram of patient enrollment, exclusion, data quality control and data analysis.

(Online completion ensured that there were no missing data in completed questionnaires).

 

https://doi.org/10.1371/journal.pone.0210581.g001

Demographic and clinical characteristics of respondents

The median age of these 884 respondents was 36 years (range 18–83); 413 (46.7%) were male. The visible body areas, such as face, scalp, neck, hands, were affected in most of the patients (n = 829, 93.8%). All but one patient had received previous treatment. The median duration of camouflage therapy was 50 months (range 1–216). The demographic and clinical characteristics were presented in Table 1.

Table 1. Demographic and clinical characteristics of the study group.

Quality of life

 

The DLQI score (mean± SD) was 5.83±5.75 (range 0–30), and 228 (25.8%) patients reported DLQI scores between 0–1, which mean no effect at all; 294 (33.3%) reported small effects; 198 (22.4%), moderate effects; 164 (18.5%), large to extremely large effects. The mean± SD score for the six domains of DLQI were 1.47±1.52 for daily activities, 1.47±1.53 for leisure, 1.25±1.14 for symptoms and feelings, 0.63±1.22 for personal relationship, 0.51±0.88 for work and school, and 0.49±0.79 for treatment. The frequency of the answers to each item of the DLQI and VIS-22 were shown in Fig 2.

Discussion

 

Impact of QoL of vitiligo and the assessment tools

Vitiligo is often perceived as a cosmetic disease, whereas it has a profound and permanent impact on patients’ quality of life (QoL). Numerous studies had revealed the association of stigmatization, distress, depression, anxiety, low self-esteem, social isolation and impact on sexual life with vitiligo[5,6]. DLQI is one of the most widely used dermatology-specific QoL instruments in vitiligo, and the DLQI scores reported by previous studies showed obvious geographical differences, with the highest mean DLQI score of 15.00 reported in a Turkish study[7], followed by two Arab studies (mean score 11.86) [8,9], and ten Indian studies (mean score 9.51)[1016], while the lowest score was 1.82 in one Italian study[17,18]. Therefore, QoL of vitiligo patients is considerably variable according to different skin phototypes and cultures. However, few studies have reported the impact of vitiligo on Chinese patients’ QoL. Although preliminary studies have shown that camouflage can help improving QoL of the patients[3,4], this have never been studied in Chinese patients.

This is the first study to evaluate the impact of vitiligo on Chinese patients who had been using camouflage. To obtain a more comprehensive profile of QoL, we conducted the study in a large vitiligo community using both dermatology-specific and vitiligo-specific QoL instruments.

Since disease-specific instruments could be more sensitive to disease-specific issues, there were four vitiligo-specific Qol instruments had been developed in recent years, including Vitiligo-specific Quality-of-Life instrument (VitiQoL) in the U.S.[19], Vitiligo Impact Patient Scale (VIPs) in France[20], Vitiligo Life Quality Index (VLQI) in Turkey[7], and Vitiligo Impact Scale-22 (VIS-22) in India[13]; and since China and India shared many similarities in culture and belief, we chose the VIS-22 to estimate the vitiligo-specific Qol in our participants. Compared with DLQI, VIS-22 covered the attitude and anxiety about the disease, as well as family worries. Nevertheless, VIS-22 did not have any questions concerned about the symptoms and sexual life.

Impairment of QoL found in Chinese vitiligo patients

Eight hundred and eighty four vitiligo patients who had been using camouflage for more than 1 month were available for final analyses. The mean total score of DLQI was 5.83. There were more than one third of the vitiligo patients experiencing a significant impairment of QoL, as 40.9% of the patients reported a moderate to extremely large QoL impairment assessed with DLQI (score 6–30).

The highest DLQI score was found in ‘daily activities’, followed by ‘leisure’ and ‘symptoms and feelings’. The high scores of VIS-22 added more detailed information of QoL in domains of attitude and anxiety about the disease, such as ‘disease incurable’, ‘worried about new lesions’, ‘the worst disease’, and ‘keep thinking about this disease’; and treatment-related burdens, such as ‘difficulties in adhering to treatment’, ‘the amount of money spent on treatment’; then ‘problems in getting married’ and the feelings of ‘embarrassment’ and ‘helpless’, while there were only small impacts on work/school life or personal relationship.

Risk factors related to QoL

The impact of vitiligo on QoL varies in patients with different clinical and demographic characteristics. In the majority of previous studies, women showed more QoL impairment than men did[18], as did young patients compared to elderly ones[10], married women with vitiligo than singles[21], and patients with involvement on exposed sites than those on unexposed sites[18,2224]. Our results showed that female patients, patients aged less than 30 y/o, patients who were single and without a committed relationship (compared with who were married), patients who were working or seeking work (compared with who retired), patients with anogenital involvement, patients who experienced pruritus or pain, with symptoms as sunburn or koebner phenomenon, and patients who had spent more than 10,000RMB (vs. <10,000 RMB) on treatment had more impaired QoL. Intriguingly, the presence of vitiligo on visible sites, such as face, neck, scalp was not associated with a poor dermatology-specific QoL, which was inconsistent with the previous studies. Several studies showed that patients had higher scores of QoL when having lesions on visible sites[22,23,25,26]. Nevertheless, there were also several studies did not find any relationship between DLQI score and visibility of lesions[6,10,27]. In our study, since most of participants had visible sites involvement (n = 829, 93.8%), the sample size of those without visible sites involvement may be too small (n = 55, 6.2%) to reach statistical significance. Meanwhile, all of our participants had been using camouflage for more than 1 month. QoL has been shown to be improved in vitiligo patients who had lesions on visible sites after use of camouflage[3,4]. Therefore, we supposed that the effectiveness of hiding the visible vitiligo lesions might have abrogated the impact on the patient’s QoL.

We found that the patients with lesions on hands had poor QoL (p = 0.052). These might be explained by the fact that acral lesions of vitiligo were usually resistant to conventional treatment[2830] as well as surgical interventions[31], and the effect of camouflage on these visible sites could not sustain for long because of frequent hand-washing.

Camouflage use and QoL in vitiligo patients

Our result showed a less QoL impairment than that reported by Wang et al.[22], who reported a mean total DLQI score of 8.40 in 101 Chinses vitiligo patients. This may be due to the difference between the target populations of these two studies, as we recruited the patients who had been using camouflage for at least one month, from the community, while in the previous study, dermatology clinic outpatients were enrolled.

There were 67 patients who finished the questionnaire were excluded from our primary analysis, as they used camouflage for less than one month. The mean DLQI score of them was higher than those who had been using camouflage for at least one month (7.22±6.83vs. 5.83±5.75), although the differences between the two groups did not reach statistically significance. One possible reason for the difference might be that continuous camouflage application improved the QoL of vitiligo patients who had lesions on visible sites[3,4]. As another evidence, in our multivariate analysis, the degree of satisfaction after camouflage therapy was positively correlated with QoL of the patients.

Several limitations in our study should be addressed. Firstly, it was an online survey, thus the clinical characteristics such as type of vitiligo, disease activity, and vitiligo extent were unable to be assessed clinically. Secondly, there might be some non-serious respondents participated in the survey, and therefore would increase noise and reduce experimental power of the study[32]. For this reason, we performed a consistency and plausibility check to make sure most of the low-quality data sets submitted by non-serious respondents were excluded from the final analysis[32,33]. Thirdly, although China and India shared many similarities in culture and belief, we found that some items in VIS-22 may not be suitable for our patients, further modification and validation is needed. Furthermore, family history was not assessed and should be considered in future studies.

Despite these limitations, our study demonstrated that vitiligo has a considerable impact on the QoL of affected patients in Chinese population even when they had been using camouflage for at least one month, and camouflage might be helpful to improve QoL of the patients.

Source: 

Mental Health and Psychosocial Quality-of-Life Burden Among Patients With Vitiligo Findings From the Global VALIANT Study

Kristen Bibeau, PhD, MSPH; Khaled Ezzedine,MD, PhD; John E. Harris, MD, PhD; Nanja van Geel, MD, PhD;
Pearl Grimes, MD; Davinder Parsad, MD; Mukta Tulpule, MBBS; Jackie Gardner, BA; Yan Valle, MSc, MBA;
Gaone Tlhong Matewa, BBA; Christine LaFiura, BA; Anouk Lindley, MBA; Haobo Ren, PhD; Iltefat H. Hamzavi, MD

IMPORTANCE Patients with vitiligo often have impaired quality of life (QOL) and experience
substantial psychosocial burden.
OBJECTIVE To explore the global association of vitiligo with QOL and mental health from the
patient perspective.
DESIGN, SETTING, AND PARTICIPANTS This qualitative study of the cross-sectional
population-based Vitiligo and Life Impact Among International Communities (VALIANT)
study was conducted from May 6, 2021, to June 21, 2021. Potential participants for this
qualitative study were recruited from an online panel in 17 countries. Of 5859 surveyed adults
(aged18 years) who reported a vitiligo diagnosis, 3919 (66.9%) completed the survey, and
3541 (60.4%) were included in the analysis.
EXPOSURES Patients were asked questions regarding their emotional well-being, including
QOL and mental health.
MAIN OUTCOMES AND MEASURES Reported analyses are descriptive and hypothesis
generating. Vitiligo Impact Patient scale (VIPs) scores ranged from 0 to 60, with higher scores
indicating more psychosocial burden.
RESULTS The median age of the 3541 patients was 38 years (range, 18-95 years), and 1933
(54.6%) were male; 1602 patients (45.2%) had more than 5%affected body surface area
(BSA; Self-Assessment Vitiligo Extent Score assessed), and 1445 patients (40.8%) had
Fitzpatrick skin types IV to VI (ie, darker skin). The mean (SD) global short-form VIPs score
was 27.3 (15.6) overall; patients from India (mean [SD], 40.2 [14.1]) reported the highest
scores (ie, most burden). The QOL burden according to the scale was profound for patients
with more than 5%affected BSA (mean [SD] score, 32.6 [14.2]), darker skin (mean [SD] score,
31.2 [15.6]), and lesions on the face (mean [SD] score, 30.0 [14.9]) or hands (mean [SD], 29.2
[15.2]). At least 40% of patients globally reported that vitiligo frequently affected aspects of
their daily lives, including choosing clothes to wear (1956 of 3541 [55.2%]). Most patients
(2103 of 3541 [59.4%]) reported concealing their vitiligo frequently. More than half of
patients (2078 of 3541 [58.7%]) reported diagnosed mental health conditions, including
anxiety (1019 of 3541 [28.8%]) and depression (866 of 3541 [24.5%]). The Patient Health
Questionnaire–9 depression screener showed that 55.0%of patients (1948 of 3541) had
moderate to severe depressive symptoms; the highest rates were in India (271 of 303
[89.4%]) and among patients with more than 5%affected BSA (1154 of 1602 [72.0%]) and
darker skin (987 of 1445 [68.3%]).
CONCLUSIONS AND RELEVANCE This qualitative study found that, globally, patients with
vitiligo reported being substantially affected in their emotional well-being, daily lives, and
psychosocial health; the burden was typically greatest among patients with more than 5%
affected BSA, darker skin types, and lesions on the face or hands. Survey findings suggest
that patients reported having altered their behavior, expressed clear discontent, and have
symptoms consistent with depression, which may be underdiagnosed.

Vitiligo is a chronic autoimmune disease characterized by the destruction of melanocytes, resulting in pale or
white patches of skin.1 Patients with vitiligo encounter significant quality-of-life (QOL) impairment in routine activities, employment, and psychosocial health.2,3 Previous reports suggest that patients with greater body surface area (BSA) involvement and visible lesions experience greater psychosocial burden.4,5 Patients with vitiligo are also more likely to have depression and anxiety than individuals without vitiligo serving as controls.6,7 Psychosocial stressors are associated with vitiligo onset or flares.8,9

There is a need to further understand the global burden of vitiligo from the patient’s perspective. Here we explore sociodemographic characteristics and QOL and describe differences in psychosocial burden across geographic regions and subgroups of disease characteristics among patients surveyed in the Vitiligo and Life Impact Among
International Communities (VALIANT) study.

Methods

Study Participants
This cross-sectional observational qualitative study provided a survey that was administered to adults (aged ≥18 years) who received a diagnosis of vitiligo from a health care professional and were recruited via an online panel from 17 countries between May 6 and June 21, 2021, using a general population sampling approach (eAppendix in Supplement 1). The study protocol received an exemption from informed consent from the Western Institutional Review Board based on survey procedures and use of deidentified data. Participants
completed a brief online screener before continuing to the 25-minute survey. The survey was designed to assess self-reported emotional well-being, QOL, and depressive symptoms in a target sample of approximately 3500 patients. Additional assessment instruments (eg, theVitiligoImpactPatient scale [VIPs] and the Patient Health Questionnaire–9 depression screener) are described in the eAppendix and eTable 1 in Supplement 1.Datawere summarizedwith descriptive statistics. This qualitative study followed the Standards forReporting Qualitative Research (SRQR) reporting guidelines.

Statistical Analysis
Analyses included comparison of the 17 countries, 7 geographic regions, and demographic and clinical characteristic
subgroups, with t tests for comparisons of mean values and χ2 tests for categorical counts. Statistical significance was conferred at P < .05 (2-sided). The software used for analysis was WinCross, version 20 (The Analytical Group).

Results

Patient Demographic Characteristics

Of 5859 participants who reported a vitiligo diagnosis were directed to the survey, 3919 (66.9%) completed the survey, 378 (6.5%)were excluded fordata quality issues (eTable2inSupplement 1), and 3541 (60.4%) were included in the analysis. The median age was 38 years (range, 18-95years); 1933 (54.6%)were male, 1603 (45.3%)were female, and 5 were nonbinary (0.1%). Race and ethnicity were not solicited in France (n = 250) or Germany (n = 250). A total of 929 of the 3041 patients with available datawere Asian (30.5%), 283were Black (9.3%), 144 were Central or South American (4.7%), 135 were Middle Eastern or North African (4.4%), and 1555were White (51.1%).

A total of 75 patients (2.5%) reported race and ethnicity as “other,” as categorized within the survey, with no further breakdown available. Thirteen patients (0.4%) preferred not to report race and ethnicity. A total of 1445 patients (40.8%) had Fitzpatrick skin types IV toVI (ie, darker skin), and1602(45.2%)
reported more than 5% affected BSA (Table).

QOL and EmotionalWell-Being

Globally, the mean (SD) total 12-itemVIPs score was 27.3 (15.6) (Figure 1). Scale scores ranged from0to 60,with higher scores indicating more psychosocial burden. Patients in India (mean [SD] score,40.2 [14.1]), Brazil (mean [SD] score, 29.7 [17.1]), and theUS(mean[SD] score,29.4 [12.8]) reportedthe highest scores (ie, the greatest burden) among countries surveyed (eFigure 1 in Supplement 1).

Worse QOL was observed among patients with more than 5%affected BSA(Vitiligo Impact Patient scale
mean [SD] score, 32.6 [14.2] vs 24.1 [13.9] for 1%-5% BSA and 21.6 [16.4] for <1%BSA; both P < .001), darker skin (mean [SD] score, 31.2 [15.6] vs 24.5 [15.0] for fairer skin; P < .001), and facial lesions (mean [SD] score, 30.0[14.9] vs 21.8 [14.9] for no facial lesions; P < .001) or hand lesions (mean [SD] score, 29.2 [15.2] vs 22.5 [14.8] for no hand lesions; P < .001).

More than 30% of patients (range across questions, 32.8%  [1160 of 3541] to 53.5% [1893 of 3541]) reported agreeing or strongly agreeing that vitiligo affected multiple aspects of their emotional well-being, including self-esteem or stigma, relationships, and careers (eFigure 2 in Supplement 1). Among all domains evaluated, patientswith more than 5% affected BSA consistently reported being more greatly affected compared with those with less extensive disease. A total of 49.0%of patients (1735 of 3541) agreed that having vitiligo made them feel
less confident or more self-conscious. Furthermore, 46.6% of patients (1649of 3541) believed that “no one understands what it’s like to live with vitiligo.” Patients also felt frustrated with their career prospects,with 41.9%(1483 of 3541) reporting that they believed that they would have been further along in their
careers if they did not have vitiligo. In contrast, 35.5% (1258 of 3541) reported that having vitiligo made them feel
empowered, suggesting that the question may have been misinterpreted.

Abbreviation: BSA, body surface area.
a Multiple answers were accepted.
bRace and ethnicity were not solicited in France (n = 250) or Germany
(n = 250).
c Category taken from the survey with no further breakdown available.
d Fitzpatrick skin types are defined as follows: type I, pale white skin; type II,
white skin; type III, light brown skin; type IV, moderate brown skin; type V,
dark brown skin; and type VI, deeply pigmented dark brown to black skin.

More than 40% of patients (range across questions, 42.9%[1520 of 3541] to 55.2% [1956 of 3541]) reported that aspects of their daily lives were frequently affected by vitiligo. Among the most
stressful daily activities were making clothing choices, attending social activities, shaking hands, and being intimate with their partner (Figure 2).Furthermore,59.4%ofpatients (2103of 3541)
reported that they frequently concealed their vitiligo with makeup or concealer or clothing, the rates of which were higher among patients with more than 5% affected BSA (1164 of 1602 [72.7%]), darker skin (955 of 1445 [66.1%]), and facial or hand lesions (1690 of 2712 [62.3%]).

Mental Health
More than half of patients (2078 of 3541 [58.7%]) reported diagnosed mental health conditions, most commonly anxiety disorder (1019 of 3541 [28.8%]) and depression (866 of 3541 [24.5%]) (eFigure 3 in Supplement 1). Rates of diagnosed mental health conditions were highest for patients with more than 5% affected BSA (73.8% [1183 of 1602] vs 52.0% [497 of 955] for 1%-5% BSA and 40.4% [398 of 984] for <1% BSA; both P < .001), darker skin (73.4%[1061 of 1445] vs 48.5%[1017 of 2096] for fairer skin; P < .001), and facial lesions (67.2%[1441 of 2143] vs 45.8% [600 of 1311] for no facial lesions; P < .001) or hand lesions (67.2% [1527 of 2274] vs 43.6% [514 of 1180] for no hand lesions; P < .001) and for those from India (90.1% [273 of 303]; P < .05 vs other countries).

Globally, 55.0% of patients (1948 of 3541) reported moderate to severe symptoms of depression according to the Patient Health Questionnaire–9, with the highest rates among patients from India (271 of 303 [89.4%]) (eFigure 4 in Supplement
1). Rates of moderate to severe depressive symptoms were greater among patients with more than 5%affected BSA (1154 of 1602 [72.0%]), darker skin (987 of 1445 [68.3%]), and facial or hand involvement (1607 of 2712 [59.3%]) than among their counterparts (eFigure 5 in Supplement 1). previous findings, the VALIANT study demonstrated frequent avoidance behavior and concealment strategies.11,12 One quarter of patients in the VALIANT study reported diagnosed depression and approximately three-tenths reported anxiety, which may substantially affect health care resources.13Furthermore, depression may be underdiagnosed, possibly owing to lack of access to mental healthcare, with more than half of patients in theVALIANT study reporting symptoms consistent
with moderate to severe depression. Regional differences were observed in the burden of vitiligo and were particularly notable in India. There is reportedly a highly negative perception of vitiligo in India, with patients reporting how having vitiligo has affected their marriage prospects, education, and employment.14 These perceptions may be a reason why patients in India reported the greatest burden among all countries
surveyed.

 

Discussion

In this first international survey to date exploring the burden of vitiligo, patients, especially those with more than 5% affected BSA, darker skin, and facial or hand involvement, reported that this burden profoundly affected their emotional well-being, daily activities, and mental health. Smaller studies have reported a higher burden for patients at least 25% affected BSA or darker skin,2,10 supporting our findings that QOL impairment was greater among patients with more than 5% affected BSA and darker skin vs their counterparts. Lesion location was also associated with disease burden, with greater QOL impairment and higher prevalence of depressive symptoms among patients with vs. without facial or hand involvement, expanding on previous results.3,11 Corroborating previous findings, the VALIANT study demonstrated frequent avoidance behavior and concealment strategies.11,12

One quarter of patients in the VALIANT study reported diagnosed depression, and approximately three-tenths reported anxiety, which may substantially affect health care resources.13Furthermore, depression may be underdiagnosed, possibly owing to lack of access to mental health care, with more than half of patients in theVALIANT study reporting symptoms consistent with moderate to severe depression. Regional differences
were observed in the burden of vitiligo and were particularly notable in India. There is reportedly a highly negative
perception of vitiligo in India,with patients reporting how having vitiligo has affected their marriage prospects, education, and employment.14 These perceptions may be a reason why patients in India reported the greatest burden among all countries surveyed.

Limitations

This study has some limitations. For example, the VALIANT survey is limited by factors observed with other online surveys, including selection and recall biases and reliance on self-report of physician diagnosis. Also, patients with lower disease burden may have been less likely to complete the survey. Some questions may also have been misread or misunderstood by patients. For example, 35.5% of patients (1258 of 3541) reported feeling empowered by their vitiligo in contrast to clinical experience, in which most patients express considerable disempowerment.15 This result could be because the terminology was interpreted differently across ethnic and national groups; therefore, translated survey validation across groups is warranted. Nonetheless, stratifications by BSA and skin type demonstrated similar trends in emotional well-being despite the fact that the questions were a mix of positive and negative characteristics. Finally, multivariate analysis was not undertaken; thus, confounding
cannot be excluded.

 

Conclusions

In this qualitative study, the results of the VALIANT survey indicate that vitiligo affects patients’ daily lives, emotional well-being, and careers. Patients altered their behavior, expressed clear discontent, and had symptoms consistent with depression, which may be underdiagnosed. Patients with more than 5% affected BSA, darker skin, and facial or hand lesions reported being more affected than their counterparts. Findings highlight the need to prioritize reduction in the psychosocial burden of vitiligo and increase efforts to educate patients and health care professionals on vitiligo, particularly in countries where patients experience the highest burden.

Source 

Advances in vitiligo: Update on therapeutic targets

Yifei Feng Yan Lu*

  • Department of Dermatology, Jiangsu Province People’s Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China

Vitiligo, whose treatment remains a serious concern and challenge, is an autoimmune skin disease characterized by patches of depigmentation. The increasing application of molecular-targeted therapy in skin diseases, such as psoriasis and systemic lupus erythematosus, has dramatically improved their condition. Besides, there is a favorable effect of repigmentation in the treatment of the above diseases combined with vitiligo, implying that molecular-targeted therapy may also have utility in vitiligo treatment. Recently, the role of cytokine and signaling pathways in vitiligo pathogenesis are increasingly recognized. Thus, investigations are underway targeting the molecules described above. In this paper, we present a synopsis of current practices in vitiligo treatment and introduce the improvement in identifying new molecular targets and applying molecular-targeted therapies, including those under development in vitiligo treatment, providing valuable insight into establishing further precision medicine for vitiligo patients.

1 Introduction

Vitiligo is a primary, circumscribed, or generalized depigmentation of the skin and mucosa, related to genetic factors, self-destruction of melanocytes, cytokines, autoimmunity, and oxidative stress (1). While the detailed molecular mechanisms still require further investigation. In recent years, various studies have showed that the IFN-γ-CXCL9/10-CXCR3 axis appears to be important in vitiligo, via inhibiting melanogenesis, inducing apoptosis of melanocytes, and further recruiting T cells to the skin. These are all involved in the JAK/STAT pathway. In addition, cytokine, including HSP70i, IL-15, IL-17/23, TNF as well as wnt signaling pathway, Tregs, miRNAs have also been proved to be involved in the pathogenesis of vitiligo.

Vitiligo can be treated by different modalities of phototherapy, surgical procedures, and topical therapies, such as glucocorticosteroids, immunosuppressive agents, calcineurin inhibitors, and vitamin D. However, current treatments for vitiligo remain suboptimal, which may not be equally effective in all vitiligo patients, and it would be inconvenient for patients to visit clinics for phototherapy. Targeted therapies, such as biologics targeting cytokines and small-molecule inhibitors targeting intracellular signaling molecules, are recently emerging as promising therapeutics for autoimmune diseases. Their applications also promote our understanding of the detailed molecular mechanism of vitiligo and are essential for guiding a more precise vitiligo treatment. In this article, details of the roles that related cytokines and pathways play as well as the efficacy of targeted therapy have been described.

2 Current treatment

Topical, systemic treatment, and phototherapy are useful for stabilization and repigmentation of vitiligo. Treatment modalities are chosen in the individual patient, based on disease severity, disease activity (stable versus progressive disease), patient preference (including cost and accessibility), and response evaluation. For rapidly progressive disease, low-dose oral glucocorticoids and phototherapy are useful in stabilizing the disease. Therapeutic options for stable, segmental vitiligo include topical therapies (eg, topical corticosteroids, topical calcineurin inhibitors), targeted phototherapy, and surgical therapy (tissue grafts and cellular grafts) (Table 1) (14). In recent years, attempts have been made to improve the repigmentation of vitiligo phototherapy by combination therapies, including NB-UVB with glucocorticoids (15), and topical calcineurin inhibitors (16). While their positive results were not confirmed in all studies. However, the method of treatment described, which were nonspecific, general, off-label, non-targeted with modest efficacy led to the problem of recurrence after stopping treatment. Therefore, efforts should be made to achieve a more comprehensive understanding of vitiligo pathogenesis to develop novel effective therapies (Table 2).

Table 1

www.frontiersin.orgTABLE 1 Current treatment modalities for vitiligo.

Table 2

www.frontiersin.orgTABLE 2 Molecular-targeted therapies for the treatment of vitiligo.

3 Small molecules

3.1 Emerging therapeutics targeting Janus-activated kinase (JAK) signaling

The Janus kinases family consists of JAK1, JAK2, JAK3, and TYK2, which is engaged in the important JAK/STAT pathway, exhibiting pleiotropic effects on transducing multiple extracellular signals involved in regulating proliferative signaling, differentiation, migration, and apoptotic properties (28).

There are no licensed JAK/STAT inhibitors available against dermatological problems, however, some of them (ruxolitinib and tofacitinib) are used to treat other conditions such as myelofibrosis and RA. However, off-label usage of these medications in the treatment of vitiligo has shown promising outcomes.

JAK-STAT inhibitors promote Sonic Hedgehog and Wnt signaling in epidermal pigmentation, with the former inducing the migration, proliferation, and differentiation of melanocyte (29). Expanding our knowledge of these medications’ efficacy and safety profiles, as well as their use in dermatological conditions, is critical for establishing their risk-benefit ratio.

3.1.1 Tofacitinib

Tofacitinib is an FDA-cleared JAK1/3 inhibitor for treating RA, PsA, and active ulcerative colitis.

Tofacitinib 5-10 mg QD/BID has demonstrated superior efficacy against vitiligo, with improvement ratios of 5.4% in 5/10 patients with sun-exposed areas or areas treated only with phototherapy (30), and a reduced rate in vitiligo area scoring index (VASI) score of 4.68 at baseline to 3.95 at 5 months in another trial (31). In addition, a decline in the number of CD8+ T cells and chemokines, such as CXCL9 and CXCL10 has been observed after tofacitinib treatment, but no variations were observed for the percentage of melanocyte-specific T cells (30).

Unfortunately, this oral medication is associated with a host of systemic side effects, including infections, malignancies, and cytopenia. Thus, topical JAK inhibitors may be more preferred. 11 vitiligo patients treated with 2% tofacitinib cream twice a day in conjunction with NB-UVB therapy thrice-weekly demonstrated a mean improvement of 70% in facial VASI. There was also a significant difference between facial and non-facial lesions (P=0.022) (32).

3.1.2 Ruxolitinib

Ruxolitinib, the first Jakinib to get FDA approval, is a JAK1/2 inhibitor designed to deal with polycythemia vera and intermediate- and high-risk primary myelofibrosis (33).

Studies have shown that except for JAK inhibition, ruxolitinib also inhibited the differentiation and migration of DCs in vitiligo, increasing CD8+ cytotoxic T cell responses (34). In a double-blind phase 2 trial, 157 recruited vitiligo patients were randomized, in a 1:1:1:1:1 ratio, to receive topical ruxolitinib cream 1.5% BID, 1.5% QD, 0.5% QD, 0.15% QD, or a vehicle for 24 weeks, with the result showing considerably decreased CXCL9 and CXCL10 expression in 1.5% BID and 1.5% QD groups, and more individuals in groups receiving ruxolitinib cream 1.5% BID, 1.5% QD and 0.5% QD achieving F-VASI50, during which 1.5% BID group produced the highest responses in F-VASI50 (58%), F-VASI75 (52%), and F-VASI90 (33%). Besides, three positive responsive groups demonstrated significant repigmentation of vitiligo lesions and acceptable tolerability with a follow-up period of 52 weeks (35). Vitiligo on the face appears to respond more vigorously to therapy than non-facial lesions, reinforced by a 20-week, open-label trial in which patients with significant facial involvement experienced a 76% improvement in facial VASI scores (36). Furthermore, better repigmentation rates could be achieved both in oral and topical ruxolitinib treatment combined with phototherapy (37).

3.1.3 Baricitinib

Baricitinib is a selective JAK1/2 inhibitor that inhibits signal transduction of numerous proinflammatory cytokines (38), approved for the treatment of RA. To our knowledge, there was only one case report describing repigmentation in vitiligo patients with baricitinib 4 mg daily for the treatment of RA. Besides, an ongoing phase 2 trial (NCT04822584) in which patients received a combination therapy of baricitinib 4mg/d and phototherapy is being performed.

3.1.4 Ifidancitinib (ATI-50002)

Ifidancitinib is another dual JAK1/3 inhibitor for alopecia areata treatment, which is now undergoing phase II clinical trials for its application in vitiligo treatment. Patients with facial NSV(NCT03468855) receiving topical ATI-50002 BID for 24 weeks presented with an improved F-VASI and the Vitiligo Noticeability Scale (VNS) (39).

3.1.5 Ritlecitinib (PF-06651600) and Brepocitinib (PF-06700841)

Ritlecitinib, an irreversible inhibitor of JAK3 and tyrosine kinase applicable to the treatment of moderate-to-severe RA (40) and Brepocitinib, a TYK2/JAK1 inhibitor, are currently undergoing evaluation of their efficacy and safety profile in active NSV in combination with phototherapy (NCT03715829) (41).

3.1.6 Cerdulatinib (PRT062070)

Cerdulatinib, an SYK/JAK dual kinase inhibitor (42), has been assessed (NCT04103060) for its safety and tolerability for vitiligo treatment in topical formation (0.37% cerudulatinib gel BID).

However, additional studies are needed to determine the best-suited drug regimen and recommended dosage forms and doses to attain the optimum curative effect and minimal toxicity. As the occurrence of depigmentation after the withdrawal of JAK inhibitors, the mechanisms underlying need further exploration, and more work need to be done to corroborate the effectiveness in combination with other therapies.

3.2 Wnt signaling and its agonists

It has been shown that Wnt/β-catenin signaling plays a pivotal role in the proliferation, migration, and differentiation of melanocytes in vitiligo patients (29), which could be inhibited by oxidative stress (43). In addition, the Wnt/β-catenin pathway participates in the activation of MITF and its downstream enzymes (44). Intradermal injection of IWR-1 (inhibitor of Wnt response 1), a chemical inhibitor of β-catenin activation, and small interfering RNA (siRNA) against Wnt7α suppressed the number of epidermal melanocytes (45). This evidence suggested that stimulation of Wnt signaling may be an adjuvant therapy for vitiligo treatment. Micro-injury (46) as well as some phenanthridine-derived Wnt-specific agonists binding with the Axin protein have been proved to promote melanogenesis (47) and induce repigmentation.

3.3 Emerging therapeutics targeting microRNAs (miRNAs)

MiRNAs, which are a highly conservative small class of non-coding RNA molecules, participate in mRNA expression regulation via degradation or repression of mRNA translation (48). Previous studies have demonstrated that miRNAs were associated with genetic polymorphisms (e.g., miR-196a-2 rs11614913), immune response (e.g., miR-133b, miR-224-3p, miR-4712-3p, miR-3940-5p, miR-21−5p), oxidative stress (e.g., miR-135a, miR-9, miR-34a, miR-183, miR-184, miR-1, miR-25, miR-211, miR-383, miR-577, miR-421) and melanocyte functions (e.g., miR-434-5p, miR-330-5p, miR-137, miR-148, miR-145, miR-155, miR-203, miR-125, miR-377, miR-2909, miR-200c, hsa-miR-149-5p) (4954), participating in pathological mechanism of vitiligo. These findings suggest that miRNAs may be involved in vitiligo pathogenesis via the modulation of vital genes expression in melanocytes and serve as novel therapeutic targets for vitiligo therapy.

There are two strategies for the therapeutic application of miRNAs: 1) anti-miRNAs, locked-nucleic acids (LNA), or antagomiRs (55) can be used to counteract the over-activation of miRNA. Short tandem target mimic (STTM)- miR-508-3p has been validated to upregulate SOX6 expression, leading to increased expression of key melanogenic genes CREB, MITF, TYR, and TYRP1/2 with increased melanogenesis (56). Besides, STTM-miR-143-5p also upregulates the expression of MYO5A, leading to an increase in the level of MITF, TYR, TYRP1, melanin, and Rab27a (57). 2) miRNA replacement, involving the reintroduction of a gene-suppressor miRNA mimic or AAV (adeno-associated virus)-mediated miRNA gain-of-function to modulate gene expression (55). A study demonstrated that the migratory capacity of melanocytes was altered by the application of miR-211 mimic through the p53-TRPM1/miR-211-MMP9 axis (58).

3.4 Emerging therapeutics targeting regulatory T-cells (Tregs)

Tregs are a suppressive CD4+ T cell subset that possesses a capacity to suppress self-reactive T cell activation and expansion (59). A clear decrease in Treg cells was observed in vitiligo skin within lesional, non-lesional, and perilesional sections (60), indicating that increasing the number of Tregs with normal function might be an important therapeutic intervention for vitiligo treatment.

Infusing purified populations of Tregs is the most direct way for the supply of Tregs. The current methods mainly include polyclonally-expanded Tregs, antigen-specific Tregs, and engineered Treg cells. In a mouse model of vitiligo, adoptive transfer of polyclonal Tregs may be effective in the short-term (61), which might however impart systemic immunosuppression (62). Besides, a TCR transgenic mouse with spontaneous vitiligo, receiving CAR Tregs treatment, developed a significant delay in depigmentation (63).

However, a limitation of infusing purified populations of Tregs might be the technical difficulty for therapeutic agent delivery to specific cells. A topical application of Tregs or the combination with CCR4 Treg homing receptor ligand CCL22 (64) by local needle-free jet injection of DNA (20) or CCL22-encoding plasmid DNA (64) may help resolve that issue. Besides, various strategies have been applied towards the modulation of Tregs function by targeting Treg-intrinsic pathways and functional modulators for Tregs. HO-1, a functional modulator of Tregs, was decreased in vitiligo Tregs. Treatment with Hemin, an agonist of HO-1, was found to enhance HO-1-induced restoration of Tregs function by up-regulating IL-10 expression (65). In addition, therapeutic method for microbiota modulation, such as neomycin treatment can significantly delay depigmentation in vitiligo mice and promote the infiltration of Tregs to the skin (66). Rapamycin, an inhibitor of PI3Kakt-mTORC1 signaling (67), efficiently halts the depigmentation process by increasing the abundance of Treg in h3TA2 mice, which effect lasted till 6 weeks after treatment (61). At present, a phase 2 clinical trial(NCT05342519) is underway for assessing the efficacy of the application of 0.1% topical rapamycin (68) (2022). In addition, nanoparticles containing rapamycin and autoantigen HEL46-61(NPHEL46-61/Rapa) were synthesized, the administration of which halted the disease progression (69). Also, the calcium-NFATc1-signaling pathway may be involved in defective Tregs function, indicating a potential therapeutic target for vitiligo treatment (70).

4 Cytokine-targeted therapies

Multiple monoclonal antibodies are available for vitiligo treatment, targeting IFN-γ, CXCL10, CXCR3, HSP70i, IL-15, IL-17/23, and TNF. In addition to full-size immunoglobulin, affibodies and nanobodies, composed of considerably smaller proteins, are currently being developed, which have higher bioavailability as well as affinity and specificity to the targeted molecules.

4.1 IFN-γ and the inhibitors

The IFN-γ-CXCL9/10-CXCR3 axis may be crucial for vitiligo pathogenesis, contributing to disease progression by inhibiting melanogenesis, inducing apoptosis of melanocytes, and further recruiting T cells to the skin (Figure 1) (71). A study showed a higher expression of IFN-γ mRNA in non-lesional and perilesional skin, especially in active vitiligo (72), which is associated with disease activity (73).

Figure 1

www.frontiersin.orgFIGURE 1 1) The immune pathogenesis of vitiligo: (A) CD8+ T cell expression of IFN-γ in vitiligo lesions activated the JAK/STAT pathway after binding to IFN-γ receptor, thus facilitating the release of CXCL9/10. The binding of CXCL9/10 to CXCR3 increased CXCR3+ T cells recruitment; (B) Maintenance of vitiligo lesions was influenced by the function of IL-15-dependent TRM cells, which produce IFN-γ and TNF-α. 2)Targeted therapeutic interventions in vitiligo mainly include therapies targeting IFN-γ-CXCL9/10-CXCR3 axis (IFN-γ neutralizing antibody, CXCL10 neutralizing antibody, and CXCR3 depleting antibody, as well as JAK inhibitors), anti-CD122 antibody (IL-15 receptor subunit) to decrease IFN-γ production and deplete autoreactive CD8+ TRM cells, TNF inhibitor to inhibit autoantibody production, and PD-L1 fusion protein to reduce the numbers of melanocyte-reactive T cells.

Anti-IFN-γ can have been proved to be effective in rheumatoid arthritis (RA), multiple sclerosis (MS), prevention of corneal rejection, autoimmune skin diseases, and others. In a recent study, vitiligo induction mice, treated with intraperitoneal injection with IFN-γ neutralizing antibody (XMG-6) at a dose of 100-500 μg twice a week, presented with significant improvement of depigmentation (17), with the same trend observed in vitiligo patients. Four patients who received intradermal perilesional injections presented with repigmentation of the treated area and boundary retreat (74). More research is warranted to be initiated for further definition of the role that IFN-γ plays in vitiligo and to examine whether IFN-γ neutralization would be more viable in reversing skin depigmentation.

4.2 CXCL10 and the inhibitors

Recent studies report a Th1/IFN-γ immune response in both human and a mouse model of vitiligo that involves elevated CXCL9, 10, and 11 productions, among which CXCL10 participated in the targeted migration of T cells (18), triggering an immune cell infiltration at the early stage (72), and involved in the downregulation of keratinocyte glycoprotein non-metastatic melanoma protein B (GPNMB) (75). A study showed that mice receiving CXCL10 neutralizing antibodies developed more repigmentation after 4 weeks’ treatment, which continued for an additional 4 weeks (18), thereby supporting CXCL10 suppression as a great therapeutic strategy.

4.3 CXCR3 antibodies

CXCR3 has been proved to be expressed in skin lesions, autoreactive T cells (18), and the vast majority of skin infiltrating CD8+ resident memory T cells (TRM), which stimulate the secretion of IFN-γ and TNF-α (76).

In a study, vitiligo mice with >75% depigmentation on their tails are treated with CXCR3 depleting antibodies for 7-8 weeks, which significantly reversed the clinical disease in a perifollicular pattern and a diminution of PMEL in the epidermis, with slightly reduced host CD8+ T cell numbers (19) compared to neutralizing antibody treatment (18). Although these results are preliminary, they may provide justification for further studies in targeting CXCR3 in vitiligo (19), which proposes the use of a depleting Ab to create a greater clinical efficacy by removing autoreactive cells rather than modulating their migration phenotype.

4.4 Inducible HSP70 (HSP70i) DNA

Indeed, HSP70i is the core participant in vitiligo predominantly through HSP70i-plasmacytoid dendritic cells (pDCs)-IFN-α-CXCL9 and CXCL10-cytotoxic T lymphocyte (CTL) axis. Pmel-1 mice vaccinated with HSP70i encoding DNA exhibited significant depigmentation, rarely seen in models knockout for HSP70i, indicating that elevated HSP70i expression alone would be enough to induce depigmentation in vitiligo prone animals (77). A study revealed that the expression of HSP-70 mRNA in skin lesions of active vitiligo patients was much higher (78), correlated with the disease activity.

Blocking HSP70i activity might have the potential to reverse vitiligo development. A recent study showed that a Sinclair swine, receiving HSP70iQ435A-encoding DNA treatment, showed remarkable repigmentation with an initial influx of T cells and increased CD4/CD8 ratios (20), which was also detected in mice with HSP70iQ435A-encoding DNA treatment, resulting in 76% restoration of skin pigmentation. Furthermore, the treatment halted T cells accumulation and transition to T cell phenotype in mice and human skin, engaging HSP70iQ435A DNA delivery as a potent effective therapeutic intervention for vitiligo (79).

4.5 IL-15 and the inhibitors

It has been established that IL-15 seems to participate in IL-17 regulation and maintenance of TRM signals (80), with the latter responsible for long-term maintenance and potential relapse of vitiligo (81). The study has demonstrated a higher serum level of IL-15 in vitiligo patients than in controls, highly associated with epidermal H2O2 content and the disease activity (8283).

In vitiligo mice, an anti-CD122 antibody that targets IL-15 signaling was reported to effectively reverse depigmentation. Anti-CD122 therapy, either systemically or locally, decreases TRM-induced IFN-γ production and results in long-term repigmentation. These findings consider CD122-targeted drugs as a valid therapy method, which results in effective and long-lasting responses in vitiligo and other tissue-specific autoimmune disorders involving TRM (21).

4.6 PD-1/PD-L1 pathway

Involvement of the PD-1/PD-L1 pathway has been shown in many autoimmune diseases, including RA, MS, and vitiligo. PD-L1 expression was found limited in normal skin, and only expressed on dermal T cells, and increased in primary melanocytes and fibroblasts after exposure to IFN-γ. No such effect was seen in vitiligo patients, indicating the absence of self-protection ability for melanocytes against T-cell attack during vitiligo pathogenesis. In agreement with this, treatment with PD-L1 fusion protein reduced the numbers of melanocyte-reactive T cells, inhibited the activation of Vβ12-expressing T cells, and increased Tregs numbers, reversing depigmentation in a Pmel-1 T-cell receptor transgenic vitiligo mouse model (26). However, PD-L1 treatment may still call for extended phototherapy treatment, especially NB-UVB therapy, which likely upregulates PD-L1 expression in an NF-κB-dependent manner (84), indicating a combination use of local PD-1/PD-L1 agonistic treatment and NB-UVB therapy as a promising option.

4.7 Other cytokine-targeted therapies under investigation

4.7.1 IL-17/23 and the inhibitors

Studies on the effect of IL-17/23 in vitiligo resulted in contradictory findings. On one hand, Th17 cells and IL-17 in vitiligo patients may inhibit function-related factors, repress melanogenesis, and dramatically induct other Th17 type cytokines as well as IL-1β production from dermal fibroblasts and keratinocytes (85). Elevated Th17 cells and IL-17/23 levels in skin lesions and serum of vitiligo patients, were positively correlated with disease activity (8687), and decreased after narrowband ultraviolet B (NBUVB) treatment (88). Primary melanocyte culture showed an increased expression of MITF and its downstream genes, increased melanin pigment, and cell proliferation after blockade with anti-IL-17RA (22). Besides, incidences of repigmentation have been documented in ustekinumab treatment of vitiligo (23). However, secukinumab treatment in patients with active non‐segmental vitiligo (NSV) contributed to disease progression in 7/8 patients with no general reduction in CXCL9/10, sCD25/27, Th1 cells, or cytotoxic cells, resulting in early termination of study (89). There are also reports of ustekinumab-induced new-onset vitiligo and alopecia areata. The above studies showed IL-17/23 signal may not play a direct role in vitiligo pathogenesis, which needs further investigation to confirm this conjecture.

4.7.2 TNF and the inhibitors

As an anti-inflammatory mediator, TNF-α is considered to play a role in vitiligo, which may promote apoptosis in melanocytes, induce B-cell activation, increase autoantibody production, and inhibit melanogenesis (90). Recent data has shown a significantly higher expression of TNF-α in vitiligo skin. TNF inhibitors are beneficial in the treatment of plaque-type psoriasis, psoriatic arthritis (PsA), RA, and inflammatory bowel disease (IBD), arousing growing interest in their use in vitiligo.

Infliximab is a chimeric anti-TNF-α monoclonal antibody specifically binding to both soluble and membrane-bound TNF (9192). Intravenous infliximab is widely licensed in the treatment of RA, psoriasis, ankylosing spondylitis (AS), IBD, uveitis, and Behcet’s disease. A 24-year-old patient with ankylosing spondylitis and refractory vitiligo improved significantly following six months of infliximab therapy at a dose of 5mg/kg intravenously in weeks 0, 2, and 6, and then every eight weeks for ten months (24). Besides, Etanercept is a monoclonal antibody targeted against TNF-α (93), which has been approved for the treatment of RA, juvenile RA, AS, psoriasis, and PsA. Treatment with etanercept 50 mg subcutaneously once or twice weekly for at least 2 months has shown a great curative effect on established vitiligo (94).

However, it has been shown that anti‐TNF‐α agents, especially adalimumab and infliximab (95), may exacerbate established vitiligo and induce new-onset vitiligo during treatment of other autoimmune diseases, including AS (96), Crohn’s disease (97), ulcerative colitis (98), psoriasis (99), and RA (100). The mechanism responsible for the TNF-α inhibitors-induced vitiligo is not fully understood. On the one hand, TNF-α inhibitors may increase the nucleosome-mediated autoantibody formation, interfere with the cytotoxic T-cell suppression of autoreactive B cells, and decrease Treg synthesis and activation. Additionally, infliximab increases pDC-produced IFN-γ, participating in further T cells recruiting. Although very rare, new-onset or exacerbations of vitiligo can occur in the anti‐TNF‐α treatment of other autoimmune diseases, the risk of which must not be ignored.

4.7.3 Rituximab

Rituximab has specific affinity for the B-lymphocyte transmembrane protein, CD20, which is expressed on B cells (101), participating in the activation of the CD8+ T cells and the ensuing autoreactive reaction (102). Rituximab is licensed for the treatment of lymphomas, leukemias, transplant rejection crisis, and a series of autoimmune diseases (103104). An intravenous infusion of Rituximab was administered to five active disseminated vitiligo patients, the three of whom exhibited a considerable improvement in both the disease’s symptoms and histology (25).

4.7.4 Abatacept

Abatacept, a fusion protein consisting of IgG1 coupled to the extracellular domain of CTLA-4 via the immunoglobulin’s Fc region, was licensed for treating moderate to severe RA. Ten eligible patients with active vitiligo have been included to receive self-injections of 125mg abatacept weekly from week 0 to week 24. Secondary endpoints will be evaluated during a 32-week follow-up visit (105).

5 Future therapeutic prospects

As a future direction, new therapeutic approaches should be developed to reduce vitiligo progression. Among the new approaches being developed, the strategy of targeting the IFN-γ-CXCL9/10-CXCR3 axis has been clinically tested. OPZELURA has been indicated for the topical treatment of nonsegmental vitiligo in adult and pediatric patients 12 years of age and older. MiRNA-based therapeutics are also in development. However, the absence of organ or tissue selectivity may also lead to off-target side effects, which must be considered and excluded in the process of miRNA-based therapeutics development. Besides, a suitable vector system, as well as the assurance of chemical and biological stability should also be taken into account. Adoptive Treg cell therapy has also been the research hotspot in recent years. However, it has always been a difficult point for reassurance for safety and the development of the delivery system.

Treating vitiligo remains a challenge. As is presented in this paper, a greater variety of precision treatments is currently being studied. With a better understanding and further validation of these therapeutic targets, patients can be stratified to achieve individualized treatment.

6 Conclusion

Current models of treatment for vitiligo are often nonspecific and general. Various therapy options are available for active vitiligo patients, including systemic glucocorticoids, phototherapy, and systemic immunosuppressants. While stable vitiligo patients may benefit from topical corticosteroids, topical calcineurin inhibitors, phototherapy, as well as transplantation procedures. Recently, a better understanding of the pathophysiological processes of vitiligo led to the advent of novel targeted therapies. To date, JAK inhibitors are the only category that has been proved to have a good tolerability profile and functional outcomes in vitiligo treatment, even though the risk of activation of latent infection and systemic side effects still existed, like other immunosuppressive agents. Research is in progress to investigate the important cytokines involved in the pathogenesis of vitiligo, including IFN-γ, CXCL10, CXCR3, HSP70i, IL-15, IL-17/23, and TNF, the blockade of which has undergone preliminary attempts in animal models and some patients. In addition, studies on miRNA-based therapeutics as well as adoptive Treg cell therapy are still primary, and more studies are necessary.

Author contributions

YFF and YL contributed to the conceptual design, writing, editing, and generation of figures for this manuscript. All authors contributed to the article and approved the submitted version.

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Image credit: Freepix

Vitiligo Treatment and Management

Vitiligo is a complex autoimmune disease that requires understanding and communication between clinician and patient. Nada Elbuluk, MD, dermatologist and clinical associate professor at the Keck School of Medicine of the University of Southern California, in Los Angeles, and David Rosmarin, MD, dermatologist and department chair at the Indiana University School of Medicine in Indianapolis, offered an overview of the condition, its prevalence, potential triggers, and treatment options in Updates in Vitiligo Management, a Dermatology Times® DermView series.

Elbuluk began by describing how she explains the disorder to patients. She tells them that because vitiligo is an autoimmune disease, their antibodies are attacking their melanocytes and when this happens, white patches appear on the skin. Elbuluk stresses that she tells patients that they did not cause their condition but rather are genetically predisposed to developing it.

“Some patients are worried they did something to cause the vitiligo,” Rosmarin said. “Maybe there were some instigating events, but we don’t want patients to blame themselves. Often, it’s idiopathic, and we don’t know why people get it. Maybe there’s a genetic predisposition, some environmental event that triggers it.”

Elbuluk and Rosmarin also discussed the common myth that vitiligo is a skin of color disease.

“It’s not,” Elbuluk noted. “It’s more visible in darker skin, so there’s a much greater contrast between vitiliginous patches in someone who has dark skin. People notice it more in darker skin. In my practice, I have patients of many different racial and ethnic backgrounds who have vitiligo.”

Elbuluk also tells patients with vitiligo that there is a 20% to 30% chance that they will develop some form of thyroid disease, and she checks thyroid-stimulating hormones (TSH) and vitamin D levels at the introductory visit. Rosmarin also screens for TSH at the first visit because 25% of patients with vitiligo go on to have an autoimmune thyroid disease.

Another topic they discuss with patients is genetic risk. According to Rosmarin, many of his patients who are in their 20s or 30s and thinking about having children tend to ask whether they will pass on vitiligo to their children and whether their parents passed it on to them.

“About 1% of the population, 0.5% to 2% in some estimates, will have vitiligo,” Rosmarin explained. “If you have a first-degree relative, then your risk is increased about 4%. It’s about sixfold higher. It’s complex, and there’s a genetic component, a predisposition.”

Wood’s lamp is a common tool used to identify vitiligo in patients with lighter Fitzpatrick skin types. According to Rosmarin, a Wood’s lamp is essential for seeing the true extent of vitiligo in fair-skinned patients. For many, the severity of disease and the extent of body surface it affects can cause emotional distress. To combat the fear of vitiligo, Rosmarin classifies patients as having either progressive or stable disease. If it is progressing, he tries to halt the process with 2-5 mg of dexamethasone, 2 days a week, for about 12 weeks.

Elbuluk always asks patients about their goals for vitiligo treatment. Many of her patients have been told that there is no way to treat vitiligo or they have been on previous treatments that failed. She tries to make each visit as educational as possible for patients.

“You hit the nail on the head,” said Rosmarin. “A lot of education takes place during these visits. I want to build on what you commented on, for quality of life. Our measures show that, when patients have [vitiligo] in exposed areas, that tends to affect their quality of life. Even more so…[with] progressive or unstable disease. They have anxiety…[about] not knowing when they’ll get a new spot. The unpredictability…[of] nonsegmental vitiligo can be quite bothersome to patients, more than even having the disease in the first place.”

In progressive vitiligo, Elbuluk and Rosmarin consider the percentage of body surface affected and the category of treatment that will work best. Combination therapy is typically more successful, especially in patients who have tried only 1 form of treatment for a brief period of time. Elbuluk also makes sure patients understand that success will not happen overnight. Phototherapy, for instance, can take at least 30 sessions or more to begin eliciting a response. Overall, Elbuluk tells her patients that with vitiligo there are 2 treatment goals: stabilization and repigmentation.

Ruxolitinib cream (Opzelura; Incyte Dermatology) is a favorite therapeutic option of both doctors. Elbuluk has transitioned many patients who failed traditional treatment to ruxolitnib cream and has seen success, and she has also seen early improvement with combination ruxolitnib and phototherapy.

“Usually, when I have a patient come in and I tell them what they should expect with the use of the [ruxolitnib] cream, I tell them it is better to use it twice a day, even though we…[know] that even once a day can help repigment patients,” Rosmarin said. “Twice a day certainly works better. I usually see patients back in 6 months, and I don’t do any lab work beforehand or as we’re using the ruxolitnib cream because from the phase 3 data, there weren’t significant changes in lab abnormalities.”

Elbuluk and Rosmarin ended their discussion by reminding colleagues to give patients hope, let them know that there are treatment options, and referring them to a vitiligo specialist if they don’t feel qualified to treat the condition. Rosmarin added that it’s crucial to educate all physicians about the different strategies available to personalize treatment.

Reference

  1. Elbuluk N, Rosmarin D. Updates in vitiligo management. DermView. November 22, 2022. Accessed November 30, 2022. https://www.dermatologytimes.com/dermview/updates-in-vitiligo-management

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World Congress of Dermatology 2023

Our president Mrs Gaone Matewa and the board member Dr Maya Tulpule was one of the patient organisation representatives at the 25th World Congress of Dermatology. The sessions at the congress were very insightful, covered a wide range of topics related to vitiligo treatments, from historical approaches to the latest advancements. Such gatherings allow for the exchange of expertise among dermatologists, scientists, and other stakeholders, including pharmaceutical representatives from different countries.

 

Moreover, the exhibition of future health technology showcased how technology is being integrated into the healthcare sector. It’s particularly exciting to see advancements in digital health that facilitate diagnosis and track treatment progress. With these developments, the future of healthcare seems promising, as it allows for more accurate and efficient approaches to patient care.

 

Thank you to the organisers and sponsors of Congress for promoting inclusion by providing a platform for patients’ representatives to voice our views, share personal experiences, and present the realities of living with vitiligo. This direct engagement with dermatologists and other healthcare professionals allows for a more comprehensive understanding of the challenges, needs, and preferences of individuals with vitiligo.

Autoimmune Etiology Of Generalized Vitiligo

I. Caroline Le Poolea, Rosalie M. Luitenb
a Department of Pathology, Oncology Institute, Loyola University, Chicago, Ill., USA;
b The Netherlands Institute for Pigment Disorders, Department of Dermatology,
Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Abstract
Vitiligo is characterized by progressive skin depigmentation resulting from an autoimmune response targeting epidermal melanocytes. Melanocytes are particularly immunogenic by virtue of the contents of their melanosomes, generating the complex radical scavenging molecule melanin in a process that involves melanogenic enzymes and structural components, including tyrosinase, MART-1, gp100, TRP-2 and TRP-1. These molecules are also prime targets of the immune response in both vitiligo and melanoma. The immunogenicity of melanosomal proteins can partly be explained by the dual role of melanosomes, involved both in melanin synthesis and processing of exogenous antigens. Melanocytes are capable of presenting antigens in the context of MHC class II, providing HLA-DR melanocytes in
perilesional vitiligo skin the option of presenting melanosomal antigens in response to trauma and local inflammation. Type I cytokine-mediated immunity to melanocytes in vitiligo involves T cells reactive with melanosomal antigens, similar to T cells observed in melanoma. In vitiligo, however, T cell tuning allows T cells with higher affinity for melanocyte differentiation antigens to enter the circulation after escaping clonal deletion in primary lymphoid organs. The resulting efficacious and progressive autoimmune response to melanocytes provides a roadmap for melanoma therapy.

Introducing Autoimmune Vitiligo
Progressive depigmentation of the skin is considered the hallmark of vitiligo, an autoimmune disease that strikes approximately 1% of the global population.
An increased incidence of vitiligo is noted among select consanguineous communities. Responses to a vitiligo questionnaire support a female gender bias of approximately 1.25. This is in concordance with an increased general prevalence of autoimmune disease noted among women, a finding which has not been adequately explained to date. The mean age of onset for human vitiligo is 28, while the median age is 13 years, reflecting a proportion of patients that
develop late-onset vitiligo  Early-onset vitiligo appears more clearly associated with hereditary factors, whereas environmental factors contribute particularly to late-onset vitiligo which displays a different distribution of the lesions . Vitiligo is generally classified according to the extent, type and distribution of the lesions, ranging from focal vitiligo to segmental, inflammatory and generalized vitiligo, and finally to universal vitiligo. Segmental vitiligo is exceptional because
of its asymmetric distribution and characteristically slow progression, suggestive of a separate, converging etiology.

Several factors may contribute to the pathogenesis of autoimmune vitiligo, including genetic predisposition, toxic metabolites interfering with melanin metabolism, neurochemical factors and specific autoimmunity against melanocytes . Interestingly, patients generally report itch immediately preceding depigmentation of the skin, suggesting a release of histamine and other inflammatory mediators by mast cells in active disease [unpubl. observation]. Furthermore, repigmentation therapies, such as steroids and UV irradiation, are immunosuppressive and the beneficial effect of such treatment indicates the involvement of autoimmunity in vitiligo [7]. Such an involvement of autoimmune reactivity in melanocyte destruction leading to vitiligo is further supported by an association between vitiligo and other autoimmune diseases (fig. 1), most notably Hashimoto’s thyroiditis. Among vitiligo patients, the incidence of Hashimoto’s thyroiditis is increased 2.5-fold compared to the general population. Other diseases reported to associate with vitiligo include diabetes, psoriasis and Raynaud’s disease.

Autoimmune reactivity in vitiligo was initially demonstrated by an increased prevalence of circulating autoantibodies to melanocytes in association with progressive disease [9]. Target antigens reported for the humoral response are primarily of intracellular, melanosomal origin. Antibodies have limited access to target antigens expressed within viable cells, and antibodies to intracellular antigens are likely generated in response to melanocyte damage. An important exception is the membrane receptor for melanin  concentrating hormone (MCHR) [10]. Antibodies binding to membrane antigens expressed exclusively by melanocytes can contribute to melanocyte destruction by antibody-mediated cellular cytotoxicity. In this regard, reduced expression of the complement associated
factors decay-accelerating factor (DAF/CD55), CD59 and membrane cofactor protein (MCP/CD46] has been demonstrated in vitiligo skin,
suggesting that vitiligo melanocytes are increasingly sensitive to complement mediated cytotoxicity.

A contribution of cytotoxic T cells in melanocyte destruction was long overlooked. As melanocytes are dispersed throughout the basal layer of the epidermis,
few T cells are required to target only the perilesional area surrounding actively depigmenting lesions. Immune infiltrates contain CD8 T cells, macrophages and to a lesser extent CD4 T cells. This was first described for patients with overt inflammatory borders surrounding the lesions. Colocalization of disappearing melanocytes was found with CD8T cells that expressed the skin-homing marker, cutaneous leukocyte-associated antigen (CLA), and the T cell activation markers perforin and granzyme B.Infiltrating T cells were also shown to express the IL-2 receptor -chain, CD25. Now commonly associated with regulatory T cells, expression of CD25 is morelikely indicative of T cell activation in progressing vitiligo, where regulatory Tcells are infrequently found in the skin [unpubl. observation].

T cell infiltrates per se are commonly observed in progressive generalized vitiligo, constituting the majority of patients. Vitiligo patients carry increased numbers of peripheral T cells reactive with melanocyte differentiation antigens, tyrosinase, gp100 or MART-1, compared to healthy donors [14–17]. The finding of CLA expression by circulating MART-1-specific T cells in vitiligo patients supports the role of skin-homing autoreactive T cells in the pathogenesis of vitiligo [16].
Melanocyte-specific cytotoxic T cells are also found in the perilesional vitiligo skin during active disease, suggesting their involvement in the depigmentation
process.

As vitiligo is not restricted to humans, but also reported in horses, dogs and chickens, animal models are available to study the etiopathology of the disease
in more detail. In particular the Smyth line chicken has proven useful to establish the involvement of an autoimmune response to melanocytes. Several
observations made in the Smyth Line chicken are in concordance with human disease, including expression of a type I cytokine pattern, cytotoxic T cell
involvement and a contribution of stress as a precipitating factor .

Vitiligo and Melanoma
The contribution of effector T cells to progressive vitiligo provides an interesting link to effective antitumor immunity in melanoma, where the majority of tumor-infiltrating T cells were found to respond to the melanosomal differentiation antigens gp100 or MART-1 [19]. It has long been recognized that vitiligo can develop in melanoma patients with an active immune response to their tumor and visible development of autoimmunity is considered a positive
prognostic factor among melanoma patients . This was recently substantiated by a markedly increased survival rate observed among melanoma patients that developed autoimmunity in response to IFN- treatment.

Clonally expanded T cells as well as autoantibodies reactive with melanocyte differentiation antigens expressed by melanocytes and melanoma cells were found in the circulation of melanoma patients with leukoderma, as well as in autoimmune vitiligo skin. The same holds true for circulating autoantibodies [28]. The development of vitiligo has frequently been observed in response to melanoma immunotherapy by vaccination with melanoma antigens,
or by adoptive transfer of melanoma-specific T cells, suggesting that the anti melanoma immune response can also attack normal melanocytes. In the adoptive transfer studies, infused T cells were found to infiltrate the depigmented skin lesions, indicating that activated T cells can cause human vitiligo. Interestingly, vitiligo was also observed after lymphocyte infusion for relapsed leukemia [34]. The development of vitiligo following vaccination in combination with anti-CTLA-4 blockade or by lymphodepletion prior to adoptive transfer suggests that a decreased regulatory T cell function favors the induction of vitiligo. Taken together, these studies show that immune responses to common antigens present on melanoma cells and normal melanocytes following specific immunotherapy may lead to skin depigmentation and tumor rejection.

The frequency of MART-1-reactive T cells among melanoma patients is not significantly different from vitiligo patients. Similar numbers of anti-
MART-1 T cells from vitiligo patients, however, effectuate a higher avidity towards peptide-loaded target cells than T cells from melanoma patients, and a distinctly higher cytotoxicity of vitiligo T cells towards melanoma cells has been observed [35]. This difference in the avidity of the T cell response in vitiligo compared to melanoma may result from T cell tuning and activation mechanisms in vitiligo patients, as described below . This is of particular interest as we study the T cell receptor (TCR) genes expressed by vitiligo and melanoma lesional T cells. Similarity among particularly -chains of TCR reactive with MART-1 among both T cell populations has been reported. As suggested by Palermo et al. [35], affinity maturation characterized by restricted TCR repertoires and increased avidity may be initiated in either disease, but is not likely to progress in the immunosuppressive melanoma environment.In animals that develop spontaneously regressing melanomas, such as Lippizaner horses or the Sinclair swine, tumor regression is similarly associated with marked depigmentation [38]. Moreover, new antimelanoma vaccines tested in mice similarly support a link between immune reactivity to normal and transformed
melanocytes. In fact, vaccine-induced depigmentation serves as a model for autoimmune vitiligo. For example, after adoptive transfer of high-avidity T cells against tyrosinase derived from albino mice, recipient pigmented mice develop depigmentation with a distribution pattern strikingly similar to vitiligo. Vaccination of gp100-specific TCR transgenic mice bearing large subcutaneous B16 melanoma tumors with gp100 peptide and IL-2 induced T cell activation in vivo, leading to tumor regression as well as vitiligo. Moreover, another murine model of vaccination with GM-CSF-producing B16 melanoma cells demonstrated that the efficacy of antitumor therapy correlated with the frequency of tyrosinase-related protein-specific cytotoxic T cells in the periphery,as well as with the extent of autoimmune skin depigmentation.

The beneficial effect of a decreased regulatory T cell function either by anti-CTLA-4 blockade or by lymphodepletion prior to adoptive transfer on the development of
vitiligo and melanoma regression was also demonstrated in these murine models. Interestingly, progressive depigmentation can be observed in mice treated with anti melanoma vaccines in the absence of tumors, as first demonstrated by Overwijk et al. This principle is illustrated in figure 2. In the pathogenesis of vitiligo, T cells are adequately activated to exert effect or function in vivo. Therefore, the activated T cell response in vitiligo represents a clinically relevant example of an effector T cell population with proven in vivo efficacy, that can serve as an example for antimelanoma T cell responses.

Challenges to the Skin: The Elicitation Phase

Approximately 50% of vitiligo patients experience a Koebner phenomenon, exhibiting new and expanding lesions initiated from a site of previous
trauma, excessive sun exposure or contact with bleaching phenols . These data support the concept that stress to the skin can precipitate
the disease. Trauma to the skin can locally generate oxygen radicals, and a reduced ability of vitiligo melanocytes to detoxify highly reactive radicals has been proposed, supported by observations of reduced dihydrobiopterin synthesis, increased H2O2 stress and reduced catalase activity in vitiligo skin [43]. These findings have ultimately led to the development of pseudocatalase treatment for vitiligo to restore the redox balance. Interestingly, protein disulfide isomerase
(PDI) is an integral part of the major histocompatibility complex (MHC) class I loading complex, and the activity of this enzyme affects the oxidation status of
the disulfide bond in the groove of the HLA-A*0201 molecule, thereby determining its accessibility to peptides.

It can thus be hypothesized that an altered redox potential following stress influences the efficiency of peptides binding the groove of MHC class I and thereby affects the visibility of the cell to infiltrating effector T cells. Among patients not exhibiting the Koebner phenomenon, it is well possible that an emotionally traumatic event such as a recent death in the family can trigger the onset of disease. Emotional stress (anxiety) and physical stress (trauma) are generally associated with elevated plasma levels of proopiomelanocortin (POMC) the precursor molecule to melanocortin peptides, including ACTH, - and -melanocyte-stimulating hormones (MSH), and -endorphin. In the skin, keratinocytes and melanocytes can also produce these melanocortins
in response to UV radiation, which subsequently enhance the biosynthesis of eumelanin in melanocytes [45]. -MSH is not only known to stimulate melanogenesis and melanocyte proliferation, it can also suppress immune responses through its effects on melanocortin receptor-expressing cells. In this respect -MSH induces down regulation of cytokine production and the expression of costimulatory molecules on dendritic cells. Surprisingly, vitiligo patients display reduced plasma levels of -MSH, which suggests decreased POMC processing in vitiligo skin .

Vitiligo patients also accumulate H2O2 in the skin, which oxidizes -MSH and further decreases its availability.
Conversely, -MSH can protect melanocytes from oxidative damage by its antioxidant effect during melanin synthesis, and therefore the reduced availability
of -MSH in vitiligo skin may enhance oxidative stress in vitiligo skin. Reduced levels of -MSH in vitiligo may therefore facilitate a local immune
response against melanocytes . The situation of oxidative stress puts intracellular protein synthesis on hold in favor of heat shock protein (HSP) synthesis, offering epidermal cells protection from impending apoptosis. Among protein expression induced by stress, HSP70 is actively secreted by melanocytes and stimulates dendritic cells to cross-present chaperoned antigens, thereby initiating an immune response against melanocytes [49]. This is of particular relevance for forms of stress with a selective effect on melanocytes, such as exposure to bleaching phenols with a structural similarity to substrates of melanogenesis. In this respect, 4-tertiary butyl phenol (4-TBP), a causative agent in occupational vitiligo, appears to be metabolized by enzymes of the melanogenic pathway converting the compounds into cytotoxic compounds exclusively in melanocytes .

At lower concentrations, 4-TBP suppresses melanogenesis through competitive inhibition of tyrosinase, whereas at higher concentrations the compound is selectively cytotoxic towards melanocytes [50]. Similarly, monobenzyl ether of hydroquinone induces depigmentation upon topical application [51]. This depigmentation treatment has been used for vitiligo patients with extensive vitiligo.

Phenolic agents, UV and to some extent mechanical injury all increase local levels of reactive oxygen species. Among these reactive oxygen species, nitric oxide may enhance depigmentation by reducing the adhesive capacity of melanocytes . Nitric oxide is toxic to melanocytes and nitric oxide synthase is inhibited by MSH, suggesting that abundant nitric oxide contributes to vitiligo pathogenesis . Other eliciting factors in vitiligo include hormones, such as estrogens, and neural factors, such as catecholamines, of which increased levels were associated with active vitiligo. The contribution of this and other mechanisms may be elucidated by studying the mode of cell death in vitiligo melanocytes. The main mechanism of melanocyte death is likely apoptosis, although the sparcity of dying melanocytes in any given stretch of skin complicates capture apoptotic melanocytes in the skin in situ . This hypothesis is supported by the fact that melanocyte-specific T cells are frequently found in perilesional vitiligo skin and that T cells are known to kill target cells by apoptosis through the release of granzyme B. Moreover, increased expression of integrins and decreased apoptosis were shown to correlate with melanocyte retention in cultured skin substitutes .

Immune Activation
In response to 4-TBP exposure, we have found that melanocytes upregulate expression of HSP70 and a larger proportion of the HSP70 appears to be
secreted by vitiligo melanocytes than by control melanocytes. Since HSP70 is known to enhance immunity to associating proteins, as shown in melanoma vaccination studies of HSP70 bound to melanosomal proteins, it may also be involved in accelerating depigmentation in vivo [49]. In response to HSP70, dendritic cells upregulate expression of the TNF family member TRAIL, enabling dendritic cells to kill melanocytes with elevated expression of TRAILR1 and TRAILR2 in response to 4-TBP. An indication of the in vivo relevance of these findings is the altered, patchy expression of HSP70 in lesional epidermis (in 3 of 3 patients) compared to nonlesional skin (fig. 3).

HSP70 is known to induce dendritic cell activation by binding to HSP receptors on these cells [49]. CD91, a receptor for HSP70, was abundantly expressed among vitiligo-infiltrating dendritic cells (data not shown), indicating that HSP-mediated dendritic cell activation through receptors for HSP70 and other relevant immunogenic stress proteins may be involved in the pathogenesis of vitiligo. In the presence of HSP70, an increased number of melanocyte-reactive T
cells is recruited from skin-draining lymph nodes and upon arrival in the skin, the cytotoxic effector function of these T cells is enhanced. Moreover, extracellular
HSP70 can induce the expression of the costimulatory molecule ICAM-1 specifically in melanocytes among a culture of ICAM-1-negative keratinocytes
[unpubl. observation]. In line with the proposed involvement of HSP70 in vitiligo, ICAM-1 is also consistently upregulated in perilesional vitiligo skin .

As a costimulatory pathway, ICAM-1/LFA-1 interactions determine in part the interaction between a T cell and its target, and thus the avidity of the T cell
response. In this regard we have proposed that differential ICAM-1 expression by melanocytes in vitiligo can contribute to T cell-mediated depigmentation [57].
Costimulation is also determined by interaction of CD28 with either B7 molecules on the melanocyte cell surface or its alternative, immunomodulating ligand CTLA-4. Genetically determined CTLA-4 deficiencies in autoimmune disease (including vitiligo) may result in preferential binding of CD28 to B7, supporting effective costimulation rather than CTLA-4-mediated immunoregulation [58]. The cytokine microenvironment in perilesional vitiligo skin is also conducive for dendritic cell activation and T cell-mediated cytotoxicity. Macrophages and dendritic cells are abundantly present in depigmenting vitiligo skin. The activation state of macrophages and dendritic cells within vitiligo skin has not been described to date. Since Langerhans cells, dendritic cells and melanophages
may each be involved in phagocytosis, antigen processing and/or presentation of melanocyte-derived antigens in skin-draining lymph nodes, it is important to assess the physiology of these cell types within perilesional areas of actively depigmenting skin. In this respect it has been shown that Langerhans cells in
perilesional vitiligo skin express elevated levels of -1,6-branched N-glycans, which appears to be indicative of Langerhans cell activation in progressive disease
[Pawelek, pers. commun.]. Similar glycosylation patterns expressed by macrophages are considered a negative prognostic indicator in breast cancer and
melanoma.

The apparent discrepancy between -1,6-branched N-glycan expression in active vitiligo representing immune activation and its expression in tumors generally representing a lack of effective immunity is best understood realizing that the glycosylation pattern reflects the abundance of cells engaged in
phagocytosis, regardless of cell type, whereas tumor-infiltrating macrophages and vitiligo-derived Langerhans cells differ in their ability to activate a specific
immune response [60]. Considering that Langerhans cells are located in close proximity to melanocytes in the epidermis, that in vitiligo lesional skin Langerhans cells are predominantly located in the basal layer of the epidermis, and that reduced contact sensitization was noted for lesional vitiligo skin, it is
likely that Langerhans cells are involved in vitiligo etiology by processing and cross-presentation of melanocyte antigens.

A contribution of immune activation to progressive depigmentation is also supported by expression of MHC class II in perilesional epidermis. Perilesional
expression of HLA-DR is relevant, as melanocytes can present antigens in the context of MHC class II. Besides presenting endogenous melanosomal peptides
in the context of MHC class II, melanocytes are also capable of processing exogenous antigens and presenting them in the context of MHC class II. This is
likely relevant to explain the extraordinary link to depigmentation observed in tuberculoid leprosy if melanocytes are killed after processing and presenting
immunodominant antigens of Mycobacterium leprae, including hsp65. In support of this theory, we have demonstrated class II restricted killing of hsp65 presenting
melanocytes in vitro. Several data support an abundance of type 1 cytokines in perilesional skin, indicating a cell-mediated immune response to melanocytes.

The polarization of the T cell response towards a type 1 response during progression of depigmentation in vitiligo has been demonstrated in a study of vitiligo-infiltrating T cells that were isolated and cultured from vitiligo skin. In this study, T cell clones derived from vitiligo-infiltrating T cells skin predominantly
exhibited type 1-like cytokine secretion profiles. Interestingly, already in uninvolved skin of these vitiligo patients microdepigmentation was observed in situ,
correlating with the extent of type 1 polarization of local skin-derived T cells. The ratio of CD4 to CD8T cells is decreased in peripheral blood of vitiligo
patients regardless of disease status [62], signifying a relative increase in cytotoxic T cells. Immunohistochemical analysis of skin tissue sections similarly
revealed a decreased CD4 to CD8T cell ratio, indicating that the shift in the balance between CD4 and CD8 T cells cultured from vitiligo skin was not due to differences in the in vitro expansion capacity of these T cell subsets. Based on these findings, the cytokine profiles observed among cultured cells
are considered representative of those found in progressive vitiligo skin. Moreover, the type 1 cytokine secretion patterns of T cells in vitiligo were confirmed
in the prime animal model for vitiligo, the Smyth line chicken [18].

Cytotoxic T cells infiltrating the skin in patients with progressive vitiligo are found in close proximity to remaining melanocytes in the skin [11]. The
CD8 T cells derived from progressively depigmenting skin were cytotoxic towards autologous melanocytes in vitro. We have recently found that melanocyte-specific T cells can induce apoptosis of melanocytes in situ in nonlesional skin of vitiligo patients [unpubl. data], indicating that the effector phase of melanocyte destruction is mediated by cytotoxic T cells.

It should be noted that T cells reactive with melanocyte differentiation antigens can be found in the peripheral blood of healthy donors and their
presence per se can therefore not be considered evidence of autoimmune phenomena. For the MART-1 antigen, it was shown that a large pool of MART-1-
specific T cells are generated in the thymus, which circulate as naïve T cells in the peripheral blood of healthy individuals [64]. Tumor-antigen-driven activation
and expansion of this T cell pool is seen in melanoma patients and may also occur during vitiligo development, where activated MART-1-specific T cells
are found in the skin. In autoimmune disease, T cells expressing high-affinity TCR fail to be clonally deleted in primary lymphoid organs and as a result, high-avidity T cells recognizing self antigens enter the circulation T cells. This is observed in autoimmune polyendocrinopathy, where the development of vitiligo highlights
the severity of disease [65]. Negative selection is dependent at least in part on presentation of peripheral antigens in the thymus, allowing only T cells with
low avidity towards encountered antigens to enter the periphery . In this respect, autoimmune regulator-dependent presentation of the melanocyte differentiation
antigen gp100 has been demonstrated. It is possible that a particular autoimmune disease reflects a lack of presentation of a select antigen or set
of antigens in the thymus, however, additional mechanisms are likely to contribute to organ-specific autoimmunity. For example, selection against high affinity
TCR can be masked by T cell tuning [36]. Here high-avidity T cells with high-affinity TCR pass clonal selection criteria by downplaying their avidity in the thymus, for example by expression of CD5 to reduce TCR signaling, or by altering CD4 or CD8 expression levels during selection. Once tuned, T cells migrate to the site expressing their native antigens and these cells propagate and undergo limited affinity maturation to express higher-affinity TCR.

Although T cell tuning may explain how high-avidity T cells enter the circulation, it does not automatically explain autoimmunity. When tuned high-avidity
T cells enter the circulation, the hyporesponsive state must be overcome for autoimmunity to arise. This can occur when the target antigen is overexpressed as in melanoma. Alternatively, the danger model proposed by Matzinger suggests that any given antigen, self or nonself, evokes an immune response
when it is presented to the immune system in combination with a danger signal. This is reflected primarily in the state of activation of antigen-presenting cells, and dendritic cell activation signals thus constitute a turning point in the immune response. Mechanical injury, UV exposure and contact with bleaching phenols may thus precipitate vitiligo by inducing such danger signals leading to activation of dendritic cells. Depending on the activation signal, dendritic cells
induce type 1 T cell responses, corresponding to the type 1 cytokine expression patterns observed in progressive vitiligo.

Immune Regulation
Differential progression of the immune response among vitiligo and melanoma patients is also determined by regulatory T cells. Melanoma
immunotherapy studies have demonstrated that depletion or suppression of regulatory T cells improves the induction of antimelanoma immune responses.
Regulatory T cells apparently interfere with antitumor reactivity in melanoma patients, preventing a successful outcome of antitumor immunotherapy.
Indeed, melanoma tissue contains the immunosuppressive cytokines IL-10 and TGF-, indicative of immunoregulation taking place within the tumor
microenvironment.

Where melanocyte-specific T cells occasionally infiltrate the skin, local immune suppression by skin-resident regulatory T cells prohibits these autoreactive
T cells from exerting effector functions in healthy individuals. Regulatory/suppressor T cells expressing immunosuppressive cytokines including
IL-10 and TGF- are continuously present in the skin, keeping ongoing immune responses in check . The regulatory T cells thereby preserve skin
homeostasis, which can be overruled in inflammatory conditions. In melanoma tissue, however, the level of immune suppression is more pronounced and
impairs most of the effector function of antitumor immune responses. In addition, local immunosurveillance of the skin immune system against the outgrowth
of melanoma cells, which is present in healthy individuals, is actively suppressed in melanoma patients, allowing tumor outgrowth.

Vitiligo patients generally lack effective immunoregulation, which allows high-avidity T cells to attack melanocytes in the skin. The association observed
between vitiligo and other autoimmune diseases is indicative of this lack of immune regulation. In the microenvironment of the vitiligo skin, infiltrating T
cells may undergo a process analogous to affinity maturation among B cells, resulting in T cells with TCR of increasing affinity, which cause progressive
depigmentation. Recent data indicate that regulatory T cell function is altered in vitiligo, and in the absence of functional, skin-infiltrating regulatory T cells the
ongoing immune response is perpetuated [unpubl. data]. Such intrinsic defect may also explain the marked difference in distribution patterns of the lesions in
patients with autoimmune vitiligo in contrast to patients that develop progressive depigmentation secondary to their disease, as in melanoma.

Intervention

(Table 1)

A definitive cure for vitiligo has yet to be found. Currently, successful therapeutic measures require a situation of stable disease to repopulate lesional vitiligo skin with melanocytes by a variety of surgical skin grafting methods in combination with (narrow-band) UVB radiation. The problem remains that patients with a
propensity to develop vitiligo run the risk of recurrent disease, and curing vitiligo is clearly a two-tiered process consisting of halting progression of depigmentation
followed by repigmentation of lesional skin. Effective measures are available to repopulate stable vitiligo lesions by surgical transplantation measures in combination with UVB treatment to stimulate melanocyte migration, proliferation and melanization . The perceived inefficacy of available vitiligo treatments results
from a lack of focus on halting disease progression, most notably by interfering with autoimmune reactivity to melanocytes. Several principal steps can be taken
towards intervention, as summarized in table 1. In the end, a two-tiered approach is necessary to successfully treat vitiligo.

Acknowledgments
This work was supported in part by NIH/NCI grant RO1CA109536, NIH/NIAMS
grant RO3AR050137 and support from the National Vitiligo Foundation (USA) to C.L.P.

R.M.L. is supported by grants from the Netherlands Organisation for Scientific Research
(NWO-VIDI 016.056.337) and the Dutch Cancer Society (UVA2006-3606).

Source:

The relationship between stress and vitiligo: Evaluating perceived stress and electronic medical record data

Abstract

Vitiligo is a T-cell mediated skin disorder characterized by progressive loss of skin color. In individuals genetically predisposed to the disease, various triggers contribute to the initiation of vitiligo. Precipitating factors can stress the skin, leading to T-cell activation and recruitment. Though hereditary factors are implicated in the pathogenesis of vitiligo, it is unknown whether precipitating, stressful events play a role in vitiligo. To understand this, we utilized a validated perceived stress scale (PSS) to measure this parameter in vitiligo patients compared to persons without vitiligo. Additionally, we probed a clinical database, using a knowledge linking software called ROCKET, to gauge stress-related conditions in the vitiligo patient population. From a pool of patients in an existing database, a hundred individuals with vitiligo and twenty-five age- and sex-matched comparison group of individuals without vitiligo completed an online survey to quantify their levels of perceived stress. In parallel, patients described specifics of their disease condition, including the affected body sites, the extent, duration and activity of their vitiligo. Perceived stress was significantly higher among vitiligo individuals compared to those without vitiligo. ROCKET analyses suggested signs of metabolic-related disease (i.e., ‘stress’) preceding vitiligo development. No correlation was found between perceived stress and the stage or the extent of disease, suggesting that elevated stress may not be a consequence of pigment loss alone. The data provide further support for stress as a precipitating factor in vitiligo development.

Introduction

Vitiligo is an acquired skin disorder characterized by a progressive loss in skin pigmentation due to the loss of melanocytes, the pigment producing cells in the skin. Among other tissues, melanocytes are present in the inner ear, eye and mucosal membranes [13] and, are therefore, also affected due to vitiligo [4]. Vitiligo affects around 0.5% of the global population and, although all ethnic groups are similarly affected, it is more noticeable and more severe in dark-skinned individuals [56]. While the onset of vitiligo usually occurs during adolescence [6], individuals developing vitiligo during adulthood have been reported [78]. Though hereditary factors predispose patients to depigmentation, in adult onset vitiligo, a relatively greater contribution to disease etiology can be attributed to stress [910].

Vitiligo predisposition is defined by variant sequences at loci associated with both the innate and adaptive immune system as well as to loci associated with melanogenesis and apoptosis [1115]. Precipitating factors have been acknowledged, including exposure to sunlight or skin trauma, leading to oxidative stress in melanocytes [1619] and T-cell mediated autoimmune responses [2021]. Indeed, while vitiligo has been established as an autoimmune entity, [21], the mechanism connecting the initiating event(s) to the induction of anti-melanocyte T-cell immunity is unknown.

Physical or environmental stressors are reported in the onset and disease progression of vitiligo [2224]. In the event of a sunburn or exposure to certain chemicals or skin trauma, free radicals and hydrogen peroxide are generated [25], and in individuals who are predisposed to vitiligo, this leads to an activation of the immune system that generates melanocyte-specific cytotoxic responses. Heat shock proteins (HSP) are cellular stress response proteins that protect a cell under stressful conditions [26]. Notably, among the family of HSP, inducible HSP70 (HSP70i) is secreted by live cells under stress [27]. Previous work from our lab showed a critical role of HSP70i from the melanocytes in accelerating autoimmune vitiligo [2829]. Stressed cells secrete HSP70i and in the extracellular milieu, HSP70i can activate dendritic cells (DCs) and aid in antigen cross-presentation [30], resulting in cytotoxic T cell responses to melanocytic antigens.

Psychological stressors also play a role in vitiligo [2324]. Events such as death of a family member, work and financial problems have been associated as preceding factors to the onset of vitiligo [24]. In addition, vitiligo patients experience severe psychological effects [3132] and exhibit anxiety [33], depression [13], social stigma [34] and impaired quality of life [3536]. Stress increases the levels of catecholamines, neuropeptides, and cortisol that are higher in vitiligo patients [3739] suggesting their role in the pathogenesis of vitiligo.

To understand the association of stress in vitiligo patients, in this study, we used a validated questionnaire [40] to assess levels of perceived stress (PSS) [41] in vitiligo and healthy age- and gender- matched individuals. Patients were asked some additional questions about their condition, and ROCKET software was used to probe a patient database to explore the prevalence and chronology of stress related conditions among vitiligo patients. The data serve to correlate stress and vitiligo, providing support for the concept that stress can influence progressive depigmentation of the skin.

Methods

Sample size

One-hundred vitiligo patients who previously emailed us about our vitiligo research efforts were contacted and invited to participate in this study. The study was approved by the Loyola University Chicago Institutional Review Board. They were also asked to identify a person in their direct environment (not a blood relative) of the same sex and of the same age +/- 5 years. Though some patients provided personal contact information, the questionnaire responses could not be linked to the submitter.

Vitiligo questionnaire

A previously published questionnaire was provided to the patients to assess and record their disease etiology [42]. Patients diagnosed with vitiligo by a physician were requested to answer questions related to their condition including their sex, disease activity, and lesional distribution. Data are shown in S1 Table.

Perceived stress scale (PSS) and scoring

The PSS is a 10-item scale, which asks participants to rate the degree to which life experiences over the past 30 days are perceived as uncontrollable. PSS is a widely used measure of general perceived stress [40]. Reliability (stability) is 0.85 and Cronbach alphas range from 0.75–0.86 [43]. The threshold for stressed individuals is set to a PSS score of 15 as described [44]. Data are shown in S1 Table.

Questionnaire administration

The vitiligo and PSS questionnaires were electronically uploaded to Google Drive. Study participants were given access to the Drive to record their own responses, while maintaining anonymity.

Relationship of clinical knowledge and events tool (ROCKET)

ROCKET software can be used to probe the Clinical Research Database or ‘CDRB’ to query a limited dataset (LDS) repository of electronic patient records without personal identifiers, covering about 9 million encounters between 1/1/2007 and 9/30/2015. The software allows the investigator to locate information related to a particular patient population (here: vitiligo patients) and compare outcomes to those among unaffected controls. All patients at all encounter types where an ICD9 code of 709.1 or an ICD10 code of L80 was assigned are included. This covers a target population of just over 1000 subjects. As psychological stress and metabolic syndrome (metabolic stress) are associated with vitiligo [4547], anemia and depression (markers for psychological stress) and hypertension and hyperlipidemia (markers for metabolic stress [48]) conditions were probed. The requested information can include demographics, encounter information, order codes, chronic disease status and calculation of comorbidities, medication and clinical lab results.

Statistical analysis

PSS among healthy and vitiligo patients, and among male and female vitiligo patients were compared. The responses from the vitiligo questionnaire were correlated to outcomes from the PSS questionnaire. Unadjusted odds ratios (OR), a measure of association between an exposure and an outcome, and 95% confidence intervals (CI) were computed for stress-related conditions in the vitiligo group compared to the general population group. A paired t-test or Mann-Whitney U-test was used to determine differences between two groups, whereas ANOVA was used to determine differences among three or more groups. Pearson’s correlation coefficients were computed to determine associations between continuous variables. Statistical analysis was performed using GraphPad Prism Software (V8), and the odds ratio were computed using STATA.

Results

Vitiligo patients experience an increase in perceived stress

We hypothesized that vitiligo patients experience more stress than individuals without vitiligo. Among 102 participating patients, 54.8% were male and 45.2% were female. At the time of completion of the PSS, 63.5% of patients described their disease activity as active, while 31.7% described their disease as stable disease and the remainder (4.8%) reported regressing disease. As patients are most distressed about vitiligo developing in the more visible, sun-exposed areas of their skin (unpublished), we tallied vitiligo development in different body parts. Among participants, 75% or more of patients developed vitiligo of their hands and of their face, which is commonly perceived as the most impactful by patients. Other commonly visible body parts include the extremities, which affected 50% or more of the sample at the time of data collection. The mean PSS score for vitiligo patients was 19.3, whereas, age and sex-matched controls had a mean PSS score of 13.8 (Fig 1, n = 22; P = 0.0396 in a paired t-test). A 2009 US probability sampling of adults documented a mean PSS score of 15.2 [44], suggesting that the present cohort of vitiligo patients had elevated PSS scores. That is, they perceived events in their life to be less manageable. We thus probed the full population of participating vitiligo patients for a more in-depth evaluation of levels of perceived stress.

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PSS scores of healthy versus and vitiligo age-matched patients were compared. Sample includes both males and females (n = 25). The dashed line indicates the cutoff score for stressed individuals (at PSS = 15). Statistical significance for PSS among the populations was determined by paired two-tailed t-test, P = 0.0396.

 

https://doi.org/10.1371/journal.pone.0227909.g001

 

Female vitiligo patients perceive more stress than affected males

Among all vitiligo participants, we compared the PSS scores between males and females (n = 55 and 47, respectively). While both groups reported a mean PSS score indicating stressed population (Fig 2A, PSS males 19.4 and PSS females 21.53), female patients perceived significantly more stress compared to male patients (P = 0.0143). An evaluation of the relationship between PSS scores per group relative to either duration of vitiligo (Fig 2B) or age (Fig 2C), revealed no significant correlations in either male or female patients.

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(A) PSS scores were compared between male (n = 56) and female (n = 47) vitiligo patients. Statistical significance was determined by Mann-Whitney test, P = 0.0143. (B-C) Scatter plot illustrates relationship between PSS scores and vitiligo duration (B, P = 0.7955); and between PSS scores and age (C, P = 0.8746). (B) and (C) include both male and female vitiligo patients. Dashed line indicates the PSS cutoff score for stressed individuals (at PSS = 15).

 

Perceived stress is not related to disease activity

Almost two-thirds of patients evaluated were in an active phase of their disease, with others experiencing disease stability or regression. There was no difference in PSS values among patients experiencing differences in disease activity (Fig 3A); thus, we next examined the possibility as to whether perceived stress may be associated with self-reported extent of depigmentation (Fig 3B). The percentage of self-reported depigmentation was divided into four categories, based on percent of depigmentation (0–25; 25–60; 51–75; and 76–100). Although no significant correlation was observed between percentage of depigmentation and PSS scores, interestingly, a wide distribution of PSS among the 0–25% depigmentation group was observed. This figure also demonstrates that PSS scores are not related to the age of participating patients. As vitiligo development is commonly believed to initiate most frequently in the second decade of life, this would suggest that patient age might reflect the duration of disease. To determine if this is the case, we probed the anonymized clinical database available at Loyola using ROCKET software.

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Fig 3. Perceived stress is not associated with disease progression and self-reported depigmentation.

(A) Violin plots depicting the distribution of PSS among the three stages of vitiligo progression. Colored dashed line and number indicate the median values. (B) Violin plots depicting the distribution of PSS in the four categories of self-reported depigmentation. Dashed line indicates the PSS cutoff score for stressed individuals (at PSS = 15).

Vitiligo is primarily diagnosed between two distinct age groups

To understand how the timing of other diagnoses and treatment relate to vitiligo development, we probed and plotted the age at diagnosis among vitiligo patients in the ROCKET database (Fig 4). The results revealed a biphasic pattern, the first one covering the first 2 decades of life peaking slightly later among males, than among females and the second peaking in the 5th decade of life. This is not dependent on the number of patients registered in the system for every age group, as the biphasic peaks were not observed for other conditions (unpublished). Instead, the distinct peaks would suggest that different etiologic factors prevail in different phases of life. This provided a framework to use the ROCKET database to probe other parameters among vitiligo patients.

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Fig 4. Bi-phasic age groups of vitiligo diagnosis.

The ROCKET database was probed to determine the number of patients diagnosed with vitiligo. Total, male and female vitiligo populations are shown.

The timing of metabolic stress and not psychological stress can support a causative relationship among vitiligo patients

Hypothyroidism is the most common autoimmune disorder associated with vitiligo [4950]. To confirm this, we initially probed the database to determine whether hypothyroidism is increasingly prevalent among vitiligo patients (not as a marker for metabolic stress). Consistent with previous literature, we observed that the percentage of patients (11.69% in vitiligo vs 3.19% in general) and the odds (OR 4.02, CI 3.29 to 4.88) of hypothyroidism diagnosis is higher among vitiligo patients (Fig 5A). We then probed the database for the prevalence of hypertension and hyperlipidemia among vitiligo patients compared to the general patient population as a possible sign of metabolic stress among patients [51]. Indeed, the percentage of being diagnosed with hypertension (20.30%; OR 2.09, CI 1.79 to 2.44) and hyperlipidemia (22.90%; OR 2.81, CI 2.42 to 3.26) were higher among vitiligo patients (Fig 5A). Upon probing the timing of diagnosis, more patients were diagnosed with these metabolic disorders prior to their vitiligo diagnosis than after, suggesting a causative factor for vitiligo (Fig 5B). As a possible sign of psychological stress, the database was probed for patients diagnosed with depression and anemia [5255]. Interestingly, while the percentage of patients and the odds of being diagnosed with depression (9.18%; OR 2.3, CI 1.84 to 2.85) and anemia (16.62%; OR 2.62, CI 2.22 to 3.1) were high among vitiligo patients (Fig 5A), the timing prior to and after vitiligo showed a similar percentage of patients diagnosed (Fig 5B). This would suggest that both conditions might involve common etiologic factors.

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Fig 5. Prevalence and timing of metabolic stress parameters among vitiligo patients.

(A) The odds of expressing a comorbidity among vitiligo patients, compared to the general patient population expressed as an odds ratio. A value of 1 indicates odds equal to the general patient population. Values greater than 1 indicates greater, and lower than 1 indicates smaller odds. The error bars indicate the upper and lower confidence intervals (B) Timing of diagnosis for indicated comorbidities compared to the diagnosis of vitiligo among patients.

To further support the role of metabolic stress in vitiligo, we probed the database for patients prescribed beta-blockers and statins [5657]. In line with our above findings, we observed that the percentage of patients and the odds of statins (17.49%; OR 1.93, CI 1.64 to 2.27) and beta-blockers (16.14%, OR 5.07, CI 3.37 to 7.33) prescription were higher among vitiligo patients (Fig 6A). In addition, more patients were prescribed the drugs prior to their vitiligo diagnosis, than after (Fig 6B). These differences are even more impressive when accounting for patient age at vitiligo diagnosis (Fig 4). Taken together, these results indicate that signs of (metabolic) stress are more frequently observed among vitiligo patients, and largely precede disease diagnosis. Thus, patients in part develop disease following signs of stress, producing a dataset informative of a potentially causative relationship.

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Fig 6. Prevalence and timing of prescription drugs for metabolic stress.

(A) Odds ratio depicting the odds of being prescribing statins of beta blockers among vitiligo patients compared to the general patient population. The error bars indicate upper and lower confidence intervals. (B) Timing of first drug prescription compared to the timing a vitiligo diagnosis was made among patients.

Discussion

To understand whether vitiligo associates with stress, the PSS and ROCKET analyses in our study newly revealed that ‘metabolic’ stress precedes and might thus contribute to vitiligo. Indeed this is in line with studies suggesting environmental and psychological stressors are triggers for the onset and progression of vitiligo [24]. Although the exact mechanism(s) by which stress influences vitiligo remains unknown, as discussed earlier, both environmental and psychological stress result in autoimmune vitiligo [21].

The PSS questionnaire is a validated tool to measure perceived stress and several studies have used this tool to estimate perceived stress in patients, including those with autoimmune disease [5859]. Among the vitiligo patients who participated in this study, female patients perceived significantly more stress than male patients did. Other studies have also found female patients to be increasingly impacted by stress [2231]. Whether women are more conscious of their stress or there are other underlying factors that attribute to their perception remains uncertain. In vitiligo, the depigmentation itself can also cause stress and in fact, self-reported depigmentation was the highest on the face and hands (S1B Fig) supporting this former notion. In the current study, neither age, nor duration of vitiligo or disease status were associated with perceived stress. PSS only measures a person’s perception of stress over the past month. It does not capture cumulative stress and it does not capture the quantity of negative life events. Thus, this limits the ability to make any inferences as to the role of cumulative life stress, which is more likely to influence vitiligo development and/or progression. It is also likely that social support and adaptive coping may buffer the impact of stress associated with vitiligo, which may explain why levels of perceived stress did not associate with vitiligo duration or characteristics.

Stress and stressors can have a profound impact on autoimmunity [60]. The timing and release of stress hormones regulate the pro- and anti-inflammatory cytokine balance that dictate immunoprotective or immunosuppressive activity [6162]. Acute or short-term stress results in an immunoprotective environment whereas chronic or long-term stress commonly result in an immunosuppressive environment [63]. Chronic stressors can, however, also promote a proinflammatory environment, resulting in dysregulated immune responses that might lead to autoimmunity [6364]. A limitation in this study is that no biochemical assays or cytokine profiles were investigated for these patients to correlate them to the PSS or vitiligo questionnaire. However, perceived stress did not correlate with disease state or duration. As stress hormones are increased in vitiligo patients [3738] and a cytokine imbalance has been assigned to oxidative stress in melanocytes, the data collectively prompt studies of a role for chronic stress in disease development.

The ROCKET analyses revealed a bimodal age of vitiligo diagnosis with the first age group peaking around 10–20 years and the second age group peaking around 50–60 years. First presented by us at the International Pigment Cell and Melanoma Research Conference in 2017, a recent GWAS study has since solidified this finding regarding vitiligo onset [65]. Diagnosis occurring at two different phases of life could implicate different etiological factors. Frequency of a stressful event was higher among adult patients compared to childhood onset [9], suggesting that stress is a precipitating factor particularly for adult onset vitiligo. In fact, the death of a loved one and work/financial problems are the most common stressful life events reported among adult vitiligo patients, and such events are consistently associated with a poor quality of life and depression [1366]. While the percentage of population affected and the odds of having depression were higher among vitiligo patients, the percentage of patients that were diagnosed with depression prior to and after vitiligo were similar in our study. This suggests that depression is neither a causative factor nor a consequence of vitiligo, but rather these conditions may share a common etiological factor. Metabolic syndrome is a cluster of disorders presenting with aberrant metabolism resulting in an increased risk of cardiovascular disease [51]. Chronic stress and stressful events present with a high risk of metabolic syndrome [6769], and vitiligo patients are at a higher risk of developing metabolic syndrome [4670]. Consistent with previous findings, the ROCKET analyses revealed that the percentage of patients and the odds of developing metabolic disorders, hypertension and hyperlipidemia, were higher among vitiligo patients (Fig 5), and these disorders are linked to oxidative stress and autoimmunity [7175]. Similarly, the odds for being prescribed statins and beta-blockers for cardiovascular disease, the major risk for metabolic syndrome, were higher for vitiligo patients. Taking into account the timing of diagnosis, patients were more frequently diagnosed with hypertension and hyperlipidemia, and more frequently so prior to their vitiligo diagnosis. This was accompanied by a greater percentage of patients prescribed statins and beta-blockers prior to their vitiligo diagnosis. A limitation of the current ROCKET analyses was that only a subset of comorbidities were available for analysis of the vitiligo patient cohort. Further, lifestyle factors, such as health behaviors, are important factors that contribute to the chronic diseases we probed, and must be considered in future studies investigating any associations of these diseases with onset and progression of vitiligo. Collectively, our data suggest that metabolic stress might be involved with the onset and progression of vitiligo. This prompts further analysis, including measurement of physiologic parameters.

In conclusion, the findings from this study indicate that vitiligo patients have high levels of perceived stress. In patients predisposed to vitiligo, metabolic and psychological stress might influence the onset and progression of vitiligo.

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Image Credit: Polina Tankilevitch

Vitiligo: interplay between oxidative stress and immune system

Abstract

Vitiligo is a multifactorial polygenic disorder with a complex pathogenesis, linked with both genetic and non-genetic factors. The precise modus operandi for vitiligo pathogenesis has remained elusive. Theories regarding loss of melanocytes are based on autoimmune, cytotoxic, oxidant–antioxidant and neural mechanisms. Reactive oxygen species (ROS) in excess have been documented in active vitiligo skin. Numerous proteins in addition to tyrosinase are affected. It is possible that oxidative stress is one among the main principal causes of vitiligo. However, there also exists ample evidence for altered immunological processes in vitiligo, particularly in chronic and progressive conditions. Both innate and adaptive arms of the immune system appear to be involved as a primary event or as a secondary promotive consequence. There is speculation on the interplay, if any, between ROS and the immune system in the pathogenesis of vitiligo. The article focuses on the scientific evidences linking oxidative stress and immune system to vitiligo pathogenesis giving credence to a convergent terminal pathway of oxidative stress–autoimmunity-mediated melanocyte loss.

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 12. 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 36, 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.

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Interplay of genes, environment and immune system in precipitation of vitiligo: interaction of genes with environment and immune system leads to vitiligo. Susceptible genes under the effect of environmental trigger like: generation of ROS by various environmental sources (UV and ionizing radiations, air and water pollution, heavy metals etc.) and repeated mechanical traumas can result into aberrant immunological responses (i.e. cellular and humoral immune response) resulting into autoimmunity.

Oxidative stress and vitiligo

Oxidative stress is considered to be one of the possible pathogenic events in melanocyte loss 78. Defective recycling of tetrahydrobiopterin in whole epidermis of patients with vitiligo is related to the intracellular production of H2O2 910. In addition, an increased intracellular production of ROS due to mitochondrial impairment 11 and a compromised antioxidant status 81213 supports the concept of a possible systemic oxidative stress in vitiligo. This accumulated oxidative stress causes DNA damage, lipid and protein peroxidation 1415 (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 1718. Several sources have been documented for the unusual production/accumulation of epidermal H2O2 [Table 18121929]. Our studies also showed systemic oxidative stress in patients with vitiligo due to an imbalance in enzymatic and non-enzymatic antioxidant systems 2025 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 (= 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 (= 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 3336. 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 3941.

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Different pathways for melanocyte loss: (i) Generation of ROS by various metabolic processes. (ii) Imbalance in ROS generation and antioxidant system leads to accumulation of free radicals resulting in oxidative stress. This accumulation causes DNA damage, synthesis of defective proteins and membrane disintegration which provokes immune system resulting in autoimmunity. (iii) Increased catecholamines inhibits mitochondrial calcium uptake which results in generation of free radicals. (iv) Exposure to UV radiation leads to spontaneous production of quinones in melanocytes which in turn results into ROS generation.

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 4344. 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 4649. Tyrosinase is the principal antigen recognized by these antibodies 4950. 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) 5253 (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 4152535561In 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 5063. 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 6569. 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 7176In 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 6478. 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 768081. 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 8485. 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 8485. 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 8990. 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 899293.

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 839697, whereas our earlier studies on CAT, GPX, MBL-2, ACE and PTPN22 polymorphisms did not show significant association 98101.

Cytokines and apoptosis

The exact pathway for loss of melanocytes is not yet known; however, apoptotic death has been suggested in vitiligo 102103. 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 105106. 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 5103. 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 119120. 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

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