Skip to main content
Category

Vitiligo research

Dermatologists Answer Your Top Vitiligo Questions

Living with vitiligo can mean navigating through plenty of unanswered questions involving the condition. You may be curious about how vitiligo will progress, what treatments are available, and whether dietary changes can help restore pigment.

“I’m thinking improving my diet may prove helpful during my struggle with vitiligo,” one MyVitiligoTeam member said. Another asked, “Stress makes spreading my vitiligo worse, and I’m also having hypothyroidism — what kind of things are you doing so vitiligo doesn’t spread?”

 

To get to the bottom of a few burning questions, MyVitiligoTeam partnered with the Global Vitiligo Foundation to host World Vitiligo Day in June. At the event, dermatologists Dr. Pearl Grimes, Dr. John Harris, Dr. Nada Elbuluk, and Dr. Victor Huang discussed a variety of topics that can help you understand more about the condition. Check out several of the questions that attendees asked, along with responses from the dermatologists.

Does puberty play a part in the progression of vitiligo?

“There is a cohort of kids who may progress during puberty, but it’s certainly not a universal phenomenon,” Dr. Grimes said. “I don’t even think it occurs in 50 percent of kids.”

Dr. Huang offered a similar take. “We do recognize from the epidemiology that half of people with vitiligo will present before the age of 20,” he said. “And when you look at the characteristics of vitiligo that people have, it seems to be different. There are at least some suggestions in larger cohorts that the folks with associated autoimmune conditions, such as thyroid disease, tend to be from the groups that present later, after puberty. So I think there is a difference between the folks who develop their vitiligo earlier on versus those who develop it later in life.”

Dr. Huang takes a multipronged approach to managing depigmentation, which means addressing small spots differently than those that involve larger sections of skin. That may include a combination of topical therapies (such as ointments and creams), phototherapy, and systemic steroids.

“Thankfully, now there’s this whole fourth category of investigational medicines that are available,” Dr. Huang noted. A new class of medications known as Janus kinase (JAK) inhibitors are under investigation and may be available later in 2021.

“Surgical treatments are available as well,” Dr. Huang said. “The idea being that, once the immune part has been resolved, if the fundamental problem is that we don’t have enough melanocytes in the area, we can borrow melanocytes from other normally pigmented parts of the body and replace them into the part where they’re missing.”

Is there a risk that vitiligo spots will return following treatment?

“Unfortunately, there is,” Dr. Elbuluk said. “I always tell patients that no matter how successful we are at gaining repigmentation back, because they are genetically predisposed to vitiligo, there’s always the chance that they could depigment again. And it could be in the same spots where they previously had vitiligo, and it could be in new spots.”

When Dr. Elbuluk sees people who have fully repigmented, she checks in with them every few months to review disease activity. If she sees new spots, she moves ahead with treatment again.

Is vitiligo passed on genetically in families?

“There is a genetic component to this,” Dr. Huang said. “But the way I talk to my patients about this is to mention that in the general population, about 1 percent to 2 percent of people will have vitiligo. If you have a first-degree relative — a mother, father, brother, or sister — the risk of vitiligo goes up to about 6 percent. Even when you look at identical twins, that only bumps up the risk to 26 percent or 27 percent. When you look at those numbers, the more closely related you are to someone genetically, the greater your risk is to get vitiligo.”

When Dr. Huang sees people with vitiligo who are thinking of starting a family, he reminds them that there’s a 94 percent chance that their child will not have vitiligo. “So while there is a strong genetic component, it’s not the only thing that drives vitiligo.”

Is there a specific diet that can help people manage vitiligo? Does going gluten-free help?

“This is a really popular question,” Dr. Elbuluk said. “Unfortunately, we don’t have any well-controlled studies that really allow us to give evidence-based recommendations about diet and vitiligo. But what we do know about the disease is that antioxidants can help the stabilization of vitiligo, meaning preventing progression of it. And they may even aid in repigmentation when people are doing other concomitant therapies, such as phototherapy, the topicals we use, etc. Based on what we know, I think there is a role for antioxidants, both in diets and as supplements in vitamins, in addition to the treatments that we do for vitiligo.”

Dr. Elbuluk noted that current data does not support any benefits of a gluten-free diet in people with vitiligo, unless they have celiac disease or gluten allergies in addition to vitiligo.

Does vitamin D play a role in vitiligo management?

“Vitamin D is really a powerful hormone that regulates so much in our body, and I think it does play a role in pigmentation,” Dr. Elbuluk said. “I do check vitamin D levels in my vitiligo patients, and if they are deficient, I recommend replacing their vitamin D so that they are within the normal range. And there is some data to support that repigmentation in vitiligo does correlate with serum levels of vitamin D.”

Dr. Grimes agreed with the importance of checking vitamin D levels in people with vitiligo. “We should really be certain that our patients have healthy vitamin D levels. And if you don’t want to check it, if you empirically have a patient take 2,000 international units of vitamin D, that’s better than not addressing it at all.”

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

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.

Source:

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

Source

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.

thumbnail

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.

thumbnail

(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.

thumbnail

Download:

  • PPT
    PowerPoint slide
  • PNG
    larger image
  • TIFF
    original image
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.

thumbnail

Download:

  • PPT
    PowerPoint slide
  • PNG
    larger image
  • TIFF
    original image
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.

thumbnail

Download:

  • PPT
    PowerPoint slide
  • PNG
    larger image
  • TIFF
    original image
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.

thumbnail

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.

Source:

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.

Details are in the caption following the image
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.

Details are in the caption following the image
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

Source: 

Prevalence of Vitiligo Among Adults in the United States

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

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

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

Abstract

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

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

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

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

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

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

Introduction

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

Worldwide prevalence estimates of vitiligo vary widely with prevalence estimates ranging from 0.004% to 2.28%.5,6 In the United States, there is a paucity of population-based studies; however, based on the few studies that have been conducted in specific subpopulations, the prevalence estimates vary from 0.05% to 1.55%. Furthermore, these estimates are either outdated, do not include patients with undiagnosed vitiligo, or are sampled from specific subgroups of the general population.712

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

Methods
Study Design

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

Study Population

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

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

Participant Survey

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

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

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

Clinician Adjudication

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

Final vitiligo adjudication was made by clinician majority, defined by at least 2 of the 3 clinicians agreeing on the categorization of vitiligo, nonvitiligo, or indeterminate. If there was no majority, the case was categorized as indeterminate. Clinicians further evaluated the self-reported laterality (ie, lesions on 1 or both sides of the body) of the vitiligo lesions and provided their own assessment of nonsegmental vitiligo or segmental vitiligo based on photographs and following the consensus classification from the 2011 Vitiligo European Taskforce consensus conference for segmental vitiligo.21 Agreement between the clinicians was assessed using the Fleiss (unweighted) κ coefficient.2224

Statistical Analysis

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

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

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

Results
Participants

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

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

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

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

Prevalence

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

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

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

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

Discussion

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

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

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

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

Limitations

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

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

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

Conclusions

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

source

Vitiligo and anxiety: A systematic review and meta-analysis

Background

Vitiligo is an acquired depigmenting skin disease that is often accompanied by mental distress. There are numerous studies dedicated to local and global prevalence of depression in patients with vitiligo but anxiety has not been recognized as a major mental problem within named population. We aimed to evaluate the prevalence of anxiety among patients with vitiligo from different countries and to compare it with patients suffering from eczema, psoriasis, and acne.

Methods

In November 2019, we conducted a systematic search for observational studies that examined the prevalence of anxiety in vitiligo patients. Fifteen studies comprising 1176 patients with vitiligo were included to our systematic review.

Results

The general prevalence of anxiety among vitiligo patients was equal to 35.8%. Statistically significant difference in anxiety rates was found among female and male patients (47.32% vs 42.4%) (P = 0.03), but the clinical relevance of this issue remains arguable. In addition, the pooled odds ratio among vitiligo and non-vitiligo patients did not indicate a statistical significance among patients coming from different continents.

Conclusions

The pooled prevalence of anxiety among vitiligo patients worldwide was comparable to other severe skin disorders. This finding accentuates the necessity of anxiety awareness in management of patients with skin diseases.

Introduction

Psychogenic effects related to various health disorders have become the issue of growing discussion in scientific literature over past decades [12]. Globally, there is an increasing rate of anxiety disorders–a group of mental health problems characterized by the feelings of worry and uneasiness that are commonly generalized and present an overreaction to a problem that appears to be threatening [3]. Anxiety disorders quite seldom occur alone and are frequently associated with depression or other mental health problems [4].

The sample of such population groups could be made of vitiligo, which is an acquired lasting skin disorder. Although the etiology of vitiligo is not fully understood yet, common manifestation includes the patches of depigmentation with typically sharp margins [5]. Although the global rate of vitiligo is approximately 1%, some populations show twofold to threefold increase in rates [6]. These patches of skin depigmentation tend to expand with time and affected individuals experience a range of emotional problems. In certain cultures individuals suffering from vitiligo may be stigmatized and could experience difficulty with finding a couple or staying employed [7]. Inevitably, this worsens psychological distress and might even lead to a suicide attempt, especially if vitiligo affects visible body parts [8].

Although the relatively many papers devoted to the issue of anxiety in vitiligo patients had been published before, there is no pooled evidence that is needed for comprehensive understanding of this problem. A 2017 systematic review and meta-analysis on the prevalence of depression among patients with vitiligo estimated that the pooled prevalence of depression was 0.253 across 25 studies [9]. A 2018 meta-analysis of the prevalence and odds of depression in patients with vitiligo found a wide range of prevalence between 8% and 33% across 17 studies, depending on the diagnostic tool used. [10]. Meanwhile, anxiety in patients with vitiligo warrants higher awareness and greater attention as it can negatively affect adherence to treatment and overall quality of life [11]. As people with vitiligo appear to experience psychological problems with higher frequency than general population, the assessment of psychological state should be performed during routine clinical evaluation [1213].

Such, the existing data indicate that patients with vitiligo possibly face a higher risk of mental distress, although the current evidence coming from pooled analyses is insufficient. In this systematic review the null hypothesis was that there is no difference in prevalence of anxiety among vitiligo and non-vitiligo persons. Therefore, the aim of this study was to evaluate the prevalence of anxiety among patients with vitiligo from different countries and to compare it with patients suffering from eczema, psoriasis, and acne by conducting a systematic review and meta-analysis of published observational studies.

The specific goals of the present systematic review and meta-analysis are:

  • To determine the prevalence of anxiety in vitiligo patients in comparison with non-vitiligo patients.
  • To investigate the impact of some variables such as gender, continent, type of skin disorder on anxiety rate among vitiligo and non-vitiligo patients.

Materials and methods

We conducted this systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [14]. Prior to quantitative and systematic synthesis we retrieved all studies that were targeted on assessment of associations between vitiligo and anxiety.

Search strategy

A comprehensive database search was performed independently by two co-authors (A.K. and L.K.) using Pubmed, PsycINFO and Cochrane Library databases. An initial literature search in the mentioned databases used such keywords as “vitiligo” and “anxiety”. The following search criteria were applied for PubMed (Ovid MEDLINE): [“Vitiligo”(MeSH)] AND [“Anxiety”(MeSH) OR “Anxiety Disorder” (MeSH) OR Anx* (title/abstract;TIAB)] (see S1 Table). This search was limited to English-language studies published from inception to 30 November 2019. Also, we looked for publications in Russian language, for which reason we applied for Cyberleninka and eLIBRARY databases to screen for studies published from inception to 30 November 2019. Unfortunately, we failed to identify such publications despite the careful search and for this reason we only included studies published in English. Subsequently, we evaluated the abstracts of all identified papers to determine if they meet the inclusion criteria. Finally, we screened the reference lists of all eligible articles in order to find additional relevant articles.

Inclusion criteria

Our inclusion criteria were as follows: (i) studies that included vitiligo patients; (ii) studies that assessed the prevalence of anxiety; (iii) studies that evaluated the prevalence of anxiety self-reporting or examination by a psychiatrist; (iv) studies that were published in English and (v) studies that were considered to be of high and medium-quality by Newcastle-Ottawa scale (≥4 points).

Exclusion criteria

Our exclusion criteria were as follows: (i) studies that did not state the rate of anxiety among vitiligo patients or provided insufficient data for calculation of anxiety rates; (ii) unavailability of the full text for full review; (iii) studies with low methodological quality, i.e. case reports, case series and commentaries; (iv) studies published in other languages apart from English and (v) studies that were considered to be of low-quality by Newcastle-Ottawa scale (<4 points). Besides, we did not include the studies that reported on anxiety during or after such psychotraumatic events as a war, natural or man-induced disaster, epidemic because they enable confounder effects.

Article selection

The initial search and selection of articles was performed independently by two co-authors (A.K and L.K.), who screened for titles and abstracts and excluded all articles that did not meet the inclusion criteria. As a next step, we retrieved the full texts of articles that were considered to be eligible and evaluated all studies on the basis of their design. Any differences of opinion on study eligibility were resolved in discussions with Y.S. The selection process following PRISMA guidelines is presented in Fig 1.

The studies had to report sufficient data, such as odds ratio (OR) and 95% confidence interval (CI), so that the corresponding standard errors (SEs) could be calculated. If such information was not available, we looked for the crude data with the number of cases.

Data extraction and study evaluation

Two reviewers (A.K. and L.K.) extracted the data from the selected articles. All selected data were arranged as a standardized form which contained:(i) last name of first author and year of publication;(ii) country of the study origin; (iii) the sample size of vitiligo and non-vitiligo groups, if available; (iv) prevalence of anxiety in vitiligo patients and in control groups, if available; (v) anxiety assessment tool; (vi) proportion of female and male patients with anxiety, if available. The quality of the included articles was assessed using the Newcastle-Ottawa scale for nonrandomized studies [15]. Studies that get ≥ 7 points on Newcastle-Ottawa scale were considered to be of high quality, 4–6 points matched the criteria of medium-quality studies and <4 points were considered to be poor-quality studies. Each article was assessed independently by two authors (A.K. and L.K.). All scoring differences were conformed through discussion with Y.S.

Statistical analysis

We carried out statistical analysis using the Review Manager software (RevMan) Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Using the random-effects model, we then calculated the prevalence and event rate of anxiety in vitiligo patients and in total study populations. The I2 value to assess heterogeneity among studies was processed. We used the random-effects model when heterogeneity across the studies was large (I2 > 60%, P< 0.05) and fixed-effects meta-analysis at small heterogeneity (I2 < 60%, P< 0.05).

We evaluated the risk of publication bias by using Egger’s graphical method. Almost all studies (more than 95%) fall in symmetrical distribution that confirms minimal risks of selection bias. Thus, the funnel plot did not suggest any publication bias (see S1 Fig).

Ethics statement

All analyses were based on previously published studies; no ethical approval or patient consent was required.

Subgroup analyses

The subgroup analyses were performed to study the impact of gender, continent and skin disorder on the prevalence of anxiety among vitiligo patients. United Nations Standard Country or Area Codes for Statistical Use service was used to classify all included studies by continent [16]. We classified such countries as Saudi Arabia, United Arabian Emirates, Turkey and Georgia as countries in the Middle East. India and Bangladesh were grouped as Southern Asia countries. African region included Ethiopia, Nigeria and Egypt. Also, we differentiated Mexico as a Southern America country and Estonia as a European country. In controlled studies prevalence of anxiety was compared between vitiligo patients and non-vitiligo groups. As for the type of skin disorder, some studies contained the data on the prevalence of anxiety among patients with eczema, atopic dermatitis, psoriasis, albinism, melasma, acquired pigmentary disorders, acne, alopecia, chronic urticaria, neurodermatosis, scabies while the others contained the data on miscellaneous skin diseases. Most commonly the control group contained patients with psoriasis, acne and eczema (nine, six and four studies, respectively).

 

Results

A search using Pubmed, Cochrane Library, Research Gate, Google Scholar, Cyberleninka and eLIBRARY allowed to identify 259 studies (Fig 1). Cochrane Library does not contain studies which met the inclusion criteria. One hundred and eighteen studies were removed as duplicates.

The titles and abstracts of remaining 141 articles were screened. Of these, 105 were excluded from subsequent analysis as they did not provide enough data to calculate the effect size (102 publications) or could not be obtained in full text (3 publications). Full texts of 36 studies were reviewed, and 21 of them were excluded for the following reasons: irrelevant outcomes (n = 7); review articles (n = 7); non-English/non-Russian language (n = 4); poor-quality by Newcastle-Ottawa scale (<4 points) (n = 3). Finally, 15 articles with 1176 cases of vitiligo were included to our study and the sample size ranged from 15 to 164. All articles provided the data on the prevalence of anxiety in vitiligo patients. Anxiety was evaluated using self-report screening tools only.

The vast majority of studies (10) included participants whose age was >18 years, in two studies patients were elder than 15 years, in one study patients were elder than 16 years, one study comprised patients elder then 17 years, and in one study the age of participants was not mentioned. Six studies from Middle East, three studies from Southern Asia, four studies from Africa, one study from Southern America and one study from Europe were included. The number of female patients with vitiligo ranged from 23 to 103, in three studies the gender proportion was not stated. The tools which were used to identify the rate of anxiety were the Hospital Anxiety and Depression Scale (HADS), the fourth (DSM-IV) and the fifth (DSM-5) editions of Diagnostic and Statistical Manual of mental disorders, 28-item General Health Questionnaires, 21-item The Depression, Anxiety and Stress Scale (DASS-21), General Anxiety Disorder (GAD-7), ES-Q, Beck Depression Inventory, Illness Perception Questionnaire (IPQ) [41723].

All studies (n = 15) were designed as cross-sectional studies. Evaluating the quality of included studies with Newcastle-Ottawa scale, we found that three studies met the criteria of fair quality, twelve studies was of good quality. Study countries, geographical regions, sample size, prevalence of anxiety among vitiligo patients, screening tools, study design and quality of included publications are presented in Table 1.

Table 2 summarizes the prevalence and event rates of anxiety in total sample and in vitiligo patients. The sample size in fifteen studies varied from 42 to 618 participants. The number of vitiligo patients in included studies ranged from 23 to 164. The prevalence of anxiety in vitiligo patients fluctuated from 4.76% to 60.0%, so the minimal and maximal event rate meanings were equal to 0.05 and 0.60, respectively.

Analyses of the global rate of anxiety among vitiligo patients using random-effects models demonstrated that prevalence was equal to 35.8%. Also, we performed the subgroup analysis of anxiety rate among vitiligo patients according to their gender, type of skin disorder and continent of residence. The statistically significant difference in prevalence rates was found comparing African, European, Middle East and South Asian countries (33.29%, 27.93%, 32.02%, 13.73% respectively; P = 0.01 using χ2- statistics) (see S2 Fig). However, there was no difference in prevalence rates based on patient gender and type of skin disorder in the subgroup analyses (see S3 Fig and S4 Fig).

The pooled odds ratio (OR) of anxiety among patients with vitiligo was 1.13 [95% CI 0.75, 1.70] (Fig 2). There was moderate heterogeneity between the studies (I2 = 66%; P = 0.0004).

The prevalence of anxiety was 40.38% for acne patients vs 32.93% for vitiligo patients, and this result was not statistically significant (P = 0.22). The prevalence of anxiety in psoriasis patients was 27.34% vs vitiligo patients 28.44%. While that in eczema patients was 33.22% vs vitiligo patients 37.59%. However, these differences were not statistically significant (see S5 Fig).

There were only four studies that reported on prevalence rates of anxiety among female and male patients with vitiligo. The prevalence of anxiety in female patients compared to male patients was higher (47.32% vs 42.4%) and this difference was statistically significant (P = 0.03) (see S6 Fig).

Grouping by continent the pooled OR among vitiligo and non-vitiligo patients was as follows: 1.82 [0.75, 4.40] in Africa (P = 0.18), 0.57 [0.25, 1.33] in Europe (P = 0.19), 0.80 [0.40, 1.63] in Middle East (P = 0.54), 1.32 [0.73, 2.40] in Southern Asia (P = 0.36) (see S7 Fig).

Discussion

This meta-analysis aimed to evaluate the prevalence of anxiety among patients with vitiligo from different countries and to compare it with patients suffering from eczema, psoriasis, and acne. We expected that patients with vitiligo have a significantly higher risk of anxiety or anxiety symptoms as compared to those who present with no pigmentary skin disorders. In fact after conducted systematic review and meta-analysis the null hypothesis was reconfirmed, there was no difference in prevalence rates of anxiety among comparison groups. About one-third of vitiligo patients have the symptoms of anxiety. We found that the difference in the prevalence of anxiety between males and females was statistically significant, but of course the clinical relevance of this issue remains disputable. When comparing the prevalence of anxiety in different skin disorders including vitiligo, patients with psoriasis, eczema and acne had no the significantly higher rates of anxiety. Similarly, we did not find statistically significant difference in prevalence of anxiety between vitiligo patients coming from various continents.

Across the studies included in this meta-analysis, the prevalence of anxiety in vitiligo patients varied from 4.76% to 60.0%. Hospital Anxiety and Depression Score (HADS) was utilized in 40.0% of studies and it presents a self-assessment scale designed for detecting mental disorders in hospital settings [17]. The fourth (DSM-IV) and fifth (DSM-5) editions of Diagnostic and Statistical Manual of mental disorders were another popular method for anxiety detection in the selected articles. Other tools for anxiety measurement comprised 28-item version of General Health Questionnaires and this was used in two studies included in this meta-analysis. Also, the selected studies utilized other tools for anxiety detection, such as DASS-21, GAD-7, ES-Q, Beck Depression Scale, IPQ. The large variety of anxiety screening tools might be the possible cause of the moderate heterogeneity observed in our systematic review. Also, the wide range of anxiety assessment tools did not allow us to perform the subgroup analysis according to this criterion. Besides, due to the lack of data on prevalence of anxiety symptoms according to severity of vitiligo it was impossible to conduct the sub-analysis of anxiety rate regarding to extent of depigmentation.

Comparison of anxiety levels in vitiligo patients depending on the continent of their residence showed that there is no statistically significant difference in anxiety rate among people living in different regions. Although the highest odds ratio (1.82 [0.75, 4.40]) was found in African vitiligo patients. We suggest that this finding might be explained by various views and levels of acceptance typical for people belonging to different cultures. Due to the fact that ethnicity correlates with skin color, the presence of achromatic spots may have a greater adverse psychological effect on participants from ethnic groups with darker skin [38]. Certain cultures are characterized by a low level of vitiligo acceptance. For example, in some regions of India, vitiligo is often called “white leprosy”, which leads to an even greater aggravation of the patient’s psychological problem [7].

The difference in the prevalence of anxiety among male and female vitiligo patients was statistically significant as females had higher rate of anxiety. This fact is concordant with the global trends of anxiety epidemiology [39]. Borimnejad and co-authors found that female patients with vitiligo have lower quality of life indicators and more psychological disorders than male patients [40]. Similar results were also reported by the Tunisian study, where women with visible skin defects could not embody themselves as employee and potential bride due to stigmatization [41].

An analysis of the studies included in our meta-analysis demonstrated that anxiety is most often associated with psoriasis, eczema and acne as compared with other dermatological diagnoses. When comparing the prevalence of anxiety in patients with different skin disorders, we found that acne patients have the highest risk of anxiety development. Even though this finding was not statistically significant a higher level of anxiety seen in acne patients could be explained by hormonal imbalance (elevated quantity of androgens) as well as by the fact that acne affects adolescents and young people at a time when they are more likely to be concerned about their body and social life [42]. Also, the prevalence of anxiety in psoriasis and vitiligo patients was very similar (27.34% vs. 28.44%, respectively). When comparing eczema and vitiligo patients, the prevalence rates of anxiety were almost comparable (33.22% vs.37.59%, respectively). Slightly higher prevalence of anxiety in vitiligo patients might be explained by the fact that most of the studies included in this meta-analysis were carried out in Asian and African countries and vitiligo in patients with dark skin phototype is associated with stigmatization and reduced quality of life [43].

Melanocytes destruction and anxiety seem to be associated strongly due to similar mechanisms of neuroendocrine dysregulation. Some studies demonstrate the role of increased levels of neuromediators in vitiligo development. Elevated levels of norepinephrine were found in microenvironment of melanocytes, urine and plasma of vitiligo patients [44]. These basic findings are confirmed by several descriptive studies. The higher levels of norepinephrine are detected in vitiligo patients at an active phase of disease [45]. Significant correlations between catecholamines’ levels and progressive form of disease were described in 56 vitiliginous subjects [46]. The link between increased level of norepinephrine and destruction of melanocytes might be an essential element of oxidative stress theory of vitiligo pathogenesis. Mental stress causes activation of the hypothalamic–pituitary–adrenal axis, which secretes catecholamines. Monoamines and their metabolites stimulate α-receptors of skin arterioles, leading to microcirculation disturbances and hypoxia. As a result, overproduced oxygen radicals cause damage of melanocytes [47]. Also, the activity of acetylcholine esterase is lower in depigmented skin and grows during repigmentation process [44]. Schaullreuter explained a substantial contribution of H2O2-mediated oxidation of acetylcholine esterase to the oxidative stress in vitiligo [48]. Two studies were the most relevant to the topic of our study. Lai Y. et al. selected 25 studies with 2708 cases of vitiligo to find the prevalence of disease among them. Analysis of the results demonstrated that patients with vitiligo were significantly more likely to suffer from depressive disorders than healthy volunteers. The total prevalence of depression among patients with vitiligo was 0.253 (95% CI 0.16–0.34; P<0.001), and the pooled odds ratio was 5.05 against the control (95%CI 2.21–11.51; P< 0,001) [9]. The second meta-analysis was conducted by Osinubi and co-authors and was aimed at establishing the prevalence of psychological symptoms or disorders in people with vitiligo. This meta-analysis included 29 publications involving 2530 patients, and the authors found that approximately one in four people with vitiligo suffered from depression, and one in seven was affected by anxiety. The authors have repeatedly emphasized the heterogeneity of the studied groups and tools used and reported that the overall prevalence of anxiety ranged from 33% to 46% [12]. In fact, the lack of control over the screening tools utilized to measure anxiety is the major limitation of the previous meta-analyses and the cause of large heterogeneity. There are several differences between this meta-analysis and our work, which mostly relate to the primary aim. While we focused exclusively on anxiety, Osinubi and co-authors covered a broad range of psychological disorders: depression, anxiety, social phobia, agoraphobia. Second, we included more studies in our meta-analysis that is explained by a two-year interval between two studies during which a number of additional publications appeared.

Our study has several strengths and limitations. Firstly, we tried to minimize publication bias strictly following the rules of study selection for systematic reviews. Secondly, our meta-analysis includes studies with different screening tools from different countries and world regions. Thirdly, our study is dedicated to evaluation of the prevalence of anxiety exclusively among vitiligo patients. However, there are certain limitations and the main one is moderate heterogeneity as a result of broad criteria for inclusion. This limitation derives from available publications on the study topic as they are often imprecise in identifying what is counted and not counted as anxiety in terms of type and severity. Due to this fact, the results of our study should be generalized with a caution. Secondly, the wide range of diagnostic tools may impact on study results. On our best knowledge, there is no unified and evidence-based tool for assessment of anxiety in patients with skin diseases. Finally, different cultural and social conditions in studies’ environment may also contribute to heterogeneity of our meta-analysis. Nevertheless, it is well-known that psychological and psychiatric disorders might be strongly associated with ethnical, cultural and social factors [4950].

Conclusions

In conclusion, the patients with vitiligo suffer from anxiety as frequently as do individuals with such severe skin conditions, as psoriasis or eczema. Although vitiligo patients present with no symptoms apart from decolorated skin patches, this pathology is accompanied with various psychological problems. Dermatologists and other specialists dealing with vitiligo patients should be aware of their predisposition to anxiety and be able to envisage correctional interventions to alleviate the burden of their mental distress. Clinical guidelines have to contain information about effective screening and management of anxiety among vitiligo patients. Finally, we did not find statistically significant impact of various risk factors on anxiety rate. This fact emphasizes the global burden of vitiligo that is not dependent on patient’s gender or ethnicity.

Source

Vitiligo and Self-Esteem: Psychological Effects

Article written by Charity Nyawira

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

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

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

The Impact of Vitiligo on Self-Esteem

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

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

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

How Vitiligo Contributes To Low Self-Image

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

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

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

Emotional Impact of Vitiligo on Children and Adults

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

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

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

Mood Disorders, Low Self-Esteem, and Vitiligo

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

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

Depression and Vitiligo in Children and Adults

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

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

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

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

Treatment for Depression and Anxiety in Vitiligo

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

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

How Parents Can Support Children and Teens With Vitiligo

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

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

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

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

Finding Self-Worth To Improve Self-Esteem With Vitiligo

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

Source