Cigarette smoking is an independent risk factor for developing vitiligo on the hands

Vitiligo presents with varying clinical features based on the type and location. Treatment tends to be more effective on the face, neck, trunk, and mid‐extremities, while the lips and distal extremities may be more resistant. Vitiligo in frequently exposed areas such as the face, arms, legs, and hands is typically associated with a lower Dermatology Life Quality Index.

Vitiligo is a multifactorial disease, with genetic factors accounting for approximately 80% of the cases and environmental factors accounting for the remaining 20%.Advances in research and genome-wide association studies led to the identification of genetic loci associated with vitiligo, many of which are shared with other autoimmune diseases.Human leukocyte antigen (HLA)-DR4 and A2 serotypes are associated with vitiligo. 5,6Variants of the gene for catalase, which degrades hydrogen peroxide, also predispose to vitiligo development. 7tiligo skin has low catalase expression, which protects cells from reactive oxygen species and an abnormal redox balance. 8emokines can increase due to oxidative stress, which induces CD8-positive cells to attack melanocytes.Melanocytes produce high levels of reactive oxygen species as a byproduct of melanogenesis. 9rious treatments are currently available for vitiligo, such as steroid therapy (topical and systemic), calcineurin inhibitors (topical), phototherapy, Janus kinase (JAK) inhibitors (systemic and topical), PDE4 inhibitor (topical), and surgical therapy. 10Phototherapy, especially narrowband UVB (NB-UVB), is the most commonly applied treatment for vitiligo. 11To improve the treatment of refractory vitiligo, physicians should consider combining therapies and identifying risk factors for vitiligo in hard-to-treat areas.The appearance of vitiligo varies depending on the type and location.
Treatment tends to be more effective on the face, neck, trunk, and mid-extremities, while the lips and distal extremities are more difficult to treat.
Studies of the NB-UVB response found that the face has the highest pigmentation response rate at 75%, followed by the trunk at 64.89% and proximal extremities at 61.89%. 12The feet (10.95%) and hands (14.88%) exhibited little to no repigmentation.Similar reports revealed that the pigmentation response to phototherapy was 76% for the face, 40% for the trunk extremities, 27% for the axillae, and only 4% for the hands and feet. 13Exposed areas such as the face, arms, legs, and hands with vitiligo are linked with a lower Dermatology Life Quality Index and can cause psychologic distress to patients.In the present study, we aimed to identify the features and risk factors of vitiligo in difficult-to-treat and exposed areas, particularly the hands. 14

| Subjects
This was a single-center, retrospective cohort study of patients with generalized vitiligo.All vitiligo patients were diagnosed by dermatologists at Nagoya City University Hospital.Our study analyzed clinical data from 337 patients with generalized vitiligo who were treated at our hospital between 2016 and 2022.To ensure ethical compliance, the study was conducted following protocols approved by the Ethics Review Board of Nagoya City University, in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research.

| Clinical data
The data collected for this study included the patient's age, sex, duration of the condition, and history of smoking and alcohol use.
The information regarding smoking and alcohol use was obtained through self-reported questionnaires.

| Statistical analysis
We utilized logistic regression models to assess the correlation between hand vitiligo and various factors such as age, sex, duration, and smoking and alcohol history.The analysis was conducted using GraphPad Prism software developed by the GraphPad Software company based in San Diego, California.

| Study characteristics
In total, 337 vitiligo patients were enrolled in this study.Of these, 89 had segmental vitiligo (SV), and 248 had non-segmental vitiligo (NSV).

| Comparative analysis of clinical characteristics of vitiligo of the hand and vitiligo not of the hand
Logistic regression models were applied to evaluate potential factors (age, sex, duration, and smoking and alcohol history) associated with hand vitiligo.Multivariate analysis revealed that only smoking history was positively associated with hand vitiligo (odds ratio [OR]: 3.130, 95% confidence interval: 1.24, 7.91).Details of the results of the univariate and multivariate analyses are summarized in Table 3.

| Site-specific characteristics of vitiligo on the hands of smokers and nonsmokers
Color-graded frequency heat maps (528 pixels) were evaluated using clinical photography.The vitiligo in nonsmokers was widely distributed throughout the hand, predominantly the fingertips and joints, whereas the vitiligo in smokers tended to be distributed mostly at the fingertips (Figure 2A,B).

| DISCUSS ION
This study aimed to examine the characteristics of vitiligo in challenging-to-treat areas, particularly the hands.Multivariate analysis revealed that a history of smoking was significantly linked to hand vitiligo.Additionally, there are specific patterns of vitiligo development in the hands of both smokers and nonsmokers.Smokers tend to have vitiligo mainly on their fingertips.In vitiligo-affected skin, there are numerous indications of early aging markers.
The vitiligo cells lack sufficient amounts of the enzyme catalase, which normally shields them from reactive oxygen species, and there is an imbalance in the redox system. 8This oxidative stress leads to the aging of melanocytes due to lipid peroxidation. 15Additionally, oxidative stress can cause endoplasmic reticulum stress, which may result in apoptosis, hinder E-cadherin interaction, and disrupt keratinocyte-melanocyte adhesion. 10 1939, over half the workers (52%) in a leather tannery developed vitiligo when their skin was exposed to hydroquinone monobenzyl ether. 16Hydroquinone monobenzyl ether is now approved by the FDA as a depigmentation therapy. 17Chemical-induced vitiligo can also be caused by a structurally similar analog to tyrosine, which is the initial substrate of melanin. 18Korean study on systemic vitiligo found that smoking can decrease the risk of the condition. 19The study analyzed a national cohort database and compared the incidence of vitiligo in nonsmokers and smokers.The results revealed that current smokers had a significantly lower risk of vitiligo than nonsmokers, with a hazard ratio of 0.51 and a 95% CI of 0.50, 0.53. 18garette smoke can cause skin pigment disorder through the activation of AhR, a transcription factor found in the skin's keratinocytes, melanocytes, and fibroblasts. 20Cigarette smoke contains 3800 components that produce various reactive oxygen species, leading to premature skin aging and other skin conditions.Watersoluble tobacco smoke extract can also cause oxidative stress and impair collagen biosynthesis. 21While cigarette smoke may cause pigment disorder through AhR activation, a different mechanism may produce vitiligo on the hands.Direct contact irritation, not smoke exposure, can cause vitiligo in some cases.Refractory vitiligo on the hands may also be caused by tobacco.
Phototherapy is currently the most effective treatment for vitiligo available.Vitiligo on the hands, however, tends to be less responsive to phototherapy.The minimal erythematous dose (MED) was measured using excimer lasers in five patients currently undergoing phototherapy.The results revealed some differences in the MED of the face and hands.The mean MED of the face was 240 (150-400), while the mean MED of the hands was 600 (450-850).
Vitiligo skin is reported to be light-adapted and the MED is 35% lower than the MED of normal skin (95% CI 31, 39%). 22Although the sample size was limited, it is possible that the MED values are higher on the hands than on the face, resulting in less effective light therapy.Additionally, vitiligo on the hands can be caused by direct contact irritation rather than smoke exposure.It is also possible that tobacco contributes to refractory cases of vitiligo on the hands.
Our findings indicate that cigarette smoking is a risk factor for developing vitiligo on the hands, particularly the fingertips.This may be due to direct contact exposure to tobacco or to exposure to cigarette smoke.
F I G U R E 2 Color-graded frequency heat maps.Smokers' vitiligo tended to be more intense at the fingertips, while nonsmokers' vitiligo tended to be more widely distributed throughout the hand with a predominance on the fingertips and joints.
Smoking(ー) Smoking(＋) Note: Multivariate logistic regression model for the risk of hand vitiligo was derived using age, duration, sex, and smoking and alcohol history.Only smoking history was associated with a risk.The odds ratio (OR) was 3.13.

TA B L E 3
Results of the multivariate analysis of the risk of hand vitiligo.
3) years.There were 116 males and 132 females.Of F I G U R E 1 Study design flowchart.We used clinical data of vitiligo patients seen in our hospital between 2016 and 2022.Of the 337 patients with general vitiligo, 248 had non-segmental vitiligo and 119 of these 248 had vitiligo on their hands.Total number of vitiligo patients seen at our hospital between 2016-2022 (n=337) NSV(non segmental vitiligo) (n=248) SV(segmental vitiligo) (n=89) Hand vitiligo(n=119) No hand vitiligo (n=129) the 248 NSV individuals, 119 (47%) had hand vitiligo.The characteristics of patients with hand vitiligo are shown in Tables Characteristics of patients with non-segmental vitiligo (n = 248).Characteristics of patients with vitiligo on their hands (n = 119).