Second Guidelines for the Diagnosis and Treatment of Vitiligo in Japan (2025)

ABSTRACT

Vitiligo is a common acquired hypopigmented disorder characterized by melanocyte damage and/or loss, primarily resulting from excessive oxidative stress and dysregulated immune responses targeting melanocytes. The initial guidelines for the diagnosis and treatment of vitiligo in Japan were published in Japanese in 2012 and in English in 2013 to provide clinical evidence for vitiligo management. Since then, there has been a substantial accumulation of pathological research and therapeutic evidence. The second guidelines for the diagnosis and treatment of vitiligo in Japan (2025) are presented as an updated resource for clinicians, incorporating worldwide expert recommendations and recent advances in basic and clinical research. These guidelines aim to provide updated knowledge for individuals with vitiligo, public health professionals, scientists, and dermatologists.

1. Introduction

Vitiligo is the most common acquired hypopigmentary disorder and significantly reduces patients' quality of life (QOL) and impairs social activities [1]. Historically, individuals from darker‐skinned ethnic groups have often experienced unjustified discrimination and persecution [1]. Recent clinical trials have demonstrated the potential to improve the QOL of individuals with vitiligo [2]. In Japan, the first diagnosis and treatment guidelines for vitiligo were published in Japanese in 2012 and in English in 2013 [3]. The European Vitiligo Study Group published clinical guidelines in 2013 [4], followed by worldwide expert recommendations issued through a global initiative in 2023 [5, 6]. The second edition of the Japanese guidelines for the diagnosis and treatment of vitiligo (2025) represents the most recent update for affected individuals in Japan. These guidelines are based on global expert recommendations [5, 6] and recent findings in vitiligo research and provide current evidence‐ and expert‐based recommendations for the clinical management of patients with vitiligo.

2. Limitations of the Guidelines

These guidelines represent a comprehensive summary of the opinions of the Japanese Guideline Development Committee based on the data available at the time of preparation. However, future studies may require revision of the conclusions and recommendations. The disclaimer was applied in accordance with the 2024 Clinical Practice Guidelines for Atopic Dermatitis [7]. These guidelines are not intended to restrict clinical practice that may vary according to individual patient circumstances or to override the professional judgment of healthcare providers. Failure to implement the contents described in these guidelines should not be construed as establishing liability in clinical practice. The use of these guidelines as references for medical disputes and litigation deviates from their original purpose. Medications and interventions are included with assigned recommendation level, even if they are uninsured or unapproved. However, inclusion in the guidelines does not imply unrestricted use. The methods of administration and indications remain subject to the contraindications and precautions specified in the respective package inserts. For each drug, clinicians should make decisions based on the package insert and the latest available safety information.

3. Definition of Evidence Level and Recommendation

Each evidence level and recommendation were determined in accordance with the instructions in the guidelines for the management of atopic dermatitis (2024) (Tables 1 and 2) [7].

TABLE 1.

Criteria for determining evidence levels and recommendation grades.

(a) Evidence level
High	The results are nearly established and unlikely to be markedly affected by future studies
BLow	There are studies that support the results, but the results are insufficient and may be markedly affected by future studies
CVery low	There are no high‐quality studies that support the results

(b) Designs of studies used as references for the determination of the evidence level
A	A large number of randomized controlled trials with high quality and consistent results Meta‐analyses of randomized controlled trials
B	Randomized controlled trials with inconsistent results Randomized controlled trials of questionable quality or the presence of a few randomized controlled trials Non‐randomized controlled trials a Many controlled before and after trials or observational studies b with consistent results
C	A few controlled before and after trials or observational studies. Case reports and expert opinions

(c) Recommendation grade
1: Strong	The benefits obtained by the recommendation treatment are judged to be large and surpass the harm or burdens caused by the treatment
2: Weak	The magnitude of the benefits obtained by the recommended treatment is uncertain, or the benefits and harm or burdens that may result from the treatment are considered nearly equal

Note: Evidence levels and treatment recommendations in accordance with atopic dermatitis guidelines and determined by the Japanese Vitiligo Task Force. Subsections (a–c) indicate different evidence and recommendation categories.

^a Including controlled crossover study.

^b Including estimation of results of active treatment group, or placebo‐controlled group, in randomized controlled trials as before and after trials or observational studies.

TABLE 2.

Clinical endorsement based on evidence levels and recommendation grades.

Clinical endorsement based on recommended level and evidence level
1A	The level of supporting evidence is high and the benefits of treatment are considered to outweigh the potential harms or burdens It is recommended to perform the treatment
1B	Although the level of supporting evidence is low (B) or very low (C), the benefits of the treatment are considered to outweigh the potential harms or burdens
1C	It is recommended to perform the recommended treatment, with the understanding that the supporting evidence is insufficient
2A 2B 2C	The magnitude of benefits expected from the treatment is uncertain or is considered to be balanced by the potential harms or burdens It is recommended to select and present the treatment options in order to discuss with the patient whether or not to proceed with the treatment

4. Epidemiology

Vitiligo affects approximately 0.5%–1% of the global population [8]. Epidemiological surveys in Japan indicate that vitiligo is the most common cause of leukoderma, accounting for approximately 60% of all cases [9]. The disease affects men and women equally and can occur at any age [10]; however, non‐segmental vitiligo most commonly develops between the ages of 10 and 30 years [11]. Among Japanese patients with non‐segmental vitiligo, 20.3% have concomitant autoimmune diseases, including thyroid diseases (12.0%) and alopecia areata (5.3%) [12]. A familial onset of vitiligo has been reported in 11.3% of Japanese patients [12], whereas higher rates of 20%–30% have been observed in Europe and the United States [13]. In prepubertal children, the Koebner phenomenon and spontaneous repigmentation occur more frequently than in postpubertal‐onset cases, and a positive family history is also more common [14]. Recent studies have shown that the age of onset increased between 1970 and 2004, with a bimodal distribution in adults [15]. Furthermore, the risk of onset was 1.89–1.96‐fold higher among spouses of affected individuals [16]. These findings suggest that lifestyle and environmental factors may influence the development of vitiligo.

5. Current Knowledge of Pathogenesis for Non‐Segmental Vitiligo (Figure 1)

FIGURE 1.

Proposed pathomechanism of melanocyte damage in non‐segmental vitiligo.

5.1. Genetic and Environmental Effects

Genetic factors are involved in the development of vitiligo. First‐degree relatives of patients and cotwins of affected individuals have a higher risk of developing the disease, and other autoimmune disorders often occur concomitantly. Genome‐wide association studies (GWAS) have identified vitiligo‐susceptible genes associated with innate and adaptive immunity. Approximately half of the identified susceptibility genes encode immune‐regulatory proteins; however, their combined effects account for only about 25% of the total genetic risk [17, 18]. GWAS have also revealed that loci regulating human leukocyte antigen class II expression are predominantly associated with childhood‐onset cases, accounting for approximately one‐third of such cases [17]. These findings indicate that environmental factors also play an important role in vitiligo pathogenesis [17, 18].

5.2. Biological Changing on the Disease Stages

In the onset stage, melanocyte damage exposes melanocyte‐derived antigens, resulting in persistent activation of antigen‐specific CD8⁺ T cells (cytotoxic T cells) and CD4⁺ T cells (including Th1/Th2 and regulatory T cells) through the maturation and activation of dendritic cells, leading to continued melanocyte destruction (Figure 1) [19, 20]. Damaged melanocyte‐derived HMGB1 promotes the production of C‐X‐C motif chemokine ligand 16 (CXCL16) from keratinocytes via the nuclear factor kappa B pathway [19], while oxidative stress promotes CXCL16 production through the endoplasmic reticulum stress pathway [21], facilitating the migration of cytotoxic T cells to the skin. In response to stress, keratinocytes present interleukin‐15 (IL‐15) on the cell membrane, stimulating the maintenance of resident memory T cells and the production of interferon‐gamma (IFN‐γ), perforin, and granzyme B [22, 23].

In the progressive stage, IL‐15 contributes to the differentiation and maintenance of natural killer (NK) cells in the epidermis and promotes the transition and activation of type 1 innate lymphoid cells (ILC1), thereby enhancing IFN‐γ production [24]. IFN‐γ stimulates CXCL9 and CXCL10 production from keratinocytes, and these cytokines attract cytotoxic T cells, NK cells, dendritic cells, and regulatory T cells to the skin, promoting further IFN‐γ production and melanocyte damage. Moreover, IFN‐γ reduces the expression of the adhesive membrane protein GPNMB in keratinocytes in a Janus kinase (JAK)‐dependent manner [25, 26, 27, 28]. It also inhibits melanin synthesis and promotes apoptosis and senescence in melanocytes [29, 30]. Histopathological changes, including epidermal thickening, hyperkeratosis, increased keratinocyte apoptosis, and reduced adhesion between melanocytes and the basement membrane, have been observed in vitiligo epidermal lesions [28, 31, 32], with IFN‐γ also potentially contributing to these processes. Significant lymphocyte infiltration is usually not observed in the upper dermis of lesional or perilesional skin during the progressive and stable phases. In addition, the involvement of keratinocytes, fibroblasts [33, 34, 35], mast cells, and macrophages has been suggested [36, 37, 38]. Recently, floating melanocytes have attracted attention as a possible non‐immunological mechanism of melanocyte loss. Persistent oxidative stress reduces the expression of E‐cadherin, leading to weakened adhesion between melanocytes and keratinocytes and subsequent melanocyte expulsion from the epidermis [39]. Matrix metalloproteinase‐9 derived from keratinocytes is reportedly involved in this process [32]. Reduced GPNMB expression in basal keratinocytes induced by IFN‐γ may also contribute to melanocyte loss [28]. Some studies have reported increased stem cell factor expression in keratinocytes during the progressive phase [40], whereas others have reported decreased expression [41], resulting in ongoing debate regarding its role in melanocyte survival and apoptosis. Furthermore, increased mast cell‐derived histamine may induce marginal pigmentation of lesions [40], along with melanocyte proliferation and migration and keratinocyte proliferation at affected sites [42, 43, 44].

Breathnach proposed a unique model in which melanocytes divide into daughter cells, one of which remains in the basal layer and fails to undergo melanogenesis, appearing as a Langerhans‐like cell at disease onset [45]. Mishima et al. identified melanosome‐bearing cells lacking Birbeck granules, termed alpha dendritic cells, and reported that the combined number of alpha dendritic cells and melanocytes remained constant from disease onset through the stable phase, suggesting a potential phenotypic transition [46]. Tobin et al. reported clear cells lacking melanin granules in long‐standing vitiligo lesions and demonstrated that dendrites could be induced in dendrite‐deficient melanocytes following hydrogen peroxide treatment [47]. Further studies are needed to clarify the interactions and fate of these cells during repigmentation.

5.3. Pathogenesis of Segmental Vitiligo

Several hypotheses have been proposed for the etiology of segmental vitiligo, including neuronal mechanisms, somatic mosaicism, neurogenic mechanisms, microvascular skin homing, and oxidative stress [48, 49]. Increasing evidence supports cytotoxic immune involvement, as melanocyte antigen‐specific cytotoxic T cells produce IFN‐γ and infiltrate the basal layer of affected skin [50, 51, 52]. The rare coexistence of systemic autoimmune diseases further suggests the involvement of localized cytotoxic immune responses against epidermal melanocytes [53, 54].

6. Chemical Leukoderma

6.1. History of Chemical Leukoderma

Chemical leukoderma resulting from exposure to defined chemical agents must be carefully distinguished from vitiligo during differential diagnosis, while also being investigated as a potential causative factor. It also serves as an important model for investigating the pathogenic mechanisms of vitiligo. Chemical leukoderma was first reported by Oliver et al. in 1939 in leather workers who developed occupational depigmentation [55]. Notably, several workers developed similar depigmented lesions in distant areas that had not been exposed to monobenzyl ether of hydroquinone (MBEH). Systematic patch testing of all components used in leather revealed that only the antioxidant MBEH elicited an inflammatory reaction at the patch test site, followed by depigmentation, leading to its identification as the causative chemical agent. Since then, various chemical agents have been reported to induce leukoderma [55, 56].

6.2. Chemical Agents Inducing Chemical Leukoderma (Depicted in Figure 2)

FIGURE 2.

Chemical structures of known agents inducing leukoderma, adapted from Mogami et al.

Most chemical agents known to induce chemical leukoderma are phenols and catechols. Phenols are structurally similar to tyrosine, an amino acid required for melanin synthesis [56, 57]. Documented depigmenting phenolic agents include MBEH [55], monomethyl ether of hydroquinone [58], 4‐tert‐butylphenol [59, 60], 4‐tert‐octylphenol [60], 4‐tert‐amylphenol [61], hydroquinone [62], kojic acid [63], thymol [64], and rhododendrol (RD) [65, 66, 67]. Other chemicals, including 4‐(4‐hydroxyphenyl)‐2‐butanone (raspberry ketone, a carbonyl derivative of RD) [68] and catechols, such as 4‐tert‐butylcatechol [69] and 4‐isopropylcatechol [70], were reported as culprits for skin depigmentation. Some cases of leukoderma were preceded by allergic contact dermatitis showing positive for patch testing due to chemical allergens including paraphenylenediamine [71, 72], azo dye [73], propyl gallate [74], dimethyl fumarate [75], and basic blue 75 [76].

6.3. Rhododendrol‐Induced Leukoderma

Cosmetics containing 2% RD [chemical name: 4‐(4‐hydroxyphenyl)‐2‐butanol; proprietary name: rhododenol], a competitive tyrosinase inhibitor that suppresses melanin synthesis, were developed and marketed in Japan in 2008 as skin‐whitening agents. However, following widespread public use, these products unexpectedly induced leukoderma rather than achieving the intended skin‐whitening effect, resulting in global recalls beginning in 2013. Subsequently, approximately 19 600 users (2.4%) were diagnosed with RD‐induced leukoderma, classified as a type of chemical leukoderma [65, 67].

6.3.1. Clinical Course of RD‐Induced Leukoderma

Recovery from RD‐induced leukoderma follows three distinct clinical patterns. Most patients (86%) exhibited leukoderma confined to the sites of RD‐containing cosmetic application. In many cases, product discontinuation alone was sufficient for recovery, whereas others required ultraviolet phototherapy or additional therapeutic interventions. The remaining 14% developed leukoderma extending beyond the initial application sites, suggesting immune involvement targeting melanocytes [77]. In approximately 40% of cases, leukoderma was preceded by inflammatory manifestations, including erythema and pruritus. Patch testing with 2% RD in petrolatum yielded positive results in 13.5% of patients (25/185 cases), with higher positivity rates in inflammatory cases than in non‐inflammatory cases (20% vs. 6.8%, respectively) [67]. Notably, there are no reports of RD‐induced allergic contact dermatitis without leukoderma, suggesting a potential association between allergic contact dermatitis and RD‐induced melanocyte cytotoxicity.

6.3.2. Clinical Features of RD‐Induced Leukoderma

Most reported cases have occurred in adult women aged 30 years or older with a history of RD‐containing cosmetic use, with the highest prevalence observed in individuals aged 60–69 years. Notably, 2.8% of patients had a history of vitiligo [77]. The clinical course typically progresses from spotty, confetti‐like depigmentation to well‐defined complete depigmentation, accompanied by leukotrichia in advanced stages. Initially, 4% of cases (0.09% of users) exhibited a vitiligo‐like progression extending beyond application sites. This proportion increased to 14% (0.34% of users) after 1 year and 5 months of follow‐up [65, 67, 77]. In chemical leukoderma, depigmentation initially occurs at sites of direct chemical exposure and may present as either complete or incomplete depigmentation. In some cases of chemical leukoderma, since depigmentation extends beyond the exposed sites, a making of differential diagnosis with classical vitiligo is challenging [56, 57]. Therefore, an accurate diagnosis with chemical leukoderma requires taking of exposure history, particularly regarding any contact with phenols and catechols, for example, at the sites where leukoderma first appeared.

6.3.3. Diagnostic Criteria for Chemical and RD‐Induced Leukoderma

RD‐induced leukoderma has been confirmed across diverse clinical presentations based on the following criteria: (1) no pre‐existing depigmentation before RD‐containing cosmetic use; (2) depigmentation occurring at application sites after use; and (3) clinical improvement, such as stabilization or repigmentation, within 1 month of discontinuation [67]. Although no standardized diagnostic criteria exist for chemical leukoderma, Ghosh proposed diagnosing and staging the condition when three of the following four criteria are met: (1) acquired leukoderma‐like depigmentation; (2) history of repeated exposure to specific chemical agents; (3) leukoderma‐like lesions corresponding to the sites; and (4) a confetti‐like depigmentation pattern [57, 78].

6.3.4. Prognosis

In a follow‐up study of 965 RD‐induced leukoderma cases conducted 1 year and 5 months after product recall, 82% demonstrated varying degrees of clinical improvement. Specifically, 3% achieved complete resolution, 13% demonstrated substantial improvement, 65% exhibited progressive repigmentation, and 1% showed minimal recovery. However, 16% were refractory, including 14% with no change and 2% with worsening depigmentation [77]. A 5‐year follow‐up study (RD‐Team 2018) of 329 cases showed complete resolution in 13%, ongoing recovery in 71%, no change in 14%, and increased depigmentation in 2%, with overall improvement observed in 84% of cases. At the time of follow‐up, 23% were receiving outpatient treatment and 77% had completed treatment. Approximately 16% remained refractory, and 14% were considered equivalent to vitiligo, with depigmentation clearly expanding beyond the application sites [79].

6.3.5. Proposed Pathomechanisms

The proposed pathomechanisms of RD‐induced leukoderma are illustrated in Figure 3 and described in detail by Inoue et al. [66] Briefly, when present in large quantities, RD is metabolized by tyrosinase into RD‐quinone, which exerts cytotoxic effects on melanocytes [80, 81]. RD‐quinone depletes intracellular glutathione, leading to accumulation of reactive oxygen species (ROS) [82]. Excessive ROS induces oxidative damage and melanocyte loss [83]. RD metabolites bind to proteins essential for melanocyte survival, causing denaturation and cell loss [84]. This cytotoxic cascade is exacerbated when glutathione reserves are depleted and cannot be replenished. Discontinuation of RD exposure may interrupt this cascade, allowing melanocyte repopulation. RD metabolites exhibit greater cytotoxicity than physiological melanin precursors.

FIGURE 3.

Proposed pathomechanism of chemical leukoderma induced by rhododendrol. Reproduced from Inoue et al., Journal of Dermatology, 2021, under the Creative Commons Attribution‐NonCommercial‐NoDerivatives 4.0 International License (CC BY‐NC‐ND 4.0).

Six main factors contribute to interindividual differences in onset and recovery. The first is the production of RD‐quinone, the initiating event in melanocyte cytotoxicity, which requires both tyrosinase synthesis in melanosome and efficient melanosomal uptake of RD as a substrate. Ultraviolet radiation and cytokines act as tyrosinase inducers and may modulate individual susceptibility [66, 79]. Moreover, CDH13/T‐cadherin, which regulates tyrosinase expression and apoptosis, has been identified as a susceptibility gene for RD‐induced leukoderma [85]. The second factor is the contribution of RD‐quinone to ROS detoxification and scavenging [86, 87]. The third factor is the activation of autophagy and the unfolded protein response, which are believed to mitigate RD toxicity [88]. The fourth factor is an immune reaction triggered by antigen presentation of melanocyte‐specific proteins [89, 90]. The fifth is the proliferation, migration, and potency of melanocyte precursor cells derived from hair follicles [91]. Finally, differences in the extent of involvement of cells other than melanocytes that contribute to depigmentation or excessive repigmentation may affect the risk of onset, symptoms, and prognosis of leukoderma.

6.3.6. Treatments

Ultraviolet phototherapy was used in approximately 20% of cases and was deemed effective or better by the physician in approximately 50% of facial leukoderma cases and 30% of leukoderma cases involving the back of the hand. In post‐treatment survey, 59% of physicians and 63% of patients reported that ultraviolet phototherapy was effective [77]. In the 2018 study, 17% of patients received ultraviolet phototherapy, of whom 72% (46/64) responded favorably. Phototherapy was effective in 89% of patients (8/9) when initiated within 1 year of onset, in 78% (14/18) when initiated 1–2 years after onset, and in 86% (12/14) when initiated 2 years or more after onset [79]. Improvement in RD‐induced leukoderma symptoms has also been reported following oral administration of natural vitamin D3 [92]. Notably, long‐term persistence of RD‐induced leukoderma is attributed to the destruction of pigment cells, as observed in vitiligo.

7. Differential Diagnosis

The diagnostic algorithms for congenital and acquired hypopigmentation disorders are shown in Figures 4 and 5, respectively. Vitiligo should be differentiated from a wide range of congenital and acquired hypopigmented or depigmented disorders. Congenital disorders include genetic pigmentary abnormalities such as piebaldism and Waardenburg syndrome. Acquired conditions that require careful differentiation include Vogt‐Koyanagi‐Harada disease, nevus depigmentosus, post‐inflammatory hypopigmentation, pityriasis alba, progressive macular hypomelanosis, and idiopathic guttate hypomelanosis. Infectious diseases, including tinea versicolor, syphilis, and Hansen disease, should also be excluded. Other important differential diagnoses include lichen striatus, halo nevus, hypopigmented or depigmented mycosis fungoides, melanoma‐ or immune checkpoint inhibitor‐related leukoderma, and drug‐induced leukoderma [93, 94, 95].

FIGURE 4.

Differential diagnosis and classification of congenital hypopigmented disorders.

FIGURE 5.

Differential diagnosis and classification of acquired hypopigmented disorders.

Although vitiligo can be diagnosed clinically in most cases, examination under Wood's lamp is particularly useful for distinguishing true depigmentation from hypopigmentation and for accurately assessing lesion extent and signs of disease activity. When the diagnosis is uncertain, additional investigations, such as detailed history taking, skin biopsy, potassium hydroxide examination for fungal infection, blood tests, or other appropriate procedures, should be performed to exclude congenital disorders, infections, and cutaneous lymphomas. Because autoimmune thyroid disease is frequently associated with vitiligo, screening for anti‐thyroid autoantibodies and assessment of thyroid function are recommended [5, 96].

8. Proposed Algorithm for the Comprehensive Management of Vitiligo

The assessment flow at the time of diagnosis and the treatment algorithms are shown in Figures 6 and 7, respectively. Management of vitiligo should follow a stepwise and comprehensive approach based on disease subtype, disease activity, extent of skin involvement, patient age, and patient preferences. At diagnosis, careful assessment of disease activity, distribution, duration, and the presence of leukotrichia is essential. Shared decision‐making is strongly encouraged, taking into account expected benefits and limitations of treatment, potential adverse effects, and psychosocial impact [5].

FIGURE 6.

Stepwise approach to the management of vitiligo.

FIGURE 7.

Proposed algorithm for the treatment of vitiligo in Japan.

The initial treatment goal should be defined as either suppression of disease progression or induction of repigmentation, and appropriate treatment modalities should be selected accordingly. In the active phase, topical therapy, phototherapy, and systemic therapy, alone or in combination, should be considered regardless of the treatment goal. In the stable phase, when the goal is to suppress disease progression, observation or maintenance therapy, such as topical treatment, may be appropriate. In patients who have remained in the stable phase for < 1 year after cessation of disease progression and whose treatment goal is repigmentation, preferably for cosmetic purposes, treatment strategies similar to those used in the active phase should be considered. In patients with a stable phase lasting for 1 year or longer, surgical interventions may be considered.

Safety and efficacy should be evaluated every 3–6 months. Through shared decision‐making, treatment goals should be regularly re‐evaluated, and decisions regarding continuation or modification of therapy should be made accordingly. As treatment duration may be long term, the benefits and risks of each option should be clearly explained, and treatment should be selected in accordance with patient preferences and goals.

9. Treatments for Vitiligo and Their Clinical Efficiencies

Each endorsement based on evidence and recommendation levels is summarized in Table 3.

TABLE 3.

Summary of recommendation levels and grades for each treatment modality.

Treatment	Evidence and recommendation level	Comments
Topical steroid	1A nonsegmental (except face and neck) 2A nonsegmental (face and neck) 2B segmental/undetermined	Caution: adverse events in cases with long term use
Vitamin D3 analog	1B (combined with UV exposure)	Concomitant UV exposure is recommended when apply topical vitamin D3 analogs
Topical tacrolimus	1A	Effective, but evaluate its repigmentation effect every 3–6 months
Topical tacrolimus (maintenance)	1B	Suppressive effect of disease recurrence
PUVA phototherapy	2A	Recently less common
Narrowband UVB phototherapy	1A	Notice an increasing risk of actinic keratosis when exposed more than 200 sessions
Excimer laser/light phototherapy	1A	Applied for the lesions intractable to topical steroid and tacrolimus less than 5% of BSA
Home phototherapy	2B	Currently not prevalent in Japan
Systemic steroid	1B	Suggested for progressive nonsegmental vitiligo cases
Systemic immunosuppressants	2B	Suggested for progressive nonsegmental vitiligo cases
Surgery	1B	Applied for the stable and cosmetic lesions more than 1 year More favorable in segmental vitiligo
Camouflage	1B	Attribute to improve the patients' QOL

9.1. Topical Corticosteroids

Topical corticosteroid therapy has been used to treat vitiligo and remains widely used worldwide. In a double‐blind study of topical betamethasone valerate in patients with vitiligo, repigmentation was observed after 4 months in 78.9% of treated sites, whereas no repigmentation occurred at placebo‐treated sites [97]. In addition, a double‐blind randomized comparison study of clobetasol propionate cream demonstrated a significantly higher repigmentation rate in the active treatment group than in the placebo group [98]. The effectiveness of topical corticosteroids has also been demonstrated in comparative controlled studies with other vitiligo treatments [99]. However, high efficacy was predominantly observed in non‐segmental vitiligo, with limited evidence supporting effectiveness in segmental or unclassifiable types. Furthermore, with the increasing use of topical non‐steroidal agents, such as tacrolimus ointment, for facial and neck lesions, topical corticosteroids are now most commonly recommended for non‐segmental vitiligo affecting sites other than the face and neck [6]. For both adults and children with non‐segmental vitiligo, the basic treatment is once‐daily application of a strong topical corticosteroid (group III) [6], with adjustment to very strong (group II) or medium (group IV) preparations according to age and treatment site. Treatment should be continued for 4–6 months in children older than 12 years and for 2–3 months in children younger than 12 years, with consideration of alternative therapies if ineffective. To prevent adverse effects, such as skin atrophy and telangiectasia, intermittent application (e.g., 2 weeks of treatment followed by 2 weeks of rest or alternative topical therapy) should be considered [8]. When corticosteroids are applied to the eyelids, close attention should be paid to complications such as glaucoma. Moreover, potential systemic adverse effects should be considered when very strong (group II) or stronger topical corticosteroids are applied to large areas for prolonged periods [6]. Based on these findings, the recommended level was set to 1 for non‐segmental vitiligo excluding the face and neck and to 2 for non‐segmental vitiligo of the face and neck, as well as for segmental and unclassifiable vitiligo. The evidence level for non‐segmental vitiligo was graded as A, reflecting multiple reliable studies and extensive clinical experience. In contrast, evidence for segmental and unclassifiable vitiligo was graded as B due to limited comparative data.

9.2. Topical Vitamin D3 Analogs

In Japan, although topical active vitamin D3 preparations for vitiligo are not covered by insurance, they were used in nearly 90% of facilities according to a national survey conducted in 2012 [3]. This widespread use is believed to reflect increasing reports of therapeutic benefit [100, 101, 102]. A study evaluating 38 patients treated with either combined topical tacalcitol and 308 nm excimer light therapy or phototherapy alone demonstrated the efficacy of combination therapy [103]. In contrast, a double‐blind study comparing tacalcitol with sunlight exposure found no significant difference in efficacy [104]. Although tacalcitol has been extensively studied, inconsistent results have made it difficult to establish definitive effectiveness [105, 106]. Possible explanations include differences between exposed and non‐exposed sites and racial variations in response. Considering the limited number of effective treatment options and the favorable safety profile of topical vitamin D3, its use is recommended at a level of 1B. It is particularly recommended for exposed areas and in combination with phototherapy. In pediatric cases in which surrounding pigmented areas become intensified [107], sunscreen use on unaffected skin is advised. Notably, combined treatment with excimer laser therapy and topical vitamin D3 has been reported to be ineffective [108].

9.3. Topical Tacrolimus

9.3.1. Early Intervention Treatment

In the 2000s, several international studies reported the efficacy of topical tacrolimus ointment for vitiligo. In a comparative study of 17 patients followed for 6 months, lesions treated twice daily showed greater improvement than those treated once daily or left untreated [109]. A prospective study comparing tacrolimus monotherapy with a placebo demonstrated enhanced efficacy when used with occlusive dressing [110]. A randomized double‐blind study in 20 pediatric patients compared tacrolimus ointment with clobetasol cream over 2 months [111], and found repigmentation in 41% and 49% patients, respectively, with no significant difference. Facial lesions showed higher response rates and good tolerability. A systematic review of 709 patients from 29 studies reported that maximal repigmentation effects were observed at approximately 6 months [112]. Because long‐term studies exceeding 1 year are limited, efficacy should be evaluated after 3–6 months of treatment.

Tacrolimus ointment has not been approved for vitiligo treatment in Japan, although it is used in approximately 70% of facilities [9]. Overseas guidelines and expert consensus recommend topical calcineurin inhibitors, including tacrolimus, for localized vitiligo [113, 114, 115]. However, regulatory agencies, including the US Food and Drug Administration, the European Medicines Agency, and the Japan Pharmaceuticals and Medical Devices Agency, have not approved this indication [116]. When tacrolimus ointment is used in combination with phototherapy, information in the package insert should be carefully considered. The efficacy and safety profile should be fully explained to patients before initiation.

9.3.2. As Maintenance Treatment

Several studies have reported a high rate of recurrence in vitiligo‐affected lesions within 1–2 years after achieving repigmentation in non‐segmental vitiligo. Cavalie et al. conducted a 24‐week randomized comparative study in 35 patients with vitiligo who had achieved > 75% repigmentation and compared the effects of twice‐weekly application of tacrolimus ointment with placebo for maintenance therapy [117]. In the analysis of 56 lesions, 9.7% of lesions in the tacrolimus group showed pigmentation loss, whereas 40% of lesions in the placebo group showed pigmentation loss. These findings suggest that maintenance therapy with a twice‐weekly tacrolimus ointment on repigmented lesions may reduce the risk of relapse. For patients with vitiligo exhibiting high lesion activity, continuous topical treatment for approximately 6 months after repigmentation may be considered.

9.4. Phototherapies

9.4.1. Psoralen Plus Ultraviolet‐A Radiation (PUVA)

Topical or oral PUVA therapy is an effective option for patients with localized lesions that do not respond to topical agents or narrowband (NB)‐UVB phototherapy, or when targeted phototherapy, such as excimer laser or light therapy is unavailable. Treatment is generally administered twice weekly, and because peak phototoxicity occurs approximately 48 h after exposure, the irradiation interval should be at least 48 h [116]. Historically, topical or oral PUVA therapy was a primary modality for repigmentation; however, NB‐UVB phototherapy has largely replaced PUVA in clinical practice. A systematic review indicated that PUVA and NB‐UVB are similarly effective [118]. Conversely, a meta‐analysis of three randomized studies comparing oral PUVA and NB‐UVB reported that the proportion of patients achieving ≥ 75% repigmentation was 60% higher in the NB‐UVB group than that in the oral PUVA group [119]. A meta‐analysis of 35 randomized and non‐randomized studies, involving 1428 patients compared repigmentation rates according to treatment duration [120]. For NB‐UVB, 13%, 19%, and 36% of patients achieved ≥ 75% repigmentation after 3, 6, and 12 months, respectively. In the PUVA group, 9% and 14% of patients achieved ≥ 75% repigmentation after 6 and 12 months, respectively. These findings indicate that phototherapy should be continued for at least 12 months to maximize therapeutic efficacy. Concerns remain regarding adverse effects associated with oral PUVA, including xeroderma, photoaging, and cataracts. Because PUVA can cause phototoxicity and gastrointestinal symptoms, eye protection for 12–24 h after treatment is required. In addition, topical PUVA on exposed areas is technically challenging, and adequate post‐treatment photoprotection is difficult. Although an increased long‐term risk of skin cancer has been reported in patients with psoriasis receiving PUVA therapy [121], a study of 1307 patients with vitiligo did not demonstrate an increased risk of skin cancer compared with controls [122].

9.4.2. NB‐UVB

The recommended protocols for NB‐UVB and excimer phototherapy are summarized in Table 4.

TABLE 4.

Concise protocol for narrowband UVB and excimer phototherapies.

	Frequency	Initial dose (mJ/cm2)	Increasing dose (mJ/cm2)	Maximum dose (mJ/cm2)	Cumulative session number
Whole body
Narrowband UVB	1–2 times/week	200–300	50–100	1500	Up to 200
Target
Excimer laser/light	1–2 times/week	100	50	750	Up to 200

Note: Caution: Protect eye and genital region during sessions. Consider a personalized indication of these phototherapies.

9.4.2.1. Progressive Non‐Segmental Vitiligo

For patients with progressive non‐segmental vitiligo, NB‐UVB is recommended as first‐line therapy to stabilize disease activity. In cases with markedly active multiple lesions, combination therapy with oral corticosteroids and NB‐UVB may be more effective than corticosteroids alone. Disease stabilization is generally expected within 1–3 months. In adults and children who are unable or unwilling to use systemic corticosteroids, NB‐UVB monotherapy may be used to stabilize progressive disease [123].

NB‐UVB irradiation is typically administered once or twice weekly. The initial dose is usually 200–300 mJ/cm² and is increased by 50–100 mJ/cm² per session, up to a maximum of 1500 mJ/cm² per session. Because repigmentation may occur without erythema, dose escalation to erythema threshold is not necessary [124]. A low irradiation dose of 282 ± 69 mJ/cm² has also been reported to be effective [124]. A cumulative limit of approximately 200 treatment sessions, including resumed therapy, is recommended, as the incidence of actinic keratosis increases after ≥ 200 phototherapy sessions [125, 126]. NB‐UVB therapy generally requires continuous treatment for 6 months to 1 year to achieve disease stabilization and repigmentation.

9.4.2.2. Non‐Segmental Vitiligo Involving 10%–40% of the Body Surface Area

Systemic NB‐UVB phototherapy is recommended as first‐line therapy for adults and children aged > 10 years with non‐segmental vitiligo involving 10%–40% of the body surface area. NB‐UVB phototherapy, which has no systemic toxicity and demonstrates good safety in both children and adults, has largely replaced PUVA as the preferred treatment for patients with lesions affecting ≥ 10% of the skin surface area. NB‐UVB can be used for both vitiligo stabilization and induction of repigmentation. Repigmentation centered on hair follicles is typically observed after 15–20 NB‐UVB sessions. If pigmentation continues and a favorable response is maintained, the treatment may be extended beyond 9–12 months, up to 24 months, followed by gradual dose reduction. This approach is also applicable to non‐segmental vitiligo involving > 40% of the body surface area.

For patients who desire treatment and present with more extensive lesions, NB‐UVB phototherapy should be proposed as first‐line therapy in preference to PUVA. Currently, NB‐UVB phototherapy is considered the first‐choice treatment for patients with widespread non‐segmental vitiligo in the non‐progressive or stable phase.

9.4.2.3. For Segmental Vitiligo

In the revised guidelines, phototherapy is recommended for patients aged ≥ 10 years with progressive segmental vitiligo or with segmental vitiligo that has transitioned to the non‐progressive phase within 6 months. NB‐UVB phototherapy may be used in patients with multiple or extensive segmental vitiligo lesions.

9.4.3. Excimer Laser or Light

Targeted phototherapy is a treatment option for patients with localized lesions affecting ≤ 5% of the body surface area that are unresponsive to topical corticosteroids or calcineurin inhibitors. Targeted phototherapy uses 308 nm excimer light or laser irradiation to selectively treat affected areas with high‐intensity light, thereby avoiding unnecessary exposure of uninvolved skin and reducing UVB‐related adverse effects. Targeted phototherapy should be administered at least once weekly, preferably twice weekly [127]. The initial irradiation dose is 100 mJ/cm², with incremental increases of 50 mJ/cm²/time per session, up to a maximum dose of 750 mJ/cm². Because the minimal erythema dose varies among devices, the initial and incremental doses should be determined based on the characteristics of each device. For LED‐based targeted phototherapy, the initial dose is 200–300 mJ/cm². Initial irradiation dose and incremental doses may be adjusted according to body region (face/neck, trunk/limbs, back of the hands, back of the feet, and toes) [113]. Taiwan‐based studies have demonstrated that a low irradiation dose of 347 ± 64 mJ/cm² is sufficient for repigmentation [124]. Although excimer light is more commonly used in Japan, excimer lasers are predominantly used in South Korea and Taiwan, reflecting regional differences in equipment availability. Recently, LED‐based irradiation devices have also been developed. A systematic review of six randomized studies (411 patients, 764 lesions) reported that excimer lamps and lasers were equally effective in achieving ≥ 50% and ≥ 75% repigmentation [128]. Excimer laser phototherapy has been reported to induce repigmentation in lesions resistant to excimer light [129]. Although more frequent treatment (e.g., three times weekly) may accelerate initial repigmentation, the final therapeutic outcome appears to depend primarily on the total number of irradiation sessions rather than frequency [130]. Similar to NB‐UVB, targeted phototherapy may be combined with topical therapies such as topical corticosteroids [4].

9.4.4. Home Phototherapy

Clinical trials and previous studies have shown that NB‐UVB therapy, when used as home phototherapy, is not considered problematic in terms of therapeutic efficacy and safety. Home phototherapy offers several advantages over outpatient irradiation, including medical and economic benefits, as well as improvements in patient QOL. In Japan, as in other countries, home phototherapy performed by patients is currently not covered by insurance and is therefore not practiced as a formal medical treatment. However, as home medical care continues to be promoted through healthcare policies, relevant systems and medical environments may be implemented at an accelerated pace in the future.

For vitiligo, achieving sufficient therapeutic outcomes without irradiation at least once weekly is difficult. Home phototherapy using NB‐UVB light, in which patients purchase ultraviolet irradiation equipment, is already practiced overseas. Systematic reviews based on clinical trial results have shown that, compared with therapy conducted at medical facilities, home phototherapy is a treatment modality that should be promoted in terms of efficacy, safety, and cost‐effectiveness [131, 132, 133, 134, 135, 136, 137]. In cases where frequent outpatient visits are difficult or in regions lacking access to dermatologists, phototherapy may be provided at home. Even for vitiligo, home phototherapy represents a viable option when weekly outpatient visits are challenging [131, 138]. Furthermore, combination therapy with home phototherapy and topical steroids has been reported to be more effective than home phototherapy alone [139]. Providing patients with detailed instructions on the proper use of irradiation equipment and ensuring regular follow‐up with a dermatologist in the outpatient setting essential for safely achieving effective treatment.

9.5. Immunosuppressants

A randomized controlled study evaluated oral cyclosporine, a calcineurin inhibitor, in patients with progressive vitiligo. In this study, 50 patients were divided into two groups: one group received oral dexamethasone (2.5 mg) for 2 consecutive days weekly for 4 months, and the other group received oral cyclosporine at 3 mg/kg/day for 4 months. Although cessation of disease progression was observed in > 80% of patients in both groups, the time to cessation was shorter in the cyclosporine group [140]. Guidance was provided regarding contraindications, medications requiring caution, and avoidance of grapefruit consumption, and trough levels were monitored. Attention should also be paid to potential adverse effects, including renal dysfunction, hypertension, hepatotoxicity, and malignancy. A randomized comparative study of oral azathioprine included 55 patients with vitiligo who were divided into two groups. One group received oral betamethasone (5 mg) for 2 consecutive days weekly, with gradual dose reduction by 1 mg per month, while the other group received oral azathioprine (50 mg twice daily), reduced to once daily after 2 months and to once every other day after an additional 2 months. At 2 and 4 months, the oral steroid group exhibited higher rates of progression cessation; however, at 6 months, the rates were comparable. Although greater repigmentation was observed in the steroid group, reversible adverse effects, such as weight gain and hypertension were more frequent [141]. Guidance was provided on contraindications to concomitant use and medications that require caution. Regarding methotrexate, a randomized comparative study in 52 patients demonstrated that oral methotrexate achieved therapeutic effects comparable to oral steroid mini‐pulse therapy [142]. In another randomized study comparing combination therapy with methotrexate and oral steroid mini‐pulse therapy versus either treatment alone, the combination group demonstrated superior repigmentation [143]. Methotrexate was administered orally once weekly. A randomized, multicenter, double‐blind, phase II trial evaluating combined oral methotrexate and NB‐UVB therapy was initiated in July 2022, and its results are awaited. For mycophenolate mofetil, a randomized comparative study evaluated oral dexamethasone (2.5 mg twice weekly) versus oral mycophenolate mofetil (up to 2 g daily) for 6 months. Although both groups exhibited high rates of disease stabilization, repigmentation was limited, and recurrence after discontinuation was more frequent in the mycophenolate mofetil group [144]. Because of reported teratogenicity, use in pregnant women is contraindicated. When using immunosuppressants, clinicians should carefully monitor for adverse effects, including myelosuppression, hepatotoxicity, malignancy, and interstitial pneumonia.

9.6. Surgical Approach

The currently reported seven surgical techniques are listed below. Surgical intervention may be considered for patients with vitiligo, particularly those with the segmental type, who have experienced disease stability for > 12 months. In addition, surgical interventions are generally limited to cosmetically sensitive lesions without Koebner's phenomenon [3, 145].

1. Minigrafting

2. Suction blister transplantation

3. Smash grafting

4. Autologous cultured epidermal sheet maintaining melanocytes

5. Cultured/non‐cultured epidermal cell suspension

6. Outer root sheath hair follicle suspension

7. Cultured melanocytes

Although methods (1–3) have been performed for several decades, method (4) was recently approved in Japan for patients aged > 12 years, and methods (5–7) comply with the Regenerative Medicine Act. The characteristics of each surgical procedure should be thoroughly understood, and procedure selection should be based on established criteria related to lesion site and size [146]. In comparisons between methods (1) and (2), the proportion of patients achieving > 75% repigmentation was 67% with method (1) and 82% for (2) [147]. Comparisons between methods (1) and (5) yielded conflicting results: some studies reported no significant differences in repigmentation rate or regeneration size [148], whereas others reported higher repigmentation rates with method (1) [149]. In randomized comparative studies of methods (2) and (5), the proportion achieving > 90% repigmentation at 16 weeks postoperatively was 27% with method (2) and 71% with method (5), with the latter showing no framing phenomenon and superior cosmetic outcomes [150]. Method (7) was reported to be superior in repigmentation efficacy in case report‐level comparisons with method (5) [151]. Conversely, a meta‐analysis of 117 studies comparing surgical treatments (excluding method 4) reported no significant differences among procedures; instead, older age, non‐segmental vitiligo, and lesions on the extremities and joint sites were associated with reduced repigmentation rates [152]. The framing phenomenon refers to a ring‐shaped residual depigmented area remaining at lesion margins after surgery. Recipient‐site preparation methods include CO₂ laser, erbium, YAG laser, and frozen blister formation, and considerable innovation has also been achieved in dressing materials for cell transplantation [153, 154]. Melanocyte depletion may occur in lesions unresponsive to conservative treatment, particularly on the extremities, and surgical replenishment may therefore be appropriate. However, higher postoperative recurrence rates are higher in non‐segmental than in segmental vitiligo. Recurrence following method (5) was reported to be 7.6% in segmental vitiligo and 24.4% in non‐segmental vitiligo [155]. Maintenance therapy with UV phototherapy and topical tacrolimus has been reported to reduce postoperative relapse. In a study of 78 patients with non‐segmental vitiligo who achieved ≥ 75% repigmentation, monthly NB‐UVB or excimer laser/light maintenance for 12 months reduced recurrence from 40.5% to 30.1% [156]. Topical tacrolimus twice weekly reduced the recurrence rate to 9.7%, compared with 40% in the placebo group [117]. An autologous cultured epidermal sheet containing melanocytes (JACEMIN) has recently been approved in Japan [157]. It is anticipated that surgical indications will expand beyond cosmetically sensitive sites to include broader lesion areas in the future.

9.7. Camouflage

The usefulness of camouflage, particularly for exposed areas, was described in the initial guidelines as a means of improving patient QOL and Dermatology Life Quality Index scores [3]. Various camouflage methods are available, and their respective advantages and limitations should be carefully considered [158, 159]. Self‐tanning cosmetics containing dihydroxyacetone react with amino acids in the stratum corneum to produce brown pigmentation, thereby masking depigmented areas. Concealer‐based makeup may be less satisfactory for some patients due to staining or removal by washing. For such cases, friction‐ and water‐resistant self‐tanning cosmetics may provide improved durability and patient satisfaction. In Japan, dihydroxyacetone is considered safe for camouflage in segmental vitiligo or leukoderma until surgical treatment becomes feasible [160].

9.8. JAK Inhibitors

The efficacy and safety of JAK inhibitors vary depending on molecular selectivity, binding mechanisms, inhibitory pathways, and routes of administration, resulting in differences in their therapeutic applications [161]. Ritlecitinib also inhibits TEC‐family kinases, making an understanding of individual drug characteristics essential. Topical ruxolitinib was approved by the US Food and Drug Administration for vitiligo treatment in 2021 based on favorable clinical trial outcomes [162, 163], although it is not currently available in Japan. Case reports have described the efficacy of tofacitinib [164], ruxolitinib [165], baricitinib [166], and topical delgocitinib [167] in individual patients. A randomized phase IIb study evaluating oral ritlecitinib for progressive non‐segmental vitiligo has also been reported [168]. JAK inhibitors are expected become an important component of conservative management for leukoderma, and future guideline revisions will incorporate emerging evidence as it becomes available.

9.9. Combination Therapy

9.9.1. Combination of Topical Ointments

A randomized comparative study comparing combination therapy with topical calcipotriol and topical betamethasone dipropionate with their respective monotherapies in 45 patients confirmed the early therapeutic effects of combination therapy, including reduced recurrence rates and fewer side effects following repigmentation [169]. Reports on combination therapy with other topical agents remain limited.

9.9.2. Combined Topical‐ and Photo‐Therapy

A prospective, blinded, left–right comparative study demonstrated the efficacy of combined topical corticosteroid therapy and UVA irradiation [170]. The study involved 96 patients with vitiligo, in whom two symmetrically located lesions were selected as target sites. One site was treated with once‐daily topical fluticasone propionate combined with twice‐weekly UVA irradiation (10 J/cm²) for 9 months, whereas the contralateral site received either treatment alone. Combination therapy was significantly more effective than monotherapy [170]. A blinded comparative study involving 84 patients evaluated combination therapy with topical corticosteroids and 308 nm excimer laser irradiation [171]. Patients receiving twice‐daily topical hydrocortisone butyrate ester combined with twice‐weekly 308 nm excimer laser treatment demonstrated greater therapeutic efficacy than those treated with excimer laser alone [172]. Recent evidence supports the efficacy of combining topical tacrolimus ointment with ultraviolet phototherapy for vitiligo. A large‐scale meta‐analysis published in 2019 reported that topical tacrolimus monotherapy promoted repigmentation, with an even higher therapeutic response observed when combined with 308 nm excimer light or laser therapy [173]. Smaller meta‐analyses have similarly demonstrated the effectiveness of this combination approach [172, 174]. The prescribing information for tacrolimus ointment should be followed to ensure appropriate use. Although the safety and efficacy of topical ruxolitinib combined with NB‐UVB phototherapy have been proposed [175], long‐term observations are warranted to confirm these findings.

10. Conclusions

In conclusion, this second version of the Japanese guidelines for the diagnosis and treatment of vitiligo incorporates global expert recommendations published in 2023. These guidelines provide updated evidence‐based information on vitiligo diagnosis and management in Japan and are intended to support physicians in the appropriate and effective clinical care of patients with vitiligo.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

N.O., K.O., Y.S., K.Y., D.T., T.K. are editorial board members of The Journal of Dermatology. To minimize bias, N.O., K.O., Y.S., K.Y., D.T., T.K. were excluded from all editorial decision‐making related to the acceptance of this article for publication.

Tanemura A., Oiso N., Okamura K., et al., “Second Guidelines for the Diagnosis and Treatment of Vitiligo in Japan (2025),” The Journal of Dermatology 53, no. 8 (2026): e620–e638, 10.1111/1346-8138.70313.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.