From Mechanisms to Clinical Practice: Advances in Vitiligo Treatment Across Western Medicine and Traditional Chinese Medicine

Abstract

Objective

To review recent advances in the pathogenic mechanisms and treatment of vitiligo and to evaluate the evidence supporting Western medicine, traditional Chinese medicine, and integrative treatment strategies.

Methods

This narrative review was based on a structured literature search of PubMed, China National Knowledge Infrastructure, and Wanfang databases, primarily covering the period from January 2015 to March 2026. The search terms included “vitiligo”, “pathogenesis”, “treatment”, “JAK inhibitors”, and “traditional Chinese medicine”. Articles published in English and Chinese were considered. Eligible publications included clinical trials, systematic reviews, meta-analyses, observational studies, and representative mechanistic studies relevant to the pathogenesis or treatment of vitiligo. Duplicate publications, articles not directly related to vitiligo, and studies with insufficient methodological reporting were excluded.

Results

Current evidence indicates that immune dysregulation and oxidative stress are central and interacting mechanisms in the initiation, progression, and recurrence of vitiligo. These mechanistic advances have supported the development of targeted and combination therapies, although the strength of evidence varies considerably among different interventions. Artificial intelligence-assisted phototherapy may improve lesion identification and irradiation planning, but current clinical evidence remains limited. JAK inhibitors, particularly topical ruxolitinib, represent an important mechanism-based therapeutic advance in non-segmental vitiligo. Surgical transplantation may provide effective repigmentation options for selected patients with stable vitiligo, although outcomes vary according to disease stability, lesion site, and surgical technique. Traditional Chinese medicine and integrative therapies may provide adjunctive clinical benefit, but the available evidence is limited by study heterogeneity and variable methodological quality.

Conclusion

Future research should prioritize difficult-to-treat acral and mucosal lesions, relapse prevention, maintenance therapy, predictive biomarkers, and the long-term efficacy and safety of targeted and combination treatments.

Introduction

Vitiligo is a chronic autoimmune depigmenting disorder. It causes the selective loss of functional melanocytes and leads to well-defined milky-white patches on the skin. Its global prevalence is estimated to range from approximately 0.5% to 2%, and the disease affects individuals across different ages, ethnic groups, and geographical regions.^1,2 Although vitiligo is not life-threatening, visible lesions can impose a considerable psychological and social burden. Anxiety, depression, stigmatization, and impaired quality of life are particularly common in patients with extensive disease or lesions involving visible areas.^2–6

The pathogenesis of vitiligo is multifactorial and remains incompletely understood.^7–11 Current evidence indicates that oxidative stress and immune dysregulation are closely related processes involved in disease initiation and progression. The IFN-γ–CXCL9/CXCL10–CXCR3 axis is considered an important pathway in the recruitment of melanocyte-reactive T cells and the subsequent destruction of melanocytes. At the same time, oxidative stress increases melanocyte vulnerability and can amplify immune injury.^12–14 These findings support the current understanding of vitiligo as an immune-mediated disease rather than solely a cosmetic disorder.

Treatment remains challenging despite these advances. Topical corticosteroids, calcineurin inhibitors, and phototherapy remain central components of current vitiligo management. However, their efficacy is often variable, and treatment usually takes a long time.^15,16 Incomplete repigmentation, relapse after treatment withdrawal, and poor responses in acral lesions remain important clinical challenges.^13,15

In recent years, new therapies have expanded the treatment landscape. JAK inhibitors have received particular attention because they interfere with IFN-γ-associated signaling and provide a mechanism-based therapeutic approach.^17,18 Phototherapy, systemic treatments, and surgical transplantation techniques have also continued to evolve. Combination therapy and the integration of traditional Chinese medicine with conventional treatment have also received increasing attention, although the supporting evidence varies substantially in design and methodological quality.¹⁹

Recent reviews have summarized the pathogenesis, conventional management, and emerging treatment of vitiligo.^5,7,10,11 However, the rapid development of targeted therapies, combination regimens, surgical techniques, and traditional Chinese medicine-related interventions has created a need for a clinically oriented synthesis that connects therapeutic mechanisms with the maturity of supporting evidence. Established treatments, early clinical interventions, and preclinical approaches should not be interpreted as having equivalent evidential support.

Accordingly, this narrative review examines vitiligo treatment through a mechanism-to-clinical-practice framework. It discusses how oxidative stress, immune activation, chemokine signaling, and persistent immune memory inform current and emerging therapies. Particular attention is given to phototherapy, JAK inhibitors, systemic treatment, surgical transplantation, traditional Chinese medicine, and combination strategies, while distinguishing established treatments from interventions that remain preliminary or investigational.

Methods

This narrative review was based on a structured literature search of PubMed, China National Knowledge Infrastructure, and Wanfang databases. The search covered articles published from January 2015 to March 2026. The search strategy combined the term “vitiligo” with terms related to disease mechanisms and treatment, including “pathogenesis”, “oxidative stress”, “immune dysregulation”, “IFN-γ”, “CXCL9”, “CXCL10”, “CXCR3”, “JAK inhibitors”, “phototherapy”, “surgical treatment”, “traditional Chinese medicine”, and “combination therapy”. Corresponding Chinese terms were used when searching the Chinese databases.

Articles published in English or Chinese were considered. Eligible publications included randomized and non-randomized clinical trials, systematic reviews, meta-analyses, clinical guidelines, expert consensus statements, observational studies, and representative mechanistic studies relevant to the pathogenesis or treatment of vitiligo. Studies were prioritized when they provided clinically relevant information on treatment efficacy, safety, disease stabilization, repigmentation, relapse, or the biological mechanisms underlying therapeutic response.

Duplicate publications, articles not directly related to vitiligo, studies with insufficient methodological information, and publications that did not contribute relevant mechanistic or clinical evidence were excluded. Titles and abstracts were initially screened for relevance, followed by full-text assessment when further evaluation was required. Reference lists of key reviews and representative studies were also examined to identify additional relevant publications.

Because this study was designed as a narrative review, no formal meta-analysis or quantitative evidence synthesis was performed. The included evidence was interpreted according to study design, sample size, duration of follow-up, consistency of findings, clinical relevance, and directness of evidence. Findings from randomized controlled trials and systematic reviews were given greater weight when assessing established treatments. Evidence derived mainly from small observational studies, single-center trials, animal studies, or in vitro experiments was identified as preliminary or investigational.

Pathogenic Mechanisms of Vitiligo: Interactions Between Oxidative Stress and Immune Dysregulation

Vitiligo develops through interactions among genetic susceptibility, environmental stressors, melanocyte-intrinsic damage, and immune dysregulation. Oxidative stress increases melanocyte vulnerability and may generate stress signals that activate local innate and adaptive immune responses. Subsequent recruitment and activation of melanocyte-reactive CD8+ T cells contribute to melanocyte destruction and lesion progression. Persistent chemokine signaling and local immune memory may sustain inflammation and contribute to recurrence at previously affected sites.

Oxidative Stress and Melanocyte Injury

Oxidative stress may serve as an initial trigger that promotes immune activation in vitiligo. Patients with vitiligo show evidence of impaired redox homeostasis, including altered antioxidant defenses and increased markers of oxidative damage.^14,20,21 Excessive reactive oxygen species can damage melanocyte DNA, proteins, lipids, and mitochondria, thereby impairing cellular function and promoting apoptosis. Experimental studies have also implicated non-apoptotic forms of regulated cell death, including necroptosis, pyroptosis, and ferroptosis, although their relative contribution to human vitiligo remains uncertain.^14,20 Impaired activation of the Nrf2–ARE antioxidant response may further reduce the ability of melanocytes to withstand hydrogen peroxide-induced injury.^21,22

Stress-Induced Innate Immune Activation

Oxidatively stressed melanocytes and keratinocytes can release damage-associated molecular patterns that link cellular injury to local immune activation. Stress-associated signals such as inducible heat shock protein 70 and high-mobility group box 1 may activate antigen-presenting cells and enhance inflammatory chemokine production. Oxidative stress can also activate the unfolded protein response in keratinocytes and increase CXCL16 expression, thereby facilitating the recruitment of CD8+ T cells to the skin.^23,24

The IFN-γ–JAK–STAT–CXCL9/CXCL10–CXCR3 Axis

The IFN-γ-associated chemokine pathway is one of the best-characterized immune mechanisms involved in active vitiligo.^13,25 Activated melanocyte-reactive CD8⁺ T cells produce IFN-γ in lesional skin. IFN-γ binds to its receptor on keratinocytes and activates JAK1/JAK2–STAT1 signaling. This signaling induces the production of CXCL9 and CXCL10 by keratinocytes. CXCL9 and CXCL10 bind to CXCR3 on effector T cells and promote their recruitment and positioning within the epidermis, thereby sustaining melanocyte-directed inflammation.¹³

Tissue-Resident Memory T Cells and Disease Recurrence

Melanocyte-reactive CD8+ tissue-resident memory T cells have been identified in lesional and clinically normal-appearing skin of patients with vitiligo, indicating that local immune memory may persist beyond visibly active lesions.^26,27 These cells can rapidly produce IFN-γ after reactivation and may restart local chemokine production, providing a possible explanation for recurrence at previously affected sites.^26,28 Keratinocyte-derived IL-15 trans-presentation supports the survival and activation of melanocyte-reactive CD8+ tissue-resident memory T cells through CD122 and downstream JAK–STAT signaling. However, IL-15/CD122-directed treatment remains investigational because current evidence in vitiligo is derived mainly from mechanistic and preclinical studies, and its clinical efficacy has not been established.²⁸

Regulatory T-Cell Dysfunction and Loss of Immune Tolerance

Regulatory T cells maintain peripheral immune tolerance by limiting autoreactive T-cell responses.²⁹ Current evidence suggests reduced peripheral regulatory T-cell counts and impaired suppressive capacity in vitiligo, while most studies report reduced FOXP3 expression in blood and lesional skin; however, the findings are not fully consistent across studies.³⁰ Defective local regulatory control may therefore permit persistent activation of melanocyte-reactive CD8+ T cells, although the magnitude and consistency of regulatory T-cell abnormalities vary among studies.^29,30 A recent human skin study further showed that clinically normal-appearing vitiligo skin contained functional memory CD8+ T cells together with stronger regulatory immune signatures than perilesional skin, suggesting that local immune regulation is spatially heterogeneous.²⁷

Taken together, oxidative injury, stress-induced innate immune activation, IFN-γ-dependent T-cell recruitment, impaired regulatory control, and tissue-resident immune memory form an interconnected pathogenic framework in vitiligo. This framework provides a biological rationale for combining suppression of active inflammation with strategies that promote melanocyte recovery and prevent disease recurrence (Figure 1).

Figure 1.

Schematic diagram of vitiligo pathogenesis: the synergistic effect of immune dysregulation and oxidative stress. The figure was created with BioGDP.com.

Established and Targeted Medical Therapies

Phototherapy: Established Clinical Use and Emerging AI Support

Phototherapy remains an established treatment for vitiligo, particularly for patients with extensive or active non-segmental disease, whereas 308-nm excimer laser or light is generally used for localized lesions.^15,31 NB-UVB exerts immunomodulatory effects by reducing pathogenic T-cell activity and inflammatory signaling, while promoting the proliferation, migration, and melanogenic activity of residual melanocytes, particularly those within follicular reservoirs.³¹ These complementary effects provide a biological rationale for combining phototherapy with topical anti-inflammatory or targeted therapies.^15,32,33 However, NB-UVB usually requires repeated sessions over several months. Frequent clinic visits, treatment-related erythema, variable responses across anatomical sites, and the resulting treatment burden may reduce adherence. Acral lesions generally respond less favorably than facial and truncal lesions.^15,16,33,34

Compared with whole-body NB-UVB, 308-nm excimer treatment allows lesion-directed irradiation and limits unnecessary exposure of uninvolved skin. However, clinical response remains dependent on lesion location, disease stability, treatment frequency, and dose adjustment.^15,34–36

Artificial intelligence is currently better regarded as an emerging support tool rather than an established therapeutic modality. AI-based image analysis may assist lesion segmentation and objective calculation of vitiligo severity scores. A recent full-body imaging study demonstrated the feasibility of translating automated lesion segmentation into clinical assessment scores, but it did not evaluate whether AI-assisted irradiation improves repigmentation.³⁷ Therefore, potential applications in lesion mapping, treatment planning, and outcome monitoring should be distinguished from proven therapeutic efficacy. Prospective comparative studies are still required to determine whether AI-assisted phototherapy improves clinical response, safety, treatment efficiency, or adherence.³⁸

Topical JAK Inhibition: Clinical Evidence and Remaining Limitations

With the confirmation of the central role of the JAK-STAT pathway in vitiligo, JAK inhibitors have shifted therapeutic strategies from nonspecific immunosuppression toward targeted intervention.³⁹

Their mechanism of action lies in directly inhibiting JAK kinases, blocking downstream IFN-γ signaling, thereby interrupting key inflammatory pathways involved in vitiligo.^17,25

Ruxolitinib cream, the first JAK inhibitor approved for topical treatment of vitiligo, demonstrated significant efficacy in two Phase III TRuE-V trials. At week 24, 29.8% of patients in TRuE-V1 and 30.9% in TRuE-V2 achieved F-VASI75, compared with 7.4% and 11.4% in the vehicle groups, respectively (P < 0.001 for both), demonstrating significantly improved facial repigmentation with favorable tolerability.^18,39 Long-term extension data published in 2026 showed that among patients who received ruxolitinib cream from the beginning of the TRuE-V studies and had not achieved F-VASI90 at week 52, 66.1% of evaluable patients achieved F-VASI75 by week. These findings indicate that repigmentation may continue to improve with prolonged treatment, although the as-observed analysis may overestimate response because slower responders were more likely to discontinue treatment.⁴⁰ However, limitations remain, including reduced efficacy in acral lesions, the need for prolonged treatment, and recurrence after treatment discontinuation has been reported in some patients.⁴¹ Compared with conventional topical therapies, including topical corticosteroids and calcineurin inhibitors, ruxolitinib cream offers a more targeted mechanism of action by inhibiting the IFN-γ/JAK-STAT pathway and is not associated with steroid-related adverse effects such as skin atrophy. Reported adverse events are generally mild and include application-site acne, pruritus, and nasopharyngitis.⁴² However, traditional agents remain widely used as first-line options because of their established efficacy, accessibility, and lower cost.⁴³ In addition, the relatively high financial cost of ruxolitinib cream may limit long-term accessibility and adherence, particularly when maintenance therapy is required, raising concerns regarding its real-world cost-effectiveness compared with traditional topical therapies.⁴¹ The 2026 randomized withdrawal phase of the TRuE-V long-term extension study provided more direct evidence on response durability. Among patients who had achieved F-VASI90 at week 52, relapse to below F-VASI75 occurred in 16 of 56 evaluable patients after treatment withdrawal and in 8 of 55 patients who continued twice-daily ruxolitinib cream. Continued treatment was associated with a lower relapse hazard than withdrawal, with a hazard ratio of 0.42 (95% CI, 0.18–0.99). Among patients who relapsed after withdrawal, 12 of 16 regained F-VASI75 after restarting treatment, with a median time of 85 days.⁴⁴ For conventional topical maintenance, a randomized double-blind placebo-controlled trial confirms that twice-weekly 0.1% tacrolimus maintenance reduces the 12-month depigmentation rate from 40.0% in the placebo group to 9.7% in the intervention group.⁴⁵ However, this tacrolimus regimen should not be directly extrapolated to ruxolitinib cream, for which the optimal reduced-frequency maintenance schedule has not yet been established. This regimen is more recommended for patients with large baseline lesions or a history of frequent relapse.^41,42 Topical JAK inhibitors are suitable for localized vitiligo, offering the advantages of high local concentration and low systemic exposure.⁴²

Topical ruxolitinib therefore represents an evidence-based mechanism-directed option for nonsegmental vitiligo, particularly for facial lesions. However, prolonged treatment requirements, weaker responses at acral sites, relapse after withdrawal, and access or affordability should be considered when interpreting its clinical value.⁴²

To enhance clinical applicability, a comparative summary of current medical therapies is presented in Table 1. The table integrates evidence from representative clinical trials and systematic reviews, highlighting differences in efficacy, safety, and clinical indications.

Table 1.

Comparison of Current Medical Therapies for Vitiligo

Therapy	Main Mechanism	Main Indication	Representative Clinical Evidence	Main Limitations and Adverse Effects	Key Advantages	Evidence Status
Topical corticosteroids	Broad local anti-inflammatory effects	Localized vitiligo	Moderate repigmentation, especially in non-acral lesions	Skin atrophy, telangiectasia	Widely available, inexpensive, and commonly used	Established first-line therapy41,43
Topical calcineurin inhibitors	Inhibition of T-cell activation	Facial, intertriginous, or other sensitive areas	Useful for repigmentation and topical maintenance	Local burning or irritation	Suitable for sensitive sites and does not cause skin atrophy	Established steroid-sparing therapy43,45
NB-UVB phototherapy	Immunomodulation and melanocyte stimulation	Generalized or active nonsegmental vitiligo	Repigmentation varies by site; facial and truncal lesions generally respond better	Frequent sessions, prolonged treatment, and lower response rates in acral lesions	Suitable for widespread disease and supported by extensive clinical experience	Established therapy supported by systematic reviews and extensive clinical use15,16,32
308-nm excimer laser	Targeted ultraviolet irradiation	Localized vitiligo	Site-dependent repigmentation in selected localized lesions	Erythema, blistering	Precise treatment with limited exposure of uninvolved skin	Established option for localized lesions15,35
Topical JAK inhibitors	Inhibition of IFN-γ–JAK1/JAK2–STAT signaling	Non-segmental vitiligo, particularly facial lesions	Approximately 30% achieved F-VASI75 at week 24 in phase III trials	Local reactions, prolonged treatment, weaker acral response, relapse, and high cost	Targeted mechanism without corticosteroid-related skin atrophy	Approved targeted therapy with phase III evidence18,39,42,44
Oral JAK inhibitors	Systemic inhibition of JAK–STAT signaling	Extensive or rapidly progressive vitiligo in selected patients	Early studies suggest benefit, particularly with phototherapy	Infection risk, lipid changes, and need for laboratory monitoring	Potential treatment option for extensive or active disease	Emerging or investigational therapy46–49
Systemic corticosteroids	Broad systemic immunosuppression	Rapidly progressive vitiligo	May stabilize active disease during short-term treatment	Metabolic adverse effects	Rapid suppression of disease activity	Established for selected active disease, but evidence is heterogeneous50–53
Antioxidants	Reduce oxidative stress	Adjunct therapy	Limited benefit as monotherapy; possible benefit with phototherapy	Heterogeneous protocols and limited high-quality evidence	Generally well tolerated and easily combined with other therapies	Adjunctive therapy with low-to-moderate evidence14,54

Notes: Evidence status provides a qualitative summary of the maturity of available clinical evidence and does not represent a formal evidence-grading system.

Abbreviations: F-VASI75, Facial Vitiligo Area Scoring Index achieving ≥75% improvement; JAK, Janus kinase; NB-UVB, narrowband ultraviolet B.

Systemic and Surgical Treatment Options

Systemic Therapy

Oral Corticosteroids

Oral glucocorticoids may be considered in selected patients with rapidly progressive vitiligo to suppress disease activity and limit the development of new lesions.^50,51 Among the reported regimens, oral mini-pulse therapy has been frequently studied, with representative protocols using dexamethasone at approximately 2.5 mg on two consecutive days per week.^51,52,55 Available studies suggest that this regimen can stabilize disease progression in some patients and may induce partial repigmentation.^51,55 However, the overall quality of evidence remains limited and heterogeneous, with most studies being small or non-randomized.

Although systemic corticosteroids may help stabilize active vitiligo, prolonged treatment is limited by adverse effects such as weight gain, hypertension, hyperglycaemia, and other metabolic disturbances. Evidence for these risks is largely derived from broader corticosteroid-treated populations rather than vitiligo-specific trials. Therefore, systemic corticosteroids are mainly used for short-term disease control rather than long-term maintenance or relapse prevention.⁵³

Antioxidants as Adjunctive Therapy

Antioxidant therapy targets the oxidative stress component of vitiligo pathogenesis by reducing reactive oxygen species and restoring redox balance in melanocytes.¹⁴ Common agents include vitamin C, vitamin E, alpha-lipoic acid, and zinc, which may enhance treatment efficacy, particularly when used in combination with phototherapy.^14,50 However, current evidence is largely derived from small or heterogeneous studies, and antioxidant monotherapy shows limited benefit. Overall, the strength of evidence supporting antioxidant therapy remains low to moderate, and it is generally considered an adjunctive rather than primary treatment option.⁵⁰

Emerging Oral JAK Inhibitors

Oral JAK inhibitors are being investigated for patients with extensive, active, or treatment-resistant vitiligo. Early studies of baricitinib and other oral JAK inhibitors have shown potential clinical activity, particularly when systemic JAK inhibition is combined with phototherapy.^46–49 However, most agents remain off-label or investigational for vitiligo, and the available evidence is based on relatively small studies with limited follow-up. Reported safety concerns include infections, headache, laboratory abnormalities, lipid changes, and rare thromboembolic events. Careful patient selection and clinical and laboratory monitoring are therefore required.^42,46,48 Due to safety considerations and limited long-term data, oral JAK inhibitors are not currently considered first-line therapies and are mainly reserved for refractory or severe cases.⁵⁶

In a Phase II proof-of-concept randomized trial involving 49 adults with extensive and active non-segmental vitiligo, treatment-emergent adverse events were reported in 65% of patients receiving baricitinib plus NB-UVB and in 58% of those assigned to the placebo calibration group. The most frequently reported events were infections and headache. One pulmonary embolism and one varicella-zoster infection occurred in the baricitinib group, and no deaths were reported. Because of the small sample size and limited follow-up, these findings do not establish the long-term safety profile of systemic JAK inhibition in vitiligo. Larger controlled trials are required.^42,46,48 Further large-scale randomized controlled trials are needed to better define optimal treatment regimens and clarify the long-term efficacy and safety of systemic therapies in vitiligo.

Surgical Therapy

Surgical treatment is generally considered for patients with stable vitiligo that has responded inadequately to medical treatment. Disease stability should be assessed using the absence of new or enlarging lesions, the absence of recent Koebner activity, and validated clinical activity measures. Definitions vary among studies, although a stability period of at least 6–12 months is commonly required and longer stability may be preferred before cell-based transplantation.^57–59 Despite favorable efficacy, surgical interventions remain limited by donor site availability, technical complexity, and the requirement for stable disease.^60,61

Tissue Transplantation

Suction Blister Epidermal Grafting (SBEG) is recognized as a safe and effective treatment, particularly suitable for cosmetically sensitive areas like the face and lips.^62,63 This technique uses negative pressure to separate the epidermis at the dermoepidermal junction. The epidermal roof of the donor blister is then transferred to a prepared recipient site. Observational studies have reported favorable repigmentation in selected patients with small, stable lesions, including lesions involving the lips. However, outcomes vary according to lesion site, surgical technique, follow-up duration, and the definition of treatment success.⁶² In recent years, long-term follow-up is still required because recurrence and incomplete color matching may occur after apparently successful grafting.⁶⁴

Autologous Split-thickness Skin Grafting (STSG) offers significant advantages in treating large-area stable vitiligo.⁶⁵ This technique uses a dermatome to obtain skin grafts containing the epidermis and a very thin papillary dermis. In a small clinical study, ultrathin split-thickness skin grafting followed by NB-UVB resulted in more than 90% repigmentation in 83% of patients. However, this estimate was derived from a non-randomized study and should not be interpreted as a general response rate for all patients undergoing STSG.^65,66

Miniature Punch Grafting (MPG) is one of the most straightforward and economical techniques in vitiligo surgical treatment.⁶⁷ The basic principle involves using a punch to extract small skin grafts from normally pigmented areas and inserting them into corresponding holes created in the recipient site. Miniature punch grafting is considered a relatively simple and cost-effective surgical technique for stable vitiligo. Recent refinements in customized short punch design may help reduce donor-site trauma and minimize cobblestone-like appearance while improving procedural precision. A 2025 technical report proposed customized short punches with diameters of 0.9–2.0 mm and lengths of 0.5–1.5 mm to improve graft-depth control and potentially reduce donor-site trauma and cobblestoning. However, these proposed advantages have not yet been confirmed in comparative clinical trials. The modified devices may also increase procedural cost and require additional equipment and surgical training.⁶⁷

Cell-Based Transplantation

Autologous cultured melanocyte transplantation allows melanocytes obtained from a relatively small donor sample to be expanded for treatment of a larger recipient area. However, the procedure requires specialized cell-culture facilities, longer preparation time, higher cost, and strict quality control. A 2024 retrospective study involving 491 patients reported excellent recoloration in 69.7% of patients and good recoloration in 18.4%, based on the response categories defined by the investigators.⁵⁸ Treatment outcomes were associated with disease stability, vitiligo type, lesion site, and the ratio between the treated area and donor-derived cell coverage. Because the study was retrospective, the reported response rates should be interpreted cautiously.⁵⁸ Multivariate regression analysis confirmed that disease stability ≥12 months, non-segmental vitiligo, and non-acral lesions were independent predictors of better outcomes, with all results showing statistically significant differences.⁵⁸ In addition, earlier systematic evidence reported a mean success rate of 48% for cultured melanocyte transplantation, although this estimate was based on older and heterogeneous studies and is not directly comparable with the more recent cohort.⁶⁸

Hair Follicle-derived Melanocyte Transplantation: Recent studies suggest that hair follicles may serve as a promising reservoir of melanocyte stem cells for transplantation-based vitiligo therapy; however, optimization of post-transplantation cell survival and engraftment efficiency remains necessary.⁵⁹

Overall, current evidence supports the efficacy of various surgical techniques in selected patients with stable vitiligo. However, most studies are retrospective or observational, and high-quality randomized controlled trials remain limited.⁶¹

To facilitate comparison of surgical approaches, Table 2 summarizes the indications, outcomes, advantages, limitations, and evidence supporting the main surgical treatments for stable vitiligo.

Table 2.

Comparison Table of Surgical Treatments for Vitiligo

Category	Technique	Core Principle	Main Indication	Main Effect	Advantages	Limitation	Evidence Type and References
Tissue Transplantation	Suction blister epidermal grafting (SBEG)	Transfer of suction-induced epidermal grafts.	Small, stable lesions, especially on the face or lips	Favorable repigmentation and color match in selected patients	Simple; minimal donor-site scarring	Limited treatment area; prolonged blister formation; possible incomplete repigmentation	Clinical use; mainly observational studies60,62–64
Tissue Transplantation	Miniature punch grafting (MPG)	Small punch graft implantation	Small stable lesions (VIDA score=0 for ≥6 months)	Moderate repigmentation	Easy and low cost	Risk of cobblestone appearance	Clinical use; mainly observational studies and technical reports60,61,67,68
Tissue Transplantation	Split-thickness skin grafting (STSG)	Split-thickness skin grafting	Large stable lesions (VIDA score=0 for ≥6 months)	High repigmentation rate	Can cover large areas	Donor site scarring.	Clinical use; mainly small non-randomized studies60,61,65,66
Cell Transplantation	Cultured melanocyte transplantation (CMT)	Cultured melanocyte suspension transfer	Stable extensive disease (VIDA score=0 for ≥12 months)	Favorable repigmentation in selected patients	Suitable for large areas	Complex and costly	Specialized clinical use; retrospective and systematic evidence58,68
Cell Transplantation	Hair Follicle-derived Melanocyte Transplantation	Melanocyte stem cell transfer	Refractory stable vitiligo (VIDA score=0 for ≥12 months)	Promising repigmentation	Easy cell source	Limited clinical evidence	Experimental; Investigational; limited early clinical evidence and review data59

Notes: Definitions of disease stability vary among studies. Surgical selection should consider recent lesion progression, new lesions, Koebner phenomenon, lesion site, and previous treatment response. The evidence categories describe study types and do not represent a formal GRADE assessment.

Abbreviations: CMT, cultured melanocyte transplantation; MPG, miniature punch grafting; SBEG, suction blister epidermal grafting; STSG, split-thickness skin grafting.

Traditional Chinese Medicine–Derived and Integrative Approaches

Traditional Chinese Medicine (TCM) has a long history of application in the clinical management of vitiligo.⁶⁹ Its potential advantage lies in its holistic therapeutic approach. From a TCM pathogenesis perspective, vitiligo is considered to originate from liver and kidney deficiency, qi and blood disharmony, and invasion by wind pathogens.⁷⁰ These concepts belong to a traditional diagnostic framework and should not be regarded as direct equivalents of immune dysregulation or oxidative stress in modern biomedical models. Current research has instead examined whether selected TCM-derived interventions may affect melanogenesis, oxidative injury, or immune signaling.⁷¹ This multi-dimensional view of pathogenesis reflects an imbalance in the body’s internal environment.

Evidence for Chinese Patent Medicines: A Bayesian network meta-analysis of 48 studies involving 4446 participants suggested that Qubai Babuqi tablets ranked favorably for short-term response, whereas vitiligo capsules or pills ranked favorably for longer-term outcomes.¹⁹

However, these findings were based mainly on indirect comparisons of Chinese patent medicines used alongside routine treatment. Differences in formulations, background therapies, treatment duration, and outcome definitions limit direct comparisons between interventions. Chinese patent medicines should therefore be considered potential adjuncts rather than established alternatives to standard vitiligo treatment.¹⁹ Some Chinese patent medicines contain plant-derived components that have been investigated for melanogenic, antioxidant, or immunomodulatory activity.^72,73 From a biomedical perspective, these ingredients may promote melanogenesis, enhance antioxidant defenses, and modulate immune responses.^54,74 For example, psoralen derived from Psoralen corylifolia is known to stimulate melanocyte activity and is widely used in combination with phototherapy.^72,75 Psoralen-related compounds are of particular interest because of their established photosensitizing properties. However, the composition and dose of multi-component preparations vary across products, making it difficult to attribute clinical effects to an individual ingredient. Dermal delivery studies suggest that microemulsion systems may improve the local retention of 8-methoxypsoralen, but these formulation studies do not establish clinical effectiveness in patients with vitiligo.^72,76

Mechanism of Fire Needling Therapy: Fire needling has been evaluated in systematic reviews and small clinical studies. A six-month randomized self-controlled trial enrolled 35 patients with stable non-segmental vitiligo, of whom 29 completed follow-up. The combination of fire needling and topical tacrolimus produced greater repigmentation than either intervention alone.^77,78 However, the sample was small, the comparison was conducted at the lesion level within the same patients, and independent multicenter confirmation is still needed. Proposed mechanisms include micro-injury-induced activation of Wnt/β-catenin signaling and recruitment of follicular melanocyte precursors, but these explanations are derived mainly from experimental studies.^79,80 Direct clinical evidence that fire needling regulates the CXCL12/CXCR4 axis in vitiligo remains insufficient.^81,82

TCM-derived New Drugs: CKBA ointment has undergone phase II clinical evaluation in adults with non-segmental vitiligo. The registered study used a multicenter, randomized, double-blind, vehicle-controlled, dose-exploration design.⁸³ However, a trial registry entry alone is insufficient to confirm the magnitude of efficacy, the optimal concentration, or long-term safety. CKBA ointment should therefore be described as an investigational topical agent until complete peer-reviewed clinical results are available.⁸³

Microbiome-Derived Experimental Approaches. Exopolysaccharides derived from Bacillus subtilis reduced depigmentation and altered cutaneous immune-cell profiles in a vitiligo-prone mouse model.^84,85 These findings suggest a possible microbiome-based immunomodulatory strategy. However, this intervention is not an established TCM treatment, and the available evidence remains preclinical. Human efficacy, clinically relevant dosing, pharmacokinetics, and long-term safety have not yet been established.

Plant-derived compounds, including Ginkgo biloba extract and naringenin, have shown antioxidant, immunomodulatory, or melanogenic activity in experimental studies.^54,86 However, clinical evidence remains limited, and these compounds cannot currently be recommended as stand-alone treatments for vitiligo. Overall, TCM-related interventions should be regarded as adjunctive or investigational approaches rather than standard-of-care therapies. Their evaluation is limited by non-standardized preparations, heterogeneous background treatments, small samples, inconsistent outcome definitions, and limited long-term follow-up. Standardized products, validated VASI-based outcomes, appropriate control groups, and well-designed multicenter randomized trials are needed before these approaches can be incorporated into routine mechanism-based treatment strategies.⁸⁷

Strategic Innovations in Combination Therapy

Monotherapy often shows limited efficacy in vitiligo due to its multifactorial pathogenesis involving immune dysregulation and oxidative stress.^14,56 A recent two-center retrospective study of 500 patients used repeated longitudinal VASI assessments to compare monotherapy with combination treatment. Combination regimens were associated with greater reductions in VASI scores over time. However, treatment allocation was non-randomized, the regimens were heterogeneous, and baseline disease severity differed between groups. These findings support further prospective evaluation but do not establish the superiority of any specific combination regimen.⁸⁸

Conventional Combination Therapies

Conventional combination therapies aim to enhance efficacy by targeting multiple pathogenic pathways, particularly immune dysregulation and melanocyte regeneration.⁵⁶

In addition, a randomized split-body pilot study suggested that apremilast combined with NB-UVB may suppress Th17-related inflammation and promote melanogenesis. However, the small sample size and pilot design limit the generalizability of these finding.⁸⁹

JAK Inhibitors + Phototherapy: JAK inhibition reduces IFN-γ-related inflammatory signaling, whereas NB-UVB promotes melanocyte activation, migration, and repigmentation. A recent systematic review and meta-analysis found that JAK inhibitor plus NB-UVB therapy improved VASI outcomes and increased the likelihood of achieving at least 50% and 75% repigmentation compared with control regimens. However, only four studies involving 217 adults were included, and the evaluated JAK inhibitors and treatment protocols varied. Therefore, this combination should be regarded as an emerging strategy rather than an established standard regimen.^90–92 Psoralen and Phototherapy: Psoralen-based phototherapy is an established photosensitizing strategy, although its clinical use is limited by differences in formulations, irradiation protocols, safety considerations, and patient selection.¹⁶ A randomized trial reported greater repigmentation with psoralen plus NB-UVB than with NB-UVB alone. However, treatment protocols, psoralen formulations, safety considerations, and patient selection vary across studies. These findings support a role for selected psoralen-based combinations but should not be generalized to all integrative treatment regimens.^15,93

Microemulsion delivery systems may improve the cutaneous penetration and retention of topical 8-methoxypsoralen. However, this evidence is mainly pharmaceutical and preclinical, and it does not establish superior clinical repigmentation in patients with vitiligo.⁷⁶

Combination Therapies Integrating Traditional Chinese Medicine

In addition, combination strategies integrating TCM with modern therapies have gained increasing attention.

Integrated TCM and Western Medicine: Fire needling combined with conventional treatment has been evaluated in small clinical studies and evidence syntheses, but the overall certainty of evidence remains limited. A randomized self-controlled trial compared fire needling, 0.1% tacrolimus ointment, and their combination in 35 patients with stable non-segmental vitiligo. Twenty-nine patients completed the six-month follow-up, and the combination produced greater repigmentation than either intervention alone. However, the small sample size and within-patient design limit the generalizability of the findings.⁷⁸ Fire needling combined with 308-nm excimer laser therapy has also been evaluated as an adjunctive approach. A systematic review and meta-analysis reported better clinical response and VASI improvement with the combination than with excimer laser alone. A subsequent retrospective cohort study suggested potential benefit in stable acral vitiligo. Nevertheless, the available studies were affected by variations in fire-needling protocols, outcome definitions, study quality, and follow-up duration. Much of the evidence was derived from single-center studies, and the recent acral study was retrospective. Therefore, this approach remains promising but cannot yet be regarded as supported by high-certainty evidence.^94,95

Overall, combination therapy may improve treatment outcomes by concurrently suppressing immune activity and promoting melanocyte recovery. However, current evidence is insufficient to identify a universally preferred regimen, and treatment selection should remain guided by disease activity, lesion site, phenotype, safety, and accessibility.

Current Challenges, Evidence Gaps, and Future Directions

Despite substantial therapeutic advances, the strength of evidence supporting different vitiligo interventions remains uneven. The available longitudinal evidence also highlights the need to evaluate treatment durability rather than relying only on short-term repigmentation endpoints. Topical anti-inflammatory agents and phototherapy remain established components of treatment, whereas JAK inhibitors provide a mechanism-based option for selected patients with non-segmental vitiligo. Surgical transplantation is mainly reserved for patients with stable disease. By contrast, several emerging interventions are supported primarily by small observational studies, single-center trials, or preclinical research and should not be interpreted as having evidence equivalent to established treatments.

Combination therapy is clinically relevant because suppression of immune activity and restoration of melanocyte function may need to occur concurrently. Important clinical gaps nevertheless remain. Acral and mucosal lesions frequently show limited repigmentation, which may be related to reduced melanocyte reservoirs and distinct local tissue environments. Treatment response also varies according to disease activity, lesion location, duration, phenotype, and access to prolonged therapy. Future studies should use standardized definitions of disease activity and stability, prespecified VASI-based outcomes, and longer follow-up periods to evaluate the durability of repigmentation and the risk of relapse.

Relapse after treatment withdrawal remains a major clinical challenge. Melanocyte-reactive tissue-resident memory T cells may persist in previously affected skin and maintain local immune memory, thereby contributing to recurrence at the same sites after treatment discontinuation.^28,96,97 Although targeting the IL-15/CD122 pathway may help reduce TRM-cell persistence, this approach remains investigational because clinical efficacy and long-term safety have not yet been established.

Immune checkpoint inhibitor-induced vitiligo represents a treatment-related depigmentation phenotype associated with antitumor immunity, but its biological relationship with spontaneous vitiligo requires further investigation.^98,99 CXCL9 and CXCL10 are candidate biomarkers of vitiligo activity, but their clinical value for treatment selection has not been established. A small clinical study found that CXCL9 measurements were associated with disease activity and the outcome of cultured melanocyte transplantation. However, available findings have not been validated in large multicenter cohorts, and standardized assays and clinically applicable thresholds remain lacking. These limitations currently prevent the routine use of CXCL9 or CXCL10 for predicting response to JAK inhibitors or other treatments.^100,101 At present, the clinical cut-off values of these biomarkers have not been uniformly validated in multicenter cohorts, which limits their routine clinical application.¹⁰¹

Maintenance therapy should be considered after successful repigmentation because recurrence may occur after treatment withdrawal. In a randomized, double-blind, placebo-controlled study, twice-weekly application of 0.1% tacrolimus reduced recurrent depigmentation from 40% in the placebo group to 9.7% in the tacrolimus group. Early withdrawal data for topical ruxolitinib suggest that repigmentation may persist for several months in some patients, although responses are not uniformly maintained and the optimal maintenance regimen remains uncertain.^45,102

Future research should prioritize standardized combination regimens, relapse prevention, maintenance treatment, and phenotype-guided strategies for difficult-to-treat lesions. Therapies targeting tissue-resident memory T cells, as well as cell-based and cell-free regenerative approaches, remain investigational and require prospective evaluation.¹⁰³ Artificial intelligence may assist lesion assessment, treatment planning, and response prediction, but its clinical value should be established in external and multicenter studies. Ultimately, progress in vitiligo care will depend not only on the development of new interventions but also on identifying which mechanism-based combination and maintenance strategy is most appropriate for each patient.

Conclusion

Vitiligo treatment is increasingly guided by advances in oxidative stress biology, IFN-γ–JAK–STAT signaling, and tissue-resident immune memory. Phototherapy and conventional topical agents remain established treatments, while topical ruxolitinib provides a validated mechanism-directed option for selected patients with non-segmental vitiligo. Surgical procedures may benefit carefully selected patients with stable disease, whereas most TCM-derived and other emerging interventions still require stronger clinical evidence. Future progress will depend on improving outcomes in acral and mucosal lesions, preventing relapse, and defining effective maintenance and combination regimens through well-designed long-term studies.

Funding Statement

The authors received no financial support for this work.

Ethics Approval and Consent to Participate

Not applicable, as this is a narrative review of published literature.

Author contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.