Bridging Molecular Mechanism and Clinical Practice in Vitiligo Treatment: An Updated Review

Vitiligo is a common acquired depigmentation disorder affecting 0.5–2% of the world’s population [1]. The clinical course of vitiligo is unpredictable, and it is often accompanied by severe psychological distress and poor quality of life [2]. Although the pathogenesis of vitiligo has not yet been fully elucidated, various hypotheses have been addressed, including autoimmunity, defects in melanocyte adhesion, failure of energetic metabolism, oxidative stress, and genetic influences [3]. Autoimmune nature of vitiligo is confirmed by the presence of antibody-mediated autoreactive CD8+ T cells which are responsible for the destruction of melanocytes. Furthermore, memory T cells are thought to remain and contribute to the recurrence of the lesions [4]. Recent data suggest regulatory T cells might play a role in promoting the immune response in vitiligo [5].

Treatment of vitiligo seeks to achieve three goals: cessation of disease progression by immune suppression, regeneration of pigmentation, and prevention of recurrence [6]. Nonsurgical and surgical interventions are available to achieve these goals. Surgical methods aim to transplant new melanocyte reservoirs into vitiligo lesions, whereas nonsurgical modalities include diverse options targeting the complex pathways involved in the pathogenesis of vitiligo (Table 1). In addition, as clinical trials on many drugs have been actively conducted, existing and upcoming nonsurgical treatments are in the limelight for the treatment of vitiligo.

Phototherapy has been the mainstay of the treatment of vitiligo, and topical agents can be used alone or in combination with phototherapy [7, 8]. Some systemic drugs, such as oral corticosteroids and immunosuppressants, help prevent further destruction of melanocytes when vitiligo spreads [9]. Minimally invasive procedures can serve to improve the efficacies of other treatments. Recently, multiple studies have elucidated the pathogenesis of vitiligo, allowing more selective and targeted therapies [10], and topical ruxolitinib, a topical Janus kinase (JAK) inhibitor, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the first treatment of non-segmental vitiligo.

This review provides a comprehensive and updated overview about vitiligo treatment options (Table 1). We reviewed the molecular mechanism, clinical efficacy, and safety data of phototherapy, topical agents, systemic agents, targeted agents, and minimally invasive procedures based on meta-analyses and randomized trials published in the literature. Integrative information on clinical outcomes and molecular mechanisms can be useful to consider appropriate options based on their molecular basis.

Narrowband ultraviolet B (NBUVB) phototherapy represents the gold-standard treatment for the management of generalized vitiligo since its efficacy in vitiligo was reported in 1997 [11, 12]. NBUVB has a narrow emission peak at wavelength of 311 nm which effectively treats various skin disorders [13]. NBUVB was shown to be superior to broadband UVB given its rapid therapeutic onset and fewer side effects. In a meta-analysis, NBUVB led to an excellent repigmentation (≥75% repigmentation) in 19.2% and 35.7% of patients with vitiligo at 6 and at 12 months, respectively [11]. Treatment with NBUVB in combination with topical steroids, topical calcineurin inhibitors (TCIs), topical vitamin D analogues, topical 5-fluorouracil (5-FU), and topical antioxidants has synergistically enhanced the efficacy [7].

NBUVB treats vitiligo by inducing repigmentation and stabilizing disease progression. Repigmentation occurs through stimulation of the quiescent melanocyte stem cells in the hair follicle bulge and migration toward the epidermis. The underlying molecular pathways of NBUVB remain to be discovered, but UV irradiation was shown to modulate the activation of the melanocyte stem cells via the tumor growth factor (TGF)-β signaling pathway and Wnt/β-catenin signaling [14]. Expression of melanocyte transcription factors microphthalmia-associated transcription factor and sex-determining region Y-box 10 following phototherapy was found to be significantly upregulated. In addition, UV exposure promotes the synthesis and release of multiple melanogenic factors from keratinocytes; both α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone enhance the function of tyrosinase through binding to melanocortin-1 receptor (MC1R) [15]. Endothelin-1 promotes melanocyte dendricity [16] and regulates the differentiation, growth, and survival of melanocytes via the microphthalmia-associated transcription factor-regulated GPNMB pathway [17]. The stem cell factor (SCF)/c-kit pathway mediates epidermal cell adhesion, migration, and proliferation of melanocyte stem cells [18]. Basic fibroblast growth factor induces melanocyte migration through increased expression of the focal adhesion kinase p125^FAK [19]. These factors further lead to the proliferation and their expression of matrix metallopeptidase (MMP)-2 activity in melanocytes and MMP-9 in keratinocytes [20, 21].

Other than melanocytogenesis, NBUVB has immunomodulatory properties [22]. UVB decreased migration of Langerhans cells, decreased the expression of stimulatory signals in dendritic cells, and restored regulatory T cells [13]. Moreover, UVB-irradiated T cells progressed to apoptosis in 20 h in an in vitro study [23], and the level of C-X-C motif chemokine ligand (CXCL10) and circulating interferon (IFN)-γ+ CD8+ T cells were significantly decreased after 24 sessions of NBUVB in patients with vitiligo [24]. UV-induced apoptosis of CD4+ and CD8+ T cells may lead to the elimination of cytotoxic T cells and resident memory T cells allowing melanocytes to repopulate (shown in Fig. 1).

Possible side effects of NBUVB in vitiligo patients include erythema, pruritus, reactivation of herpes simplex, and tanning of uninvolved skin. Eye protection is warranted although cataract is not a problem with NBUVB [25].

First introduced in 1948, psoralen ultraviolet A (PUVA) phototherapy consists of UVA light irradiation that covers 320–400 nm after taking an oral or topical photosensitizer (8-methoxypsoralen; methoxsalen) [26]. PUVA phototherapy showed an excellent repigmentation (≥75% repigmentation) in 8.5% and 13.6% at 6 and 12 months, respectively [11]. It has largely been replaced by NBUVB due to the potential risk for skin cancer and phototoxic side effects such as burning, erythema, and nausea.

PUVA phototherapy may affect immunologic processes of vitiligo through depleting Langerhans cells and melanocyte antigens in the vitiliginous epidermis [21, 27, 28], inducing apoptosis of lymphocytes, and restoring regulatory T cells [29‒31]. In addition, PUVA also stimulates melanogenesis: the photoconjugation of psoralens to DNA strands leads to mitosis, proliferation of melanocytes, and subsequent increased synthesis of tyrosinase [26].

The 308-nm excimer laser/light (EL) is the treatment of choice for stable localized vitiligo or extensive vitiligo though it could be time consuming [32]. It emits a wavelength of 308 nm produced using xenon and chlorine gases and shares the properties of lasers, allowing selective treatment with monochromatic coherent beam with high fluences. EL therapy showed greater efficacy with more rapid repigmentation compared to NBUVB in various studies [33], while some research reported no difference between the modalities [34]. The meta-analysis showed no significant difference between the EL and NBUVB (relative risk [RR], 1.81; 95% confidence interval [CI], 0.11–29.52) [35]. Common side effects of EL included erythema, blistering, burning sensation, pruritus, perilesional hyperpigmentation, and dryness.

EL is expected to exert similar photobiological effects to those of NBUVB as their wavelengths are very close to one another. EL significantly increased the melanin content and stimulated tyrosinase activity through the Wnt/β-catenin pathway [36]. Also, it effectively reduced T cells and promoted regulatory T cells, TGF-β, and interleukin (IL)-10 [37]. Meanwhile, EL can deliver a higher power per unit area compared to NBUVB. An in vitro study showed that EL induced melanoblast differentiation more efficiently [38, 39]: EL induced higher tyrosinase expression at the same fluence and activated less cyclobutane pyrimidine formation compared to NBUVB [40]. These results indicate that EL may be less carcinogenic compared to NBUVB at an equivalent fluence.

Recently, a gain-switched titanium:sapphire laser (TSL) device that emits UV light at a 311-nm wavelength was developed. Unlike EL therapy, TSL requires no periodic gas charging because a solid laser medium is employed. TSL has shown a comparable efficacy to that of the EL and exhibited good safety profiles in several clinical studies [41, 42]. Owing to the shared wavelength, the therapeutic mechanism of TSL in vitiligo may be similar to that of NBUVB and EL [41] modulating immune cells and increasing melanogenesis, which has been further supported by the increased levels of melanogenic cytokines, including endothelin-1, SCF, and Wnt7a after TSL irradiation [41].

Topical calcineurin inhibitors (TCIs) are potent immunomodulators, and tacrolimus and pimecrolimus are widely used to treat vitiligo. TCIs inhibit calcineurin-mediated phosphorylation of the transcription factor, the nuclear factor of activated T (NFAT) cells, thereby preventing T-cell activation and various inflammatory cytokines (shown in Fig. 1) [43]. A meta-analysis demonstrated that 55.0% of patients showed ≥25% repigmentation after TCI monotherapy at a median of 3 months [44]. In another meta-analysis, TCI was comparable to medium-potent and super-potent topical corticosteroids in achieving ≥75% repigmentation (RR of improvement, 0.78; 95% CI, 0.56–1.08), while less effective in terms of ≥50% repigmentation (RR, 0.72; 95% CI, 0.58–0.89) [45]. TCI further increased the treatment success rate when combined with EL compared with EL monotherapy (RR, 1.93; 95% CI, 1.28–2.91) [46]. In addition, topical tacrolimus was also effective in preventing the recurrence of vitiligo [47]. Potential side effects include burning sensation, erythema, and pruritus [48].

The mechanism of action of TCIs in the treatment of vitiligo includes immunosuppression, melanocyte proliferation, and the reduction of oxidative stress. TCI-treated vitiligo lesions exhibited downregulation of proinflammatory cytokines, such as IL-2, IL-3, IL-4, IL-5, IFN, tumor necrosis factor (TNF)-α, and granulocyte-stimulating factors, and upregulation of anti-inflammatory cytokines such as IL-10 [49, 50]. TCIs also promoted the migration and proliferation of melanocytes. In vitro study showed the activities of SCF, MMP-2, and MMP-9 were significantly increased in the keratinocyte supernatant [51‒53]. Multiple studies have demonstrated that tacrolimus increased melanin contents, the level of dopa oxidase activity, and tyrosinase expression [54, 55]. In a randomized clinical trial, a significant reduction in oxidative stress and an increase of antioxidant capacity were observed in the serum of patients treated with topical tacrolimus [56].

Topical corticosteroids are commonly used to treat vitiligo. Treatment with topical betamethasone dipropionate 0.05% cream twice daily showed moderate improvement (25–50% repigmentation) in 46.7% of patients with vitiligo at 3 months [57]. In a randomized controlled trial, a comparison of topical clobetasol propionate 0.05% and tacrolimus 0.1% in patients with vitiligo showed comparable efficacy (58.0% vs. 51.9%) [58]. In addition, the combination of a mid-potent topical corticosteroid and NBUVB or EL significantly increased the repigmentation response compared to phototherapy alone [59‒61]. Considering the possible side effects, once-daily use of a mid-potent topical corticosteroid for a short time would be able to limit the associated side effects, such as atrophy, hypertrichosis, and telangiectasia [59]. A few studies about the efficacy of intralesional triamcinolone injection in vitiligo exist; while some studies reported a successful repigmentation after intralesional triamcinolone injections [3, 62], another study observed no significant difference between corticosteroid and placebo [63].

Topical corticosteroids can be effective in vitiligo owing to their anti-inflammatory and immunosuppressive effects. They inhibit the activity of transcription factors such as nuclear factor-kappa B, activator protein 1, and NFAT by binding to cytoplasmic glucocorticoid receptor [64]. They also suppress leukocyte and monocyte migration and phagocytosis, and also inhibit phospholipase A2 and the release of arachidonic acid which modulates the production of prostaglandins and leukotrienes [65]. Furthermore, corticosteroids have been shown to induce pigmentation through TNF-α suppression [49].

Topical 5-FU was first introduced for the treatment of vitiligo by Tsuji and Hamada in 1983 [66]. Multiple studies have reported effective repigmentation of vitiligo by combination of topical 5-FU with microneedling, dermabrasion, and laser treatments [67‒71]. A 5-FU cream applied after epidermal abrasion, once daily for 7–10 days, led to >75% repigmentation in 64% of the patients [66]. Another study showed 5-FU cream combined with erbium:YAG laser was superior compared with 5-FU cream monotherapy in terms of mean repigmentation area assessed by image analysis (12 ± 7% vs. 1.4 ± 0.8%) [72]. In a network meta-analysis, combination of NBUVB, erbium:YAG laser, and topical 5-FU yielded superior repigmentation compared to NBUVB alone (odds ratio, 10.74; 95% CI, 4.05–28.49) [73]. The most common side effects were pain and erythema on the application sites [70, 72].

5-FU is an antimetabolite analog of the pyrimidine uracil that inhibits thymidylate synthase, an enzyme essential for the synthesis of thymidine, a component of DNA [74]. Its action mechanism in vitiligo is a selective stimulation of melanocytes of hair follicles, leading them to migrate during epithelization and induce pigmentation. In vitro, 5-FU at low concentration selectively destroyed keratinocytes in 3 weeks, while melanocytes remained intact and continued to proliferate [75]. Application of 5-FU with dermabrasion induced the release of inflammatory mediators, such as leukotrienes C4 and D4 which stimulate proliferation and migration of melanocytes [75].

Treatment with systemic corticosteroids is considered in patients with generalized or progressive vitiligo as means to stabilize the disease [32]. A recent study demonstrated that a single course of 500 mg of intravenous methylprednisolone daily for 3 consecutive days halted the progression of disease in 56% of patients with progressive vitiligo and led to >25% repigmentation in 63% of vitiligo patients at 6 months [76]. In addition, oral administration of 5 mg of betamethasone/dexamethasone oral mini-pulse (OMP) on 2 consecutive days per week achieved an arrest of disease progression in 89% of patients [77]. In another randomized controlled trial, OMP (oral prednisone 30 mg/day on 2 consecutive days every week for 3 months) in combination with phototherapy maintained the repigmentation for a longer period of time compared with steroid therapy alone (13% vs. 40% recurrence at 3 months, p value 0.04) [78]. However, a consensus has not been established yet in terms of dosage or modalities for the treatment of vitiligo. Common side effects included weight gain, acneiform eruption, menstrual disturbance, hypertrichosis, and epigastric discomfort [79].

Corticosteroids are well known for their potent anti-inflammatory and immunosuppressive functions, which therefore have been used to treat numerous dermatologic diseases. It inhibits T-cell activity, suppresses B-cell antibody responses, and inhibits the production of various inflammatory cytokines, thereby stabilizing the progression of vitiligo and stimulating repigmentation [80]. Antibody-mediated cytotoxicity against melanocytes was significantly decreased following treatment with systemic corticosteroids in patients with progressive vitiligo [81].

Mycophenolate mofetil (MMF) is also effective in stabilizing the active progressive vitiligo. In a randomized, investigator-blinded pilot study, no significant difference was observed between OMP dexamethasone group and MMF group in terms of disease stabilization of vitiligo measured by achieving Vitiligo Disease Activity Index 2+ on the 180th day (72% vs. 68%, p value 0.61) [82].

MMF acts by inhibiting the enzyme inosine-5′ monophosphate dehydrogenase, thereby depleting guanosine triphosphate, guanosine diphosphate, and guanosine monophosphate in the de novo purine synthesis pathway. It suppresses the recruitment of lymphocytes and monocytes into sites of inflammation including the skin [83]. An in vitro study showed that MMF decreased the adhesion and penetration of T cells to endothelial cells by reducing vascular cell adhesion molecule 1, E-selection, and P-selectin expression [84].

Cyclosporine is a well-known immunosuppressive drug which has been prescribed in solid organ transplant recipients, and it has been shown effective in controlling various chronic skin diseases. An open-label, single-arm study showed that 3 mg/kg per day of cyclosporine halted disease progression in 61% of the patients at 12 weeks assessed using Vitiligo Area Scoring Index (VASI) change pre- and posttreatment [85]. Another randomized controlled study demonstrated that cyclosporine led to the arrest of disease progression measured by change of Vitiligo Disease Activity Index from 4+ to 3+ at 6 months with no significant difference with OMP steroid group (84% vs. 88%, p value 1.00) in active vitiligo patients; however, the mean time to arrest was significantly lower in cyclosporine group compared with OMP steroid group (10.92 weeks vs. 13.90 weeks, p value 0.01) [86]. Cyclosporine binds to calcineurin and inhibits the nuclear translocation of NFAT, which is required for the transcription of genes encoding cytokines including IL-2 and IL-4. Additional mechanisms include inhibition of Langerhans cells and dermal dendritic cells and thus decreased cytotoxic T-cell activation [87, 88]. Inhibition of T-cell activity by cyclosporine may contribute to the stabilization of disease progression (shown in Fig. 1).

Methotrexate (MTX) is one of the time-tested immunomodulatory agents extensively used in various autoimmune diseases with good efficacy and safety on long-term basis although there is limited research suggesting the efficacy of MTX in vitiligo. In a prospective randomized open-label study, 76% of the low-dose MTX (10 mg weekly) group and 75% of OMP (dexamethasone 2.5 mg on 2 consecutive days in a week) group achieved disease stabilization defined as absence of new lesion at 24 weeks, statistically not significant [79].

MTX shows anti-inflammatory, immunomodulatory, and antiproliferative properties by interfering with the folate pathway, adenosine, prostaglandins, leukotrienes, and cytokines [89]. MTX inhibits purine and pyrimidine synthesis, translocation of nuclear factor-κB to the nucleus, and increases T-cell apoptosis via nitric oxide synthase uncoupling [90]. It was reported that levels of the anti-inflammatory cytokines IL-4 and IL-10 were increased while levels of IL-1, IL-2, and IFN-β were decreased after MTX treatment. Inhibition of T cells that are capable of TNF-α production [91] and modulation of inflammatory cytokines and reactive oxygen species by MTX may have led to the disease stabilization of vitiligo [92].

Oral minocycline has been used to treat vitiligo, although only a limited number of studies exist on this topic. Administration of 100 mg of minocycline once daily effectively halted disease progression [93], and no statistical difference was noted between minocycline group and dexamethasone OMP therapy group in achieving disease stability (76% vs. 88%, p value 0.6) [94]. However, another randomized comparative study suggested that minocycline was less effective compared to NBUVB in terms of disease stabilization (33.3% vs. 76.1%, p value <0.001) [95]. Taken together, minocycline may be helpful when other medications or phototherapy is not suitable.

Minocycline is characterized by anti-inflammatory, antimicrobial, and immunomodulatory actions. It also inhibits free radical production, interferes with protein synthesis, and modulates MMP activity [96]. An in vitro study suggested that minocycline could protect melanocytes from apoptosis via the inhibition of H₂O₂-induced Jun N-terminal kinase and p38 mitogen-activated protein kinase signaling [97]. These antioxidant and anti-apoptotic properties of minocycline seem to contribute to the treatment of vitiligo. Potential pitfalls include facial, nail, and mucosal and cutaneous hyperpigmentation, photosensitivity, nausea, vomiting, and headache [94].

Afamelanotide is a synthetic analog of α-MSH which is a potent skin-tanning agent. α-MSH is a critical regulatory protein that binds to MC1R and stimulates melanogenesis and melanocyte proliferation leading to increased expression of eumelanin. In a randomized clinical trial, the combination of phototherapy and a subcutaneous 16-mg afamelanotide implant induced 48.64% repigmentation and 33.26% in the NBUVB monotherapy assessed by the changes in VASI at day 180; combination therapy showed a superior response starting at day 56 (p value <0.05) [98]. Afamelanotide in combination with phototherapy is suggested to induce differentiation of melanoblasts and upregulate MC1R. However, potential adverse effects include hyperpigmentation of unaffected skin by afamelanotide and erythema and pruritus induced by light-based treatment modalities [98].

The oxidative stress often postulated an initial pathogenic event in vitiligo. Dysfunction of unfolded protein response system of melanocytes upon external stimuli ultimately leads to autoimmune activation and melanocyte destruction (shown in Fig. 1) [99, 100]. Moreover, vitiligo patients have impaired antioxidant function showing decreased level of superoxide dismutase, catalase, and increased lipid peroxidation [101].

A number of studies have reported the efficacy of antioxidants alone or in combination with other therapies in the treatment of vitiligo [102]. In slow-spreading vitiligo, arrest of disease progression at 6 months was achieved in 80% of the patients treated by Ginkgo biloba extract 40 mg three times daily and 36% in placebo group (p value 0.006); ≥75% repigmentation was noted in 40% and 9% of treatment group and placebo group, respectively [103]. Polypodium leucotomos 480 mg twice daily in combination with NBUVB showed beneficial results in repigmentation; regarding the head and neck area, ≥75% repigmentation was maintained in 75% of the patients with combination versus 15% of the patients with NBUVB alone at 3 months (p value <0.001) [104]. Selenium, zinc, biotin, nicotinamide, polyphenols, vitamins, folic acid, and alpha-lipoic acid also showed beneficial results in the repigmentation of vitiligo patients [105, 106]. However, varying response was reported due to varying dosage of antioxidants and insufficient evidence. In in vivo results of vitiligo skin, topical application of pseudocatalase was followed by reduction of the H₂O₂ level [107]. However, a randomized clinical trial showed no additional benefit of pseudocatalase cream compared with placebo cream, combined with NBUVB, in terms of mean percentage area (p value 0.04 for left face, p value 0.43 for right face) [107, 108].

These antioxidant agents are well known for anti-inflammatory and immunomodulatory properties. They are considered to contribute to the treatment of vitiligo by the inhibition of T-cell proliferation; the downregulation of inflammatory cytokines such as IL-2, IFN-γ, TNF-α, and IL-6; and the upregulation of IL-10 [109].

As multiple studies have unveiled the pathogenesis of vitiligo, more selective targeted therapy became possible, unlike existing treatment strategies. In the treatment of vitiligo, inhibition of the IFN-γ-induced JAK/STAT pathway could be an attractive treatment target as the IFN-γ-CXCL10 signaling axis has been implicated in the pathogenesis of vitiligo (shown in Fig. 1) [110, 111]. Furthermore, IL-15 and Th2 cytokines mediated by JAK/STAT pathway have been identified as important pathogenic cytokines in vitiligo [10].

Multiple case series have reported promising results of oral tofacitinib, baricitinib, and ruxolitinib in the treatment of vitiligo [112‒115]. Topical ruxolitinib 1.5% cream has shown its efficacy in a randomized double-blind multicenter study achieving a 50% improvement in facial VASI in 50% of the patients with vitiligo compared with 3% in placebo group (odds ratio, 24.7) [116]. Treatment-associated adverse effects included acne and pruritus [116]. Based on its efficacy and safety, topical ruxolitinib has become the first FDA/EMA-approved cream in treatment of vitiligo. Specifically, topical ruxolitinib, JAK1/2 inhibitor, led to a significant reduction in circulating inflammatory chemokines, including CXCL10, CCL18, and soluble CD27, which primarily recruits CD8+ T cells to the skin. This markedly reduced activation, and proliferation of T cells may contribute to the immunomodulating activity of JAK inhibitors [117].

Ritlecitinib is an JAK3/TEC inhibitor that blocks γ common chain cytokine signaling and inhibits the function of CD8+ T cells and natural killer cells [118]. In a phase 2b study, oral ritlecitinib achieved a significantly better repigmentation compared to placebo in % change from baseline in F-VASI at week 24 (−21.2 vs. 2.1, p value <0.001) [119]. Consistently higher proportion of patients showed improvement when administered through week 48, and based on these results, phase 3 study is ongoing.

Given that IFN-γ signaling is mediated by JAK 1/2, blocking JAK1 and JAK2 seems to be effective in the treatment of vitiligo, and selectively targeting of JAK1 is expected to increase efficacy and reduce unwanted side effects. Upadacitinib is a selective JAK1 inhibitor used to treat atopic dermatitis, rheumatoid arthritis, and ankylosing spondylitis. A case series showed that an average improvement in pigmentation of 51.4% was observed in patients with facial vitiligo and 16.8% improvement in acral vitiligo [120]. In a phase 2b study, upadacitinib achieved the primary endpoint of % change from baseline in F-VASI at week 24, with improvements in both 11 mg (−35.6%) and 22 mg (−34.0%) versus placebo (−14.4%; p value ≤0.01 and p value ≤0.05, respectively).

Another oral JAK1 inhibitor, povorcitinib, showed a promising result from a 52-week, double-blind, placebo-controlled phase 2b trial. At week 24, T-VASI change from baseline with povorcitinib was statistically superior to placebo: −19.1%, −17.8%, −15.7%, and +2.3% for 15 mg, 45 mg, 75 mg, and placebo, respectively (p value <0.01). Percentages of patients with F-VASI50 at week 24 were higher for povorcitinib than placebo: 16.3%, 34.9%, and 23.8% for 15, 45, and 75 mg, respectively, compared to 7.0% for placebo [121]. Improved repigmentation was seen across treatment groups at week 52.

Baricitinib, a JAK1/2 selective inhibitor, showed beneficial effect when used in combination with phototherapy. The percentage improvement from baseline of T-VASI was 44.8% and 9.2% at week 36 and 65.2% and −4.4% for F-VASI in combination and phototherapy monotherapy group, respectively [122]. Baricitinib 25 μm significantly promoted tyrosinase activity, melanin content, TYR, and TRP-1 gene expression of damaged melanocytes in vitro [123].

Oral administration of JAK inhibitors can be associated with increased risk of infection as JAK mediates pathways of numerous cytokines. Potential adverse effects include upper respiratory infection, lipid elevation, reactivation of herpes virus, gastrointestinal side effects, anemia, lymphopenia. Although rare, increased risks of intestinal perforation, nonmelanoma skin cancers, solid tumors, and venous thrombosis have been reported after the use of JAK inhibitors, which further needs to be validated [111].

The basic principle of fractional CO₂ laser application is fractional photothermolysis, which triggers the wound-healing process and a series of biochemical reactions such as local capillary proliferation, increased blood supply, and pigment generation. In a meta-analysis, combination of fractional CO₂ laser therapy was found to be more effective than conventional therapies alone including topical steroids, sun exposure, salicylic solution, and NBUVB in terms of excellent repigmentation (≥75% repigmentation) rate (28.4% vs. 8.5%; RR, 2.80; 95% CI, 1.29–6.07) and significantly reduced the treatment failure (<25% repigmentation) rate (33.3% vs. 65.9%; RR, 0.57; 95% CI, 0.43–0.75) [124]. This ablative laser benefits the treatment of vitiligo by several mechanisms. The induction of various melanogenic cytokines, such as MMP-2, during the wound-healing process may stimulate the migration of melanocytic stem cells from hair follicles [125]. The serum levels of IL-4, IL-10, IL-17, and IL-23 were significantly decreased after CO₂ fractional laser therapy, suggesting that it could restore the Th balance of the immune system allowing melanocytes to gradually recover [126]. In addition, impairment of the skin barrier could increase the penetration of UV radiation. In a randomized controlled trial, use of a fractional CO₂ laser combined with NBUVB showed significantly improved repigmentation results compared to NBUVB alone [127]. Lastly, several studies proposed that fractional CO₂ laser therapy can facilitate the delivery of topical agents through microscopic treatment zones [128]. The most common side effects of fractional CO₂ laser were pain followed by burning sensation, erythema, edema, and oozing, and no scarring or Koebner phenomenon has been reported but should be cautious when using the ablative lasers [124].

Microneedling, known as percutaneous collagen induction therapy, has been used in various diseases including skin rejuvenation, scar, and hair growth. It creates micro-channels at the level of the dermis inducing neocollagenesis and neovascularization using various devices including rollers, stampers, and pens with varying needle lengths.

Microneedling was effective in vitiligo either alone or in combination with topical tacrolimus, 5-FU, calcipotriol and betamethasone, and NBUVB. In a clinical study, vitiligo lesions treated with microneedling and tacrolimus showed better treatment success (>50% repigmentation) compared to tacrolimus monotherapy (76.6% vs. 36.6%, p value 0.03) and also histopathologically confirmed increased HMB-45 expression (66.6% vs. 30%, p value 0.04) [129]. Although the mechanism at play is not yet clear, upregulation of multiple growth factors, such as platelet-derived growth factor, TGF-α and TGF-β, connective tissue-activating protein, connective tissue growth factor, and fibroblast growth factor during microneedling were observed [130]. These data indicate that microneedling may have the potential to stimulate melanocyte migration through the release of various growth factors. In addition, microneedling works as an effective intraepidermal and intradermal delivery method for pharmaceuticals, which may increase the penetration of topical agents.

A remarkable progress has been made in the development of therapeutics for vitiligo for recent decades. In 2022, ruxolitinib cream has been approved by FDA for the first treatment of vitiligo, and numerous medicines are undergoing clinical trials. The upcoming targeted therapeutics will ultimately contribute to greatly improved outcome of vitiligo patients. However, currently, there is no definitively superior choice or entirely adequate therapy for vitiligo. At the same time, the conventional treatment options still remain as very powerful and irreplaceable tools. Therefore, it is essential to reduce the gap in the knowledge of the molecular aspects and the therapeutics which should be addressed in the future research.

Various modalities can be used to treat vitiligo patients based on their molecular mechanism of action.

The authors have no conflicts of interest to declare.

This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2020R1I1A1A01074967).

Substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work; and drafting the work or revising it critically for important intellectual content: H.J.J. and J.M.B. Final approval of the version to be published: J.M.B. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.