FormalPara Key Points

Vitiligo is a chronic autoimmune disease leading to white patches, which can have a profound impact on a patient’s quality of life.

The T-helper (Th) 1 pathway is overactive with interferon-γ driving the pathogenesis and signaling via Janus kinase (JAK) 1 and JAK2.

Topical corticosteroids, topical calcineurin inhibitors, oral corticosteroids, and phototherapy are among the most common treatments. The US FDA has approved the JAK1 and JAK2 inhibitor ruxolitinib cream as the first treatment to repigment patients with vitiligo.

1 Introduction

Approximately 0.5–2% of the population worldwide is affected by vitiligo, a chronic autoimmune disease characterized by the selective loss of melanocytes, resulting in depigmented patches of skin [1, 2]. The disease affects both males and females and all races and ethnicities [3]. About 50% of patients show clinically apparent depigmented lesions before age 20 years, and nearly 70–80% before age 30 years, but the disease can manifest itself at any age [4]. Although patients with vitiligo are not in physical pain, the psychological burden of the disease can be devastating, especially for darker-skinned individuals in whom depigmented areas are more easily detectable, particularly if present on visible areas of the skin. Thus, psychologically, vitiligo can lead to negative self-esteem, depression, social isolation, stigmatization, and overall decreased quality of life [3, 5,6,7,8,9,10]. Vitiligo is classified as either nonsegmental or segmental, as determined by the 2011 Vitiligo Global Issues Consensus Conference, and treatment and prognosis for both classifications vary [11]. Until recently, there have been no US FDA-approved treatments for repigmenting vitiligo. Therapeutic options are based on several published consensus guidelines [12,13,14,15], but available options are not always effective, may have adverse effects, and disease often returns after discontinuing therapy. Additionally, acral areas, such as the hands and feet, are notoriously difficult to repigment with conventional methods compared with areas such as the face and trunk [16]. In general, first-line treatment consists of topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs), second-line therapies consist of phototherapy and systemic corticosteroids, and third-line treatment consists of surgical procedures and depigmenting therapy [14, 15, 17,18,19,20], although an element of personalization must be kept in mind when determining a treatment approach. There is a strong need for targeted, safe therapies that are effective and long-lasting, and this goal is within reach given our increased knowledge of the specific pathways involved in the pathogenesis of vitiligo. For this narrative review, PubMed was searched using terms including, but not limited to, vitiligo pathogenesis, vitiligo treatment, and the relevant vitiligo treatment modalities included in this article (TCSs, TCIs, oral corticosteroids, phototherapy, surgical treatment, depigmentation therapy, minocycline, methotrexate, azathioprine, levamisole, apremilast, Ginkgo biloba (GB), Polypodium leucotomos (PL), and topical/oral Janus kinase (JAK) inhibitors). This paper aims to provide an overview of the pathogenesis of vitiligo and a comprehensive review of the therapeutic options available for vitiligo.

2 Pathogenesis

There has been much debate over the underlying pathogenesis of vitiligo, but recent research has led to a more concrete understanding of the mechanisms behind this disease. There is now a consensus that vitiligo is an autoimmune disease driven by the combination of stress and immune responses, together with genetic predisposition and environmental exposures [11, 21].

2.1 Genetics

There have been several genome-wide association studies (GWAS) in European and Chinese populations that have discovered nearly 50 genetic loci associated with vitiligo, confirming this genetic contribution [22,23,24,25,26,27,28,29,30]. Several of these genes are involved in other autoimmune diseases, such as thyroid disease, which is a common comorbidity among patients with vitiligo, in addition to type I diabetes and rheumatoid arthritis [26, 31,32,33]. Furthermore, the risk of developing vitiligo increases to 6.1% if a sibling has vitiligo, and is as high as 23% in identical twins [34]. There are reports of familial clusters of cases [35], and among patients with vitiligo, about 20% have at least one first-degree relative with the disease [36].

2.2 Oxidative Stress

There is still discussion over what first initiates the onset of vitiligo, but one widely accepted hypothesis is the role of oxidative stress [37,38,39,40]. In response to stress, reactive oxygen species (ROS) are released from melanocytes. ROS generation can be triggered by many different stimuli [41], including mitochondria, which have proven to be altered in vitiligo patients [42, 43], membrane lipid defects [44], and the synthesis of melanin itself [45]. The melanin biosynthesis pathway is an energy-consuming process that is directly toxic to melanocytes, generating a pro-oxidant state in the skin [45]. Melanogenesis, which requires the production of numerous proteins, increases the risk of forming misfolded proteins and activating the unfolded protein response stress pathway, and the production of ROS from energy metabolism in mitochondria [45,46,47]. Melanocytes in patients with vitiligo may be more sensitive to pro-oxidant stimuli [38, 39]. Ultraviolet (UV) light, while a well-established treatment for vitiligo, can also induce the production of ROS, hydrogen peroxide (H2O2), and superoxide anions [48]. The melanocytes of patients with vitiligo may also have intrinsic defects, which is suggested by findings that melanocytes cultured from non-lesional skin of patients with vitiligo are more difficult to grow in vitro compared with healthy controls [49] and require the addition of growth factors [50].

2.3 T-helper 1 Pathway, Interferon-γ, and CXC Chemokine Ligand (CXCL) 9/CXCL10

Cytotoxic CD8+ T cells that target melanocytes are present in both the serum of vitiligo patients and the epidermis and dermis of vitiligo lesions [51, 52]. A key study showed definitive evidence of a T-cell cytotoxic effect on melanocytes, causing targeted autoimmune destruction. T cells that were reactive to melanocyte antigen-specific stimulation were obtained from perilesional skin and were transferred to areas of normal skin pigmentation, where they induced depigmentation, effectively killing melanocytes [53].

CD8+ T cells, which are involved in the T-helper (Th) 1 pathway of the immune system, produce several cytokines, including interferon (IFN)-γ, among others, which are upregulated in vitiligo lesions [53,54,55]. IFNγ directly induces melanocyte apoptosis and inhibits melanogenesis in vitro [56], and also induces several chemokines including CXC chemokine ligand (CXCL) 9, CXCL10, and CXCL11, all of which have been reported to be increased in the serum and lesions of patients with vitiligo [57]. CD8+ T cells are recruited to melanocytes in the epidermis via these IFNγ-induced chemokines, making IFNγ central to this process [54]. IFNγ activates JAK1 and 2, which are intracellular signaling enzymes used to exert its effect [54, 57, 58]. Thus, the JAK/signal transducer and activator of transcription (STAT) pathway has been found to be a major contributor to the pathogenesis of vitiligo, and an appealing therapeutic target. Additionally, disease activity has been found to correlate with levels of CXCL10 in vitiligo patients [59, 60]. In a study by Rashighi and colleagues, it was found that CXCL9 is primarily involved in the recruitment of T cells to the skin, whereas CXCL10 is required for localization of the CD8 T+ cells within the epidermis. The study also showed that blocking CXCL10 both prevents and reverses vitiligo [57].

2.4 Tissue-Resident Memory T Cells

After a T-cell-mediated immune response occurs, tissue-resident memory T cells (TRMs) develop and persist in nonlymphoid tissues, including the skin [61], explaining the recurrence of depigmentation in the same location after therapies are stopped. In vitiligo lesions, autoreactive CD8+CD69+CD49a+CD103+ TRMs require interleukin (IL)-15 for their maintenance [62,63,64]. Several studies have shown the presence of CD8+ TRMs in active and stable vitiligo lesions [63], in addition to elevated levels of IL-15 in the serum of vitiligo patients [65]. Due to the ability of these TRMs to secrete perforin, IFNγ, and granzyme B after being stimulated by IL-15, they have a cytotoxic effect on melanocytes, causing the depigmentation seen in vitiligo [66]. One study found that treating lesions in a mice model with anti-CD122 (an antibody against the CD122 subunit of the IL-15 receptor) led to repigmentation [67]. On the other hand, treatments that aim to inhibit TRMs but not deplete them from the skin are not durable [61, 68].

2.5 WNT Signaling

The WNT pathway is important for melanocyte differentiation [69], and there is an alteration of the WNT/beta (β) catenin pathway in vitiligo lesions [70]. After oxidative stress in pre-melanocytes following ex vivo stimulation with WNT activators, there is a decrease in lymphoid enhancer-binding factor/T-cell factor (LEF/TCF) expression [71]. Additionally, the WNT pathway is involved in the regulation of E-cadherin expression, which is decreased in vitiligo lesions [72]. When using an ex vivo model of vitiligo, there is increased expression of melanocyte markers when treatment with WNT agonists or GSK3beta was applied [71]. A more recent study showed that micropigmentation in a vitiligo mouse model induced a repair process mediated by the WNT/β-catenin pathway in which the micro-injury stimulated hair follicle melanocyte stem cells to move towards the epidermis [73].

3 Treatments

The treatment of vitiligo depends on many factors, including the type of vitiligo (nonsegmental versus segmental), the stage of disease, and patient preference. This, combined with several different published therapeutic consensus guidelines, makes the treatment of vitiligo particularly challenging. Our vitiligo treatment algorithm can be found in Fig. 1.

Fig. 1
figure 1

Therapeutic algorithm for vitiligo. NB-UVB narrow-band ultraviolet-B, PUVA psoralen plus UVA, JAK Janus kinase. 1Can consider methotrexate, minocycline, azathioprine, or levamisole. 2Includes NB-UVB, excimer laser/lamp, PUVA. Can consider the addition of Ginkgo biloba or Polypodium leucotomos. 3Includes topical corticosteroids, topical calcineurin inhibitors, topical JAK inhibitors. 4Can consider apremilast. 5Includes tissue grafts (suction blister, split-thickness, full-thickness punch/minipunch) and cellular grafts (cultured epidermal graft, cultured melanocyte transplantation, noncultured epidermal or noncultured hair follicle suspensions). Can also consider platelet rich plasma or micropigmentation for refractory disease. 6Includes NB-UVB, PUVA. Can consider the addition of Ginkgo biloba or Polypodium leucotomos. 7Includes topical corticosteroids, topical calcineurin inhibitors. 8Can include methotrexate, minocycline, azathioprine, levamisole, apremilast, supplements. 9Includes bleaching creams, laser, cryotherapy, or phenols.

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3.1 Topical Therapies

3.1.1 Cosmetic Camouflage

One strategy to lessen the burden of vitiligo is the use of camouflage via concealers and self-tanning products, which can be used throughout the long-term treatment process, often as an adjunct to medical therapy [74]. These products can significantly improve the self-esteem and quality of life of vitiligo patients [75,78,79,78]. Dihydroxyacetone (DHA)-containing camouflage, the active ingredient in sunless tanning agents, including creams and spray tans, has been found to not interfere with the underlying medical management of vitiligo lesions, making it a safe option for these patients [79]. It is also convenient, allowing patients to camouflage their vitiligo lesions temporarily [80,83,84,83] without requiring medical treatment [84], and different concentrations can be used for different skin types to achieve color matching [82].

3.1.2 Topical Corticosteroids

TCSs are considered a first-line treatment for vitiligo due to their ability to dampen the immune response, and are effective as monotherapy or in combination therapy. The primary endpoint of TCS use is disease stabilization. Although repigmentation can also occur, this is particularly true with concomitant UV exposure [85]. In a meta-analysis that assessed the effectiveness of nonsurgical options for vitiligo, 56% and 55% of patients receiving class 3 and class 4 corticosteroids, respectively, achieved ≥ 75% repigmentation, with more adverse effects occurring in the class 4 corticosteroid group [86]. Adverse effects, which are more common when used for long periods of time in sensitive areas of the skin such as the face, axilla, and genitals, include local skin atrophy, telangiectasia, acneiform eruptions, hypopigmentation, striae, and hypertrichosis [87]. In a retrospective study evaluating the efficacy and safety of high-potency corticosteroid use in children with vitiligo, 64% showed repigmentation of the lesions (45/70), demonstrating efficacy, but cortisol levels were abnormal in 29% of patients, suggesting possible systemic absorption, particularly when used in sensitive areas of the skin such as the head or neck [88]. However, it is important to note that the amount of TCS was not quantified, and 75% of patients were prescribed TCSs three times daily, compared with the more standard once-daily regimen. Of the two patients who were diagnosed with corticosteroid-induced adrenal suppression, laboratory abnormalities resolved after corticosteroid discontinuation [88].

Thus, although effective in inducing repigmentation, concern regarding the possible adverse effects of TCSs has led to the use of TCIs, which have become a standard therapy for vitiligo patients, especially for sensitive areas, such as the face, and in pediatric populations.

3.1.3 Topical Calcineurin Inhibitors

TCIs, such as tacrolimus, are commonly used as treatments for vitiligo. TCIs have been proven to be effective as monotherapy or in combination therapy, especially when used concomitantly with phototherapy [89]. They have mild adverse effects, which can include a burning sensation, erythema, or pruritus after application, and they have been found to be as effective as TCSs, providing a reliable alternative for long-term therapy [89,92,93,94,95,94]. In a randomized controlled study that compared the efficacy of topical tacrolimus 0.03% ointment compared to 1% hydrocortisone acetate ointment, the 24-week Vitiligo Area Scoring Index (VASI) score was significantly lower for those receiving tacrolimus, and repigmentation rates were 45.2% compared with 0.0% in the hydrocortisone group [95]. Topical tacrolimus is especially effective as a monotherapy in those patients with vitiligo lesions on the face and neck [95,98,97]. Cavalié and colleagues conducted a randomized, double-blind study to determine the efficacy of a twice-weekly application of 0.1% tacrolimus ointment as maintenance therapy and found this regimen to be successful in preventing relapses [98].

Topical tacrolimus 0.03% ointment and pimecrolimus 1% cream are suitable for childhood vitiligo and for infants with vitiligo under 2 years of age, with a low incidence of adverse effects consisting mainly of mild local redness and burning [99, 100]. In a study to evaluate the safety and efficacy of tacrolimus 0.03% ointment in infants under 2 years of age, repigmentation was 100% and there was no evidence of any metabolic or physical changes after 6 months of treatment [101]. This provides reassuring evidence for the use of TCIs for even the youngest vitiligo patients.

Since oral calcineurin inhibitors have an increased risk of malignancy, including lymphomas, there is a black-box warning for TCIs. A recent multicenter retrospective cohort study of 25,694 vitiligo patients who received TCIs, phototherapy for 6 weeks or more, or a combination of the two, found no substantial increased risk of skin cancer or lymphoma [102].

3.1.4 Depigmentation Therapies

Depigmentation can be achieved with bleaching creams such as monobenzone (monobenzyl ether of hydroquinone [MBEH]), laser, cryotherapy, or phenols. This route is generally an option for patients with extensive vitiligo lesions (vitiligo universalis). MBEH cream, with the most common concentration at 20%, is highly effective at inducing depigmentation of unaffected vitiligo skin, with minimal adverse effects, consisting mainly of local skin irritation [103,105,106,106]. MBEH is supposedly a permanent depigmenting agent, but patients should be counseled that there is a risk for repigmentation [106, 107]. Trichloroacetic acid (TCA) 100% concentration [108] and 88% phenol [109, 110] have also been shown to be effective for depigmentation. Lasers and cryotherapy have also been used to induce local depigmentation [104, 111,113,114,115,116,117,118,119,119].

3.2 Oral Therapies

3.2.1 Oral Corticosteroids

Oral corticosteroids, which suppress the immune response, are used primarily in cases of rapidly progressive vitiligo. They are particularly helpful in halting the disease process, and, in some cases, can lead to repigmentation of active vitiligo lesions [120, 121]. Long-term therapy with daily oral corticosteroids is not recommended due to the adverse effect profile, which includes skin atrophy, striae, weight gain, hyperglycemia, hypertension, Cushing’s syndrome, suppression of the hypothalamic-pituitary axis, and osteoporosis [121, 122]. Because of this risk, low dose or short pulses of oral corticosteroids, known as oral mini-pulse (OMP) therapy, is recommended. One study evaluated betamethasone/dexamethasone 5 mg as a single dose by mouth on 2 consecutive days per week in 40 patients with extensive and/or fast-spreading vitiligo, with patients evaluated every 2–4 months. 89% of the 36 patients with active disease had arrest of progression of disease, and 2 patients needed an increase in dose to 7.5 mg per day to achieve suppression of disease, over the first 1–3 months of treatment. There was almost complete repigmentation (> 90%) in three patients and < 10% response in 14 patients, and treatment resulted in tolerable adverse effects. [123]. Another study that evaluated the efficacy of 10 mg dexamethasone pulse therapy (2 consecutive days per week for a maximum period of 24 weeks) in 29 patients found similar results. Vitiligo progression was halted in 88% of patients with active disease, with marked repigmentation in 2 patients (6.9%), moderate or slight repigmentation in 3 patients (10.3%), and no repigmentation in 21 patients (72.4%), with mild–moderate adverse effects consisting of weight gain, insomnia, acne, menstrual disturbance, hypertrichosis, and agitation in 69% of the patients [124]. Similar results were seen in studies that examined 100 patients taking prednisolone [125] and 444 patients taking dexamethasone 2.5 mg [126]. However, a systematic review evaluating the efficacy of OMP monotherapy compared with other treatments for vitiligo found no definitive conclusion due to the heterogeneity of the four randomized controlled studies included [127], suggesting that further studies are needed to evaluate OMP monotherapy.

3.3 Phototherapy

It is well-established that phototherapy is a validated treatment for vitiligo. The different phototherapies are defined based on the wavelengths of light used: narrow-band UV-B light (NB-UVB; 311–313 nm), 308 nm excimer laser or lamp, and psoralen plus UVA (PUVA; 320–380 nm). All formulations are effective and well-tolerated in adults as well as children [128,130,131,131].

3.3.1 Narrow Band UV-B (NB-UVB)

There have been several studies showing the efficacy and safety of NB-UVB therapy for the treatment of vitiligo in various patient populations. In a systematic review, 62.1% of patients receiving NB-UVB had ≥ 25% response at 3 months, 74.2% at 6 months, and 75% at 12 months, and ≥ 75% response in 13.0%, 19.2%, and 35.7% of patients at 3, 6, and 12 months, respectively [131]. NB-UVB is also more effective in younger patients [132], when treating early lesions, and in patients with non-segmental vitiligo compared with segmental vitiligo [133]. Additionally, NB-UVB leads to high levels of patient and physician satisfaction [134] and has been shown to improve quality of life [135]. NB-UVB is well-tolerated, with adverse effects consisting of erythema, burning, xerosis, pruritus, and photodamage after treatments [136].

Phototherapy is very time-intensive, requiring multiple treatments per week, and it can be challenging for patients to have access to the necessary equipment. A systematic review evaluating the effectiveness of home-based phototherapy found no significant difference in repigmentation rates among the groups, although only three studies were included, which varied in terms of quality and treatment regimens. Home-based therapy did afford more adherence to treatment due to its convenience, but more studies need to be conducted to determine the efficacy and safety of home-based treatments, given the possible advantages [137]. Additionally, a topical band-pass filter cream that selectively filters solar radiation to allow the spectrum of NB-UVB to pass toward vitiligo lesions has shown promise in treating segmental vitiligo lesions [138].

3.3.2 Excimer Laser and Lamp

The 308 nm monochromatic excimer light (MEL) is effective in the treatment of vitiligo [139,141,141]. Formulations can be in the form of a lamp or laser, with the lamp able to treat a larger surface area compared with the more localized laser. In a systematic review and meta-analysis that included six studies, no significant difference was found in efficacy between the excimer lamps and excimer lasers, or the excimer lamps and NB-UVB, suggesting that all are effective treatments for vitiligo, with mild adverse effects consisting of a local burning sensation, dryness, and pruritus [130]. Similar results were seen in another systematic review [142] and in a prospective analysis that examined the efficacy of the excimer lamp in the treatment of refractory vitiligo lesions [143].

For patients with localized lesions, the excimer laser is promising [144,146,147,148,149,150,151,152,152], particularly on the face [153,155,156,157,157]. There is more effective repigmentation when the excimer laser is used on lesions earlier in the disease process [155], particularly in patients with segmental vitiligo [158, 159]. In a recent chart review of pediatric patients with vitiligo treated with the 308 nm laser, after an average of 3.38 years, repigmentation was stable in 80% of facial, 40% of body, and 20% of extremity lesions [160].

In a retrospective study that evaluated the efficacy of targeted phototherapy with excimer light (EL) compared with targeted UVB, it was found that patients treated with EL had more significant repigmentation [161], which is similar to the results from a study by Poolsuwan and colleagues [162]. Of note, EL therapy was recently shown to be not effective in treating residual depigmentation after whole-body NB-UVB therapy [163].

Although repigmentation occurs fastest with laser treatments three times weekly, repigmentation overall seems to depend on the overall number of treatments rather than the frequency of treatments [164, 165], suggesting that the cumulative UV dose is most important [158]. There have been studies showing repigmentation with even weekly treatment [166] for 6 months, and pigmentation persistence in the majority of patients after 2 years [167].

Laser treatments have shown improvement in the quality of life of patients with vitiligo [166, 168, 169]. In terms of safety, there is no increased risk of skin cancer or premalignant skin lesions in patients treated with the excimer laser [170]. Due to the plateau effect of treatment [146], a cyclic treatment option using the excimer laser was studied which showed that it may be a promising algorithm leading to more patient compliance, although larger studies must be conducted [171].

3.3.3 Psoralen Plus UVA (PUVA)

PUVA requires the administration of a photosensitizer, known as psoralen, either topically or orally, followed by the administration of UV light. However, there are concerns regarding the long-term adverse effects, which can include eye toxicity, photoaging, and cutaneous malignancy, in addition to short-term adverse effects, including erythema, pruritus, xerosis, hyperpigmentation, headache, dizziness, bronchoconstriction, and depression, among others [172]. Several studies have shown PUVA to be effective in repigmenting, particularly of the face and trunk [173,175,176,176], with acral areas most resistant to treatment. After treatment with PUVA, on a histopathological level, there is an increase in active melanocytes that leads to reduced levels of melanocyte and keratinocyte degeneration [177], and treatment creates a favorable environment for the growth of melanocytes [178]. Although repigmentation can occur, relapse is common, especially in older patients [179]. In a systematic review, ≥ 25% repigmentation occurred in 51.4% of patients at 6 months, 61.6% of patients at 12 months after receiving PUVA therapy, and ≥ 75% repigmentation occurred in 8.5% of patients at 6 months and 13.6% of patients at 12 months, suggesting longer treatments result in improved results [131]. PUVA has fallen out of favor due to NB-UVB’s decreased adverse effect profile, its increased efficacy [180, 181], and its ability to induce disease stability (80% for NB-UVB vs. 40% for PUVA in one study) [182].

3.4 Combination Therapy

Combination treatments, particularly those with phototherapy [183], are extremely effective for patients with vitiligo, including children [184]. Tacrolimus in combination with a TCS is also a proven therapy [185].

Several meta-analyses have found TCIs to be effective when combined with phototherapy [89, 96, 186,188,188]. This conclusion is also supported by a randomized double-blind trial that found topical tacrolimus 0.1% combined with NB-UVB to be more effective than NB-UVB monotherapy [189]. More successful repigmentation has been documented with combined treatment of vitiligo lesions with the excimer laser and topical tacrolimus, as documented in a systematic review [190], and with microneedling in combination with topical pimecrolimus 1% [191]. Two systematic reviews found the combination of topical vitamin D analogs such as calcipotriol or tacalcitol and NB-UVB may enhance the treatment response [192, 193]. Furthermore, a recent study showed promising results for the combination of EL and topical calcipotriol for the treatment of acral vitiligo [194]. A three-arm randomized controlled trial evaluating the effectiveness of hand-held NB-UVB monotherapy, TCS monotherapy, or combination treatment found the combination to be more effective than TCS monotherapy [195]. There have also been several studies showing increased response to treatment and disease arrest in patients receiving combination OMP and NB-UVB compared with NB-UVB monotherapy [196,198,199,199].

3.5 Procedures

3.5.1 Surgical Grafting

There are several surgical procedures that can be performed in patients with refractory and stable vitiligo. Disease stability refers to a period of disease inactivity ranging from 6 months to 2 years, with no koebnerization [12,13,14,15, 200, 201]. The goal is to transfer healthy melanocytes to the depigmented lesion. These techniques include tissue grafts (suction blister [SBG], split-thickness and full-thickness punch/minipunch grafts) and cellular grafts (cultured epidermal graft [CEG], cultured melanocyte transplantation [CMT], noncultured epidermal suspension [NES] or noncultured hair follicle suspensions [NHFS]) [200, 201]. In a systematic review by Ju and colleagues that evaluated surgical techniques, the rate of pigmentation > 50% after surgical intervention was 81.01% in 92 studies and > 90% in 52.69% of patients in 106 studies [202].

In minigraft and punch grafting, 1 mm and 1.5–2 mm full-thickness punches are taken from non-lesional skin and implanted in lesional skin, respectively. These procedures are widely available, easy to perform in the outpatient setting, and are inexpensive, with many devices available for use. After about 2–3 weeks, repigmentation usually appears, with coalescing of individual lesions over the subsequent 4–6 months [200, 201, 203,205,205]. However, there is risk for cobblestone appearance, but newer devices have been created to reduce these risks [206, 207]. A recent study has shown that the combination of mini-punch grafting with weekly transverse needling has fast increased repigmentation compared with mini-punch grafting alone [208].

In split-thickness skin grafting, thin donor grafts are obtained using a dermatome, are de-epithelialized, and then transferred to vitiligo lesions. This procedure is difficult to perform on large areas of skin, can cause uneven pigmentation, can lead to scarring of the donor site, and can cause a peripheral halo due to contraction of the graft [200,202,203,203, 209].

For suction blister grafting, blisters at the dermoepidermal junction are created on pigmented skin using negative pressure, with the resultant roofs of the blisters transferred to vitiligo lesions [202, 203, 209]. This procedure reduces the risk of scarring compared with other surgical techniques, has more uniform color matching results, and has shown to be effective in most areas of the body, including the lips and eyelids [210,212,212], however melanocytes do not always thrive when transplanted and there is a risk for hemorrhagic blisters [201].

For larger areas affected by vitiligo, NES, NHFS, CMT, or CEG can be used, although the process for each is time-consuming. NES, also known as the melanocyte keratinocyte transplant procedure, which cannot be used on the palms and soles, involves obtaining a thin donor sample, followed by cellular separation of the dermis and epidermis, with the resulting epidermis cellular pellet placed over the depigmented areas. Studies have shown good color matching results [200, 203]. In NHFS, 1 mm punch biopsies are performed on the scalp to obtain hair follicles, which tend to have numerous melanocytes. The resulting cellular pellet is then applied to the depigmented area [200, 203, 213, 214]. For CMT, the epidermis is isolated from donor grafts and melanocytes are cultured with growth factors for about 15–30 days, after which they are applied to the depigmented areas [200, 203, 215, 216]. CEG is similar, but both melanocytes and keratinocytes are cultured. Cultured grafts require more specialized equipment and time [200].

In a systematic review evaluating the efficacy of surgical treatment combined with phototherapy, limited evidence was found to suggest that phototherapy enhances surgical techniques when it comes to vitiligo [217].

3.5.2 Platelet-Rich Plasma (PRP)

Platelet-rich plasma (PRP) is an alternative surgical technique that has gained interest for the treatment of vitiligo. In a systematic review that examined the utility of PRP in dermatology, two vitiligo studies were included, both showing an adjunctive benefit of PRP in stable vitiligo [218]. A recent prospective study of 10 patients with refractory stable vitiligo who were treated with PRP showed improvement after a mean of 1.5 sessions, which were well tolerated by patients [219]. PRP is most useful as an adjunct to treatment [220,222,223,224,225,226,227,228,229,230,231,232,232].

3.5.3 Micropigmentation

Micropigmentation, more commonly known as medical tattooing, can be a treatment option for patients who are resistant to conventional therapy. In this procedure, pigment is injected into the dermis manually or via an electrically driven needle [233], and there has been success in treating vitiligo [234, 235]. It is particularly useful for acral [236] and mucosal areas [237, 238], which are typically most resistant to traditional treatments, with minimal local reactions consisting of erythema and swelling that resolve after a few days. While difficult to achieve color matching, excellent results are possible with experienced experts, with one study showing color matching in 80% (20/25) of lesions in patients with Fitzpatrick skin types III and IV who underwent the procedure [239].

3.6 Alternate Oral Therapies

3.6.1 Methotrexate

Methotrexate, a folate antagonist used in the treatment of autoimmune diseases, has been proposed as a treatment for vitiligo. In a randomized comparative study examining the efficacy of methotrexate compared with OMP therapy, there was no difference in the number of patients who developed new lesions and there was a comparable reduction in the vitiligo disease activity score, suggesting no difference in efficacy between the two treatments [240]. There are limited case reports of patients repigmenting with methotrexate [241,243,243]. This suggests that methotrexate may be an alternative, corticosteroid-sparing treatment for vitiligo patients in whom corticosteroids are contraindicated or phototherapy is not feasible, although additional larger-scale, randomized trials need to be conducted.

3.6.2 Minocycline

Minocycline has been proposed as a treatment for vitiligo due to its antioxidant and anti-inflammatory activity, in addition to its ability to attenuate oxidative stress [244]. A study assessing the effect of minocycline 100 mg daily in 32 patients with gradually progressive vitiligo was completed, with 29 patients showing arrest of disease progression at study completion and 10 patients showing arrest of depigmentation after just 4 weeks of treatment [245]. Additionally, minocycline and OMP therapy are equally effective in halting disease activity in vitiligo [246], however NB-UVB is suggested to be superior to minocycline in inducing disease stability and repigmentation [247]. Most recently, a randomized, double-blind, placebo-controlled trial was conducted to determine the efficacy and safety of minocycline and NB-UVB, which showed that the combination therapy does not augment the results of NB-UVB monotherapy and may cause hyperpigmentation of the skin [248]. However, in general, studies evaluating the effect of minocycline need to be conducted on a larger scale with randomized controlled trials to see if there is any beneficial effect of adding this antibiotic to the vitiligo treatment regimen.

3.6.3 Azathioprine

Azathioprine, an immunomodulator that is used in the treatment of several other autoimmune diseases, has been proposed as a treatment for vitiligo. In a study that evaluated the efficacy of low-dose azathioprine (0.6–0.75 mg/kg per day with a maximum single dose of 50 mg) combined with oral PUVA versus oral PUVA monotherapy, combination therapy resulted in earlier perifollicular repigmentation, and the mean total repigmentation rate was 58.4% for the combination group compared to 24.8% for the oral PUVA monotherapy group at 4 months. Although no validated vitiligo assessment measures were used, azathioprine was well tolerated among study participants [249]. In a randomized study comparing the effect of OMP betamethasone therapy and oral azathioprine in halting disease progression and inducing repigmentation in patients with progressive nonsegmental vitiligo, oral azathioprine therapy was found to be inferior to OMP, but may have fewer adverse effects [250], providing a possible alternative for patients with active disease, although additional large-scale studies must be conducted to validate these results.

3.6.4 Levamisole

Levamisole, an antiparasitic agent with immunomodulating properties that is generally well tolerated, has also been postulated as a treatment option for vitiligo [251, 252]. A randomized controlled trial assessed the efficacy of levamisole (150 mg on 2 consecutive days per week for adults; 100 mg on 2 consecutive days per week in children aged 6–12 years) compared with placebo in the treatment of slowly spreading vitiligo. Although the proportion of patients who stopped developing new lesions was higher for the levamisole group, this difference was only significant at month 4 after 6 months of treatment [252]. It is important to note that although this study suggests that levamisole may not be as effective in inducing cessation of disease activity as previously reported in an open trial study [253], these patients were also concomitantly applying topical mometasone furoate 0.1% cream once daily, and the study lacked sufficient power [252]. Thus, additional placebo-controlled studies with larger patient populations must be conducted to determine levamisole’s efficacy in treating vitiligo.

3.6.5 Apremilast

Apremilast, an oral phosphodiesterase-4 (PDE-4) inhibitor approved for the treatment of psoriasis, has potential as a therapeutic modality for vitiligo that is generally well tolerated, with adverse effects consisting primarily of gastrointestinal disturbances and headache. A case series of 13 patients treated with oral apremilast controlled progression of disease and induced repigmentation in 61.5% of patients [254]. A subsequent randomized controlled study that evaluated the efficacy of apremilast in combination with NB-UVB versus placebo and NB-UVB in patients with vitiligo found no added benefit of apremilast combination therapy compared with NB-UVB monotherapy in a study population that included a higher proportion of lighter skin types [255]. In a more recent randomized split-body pilot study that compared the combination of apremilast and NB-UVB with NB-UVB monotherapy in skin types IV–VI in the treatment of vitiligo found that apremilast may potentiate the effects of NB-UVB in inducing repigmentation [256]. Tissue samples of patients with darker skin types treated with this combination therapy resulted in decreased levels of CD8+ T cells, among other markers, and increased levels of melanogenesis markers, again supporting the findings that apremilast may increase the repigmentation effects of NB-UVB in patients with skin types IV–VI with vitiligo [257]. Despite these findings, apremilast has not been studied as monotherapy in a randomized trial, therefore larger trials must be conducted to confirm the efficacy of apremilast.

3.7 Supplements

The use of antioxidants, GB, PL, lipoic acid, and vitamin C/E has shown promising results, as demonstrated by a systematic review and meta-analysis that showed antioxidants in combination with phototherapy are more effective than phototherapy monotherapy for the treatment of vitiligo [258, 259].

3.7.1  Ginkgo biloba

GB is an antioxidant with immunomodulatory properties. Parsad and colleagues found that among patients with limited and slow-spreading vitiligo who were given GB extract 40 mg three times daily compared with placebo, there was cessation of active progression of disease [260]. In a similar study, the administration of 60 mg of GB twice daily showed significant improvement in total VASI and Vitiligo European Task Force (VETF) spread [261]. These studies suggest that GB may be an effective therapy to halt disease progression in patients with vitiligo, although additional larger, randomized studies are needed to evaluate this effect.

3.7.2 Polypodium l eucotomos

PL is a tropical fern that has beneficial properties for skin, used by Native Americans to treat several inflammatory disorders. PL extracts from fern leaves can be given orally or topically and have been shown to decrease levels of free radicals, lipid peroxidation, and ROS, thereby demonstrating an immunomodulating effect [262, 263]. In two randomized placebo-controlled studies, oral PL (480 mg twice daily or 250 mg three times daily) combined with NB-UVB showed a statistically significant increase in the repigmentation rate compared with NB-UVB and placebo in patients with vitiligo [264, 265]. However, no studies have demonstrated efficacy of PL monotherapy in the absence of concomitant phototherapy.

3.8 Janus Kinase Inhibitors

There has been increasing evidence for success of both oral and topical JAK inhibitors [266]. With increased understanding of the involvement of the JAK/STAT pathway in the pathogenesis of vitiligo, treatments with JAK inhibitors have led to key new therapeutic options for patients. The JAK1/2 inhibitor ruxolitinib cream is the first FDA-approved treatment to repigment patients 12 years of age and older with nonsegmental vitiligo affecting ≤ 10% of total body surface area (BSA).

3.8.1 Topical

Two 52-week phase III studies were conducted in 674 adolescent and adult patients to evaluate the efficacy and safety of ruxolitinib cream in patients with nonsegmental vitiligo affecting ≤ 10% of total BSA, including facial and nonfacial depigmented areas. Patients were randomized to receive either ruxolitinib 1.5% cream twice daily or placebo cream for 24 weeks, followed by a 28-week open-label extension. By week 24, ruxolitinib cream was found to be superior to placebo in terms of the primary endpoint, with nearly 30% of patients achieving ≥ 75% improvement from baseline in the facial Vitiligo Area Scoring Index (F-VASI75). By week 52, approximately 50% of patients who applied ruxolitinib cream from day 1 achieved F-VASI75, and approximately 30% of crossover patients who received ruxolitinib cream for 28 weeks achieved F-VASI75, which is consistent with the week-24 data for patients who applied the cream from day 1. Approximately 30% of patients who received ruxolitinib for 52 weeks achieved F-VASI90, 75% achieved F-VASI50, and 50% achieved total body (T)-VASI50. A response on the Vitiligo Noticeability Scale (VNS) of ‘a lot less noticeable’ or ‘no longer noticeable’ was achieved in 39.9% and 32.8%, respectively, of patients in each of the two phase III trials. Importantly, ruxolitinib cream was well tolerated, with no clinically significant application site reactions or serious adverse events. The most common adverse effects consisted of application site acne present in about 6.3–6.6% of patients and application site pruritus present in about 5.3–5.4% of patients [267, 268]. The phase II trial showed similar results, however the trial did not include adolescents, included segmental vitiligo patients, and allowed up to 20% BSA use of ruxolitinib cream. Additionally, although longer duration of therapy was associated with increased repigmentation, low numbers of patients by week 156 limited the available data [269, 270].

There were increased F-VASI75 response rates for ruxolitinib cream compared with placebo at week 24 across all age groups, regardless of sex, geographic region, race, Fitzpatrick skin phototype, and baseline clinical characteristics (facial BSA, disease stability, and prior therapy) [271]. Compared with adults, adolescents who received ruxolitinib cream achieved similar results regarding F-VASI75 at weeks 24 and 52. However, T-VASI50 was 25.4% and 60% at weeks 24 and 52, respectively, for adolescents, which is numerically higher than the T-VASI50 for adults (22.9% and 49.7%, respectively). VNS response was different for adolescents, with 56.0% achieving response compared with 33% for adults at week 52. Ruxolitinib cream was well tolerated in adolescents, with no serious treatment-related adverse events [272].

It is important to note that ruxolitinib cream produced clinically meaningful repigmentation of all body regions in adults and adolescents through week 52 in both phase III trials. The body regions specifically examined were head and neck (excluding face), hands, upper extremities, trunk (including genitals), lower extremities, feet, and total body (excluding face). By week 24, VASI50 was achieved in higher percentages of patients applying ruxolitinib cream versus placebo regardless of the body region, and by week 52, this percentage increased, including in those patients who crossed over to ruxolitinib from vehicle after week 24. Although there was a slight taper in VASI50 response after 46 weeks for the hands and feet, which are two areas that are historically the most resistant to repigmentation with conventional treatment modalities, the response rates were still clinically meaningful [273]. The results of the phase II trials were similar [274].

Maintenance of pigmentation in patients who received ruxolitinib for 52 weeks or more in the phase II trial after discontinuation showed maintenance for up to 6 months, although this portion of the 156-week study included low numbers of patients [270, 275]. Additionally, CXCL9, CXCL10, and IL-15 levels do not seem to be predictive of maintenance response [275]. Since up to 40% of patients can experience relapse after discontinuing conventional therapy [276], further studies as to the durability and whether ruxolitinib cream can be used as a maintenance drug need to be conducted.

The combination of topical JAK inhibitors and phototherapy may also lead to more significant repigmentation [266, 277,279,279]. In the phase II ruxolitinib trial, 19 patients received add-on NB-UVB during the open-label treatment period, resulting in some additional benefit in terms of facial and total body repigmentation. This study was part of an open-label design, included a low number of patients, and the phototherapy regimens were heterogeneous [279]. However, concomitant use of phototherapy needs to be evaluated in larger scale studies to make a definitive statement regarding the efficacy of this combination.

3.8.2 Oral

Data for the use of oral JAK inhibitors consists mainly of case series and case reports. Craiglow and colleagues reported the first use of oral tofacitinib, a JAK1/3 inhibitor, to treat generalized vitiligo. After 5 months, the patient significantly repigmented on the face and upper extremities [280]. Since this report, additional case reports have shown promising results for the use of tofacitinib [281,283,283], the JAK1/2 inhibitor baricitinib [284, 285], and oral ruxolitinib [286]. Importantly, when oral JAK inhibitors have been discontinued after successful repigmentation, there are reports of loss of response [284, 286].

A phase IIb study evaluating the efficacy and safety of ritlecitinib, an oral JAK 3/TEC inhibitor, has been conducted. Patients with active, non-segmental vitiligo were randomized in a 24-week dose-ranging period in which patients received either placebo or ritlecitinib 10, 30, or 50 mg with or without a 4-week induction period of 100 or 200 mg, followed by a 24-week open-label extension period. After 24 weeks, ritlecitinib 50 mg daily with or without induction met the primary endpoint, the percentage change from baseline (%CFB) in F-VASI, and met the key secondary endpoint F-VASI75. After 48 weeks, the %CFB for all treatment regimens was larger between week 24 and week 48 compared with day 1 and week 24, which was a similar trend for centrally read F-VASI, locally read F-VASI, locally read T-VASI, and patient global impression of change (PGIC), suggesting continued improvements over the course of the study. Although ritlecitinib was well tolerated in patients who completed the study, it should be noted that several patients dropped out of the study, and the extension period was not placebo-controlled [287]. Thus, although promising, larger randomized controlled studies must be conducted in order to verify the efficacy and safety of ritlecitinib.

It has been suggested that oral tofacitinib used together with low-dose phototherapy may provide enhanced repigmentation. Five of 10 patients who received tofacitinib 5–10 mg daily or twice daily for an average of 9.9 months achieved some degree of repigmentation in sun-exposed areas or while receiving concomitant NB-UVB. Suction blister sampling of one patient before and after treatment revealed decreased T-cell numbers and CXCL9 and CXCL10 in the skin [288]. An additional two cases reported similar results [289]. The NB-UVB dose used in these series is much lower than the dose required for repigmentation when used as monotherapy. The theory behind this combination strategy is that tofacitinib suppresses the immune response, while low-dose NB-UVB or sunlight stimulates melanocyte regeneration [288, 289]. Similar results of increased repigmentation with tofacitinib/NB-UVB combination therapy were seen in an additional study [290] and a case report [291].

It is important to note that JAK inhibitors, both the oral and topical formulation, have black-box warnings for malignancy, infection, major adverse cardiovascular events, thrombosis, and mortality. There are also warnings for cytopenias, gastrointestinal perforation, hepatotoxicity, lipid abnormalities, interstitial lung disease, and tuberculosis [292]. For vitiligo patients treated with oral JAK inhibitors, the most common treatment-related adverse events have consisted of upper respiratory tract infections, headaches, nasopharyngitis, hyperlipidemia, weight gain, arthralgia, and diarrhea [266, 287].

3.9 Emerging Therapies

In addition to further work into the development of JAK inhibitors, there are several other areas of investigation that are promising based on our increased understanding of vitiligo pathogenesis. WNT agonists and other treatments that target different aspects of this pathway have been proposed [71, 73, 293, 294]. Other potential therapeutic targets include targeting the IL-15 pathway [67], HSP70 proteins [295], and NK cells and CD8+ T cells [296]. Increasing the Treg pool [297] and the development of anti-CXCR3B antibodies to prevent the initial melanocyte apoptosis [47, 298] are also possibilities.

4 Conclusion

Vitiligo is a chronic autoimmune disease characterized by loss of melanocytes, leading to depigmentation that can have a significant impact on mental health. Although many treatments are available for vitiligo, most are off-label and carry varying risks of adverse effects. Over recent years, there has been significant progress in our understanding of the pathogenesis of vitiligo, specifically the involvement of the JAK/STAT pathway. Although there is an overall algorithm for treatment, strategies to combat vitiligo are highly personalized and must consider the goals of the patient, how bothersome the disease is to the patient, the areas of involvement, and the type of vitiligo present. The approval of ruxolitinib cream for repigmentation is a monumental milestone for the vitiligo community. Continued research into the pathogenesis of vitiligo will expand upon these advances, leading to the development of novel therapeutics.