Up-and-Coming Drugs for the Treatment of Vitiligo

Abstract

Vitiligo is a chronic autoimmune disease that causes depigmented patches on the skin. It affects 0.5%–2.0% of the global population. It goes beyond physical appearance, often leading to stigmatization, low self-esteem, and depression, burdening patients with psychosocial challenges. The pathogenesis of vitiligo involves the loss of melanocytes due to autoreactive CD8+ T cells, triggered by environmental stressors and exacerbated by cellular vulnerabilities and immune responses. The release of danger signals and pro-inflammatory factors initiates an immune cascade perpetuating melanocyte destruction, mainly driven by interferon-γ and the C-X-C motif chemokine ligand 9/10-chemokine receptor 3 axis. Long-lasting tissue-resident memory T cells (Trms) and cytokines contribute to lesion persistence. Current treatments focus on topical steroids and tacrolimus, systemic steroids, and phototherapies, but their efficacy remains suboptimal, necessitating the development of new therapeutic options. Building on recent advancements in understanding the immunological mechanisms in vitiligo pathogenesis, with the initiation of Food and Drug Administration approval of topical ruxolitinib, various potential treatment options such as JAK inhibitors, cytokine blockers, and Trm or regulatory T cell targeting agents are being clinically researched and anticipated for vitiligo based on both preclinical and clinical data. This review aims to categorize and summarize the diverse investigational drugs currently undergoing clinical trials for vitiligo. By examining clinical outcomes, it is anticipated that this review will bring hope to dermatologists and patients regarding vitiligo, a condition that has historically posed challenges and transform it into a realm of potential possibilities.

INTRODUCTION

Vitiligo is an acquired, chronic autoimmune disease resulting in depigmented, non-scaly patches of the skin¹. The exact prevalence varies depending on studies, but it is known to affects 0.5%–2.0% of the global population without any significant difference based on sex, ethnicity, or geographic region²,³,⁴.

Vitiligo can result in feelings of stigmatization, diminished self-esteem, and depression, which impose a significant psychosocial burden on patients⁵. Patients with vitiligo experience altered behavior, anxiety disorder, social phobia, sleep disorder, cognitive and emotional impairment⁶. Given that approximately half of vitiligo patients develop disease before the age of 20, nearly 80% before reaching 30, this poses a serious concern as individuals in this age group are expected to be actively involved in the physical, economic, and social aspects of the community⁷. The responsibility to address this issue lies not only with dermatologists but also with our society, necessitating a more concerted effort. Aligned with this imperative, an international consensus statement comprising expert-based recommendations for vitiligo treatment was published⁸. Interestingly, before offering treatment recommendations, the experts highlighted the importance of the shared decision-making concept to make patients aware of therapeutic choices and treatment goals⁹. This is essential to manage vitiligo, as obvious repigmentation may not be achievable in several weeks or months. Long-term treatment is often inevitable due to the high relapse rate along with the chronic disease course².

The hallmark of vitiligo is the loss of epidermal melanocytes due to autoreactive CD8+ cytotoxic T cells¹. When vitiligo initiates, ultraviolet, chemical, and mechanical stress, damage predisposed melanocytes². These cells express danger signals and release exosomes carrying melanocyte-specific antigens, damage-associated molecular patterns, heat-shock protein 70 (HSP70), high-mobility group protein B1, adenosine 5’-triphospate, calreticulin, and micro-RNAs¹⁰,¹¹,¹²,¹³,¹⁴. In turn, these molecules and proinflammatory factors initiate the innate immune cascade, thereby activating adaptive immune response through interferon-gamma (IFN-γ) and the C-X-C motif chemokine ligand 9/10-chemokine receptor 3 (CXCL9/10-CXCR3) axis¹⁵,¹⁶. The binding of IFN-γ, which plays a pivotal role in vitiligo to its receptor activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and promotes CXCL9/10 secretion from keratinocytes, which enhances melanocyte-specific CD8+ T cell infiltration via CXCR3, establishing a positive feedback loop¹⁷. Further, developed vitiligo lesion persists by long-lasting melanocyte-reactive tissue-resident memory T cells (Trms) in the skin, facilitated by interleukin (IL)-15-dependent signaling¹⁸,¹⁹. In addition, various factors such as E-cadherin disruption by matrix metalloproteinase (MMP), ISG15 overexpression, and regulatory T cells (Tregs), are also involved in the pathogenesis of vitiligo²⁰,²¹,²². Consequently, conventional treatments primarily involve immune modulators including topical calcineurin inhibitors, topical steroids, phototherapies, systemic therapies like oral steroids⁸,²³. Nevertheless, these choices remain suboptimal, leading to the exploration of new potential treatments for vitiligo. Despite the necessity to customize treatment for each individual and specific lesions, there remains a demand for practical and well-tolerated therapeutic options.

Recently, both the Food and Drug Administration (FDA) and the European Medicines Agency approved ruxolitinib cream, marking the first topical JAK inhibitor for vitiligo treatment. However, accessibility remains a challenge in Korea due to its cost and insurance uncertainties, prompting a closer look at systemic JAK inhibitors, which already have shown efficacy in atopic dermatitis and rheumatologic diseases.

As our understanding of vitiligo’s pathomechanism continues to evolve beyond the JAK/STAT pathways, we stand on the beginning of a new era in vitiligo management. This review explores the most recent development in vitiligo management, providing insight into treatments currently under assessment. To ensure our comprehension, the pathogenesis and upcoming treatments of vitiligo that will be discussed are depicted in Fig. 1.

Fig. 1. The immune pathogenesis and upcoming treatments of vitiligo. (A) Vitiligo pathogenesis is initiated by external oxidative stressors such as UV radiation, chemicals, and trauma, triggering melanocytes to release ROS, HSP70, and DAMPs. These molecules activate innate immunity, setting off a cascade of events. Autoreactive CD8+ T cells are activated, producing IFN-γ and inducing keratinocytes to secrete chemokines CXCL9 and CXCL10, which recruit additional immune cells via the CXCR3 chemokine receptor. This sets up a positive-feedback loop, perpetuating the progression of vitiligo. Trms contribute significantly to the maintenance and recurrence of vitiligo through IL-15-dependent survival signals. Tregs are pivotal in maintaining self-tolerance by suppressing the activity of autoreactive CD8+ T cells, sustained by IL-2 signals. (B) Schematic representation of the melanocyte signaling pathway and potential treatments of vitiligo. MC1R, a receptor of α-MSH, is a key driver of melanocyte growth, differentiation, and survival. The activation of MC1R, cAMP, CREB, and the MITF pathway regulates melanin-forming genes and oxidative stresses.

α-MSH: α-melanocyte-stimulating hormone, AMP: adenosine monophosphate, cAMP: cyclic adenosine monophosphate, CREB: cAMP response element-binding protein, CXCL: C-X-C motif chemokine ligand, CXCR: C -X-C motif chemokine receptor, DAMP: damage-associated molecular pattern, HSP: heat-shock protein, IFN: interferon, IL: interleukin, MC1R: melanocortin 1 receptor, MITF: microphthalmia-associated transcription factor, mTOR: mammalian target of rapamycin, NF-κB: nuclear factor κ-light-chain-enhancer of activated B, PDE: phosphodiesterase, PKA: protein kinase A, ROS: reactive oxygen species, Treg: regulatory T cell, Trm: tissue-resident memory T cell, Tyr: tyrosinase, UV: ultraviolet.

JAK/STAT PATHWAYS

The JAK family, comprising JAK1–3, and tyrosine kinase 2 (TYK2), plays an essential role in transmitting extracellular signals of many cytokines²⁴. In vitiligo, IFN-γ binds to cell-surface receptors related to JAK1 and JAK2²⁵,²⁶. During relapse or flare-up of vitiligo, oxidative stress induces keratinocytes to produce IL-15, and its membrane receptor IL-15Rα, which activates Trms, involves JAK1 and JAK3²⁷. Besides, all members of JAK family have been critically involved in the pathogenesis of vitiligo. Upon oxidative stress, HSP70 released from melanocyte exosome activates plasmacytoid dendritic cells (pDCs) to produce type 1 IFNs through JAK1/TYK2 signal, which also induce expression of CXCL9 and CXCL10 by keratinocytes²⁸. Not only epidermal cells but dermal fibroblasts are IFN-γ responsive, as well as required to recruit CD8+ cytotoxic T cells²⁹. As a result, existing and forthcoming JAK inhibitors are actively engaged in the pathogenesis of vitiligo and are highly anticipated.

Ruxolitinib is a small-molecule inhibitor mainly targeting JAK1 and JAK2, initially utilized for treating polycythemia vera and primary myelofibrosis³⁰,³¹. Along with the interference of IFN-γ and the downstream signals, ruxolitinib demonstrated inhibition of the differentiation and migratory capacity of DCs in vivo, reducing the induction of cytotoxic T-cell responses and antigen-specific T-cell responses, which are critically implicated in the pathomechanism of vitiligo³¹. A male patient who had coexistent vitiligo and alopecia areata also supported preclinical studies presenting rapid skin repigmentation and a decrease in serum CXCL10 along with hair growth using oral ruxolitinib³².

A prior phase 2 trial of topical ruxolitinib demonstrated notable repigmentation in adult vitiligo patients³³. Patients were randomly assigned to groups receiving 1.5% twice daily, 1.5% once daily, 0.5% once daily, 0.15% once daily, or vehicle twice daily, demonstrating dose-dependent responses. By week 24, the Facial Vitiligo Area Scoring Index (F-VASI) 50 response rate was 45%, and the F-VASI75 response rate was 30%, with further increases to 58% and 52%, respectively, in the 1.5% twice daily group by week 52³³. In recent 2 phase 3 randomized trials, Topical Ruxolitinib Evaluation in Vitiligo Study 1 [TRuE-V1] and 2 [TRuE-V2] which were performed in North America and Europe, a total of 674 vitiligo patients were randomized in a 2:1 ratio to receive topical 1.5% ruxolitinib cream twice a day or a vehicle for 24 weeks, with the result showing greater achievement of F-VASI75 in ruxolitinib cream (29.8%, 30.9%) compared with the placebo group (7.4%, 11.4%)³⁴. After 24 weeks, all patients could apply ruxolitinib cream through 52 weeks, with the result showing the highest F-VASI75 (52.6%) and F-VASI90 (32.9%) at 52 weeks in the patient group who applied ruxolitinib throughout 52 weeks³⁴. Considering the higher likelihood of favorable response in facial lesions, it is important to note that the clinical trial specifically enrolled patients with nonsegmental vitiligo featuring depigmented patches covering less than 10% of the total body surface area (BSA), with at least 0.5% of BSA on the face and 3% of BSA on non-facial areas. In 2 trials, the Total Vitiligo Area Scoring Index (T-VASI) 50 response was 20.6%/23.9% at week 24 and 53.2%/49.2% at week 52 respectively. This was comparatively lower than F-VASI50 response, indicating the challenge of treating non-facial lesions and delayed time till the repigmentation³⁴. However, it is encouraging that almost half of the patients achieved T-VASI 50 and F-VASI75. At the same time, nearly one-third reached F-VASI90 after just one year of topical ruxolitinib monotherapy, with no significant adverse events reported.

In light of the limited response observed in some patients following treatment with ruxolitinib cream, recent findings from the TRuE-V long-term extension study (weeks 52–104) offer encouraging insights. Among those who exhibited either no or minimal (<25%) repigmentation at week 24, a notable proportion demonstrated significant improvement by week 104. Specifically, 54.9% (39 of 71) attained F-VASI75, while 50.0% (53 of 106) achieved T-VASI50³⁵. These findings underscore the continued treatment with ruxolitinib cream to yield favorable outcomes. Furthermore, combining phototherapy with ruxolitinib cream has shown potential to enhance repigmentation, particularly in ruxolitinib poor-responders, as evidenced by improved responses with concomitant phototherapy, which was well-tolerated³⁶. Unlike in clinical trials, many physicians explore treatment optimization in daily practice, and the combination therapy holds significant promise. A study on the combination of ruxolitinib cream and phototherapy (NCT05247489) has been completed but is yet to be published³⁷. Additionally, an ongoing open-label phase 2 study is investigating ruxolitinib cream in patients with genital vitiligo (NCT05750823)³⁸.

Tofacitinib is a JAK1 and JAK3, partially JAK2 and TYK2, inhibitors used for the oral treatment of moderate-to-severe rheumatoid arthritis³⁹. In a female patient with recalcitrant vitiligo covering 10% of BSA, oral tofacitinib was reported to be effective⁴⁰. After 5 months of treatment, full repigmentation of the forehead and hands was achieved, while 5% of total BSA remained unresponsive. In harmony with the case report, a retrospective study using oral tofacitinib presented a mean decrease of 5.4% BSA in 5 of 10 vitiligo patients, which occurred particularly in sun-exposed or phototherapy-experienced areas⁴¹. In this study, tofacitinib successfully reduced T cell numbers and chemokines in both responsive and non-responsive skin lesions, implying phototherapy is required to regenerate melanocytes.

In relation to the impact on Trm cells by JAK inhibitors, it has been revealed that while JAK inhibitors help prevent vitiligo progression by blocking T cell recruitment to the skin, they are unable to eliminate established T cells. This finding indicates that if the treatment is discontinued, the disease may progress again, and a durable treatment cannot be achieved⁴². Given the safety warning of systemic JAK inhibitors issued by the FDA, particularly tofacitinib, which increased risk of serious heart-related events, topical use is more desirable. When using 2% tofacitinib cream combined with phototherapy, repigmentation outcomes were reported for 11 vitiligo patients with a mean improvement of 70% in F-VASI⁴³. The exploration of tofacitinib in this regard remains in the early phase I (NCT05293119)⁴⁴.

Baricitinib primarily targets the JAK1 and JAK2 inhibition and their downstream pathways⁴⁵. The efficacy of oral baricitinib in treating vitiligo was exhibited in a male patient with rheumatoid arthritis who had vitiligo unresponsive to tofacitinib. Following the substitution of tofacitinib with baricitinib, full repigmentation on the forearms and hands was seen, suggesting the potential of baricitinib for vitiligo treatment⁴⁶. Clinical studies using baricitinib are limited, however, one study described 4 patients with repigmentation rates of 59.29%–74.18% after 12 weeks of oral baricitinib, without marked side effects⁴⁷. Also, baricitinib was shown to foster tyrosinase (TYR) activity, TYR, TYR-related protein-1gene expression, and melanin synthesis in cultured melanocytes⁴⁷. Given that IFN-γ is mediated via JAK1/2, baricitinib could be effective and promising, with good safety profiles as evidenced in atopic dermatitis and alopecia areata⁴⁸. A Phase 2 trial investigating combination therapy with baricitinib and phototherapy has been completed (NCT04822584)⁴⁹.

Upadacitinib is a selective JAK1 inhibitor utilized in rheumatologic diseases and atopic dermatitis⁵⁰. A 16-year-old boy with co-existing vitiligo and atopic dermatitis was reported to undergo oral upadacitinib treatment, resulting in improved repigmentation on the face and neck, particularly in sun-exposed areas⁵¹. In 12 patients with recalcitrant vitiligo, 7 patients presented an average improvement in pigmentation of 51.4% without relevance to age, sex, disease duration, or Fitzpatrick skin type⁵⁰. Facial lesions demonstrated superior results compared to acral lesions, consistent with findings from previous literature. The impact of upadacitinib on quality of life in nonsegmental vitiligo patients was recently reported as part of a phase 2 study⁵². Patients were randomly assigned to receive either 6 mg, 11 mg, or 22 mg of upadacitinib or placebo. Treatment with upadacitinib 22 mg resulted in more patients reporting less noticeable vitiligo lesions (11.6% vs. 0% with placebo, p<0.05) and showed significant reductions in Dermatology Life Quality Index scores compared to placebo (−2.2 vs. −0.6, p<0.05). Also, upadacitinib at all doses improved Patient’s Global Impression of Change-Vitiligo (6 mg: 34.7%, 11 mg 55.3%, 22 mg 60.5% vs. placebo: 19.6%, p<0.05). A phase 3 study to evaluate the efficacy of upadacitinib in nonsegmental vitiligo is ongoing (NCT06118411)⁵³.

Ritlecitinib is an irreversible oral JAK3 and TYKs expressed in the hepatocellular carcinoma (TEC) inhibitor presenting high selectivity⁵⁴. Since the JAK3 subtype is associated with the common γc receptor subunit of IL-2, 4, 7, 9, 15, and 21, ritlecitinib was recently approved for the treatment of severe alopecia areata in the USA and Japan, owing to its potent targeting of IL-15⁵⁵. In alopecia areata, IL-15 signaling stimulates the survival of CD8+ memory T cells, promotes the increase and maintenance of T cells and NK cells, and induces CD8+ T cells to produce IFN-γ, which parallels the pathogenesis of vitiligo⁵⁶. In vitiligo, IL-2 and IL-15 stimulation on Trm cells leads to the secretion of perforin, granzyme B, and IFN-γ, resulting in a cytotoxic effect on melanocytes⁵⁷. Further, they also produce CXCL9 and CXCL10, which facilitate their recruitment to the skin upon interaction with the CXCR3 on the surface of recirculating Trm cells⁵⁸. Hence, ritlecitinib presents an encouraging prospect in suppressing downstream signals from IL-2 and IL-15, as well as the cytolytic function of CD8+ T cells and NK cells through the inhibition of TEC kinases⁵⁹. In this regard, a randomized phase 2b clinical trial has evaluated the efficacy and safety of oral ritlecitinib for treating active, nonsegmental vitiligo in 364 patients⁵⁴. Patients were randomized into 5 treatment groups or placebo. Two groups received a loading dose of either 200 mg/day or 100 mg/day during the first 4 weeks, followed by a maintenance dose of 50 mg daily for the subsequent 20 weeks. Three groups received daily doses of 50 mg, 30 mg, or 10 mg for 24 weeks without a loading dose. The mean percentage change in F-VASI from baseline at week 24, the primary endpoint, was most remarkable in the 50 mg daily group with a loading dose (−21.2%) followed by the 50 mg or 30 mg daily groups without a loading dose (−18.5% and −14.6%, respectively), all showing statistically significant differences compared to the placebo. The achievement of F-VASI at week 24 was also higher in the 50 mg daily group, with the highest percentage of 12.1% in the 200 mg loading group. After 24 weeks, extended treatment was administered to all participants and improvements in both F-VASI and T-VASI were demonstrated, indicating the benefit of a longer treatment period. Interestingly, patient satisfaction and a decrease in T-VASI at week 48 were notable in the 30 mg daily group, requiring a decision on the optimal dose. A major limitation of this study was the exclusion of patients with stable vitiligo, with the study population primarily consisting of white individuals. Nevertheless, even stable lesions of the enrolled subjects showed some repigmentation with retilecitinib⁵⁴. Currently, an international phase 3 study is ongoing to evaluate the efficacy and safety of ritlecitinib (50 mg daily) in both active and stable nonsegmental vitiligo patients (NCT05583526)⁶⁰.

With the rapid expansion in the number of JAK inhibitors and their indications, clinical trials of novel drugs are continually being registered. Ifidancitinib (ATI-500002), a JAK1/3 inhibitor, underwent a phase 2 clinical trial to evaluate the safety, tolerability, and efficacy of its topical application (0.46% solution) for treating facial nonsegmental vitiligo⁶¹. The trial presented improvements in photographic analysis score, F-VASI, and Vitiligo Noticeability Scale at week 24. Delgocitinib, a topical pan-JAK inhibitor, has not yet undergone evaluation for vitiligo treatment. However, it is primed for broader application based on the safety proven in atopic dermatitis and the effectiveness in some cases of vitiligo treatment⁶²,⁶³.

Brepocitinib is an oral TYK2/JAK1 inhibitor used in various autoimmune diseases such as psoriasis, ulcerative colitis, Crohn’s disease, and alopecia areata⁶⁴. A phase 2b study of ritlecitinib and brepocitinib, with or without phototherapy, has been completed in active nonsegmental vitiligo treatment (NCT03715829)⁶⁵. In the study, a subgroup received brepocitinib as an extension of ritlecitinib. While the tolerability of brepocitinib was favorable, its efficacy remains to be determined. Povorcitinib (INCB054707) is an oral selective JAK1 inhibitor for hidradenitis suppurativa⁶⁶. A phase 3 clinical trial is ongoing to assess the efficacy and safety of povorcitinib in nonsegmental vitiligo patients (NCT06113445, NCT06113471)⁶⁷,⁶⁸. The preceding phase 2 study included 171 participants with nonsegmental vitiligo who were randomly assigned to receive either 15 mg, 45 mg, or 75 mg of povorcitinib or a placebo for 24 weeks. Subsequently, they continued with either 45 mg or 75 mg of povorcitinib during the 28-week extension period. The primary endpoint was the percentage change from baseline in T-VASI at week 24, which demonstrated favorable outcomes in the treatment group (NCT04818346)⁶⁹. Although selective JAK1 inhibitors like ARQ-252 and SHR0302 were evaluated topically for vitiligo treatment, their phase 2 clinical trials were terminated⁷⁰,⁷¹. This could be due to formulation inefficiency rather than issues with the mechanism itself, especially considering the demonstrated efficacy of ivarmacitinib (SHR0302) in alopecia areata when administered orally⁷².

Given the propensity for relapse in vitiligo, ensuring the durability and maintenance of treatment efficacy is crucial. Relapse after discontinuation of JAK inhibitors remains a clinical concern similar to conventional treatments. In practice, topical tacrolimus can be applied 2–3 times weekly to sustain repigmentation⁷³. Similarly, this strategy may be adapted for topical JAK inhibitors, with the addition of phototherapy as a viable option to optimize treatment efficacy. Introducing a safe and effective oral JAK inhibitor for treating widespread vitiligo is eagerly awaited, representing a pressing need to provide a better treatment option for precise medicine.

CYTOKINES: IFN-α, IL-15, IL-2

In the pathogenesis of autoimmune diseases such as vitiligo and cutaneous lupus erythematosus, HSP70-pDCs-IFN-α-CXCL9/10 axis has been suggested²⁸,⁷⁴. Anifrolumab is a human monoclonal antibody targeting type I IFN receptor subunit 1, approved by the FDA for treating moderate-to-severe systemic lupus erythematosus⁷⁵. A phase 2 clinical trial is currently underway to evaluate the efficacy and tolerability of anifrolumab in combination with phototherapy, compared to phototherapy alone, in adult patients with progressive vitiligo (NCT05917561)⁷⁶. However, the role of type 1 IFN is still unclear in vitiligo. Despite the suggestion that type 1 IFN plays a role in the initiation of vitiligo, mouse studies do not support the hypothesis, as robust, severe viral-induced vitiligo was observed in mice lacking the IFN-α receptor⁷⁷,⁷⁸. Further understanding of the role of type 1 IFN will be followed with the results of the anifrolumab study.

As previously mentioned, IL-15 is crucial for the survival of Trm cells, which are responsible for disease maintenance and relapse by promoting the recruitment and proliferation of cytotoxic CD8+ T cells¹. Also, IL-15 level was found to be elevated in the sera of vitiligo patients, correlating with disease severity⁷⁹. In this regard, neutralization of IL-15 could be an effective strategy for vitiligo patients. AMG 714 is a fully human immunoglobulin monoclonal antibody (IgG1κ) that binds to IL-15 and directly blocks IL-15-induced signals of T-cell activation and proliferation⁸⁰. A phase 2 clinical trial is ongoing to evaluate the efficacy of AMG 714 in active or stable nonsegmental vitiligo (NCT04338581)⁸¹. The primary endpoint is the percentage change from baseline (≥35%) in F-VASI at week 24.

Tregs play a pivotal role in maintaining self-tolerance by suppressing the activity of autoreactive effector T cells and have been highlighted to understand the pathomechanism underlying vitiligo¹. Following the identification of the polymorphism of FOXP3, the essential transcription factor of Tregs, the disrupted Tregs arose as a promising therapeutic target in vitiligo, yet the exact cause of their dysfunction has not been determined²¹,⁸². IL-2 is essential for Tregs survival and functionality in peripheral tissues⁸³. In line with this, low-dose IL-2 therapy has been used to induce the expansion of Tregs to regain immune homeostasis in autoimmunity. In preclinical studies, MK 6194 (PT 101), an IL-2 mutein Fc fusion protein, demonstrated promise in selectively activating and expanding Tregs in humanized NSG mice and non-human primates without significant impact on other immune cells or cytokines⁸⁴. This expansion enhanced Treg function and stability by increased expression of FOXP3 and CD25, offering potential therapeutic avenues for vitiligo⁸⁴. An international phase 2 study to assess the efficacy, safety, and tolerability of MK-6194 is recruiting patients with nonsegmental vitiligo (NCT06113328)⁸⁵.

IMMUNE CHECKPOINTS

Abatacept is an immunoglobulin G1 fusion protein that binds to the extracellular domain of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) via the Fc segment, which is approved for treating moderate-to-severe rheumatoid arthritis⁸⁶,⁸⁷. CTLA-4 negatively regulates T-cell activation and is involved in self-tolerance, expressed on Tregs⁸⁶. In vitiligo patients, soluble CTLA4 and full-length CTLA4 mRNA are reduced²¹. Also, CTLA-4 expression of Tregs is downregulated, resulting in a decrease of inhibition on autoreactive CD8+ T cells⁸⁸. Abatacept may thus be therapeutically beneficial for vitiligo, with a phase 1 study underway (NCT02281058)⁸⁹.

PHOSPHODIESTERASE TYPE 4 (PDE4)

PDE4 is an intracellular enzyme that is responsible for degrading cyclic adenosine monophosphate (cAMP), which mediates signal transduction through protein kinase A (PKA)⁹⁰. PKA activates cAMP response element-binding protein (CREB) stimulating transcription of microphthalmia-associated transcription factor (MITF) that regulates key melanin-forming genes and protects against oxidative stresses⁹¹,⁹². These are in the downstream of melanocortin 1 receptor (MC1R), a receptor of α-melanocyte-stimulating hormone (α-MSH)⁹². Also, PKA is linked to the inhibition of nuclear factor κ-light-chain-enhancer of activated B that promotes Th1 cell differentiation by regulating T cell receptor signaling⁹³. Therefore, PDE4 inhibition leads to an increase in the cAMP pathway, which may play a protective role for vitiligo through anti-oxidative, anti-inflammatory, and pro-melanogenic effects. However, the efficacy of apremilast, an oral PDE4 inhibitor, appears contradictory. While a phase 2 clinical trial involving 80 vitiligo patients ended up with no additional benefit when combined with conventional phototherapy, several studies have suggested that apremilast may potentiate phototherapy and halt disease progression, particularly advantageous to patients with darker skin⁹⁴,⁹⁵,⁹⁶,⁹⁷,⁹⁸. There are few case reports supporting the use of crisaborole, a topical PDE4 inhibitor⁹⁹,¹⁰⁰. A phase 2 study of 2% crisaborole ointment and 0.01% PF-07038124 (PDE4 inhibitor) ointment with or without phototherapy has been registered (NCT05298033)¹⁰¹.

α-MSH

Afamelanotide is the synthetic analog of α-MSH used in erythropoietic protoporphyria and photodermatoses¹⁰². It binds MC1R with high activity and stability, activating downstream signals of melanogenesis and anti-inflammation in melanocytes, keratinocytes, endothelial cells, fibroblasts, and mast cells¹⁰³,¹⁰⁴. Several studies have been conducted for the efficacy and safety of afamelanotide in the treatment of vitiligo¹⁰⁵,¹⁰⁶,¹⁰⁷. The study designs were identical: subcutaneous implants containing 16 mg of afamelanotide were administered monthly with preceding phototherapy. In a randomized trial, the afamelanotide with phototherapy group (48.64%) exhibited a superior repigmentation rate compared to the narrowband ultraviolet B (NBUVB) monotherapy group (33.26%) at day 168¹⁰⁶. An open-label study also demonstrated the efficacy and tolerability of afamelanotide¹⁰⁷. A major limitation is that MC1R, the afamelanotide binding target, is not expressed in melanoblasts in the hair bulge¹⁰⁸,¹⁰⁹. While afamelanotide can stimulate MC1R in epidermal melanocytes, which might be destroyed in vitiligo lesions, it cannot regenerate melanocytes themselves from stem cells. Although these studies showed better results in dark-skinned individuals, most patients were Fitzpatrick skin types III–V, limiting generalizability to fair-skinned patients. Lastly, concerns regarding hyperpigmentation may be significant for some patients. Currently, a phase 2 study is underway to evaluate the efficacy of afamelanotide implant monotherapy (NCT05210582), and a phase 3 study is ongoing to compare the efficacy of afamelanotide combined with NBUVB vs. NBUVB monotherapy (NCT06109649)¹¹⁰,¹¹¹.

PROSTAGLANDIN

Latanoprost and bimatoprost, the analogs of prostaglandin F2 alpha (PGF2α) and prostamide, are utilized to treat glaucoma but have been reported to cause periocular skin hyperpigmentation¹¹². A preclinical study suggested that latanoprost stimulates TYR expression and activity followed by melanogenesis¹¹³. Subsequently, numerous clinical studies reported the efficacy of topical latanoprost and bimatoprost with the combination of phototherapy and microneedling¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷. However, the exact mechanism underlying the improvement of vitiligo remains to be elucidated, as levels of PGF2α were found to be greatly higher in the lesional and non-lesional skin of vitiligo patients compared to healthy controls¹¹⁸.

T-CELL METABOLISM

Given the critical role of oxidative stress in vitiligo pathogenesis and the defective autophagic process observed in vitiligo patients, promoting autophagy has emerged as a potential treatment approach¹¹⁹. Since the mammalian target of rapamycin (mTOR) is a negative suppressor of autophagy, exploring the use of rapamycin, an inhibitor of mTOR, might be worthwhile¹²⁰. An in vitro study reported rapamycin treatment upregulated the expression of MITF, TYR, TYRP1/2 in melanocytes¹²¹. Moreover, the mTOR pathway is implicated in the depletion of Tregs, as seen in lupus erythematous¹²². Rapamycin has been shown to increase Tregs in h3TA2 mice study, leading to the remission of progressive or established depigmentation¹²³. Rapamycin is under evaluation for its efficacy and tolerability in treating nonsegmental vitiligo through daily application of 0.1% or 0.001% cream to lesions covering less than 2% of BSA (NCT05342519)¹²⁴.

There is an ongoing phase 2 study to investigate the efficacy and safety of metformin in vitiligo (NCT05607316)¹²⁵. Metformin, a cornerstone treatment for type 2 diabetes for over decades, is recognized for its diverse actions, including antiproliferative and antioxidant effects¹²⁶. Additionally, it appears to be associated with a reduced risk of incident vitiligo¹²⁷. Metformin activates 5’-AMP-activated protein kinase (AMPK) pathways and promotes mitochondrial respiration and oxidation in anti-inflammatory cells, such as Tregs and M2 macrophages, while limiting the glycolytic capacity of pro-inflammatory neutrophils, M1 macrophages, and effector T cells¹²⁸,¹²⁹. Moreover, studies have shown that metformin can reduce mTOR signaling via either AMPK-dependent or AMPK-independent pathways, increasing Tregs¹²⁶. Metformin is a mitochondrial metabolism inhibitor that can restore T cell metabolism and decrease IFN-γ production¹³⁰. These pleiotropic effects of metformin position it as a potential newcomer among established treatments for vitiligo.

A summary of current clinical trials in vitiligo is listed in Table 1.

Table 1. Clinical trials of emerging treatments in vitiligo.

NCT ID	Treatments	Classification	Type of vitiligo	Phase	Status
NCT05750823	Ruxolitinib	JAK 1/2 inhibitor	Nonsegmental vitiligo with genital involvement	2	Recruiting
NCT05247489	Ruxolitinib and Phototherapy	JAK 1/2 inhibitor	Nonsegmental vitiligo	2	Completed
NCT05293119	Tofacitinib	JAK 1/3 inhibitor	Nonsegmental vitiligo	1	Not yet recruiting
NCT04822584	Baricitinib and Phototherapy	JAK 1/2 inhibitor	Active nonsegmental vitiligo	2	Completed
NCT06118411	Upadacitinib	JAK 1 inhibitor	Nonsegmental vitiligo	3	Enrolling by invitation
NCT05583526	Ritlecitinib	JAK 3 and TEC inhibitor	Nonsegmental vitiligo (active and stable)	3	Recruiting
NCT03715829	Ritlecitinib and Brepocitinib	JAK 3 and TEC inhibitor and JAK1 and TYK2 inhibitor	Active nonsegmental vitiligo	2	Completed
NCT03468855	Ifidancitinib	JAK 1/3 inhibitor	Active nonsegmental vitiligo	2	Completed
NCT06113445	Povorcitinib	JAK 1 inhibitor	Nonsegmental vitiligo	3	Recruiting
NCT06113471
NCT05917561	Anifrolumab	Anti-IFN-α monoclonal antibody	Active nonsegmental vitiligo	2	Recruiting
NCT04338581	AMG 714	Anti-IL-15 monoclonal antibody	Nonsegmental vitiligo (active and stable)	2	Recruiting
NCT06113328	MK-6194	IL-2 mutein Fc fusion protein	Nonsegmental vitiligo	2	Recruiting
NCT02281058	Abatacept	Immunoglobulin G1 fusion protein (CTLA-4)	Active nonsegmental vitiligo	1	Unknown status
NCT05298033	Crisaborole	PDE4 inhibitor	Nonsegmental vitiligo (active and stable)	2	Active, not recruiting
NCT05210582	Afamelanotide	α-MSH analog	Stable of slowly progressive nonsegmental vitiligo, Fitzpatrick skin types IV–VI	2	Recruiting
NCT06109649	Afamelanotide and Phototherapy	α-MSH analog	Active or stable vitiligo, Fitzpatrick skin types IV–VI	3	Recruiting
NCT05342519	Rapamycin	mTOR inhibitor	Nonsegmental vitiligo	2	Active, not recruiting
NCT05607316	Metformin	Mitochondrial metabolism inhibitor (dimethyl biguanide)	Stable vitiligo	2	Recruiting

JAK: Janus kinase, TEC: hepatocellular carcinoma, TYK: tyrosine kinase, IFN: interferon, IL: interleukin, CTLA-4: cytotoxic T lymphocyte-associated antigen-4, PDE4: phosphodiesterase type 4, α-MSH: α-melanocyte-stimulating hormone, mTOR: mammalian target of rapamycin.

CONCLUSION

The immunopathogenesis of vitiligo remains intricate and incompletely understood. This complexity poses challenges for treatment, compounded by the unpredictable clinical course of the disease. Recent insights have illuminated various immunological mechanisms and signaling pathways in vitiligo pathogenesis, encompassing JAK/STAT signals, the IFN-γ-CXCL9/10-CXCR3 pathway, Tregs, and Trm cells. In addition to JAK inhibitors, potential treatment candidates are suggested by both clinical and preclinical data, such as anti-IFN-γ and CXCL10 neutralizing antibodies, as well as CXCR3 depleting antibodies¹³¹,¹³²,¹³³. Regarding Trm cells, antibodies targeting against CD122, which exhibit high expression in melanocyte-specific Trm cells and bind to soluble IL-15, may represent a promising option for biologic therapy in vitiligo management¹⁹. There is growing optimism for melanocyte regeneration strategies that promote melanocyte proliferation, migration, and melanoblast differentiation by activating the Wnt/β-catenin pathway, offering potential alternatives to phototherapy¹³⁴. In vitro studies using both normal and vitiligo-affected melanocytes, treatment with β-catenin agonist, SKL2001, has shown promise in attenuating H₂O₂-induced reactive oxygen species accumulation and reducing cell apoptosis¹³⁵. Adhesion molecules also hold significant interest in vitiligo pathogenesis. IFN-γ and TNF-α have been implicated in the shedding of E-cadherin through MMP-9 release, leading to melanocyte detachment²⁰. Strategies targeting remodeling adhesion molecules, such as integrin, laminin, discoidin domain receptor 1, and inhibition of MMPs, may represent future therapeutic approaches for vitiligo.

In conclusion, while significant advancements have been made in understanding vitiligo pathogenesis, much remains to be discovered. Newer therapies offer hope for more targeted and effective treatment, but further research is essential to unlock the full potential of these approaches and improve outcomes for patients with vitiligo.