Beyond Face Value: Targeted Therapies for Vitiligo and Strategies for Improving Patient Quality of Life

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Vitiligo, an acquired leukoderma, is characterized by progressive melanocyte loss leading to sharply demarcated, depigmented macules and patches. It is one of the most prevalent pigmentary disorders, affecting approximately 0.5% to 1% of the global population, irrespective of ethnicity, age, or gender.¹ The chronic and often progressive nature of vitiligo significantly impacts patients’ physical appearance and psychological well-being, and thus their quality of life (QoL). Despite the recent strides in understanding vitiligo’s complex pathogenesis and the development of groundbreaking treatments, significant gaps in effective management and equitable access to care persist. Addressing these unmet needs requires a multidisciplinary approach that integrates medical, psychological, and societal support.

In this article, we discuss the pathogenesis and clinical features of vitiligo, and its profound effects on QoL. Additionally, we touch on recent clinical data for current and emerging treatments, including Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-targeted approaches, as well as integration of multidisciplinary care plans. Strategies to enhance treatment outcomes are also outlined.

Vitiligo Pathogenesis

Vitiligo has a complex pathogenesis involving both genetic and nongenetic factors. The widely accepted principle is that the clinical presentation arises from the destruction of melanocytes by various proposed mechanisms, including intrinsic melanocyte defects and cytotoxic, autoimmune, neural, and oxidant-antioxidant pathways.² Genetically, at least 54 loci have been identified as contributing to vitiligo susceptibility. Most of these genes encode proteins involved in immunoregulation, apoptosis, and melanocyte function. Oxidative stress plays a crucial role in triggering autoimmune responses associated with the disease. Additionally, the neural hypothesis, first proposed by Lerner in 1959, suggests that nerve endings in the skin may release cytotoxic substances that result in melanocyte destruction.

A key mechanism of particular interest in recent years lies in autoimmunity. When melanocytes are exposed to cellular stress due to environmental triggers, they signal innate immunity to activate T cells, resulting in an autoimmune response that ultimately establishes an IFN-γ-STAT1-CXCL10 signaling axis—the primary inflammatory pathway driving the progression and maintenance of vitiligo.³ Key cytokines, CXCL9 and CXCL10, recruit CD8+ T cells, which target melanocytes and release IFN-γ. IFN-γ binds to its receptor (IFN-γR), activating the JAK/STAT pathway in keratinocytes, further increasing CXCL9/10 production. This creates a positive feedback loop that attracts more autoreactive T cells and amplifies inflammation.³ Ultimately, T-cell-mediated melanocyte destruction results in depigmentation.

Clinical Presentation of Vitiligo

Vitiligo is broadly classified into 2 major forms: segmental vitiligo (SV) and nonsegmental vitiligo (NSV). SV typically presents as segmental, dermatomal depigmented patches and can be uni-, bi-, or multi-segmental. It tends to have a more rapid progression but stabilizes earlier compared to NSV. SV often has an earlier age of onset, with early follicular involvement (leukotrichia) being an indicator of disease.¹ NSV is the most common subtype and may progress unpredictably, often with a bilateral and symmetric distribution. NSV subtypes include common (formerly known as vitiligo vulgaris), acrofacial, universal, and focal.¹

Other clinical variants add to the diagnostic complexity of vitiligo:

• Inflammatory vitiligo—margins of vitiligo with raised erythematous, inflammatory borders⁴
• Trichrome vitiligo—three distinct zones, including a depigmented zone, a uniformly hypopigmented intermediate band, and a zone of normal skin; this variant is most prominent in Black patients⁵
• Vitiligo ponctué (confetti type) —tiny punctate-like depigmented macules on a hyperpigmented macule⁶ 
• Blue vitiligo—vitiligo developing on postinflammatory hyperpigmented lesions, conferring a bluish tint⁷ 
• Quadrichrome vitiligo—four colors (areas of perifollicular hyperpigmentation, depigmentation, normal color, and hypopigmentation)⁸
• Pentachrome vitiligo—five colors (depigmentation, normal skin, hypopigmentation, perifollicular hyperpigmentation, and black with blue hue)⁹

It is also important to be aware of potential comorbidities associated with vitiligo. These include autoimmune thyroid dysfunction, such as hyperthyroidism or hypothyroidism, and endocrinopathies, including type 1 and 2 diabetes and Addison disease.¹⁰ In patients who have new-onset vitiligo with systemic symptoms, thyroid screening with antithyroid peroxidase antibody is recommended.¹ New-onset vitiligo may be seen in patients with metastatic melanoma. It can occur spontaneously and may herald metastatic disease, or it can be triggered by immunotherapy, such as with BRAF inhibitors or PD-1 inhibitors.^11,12 In the latter setting, it is considered a good prognostic sign. Diagnostic tools, including Wood’s lamp examination, help differentiate vitiligo from other hypopigmented conditions and can aid in determining the extent of affected areas.¹³ Recognizing these diverse presentations is critical for tailored therapeutic strategies.

Impact of Vitiligo on QoL: Burden and Unmet Needs

Vitiligo imposes significant psychosocial burdens on affected individuals, influencing their emotional well-being, social interactions, and daily activities. A global cross-sectional study performed by Bibeau et al. involving 3541 participants highlighted the profound QoL impairment associated with vitiligo.¹⁴ The study reported higher psychosocial burden scores in patients with darker skin tones, facial or hand involvement, and greater than 5% body surface area (BSA) affected. Patients in India, Brazil, and the United States reported the highest burden among surveyed countries. Forty-nine percent of surveyed participants agreed that vitiligo made them feel less confident or more self-conscious, 46.6% believed that “no one understands what it is like to live with vitiligo,” and 55.2% reported that aspects of their daily lives were frequently affected by vitiligo. The most stressful daily activities included choosing clothes, social activities, shaking hands, and inter-partner intimacy. Patients with greater than 5% BSA affected consistently reported increased burden across all these domains resulting in frequent avoidance behaviors to avoid stigmatization and ridicule.

Vitiligo is also associated with higher rates of depression, anxiety, and eating disorders, yet these are often underdiagnosed due to lack of access to mental health care. About 25% of study patients were diagnosed with depression, which is a possible missed health opportunity to provide mental health interventions for these vulnerable patients. Dermatologists should adopt a holistic approach to care, incorporating psychological assessments, depression screening, and counseling as part of routine management.

Treatment Strategies for Vitiligo

Our increased understanding of vitiligo’s complex pathogenies has allowed us to develop an array of treatment options that target various disease pathways. Treatment strategies include non-surgical and surgical approaches. Similar to other diseases in dermatology, topical interventions and phototherapy are treatment mainstays, and exciting emerging therapies are centered around the JAK/STAT pathway.

Topical Corticosteroids and Topical Calcineurin Inhibitors

Potent and ultrapotent topical corticosteroids that can aid in repigmentation are the cornerstone of initial therapy for vitiligo, particularly for localized lesions. Cyclical application is recommended to avoid adverse effects. Topical calcineurin inhibitors, such as tacrolimus ointment 0.03% or 0.1% or pimecrolimus 1% cream, offer an alternative for sensitive areas like the face and intertriginous sites. These are applied twice daily and can be used on “off” days from corticosteroids to minimize negative side effects.

Phototherapy

Narrowband ultraviolet B (NB-UVB) (311 nm) and excimer laser (308 nm) are often a “go-to” for phototherapy treatments, requiring approximately 48 treatments for most patients to determine if phototherapy will work for their vitiligo.^15,16 Combining phototherapy with topical treatment enhances results, with the following improvement rates being reported: 25% improvement after 3 months, 50% after 6 months, and 75% after 9 months.¹⁷

Oral Mini-Pulse Therapy

Oral mini-pulse (OMP) therapy is defined as the use of cyclical pulsed dose systemic corticosteroids in doses much smaller than those used in typical pulsed therapy.¹⁸ It is used to arrest rapidly progressing vitiligo, as well as to treat vitiliginous lesions. The 2 most commonly used corticosteroids are betamethasone and dexamethasone. For example, dexamethasone 4 mg daily on 2 consecutive days per week is a common regimen. Notably, because of negative side effects and the lack of evidence regarding its efficacy, OMP therapy remains controversial. A 2021 systematic review found that 32% of patients achieved a repigmentation rate of greater than 75% when OMP therapy was administered as monotherapy; however, there was no difference between OMP therapy and other treatments in arresting vitiligo progression.¹⁸ In summary, OMP therapy has not demonstrated additional value compared to other treatments.

JAK Inhibitors

JAK inhibitors represent a paradigm shift in vitiligo management by targeting the underlying inflammatory pathways and disrupting the T-cell driven positive feedback loop mentioned earlier. The JAK family consists of 4 receptor-associated tyrosine kinases: JAK1, JAK2, JAK3, and TYK2.¹⁹ These kinases function similarly, primarily in conjunction with type I and II cytokine receptors, which play crucial roles in immune responses. Recent clinical trials, case reports, and case series have demonstrated JAK inhibitors as promising and emerging treatments for vitiligo.²⁰ Herein, we will discuss US Food and Drug Administration (FDA)-approved JAK inhibitor trials for the treatment of vitiligo.

TRuE-V1 and TRuE-V2 Trials

Topical ruxolitinib 1.5% cream was the first JAK inhibitor approved for NSV repigmentation, marking a significant milestone in vitiligo management. The TRuE-V1 and TRuE-V2 trials collectively enrolled 674 patients with vitiligo involving 10% or less of their total BSA, including at least 0.5% on the face.²¹ Participants applied either 1.5% ruxolitinib cream or a vehicle cream to all lesions twice daily for 24 weeks. The primary endpoint was achieving at least a 75% improvement from baseline in the Facial Vitiligo Area Scoring Index (F-VASI) by week 24. Secondary endpoints included the proportion of patients achieving 50% or greater and 90% or greater improvement in F-VASI, respectively; 50% or greater improvement in the Total Vitiligo Area Scoring Index (T-VASI); and a Vitiligo Noticeability Scale rating of “a lot less noticeable” or “no longer noticeable” at week 24. Additional measures included the percentage change from baseline in facial BSA and assessments of safety and tolerability.

At week 24, the percentage of patients achieving F-VASI75 was significantly higher in the ruxolitinib cream group compared to the vehicle group. In TRuE-V1, 29.8% of patients in the ruxolitinib group achieved F-VASI75 vs 7.4% in the vehicle group (relative risk [RR], 4.0; 95% CI, 1.9–8.4; P < 0.001). Similarly, in TRuE-V2, 30.9% of ruxolitinib-treated patients achieved F-VASI75 compared to 11.4% in the vehicle group (RR, 2.7; 95% CI, 1.5–4.9; P < 0.001). Key secondary endpoints also demonstrated the efficacy of ruxolitinib cream. Among patients who used ruxolitinib cream for 52 weeks, adverse events were reported in 54.8% (TRuE-V1) and 62.3% (TRuE-V2). The most common adverse events included acne (6.3% and 6.6%), nasopharyngitis (5.4% and 6.1%), and pruritus (5.4% and 5.3%).

The TRuE-V1 and TRuE-V2 studies were extended from weeks 52 to 104, dividing participants into 2 cohorts (A and B) based on their week 52 facial repigmentation outcomes.²²

• Cohort A included patients who achieved complete or near-complete facial repigmentation (F-VASI90). These participants were randomized to receive either ruxolitinib cream or a vehicle twice daily through week 104 to evaluate relapse and response maintenance. During the extension period, 29% of patients in the vehicle group relapsed, but 75% regained F-VASI75 and 69% regained F-VASI90 within a median of 12 weeks upon reinitiating treatment. In contrast, 62% of patients in the ruxolitinib group maintained their F-VASI90 response for 1 year.
• Cohort B included patients who did not achieve F-VASI90 by week 52 but who were continued on ruxolitinib cream to evaluate long-term efficacy and safety. Improvements in both facial and total body repigmentation were observed. Among patients treated with ruxolitinib cream from day 1, the proportion achieving F-VASI75 more than doubled from week 52 (31%) to week 104 (66%), with 34% attaining F-VASI90 by week 104. Additionally, T-VASI50 increased from 43% at week 52 to 64% at week 104.

BARVIT Clinical Trial

The BARVIT study is a phase 2 randomized trial that explored the combination of oral baricitinib with NB-UVB in the treatment of adult participants with progressive NSV.²³ The experimental group received oral baricitinib 4 mg daily with NB-UVB phototherapy twice weekly for 24 weeks. NB-UVB started at 12 weeks. The placebo group received a placebo plus NB-UVB twice per week for 24 weeks and similarly NB-UVB began at 12 weeks. Follow-up visits were at 12-week intervals at 12, 24, 36, and 48 weeks.

Oral baricitinib combined with NB-UVB showed "clinically meaningful superiority" to the placebo combined with this type of phototherapy. After 36 weeks of treatment, there was about a 65% change from the baseline F-VASI score and a 45% change in T-VASI score in the baricitinib and phototherapy-treated patients. Corresponding values in the placebo arm were about -4% and 9% in the F-VASI and T-VASI scores. Overall, the BARVIT study demonstrated enhanced repigmentation outcomes with combined baricitinib and phototherapy compared to phototherapy alone. While these results are promising, larger studies are needed to validate the long-term safety and efficacy of this combination therapy. Oral baricitinib may join topical ruxolitinib as a possible treatment for NSV.

Surgical Interventions

Surgical interventions are most effective for late-stage SV and can be considered for refractory, stable disease. Surgical options are categorized into tissue grafts (mini-punch grafts and suction blister epidermal grafts) and cellular grafts (cultured grafts and noncultured epidermal suspension grafts).²⁴ Tissue grafts involve direct transfer of donor tissue to recipient sites in a 1:1 ratio, whereas cellular grafts cover larger areas, using keratinocyte and melanocyte suspensions with donor-to-recipient ratios up to 1:10. Among the various grafts, noncultured epidermal suspension grafts offer superior pigmentation quality and extent compared to other methods. Factors influencing surgical success include disease stability and recipient site. Grafts on the head and neck demonstrate the best response, whereas acrofacial areas and joints fare poorly due to repeated friction and motion. Surgical interventions typically yield significant repigmentation, with improvement rates of 68% or greater reported in certain cases after a single session.²⁵ Relapse is rare in successfully treated patients.

Multidisciplinary Care

Vitiligo’s multifaceted impact necessitates a multidisciplinary approach to care involving dermatologists, primary care providers, psychiatrists, and pharmacists in collaboration to address both the physical and psychological dimensions of the disease. A team approach must be implemented to coordinate care by specialists who can address potential autoimmune comorbidities, including rheumatology, endocrinology, gastroenterology, hematology, ophthalmology, and neurology, if necessary. As a member of the treatment team for a patient with vitiligo, dermatology functions to optimize evidence-based treatment, address barriers to acquiring treatment, and screen for depression and facilitate access to psychiatry and support groups. Psychiatry can function to perform cognitive behavioral therapy and pharmacologic treatment of psychiatric comorbidities. Pharmacy functions to provide access to medications and reinforce patient education on topical and systemic agents regarding mechanisms of action and side effects. Multidisciplinary care models enhance patient outcomes by ensuring comprehensive, coordinated, and patient-centered care.²⁶

Costs of Vitiligo Care

The economic burden of vitiligo is substantial, encompassing direct medical costs, such as outpatient visits and treatments, and indirect costs, including lost productivity. In 2017, the American Academy of Dermatology published a Burden of Skin Disease brief estimating that "more than 150,000 Americans across all age ranges were treated for vitiligo in 2013."²⁷ The health care cost was "more than $328 per patient, about 3 times more than rosacea and twice as much as acne."²⁷ This resulted in "total medical costs of $49 million and lost productivity of $6 million."²⁷ These estimates are thought to be understated due to the frequency of off-label therapeutics in vitiligo.

A 2024 retrospective cohort analysis using the Merative MarketScan Commercial Database assessed health care costs and health care resource utilization (HCRU) for 49,512 patients with vitiligo compared to 99,024 people without vitiligo in the United States between January 2007 and December 2021.²⁸ Compared to controls, patients with vitiligo incurred significantly higher all-cause costs ($15,551 vs $7,735) and vitiligo-related costs ($3,490 vs $54). Mental health-related HCRU was also significantly higher among patients with vitiligo. "Taken together, health care costs and HCRU were significantly higher among patients with vitiligo than among controls," according to the analysis.²⁸ "In this analysis, the increased costs were associated with significantly higher inpatient costs, emergency room visits, ambulatory visits, number of prescriptions and prescriptions costs, and other costs (such as medical equipment and home health care), illustrating the importance of independently evaluating the economic burden of different skin conditions."²⁸ The results showed that "the economic burden of vitiligo was comparable with those of other well-studied dermatologic conditions, such as atopic dermatitis and psoriasis."²⁸

Vitiligo in Underrepresented Communities

An All of Us database analysis found that individuals with skin of color (SOC) had a higher adjusted odds of vitiligo diagnosis compared with White individuals: Black patients (odds ratio [OR], 1.71; 95% CI, 1.40–2.08), Hispanic patients (OR, 2.25; 95% CI, 1.87–2.71), and other non-White patients (OR, 1.60; 95% CI, 1.22–2.08).²⁹ "Lower odds were observed in those without health insurance (OR, 0.64; 95% CI, 0.43–0.91)," according to the analysis.²⁹ "Possible explanations include increased psychosocial burden in patients with SOC, leading to medical presentation, easier detection of depigmentation in darker skin, or some pathogenic mechanism by which vitiligo occurs more frequently in SOC."²⁹ This analysis concluded that "clinicians should be mindful of possible underdiagnosis and delayed diagnosis of vitiligo in uninsured and underrepresented communities in the United States."²⁹

Conclusion

Vitiligo is a cutaneous disorder with various subtypes and comorbidities that warrant screening and management. Evidence demonstrates the high mental health burden of vitiligo, particularly major depressive disorder, lower-self-esteem, and higher risk of self-harm, all compounded by cultural stigma. Additionally, vitiligo incurs high direct and indirect costs for patients and the health care system, requiring multidisciplinary strategies for management. While there have been major clinical advances in vitiligo therapeutics, we must not forget the critical unmet needs in other facets of holistic vitiligo management that must be addressed.

Disclosure: Dr Taylor has served as a consultant, advisory board member, investigator, and/or speaker for AbbVie, Allergan Aesthetics, Arcutis, Armis Biopharma, Avita Medical, Beiersdorf, Biorez, Bristol-Myers Squibb, Cara Therapeutics, Catalyst Medical Education, Concert Pharmaceuticals, Croma-Pharma GmbH, Dermsquared, Dior, Eli Lilly and Company, EPI Health, Estée Lauder, Evolus, Galderma, Glo Getter, Hugel America, Incyte, Johnson & Johnson Innovate Medicine, LearnSkin, L’Oreal USA, Medscape, MJH Life Sciences, Pfizer, Piction Health, Sanofi, Scientis US, UCB, and Vichy Laboratories. She also serves on the board of directors for Mercer Strategies; has received stock options for Armis Biopharma, Glo Getter, and Piction Health; and has received royalties from McGraw-Hill. Iain Noel Encarnacion and Noelle Desir report no relevant financial relationships.