Oral JΑΚ Inhibitors in Vitiligo Treatment

Abstract

Introduction

Vitiligo is an acquired disorder of skin pigmentation characterized by impaired melanocyte function and the appearance of well-outlined, white skin spots. Worldwide the incidence ranges between 0.5% and 2%. It has a negative impact on the quality of life of patients causing anxiety, depression, and social stigma. This comprehensive review aims to consolidate the current evidence concerning vitiligo treatment with oral Janus kinase (JAK) inhibitors.

Methods

Three databases (PubMed, Medline, and Embase) were searched to identify all articles discussing vitiligo treatment with oral JAK inhibitors up to April 2025.

Results

We identified 217 articles encompassing vitiligo treatment with the JAK inhibitors baricitinib, tofacitinib, upadacitinib, ritlecitinib, ruxolitinib, prebocitinib, and povorcitinib.

Limitations

The data primarily stem from observational studies, case reports, case series, pilot studies, reviews, and meta-analyses. The establishment of treatment protocols necessitates more extensive and well-controlled studies.

Conclusions

Oral JAK inhibitors could present an effective and safe option for patients with vitiligo; however. there is a need for further long-term studies and more data about treatment procedures.

Key Summary Points

Vitiligo is an acquired disorder of skin pigmentation characterized by impaired melanocyte function and the appearance of well-outlined, white skin spots. Worldwide, the incidence ranges between 0.50% and 2%.

Vitiligo has a negative impact on the quality of life of patients causing anxiety, depression, and social stigma.

Current treatment options such as topical and systemic corticosteroids, phototherapy, calcineurin inhibitors, excimer laser, skin discoloration, and surgical techniques offer limited efficacy and some of them are associated with significant side effects in long-term use, underscoring the need for safer and more effective therapies.

A new topical Janus kinase (JAK) inhibitor, ruxolitinib cream, has been authorized for the treatment of non-segmental vitiligo with facial involvement in adults and adolescents from 12 years of age. The cream is applied to the depigmented skin areas up to a maximum of 10% of body surface area (BSA). No more than two tubes of 100 g should be used per month.

Oral JAK inhibitors could be an option for patients with vitiligo, especially those with extensive non-segmental vitiligo, when the BSA is higher than 10%, or those not responding to the topical JAK inhibition.

Treatment with oral JAK inhibitors could be an effective and safe option for patients with vitiligo. But there is a need for further long-term studies to establish specific treatment protocols, optimize combination therapies, and address safety issues.

Introduction

Vitiligo is an acquired disorder of skin pigmentation characterized by impaired melanocyte function and the appearance of well-outlined, white skin spots [1]. Worldwide the incidence ranges between 0.50% and 2%. The onset of vitiligo is observed at all ages, but more often between 10 and 30 years of age. It has a negative impact on the patients’ quality of life causing anxiety, depression, and social stigma [2]. Patients report problems in their personal life and work which lead to low self-esteem and social isolation. For several years, treatment included topical and systemic corticosteroids, phototherapy, calcineurin inhibitors, excimer laser, skin discoloration, and surgical techniques. In 2023, the topical Janus kinase (JAK) inhibitor ruxolitinib 15 mg/g cream was authorized for vitiligo treatment; however, it can only be used in cases with less than 10% of body surface area (BSA) discoloration. For the patients with extensive vitiligo lesions or those not responding to topical JAK inhibition, treatment options are still urgently needed. With the rationale of topical JAK inhibition proven to be efficacious, in this article we explore clinical questions regarding the use of oral JAK inhibitors for vitiligo.

Methods

A comprehensive search of PubMed, MEDLINE, and EMBASE up to April 2025 was conducted for articles discussing vitiligo treatment with oral JAK inhibitors. The search encompassed MeSH terms such as “vitiligo”, “treatment”, “oral JAK inhibitors”, “baricitinib”, “tofacitinib”, “upadacitinib”, “ritlecitinib”, “ruxolitinib”, “prebocitinib”, and “povorcitinib”.

The search yielded 217 articles, including observational studies, pilot studies, case reports, reviews, original articles, and meta-analyses. We further filtered duplicates and selected studies according to title, abstract, and keywords. Articles were limited to those available in English language. Irrelevant references were excluded from consideration. In total, we identified 20 articles covering the treatment of vitiligo with oral JAK inhibitors.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of authors. Ethical approval was not required.

The JAK Family and Vitiligo

The JAK family—comprising JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)—is a group of intracellular, non-receptor tyrosine kinases that transmit cytokine-mediated signals via the JAK-STAT pathway. In recent years, the role of this pathway in the progression of autoimmune and autoinflammatory disorders has been extensively studied and a series of novel drugs targeting the pathway have been developed.

Vitiligo pathogenesis involves self-reactive CD8⁺ T cells which produce interferon-gamma (IFNγ) and end up destructing melanocytes [3, 4]. Recent studies have revealed that IFNγ and the related chemokine (C-X-C motif) ligand (CXCL) 9 and 10 appear as key drivers of vitiligo pathogenesis and are mediated by JAK/signal transducer and activator of transcription (STAT) pathway in local keratinocytes [5, 6]. This signaling cascade amplifies the immune response by recruiting additional CD8⁺ T cells and leading to further exacerbating melanocyte damage.

Treatment Option for Vitiligo

Narrowband ultraviolet B (NB-UVB) phototherapy has been one of the first-line therapeutic options for treating generalized vitiligo and is typically combined with other therapies to improve its efficacy. However, treatment resistance is often encountered [6]. Further conventional treatments include topical corticosteroids, topical calcineurin inhibitors, oral corticosteroids, excimer laser, and surgical procedures.

A new topical JAK inhibitor, ruxolitinib 15 mg/g cream, has been marketed for the treatment of non-segmental vitiligo (NSV) with facial involvement in adults and adolescents from 12 years of age. The cream is applied to the depigmented skin areas up to a maximum of 10% BSA. No more than two tubes of 100 g should be used per month. However, skin involvement might be higher than 10% BSA, without lesions on the face. Thus, oral JAK inhibitors could be a treatment option, especially for patients without facial involvement, extensive NSV (BSA > 10%), or not responding well to the topical treatments.

Oral JAK Inhibitors

A wide group of JAK inhibitors are currently used to treat a variety of autoimmune conditions, e.g., the skin disorders atopic dermatitis and alopecia areata. Depending on the selectivity of each agent, all four JAKs (JAK1, JAK2, JAK3, and TYK2) or only specific kinases may be blocked, at least in low dosages. In vitiligo treatment, JAK inhibitors operate by inhibiting pathogenic T cells that target melanocytes [7]. Furthermore, they can block the IFNγ signaling pathway and related chemokines, which mediate melanocyte destruction.

In the treatment of vitiligo, a few published case reports, case series, and open-label studies have shown superior repigmentation rates in patients treated with JAK inhibitors compared to those treated with the established treatment options, especially when combined with concomitant phototherapies [8]. All published cases are summarized in Table 1.

Table 1.

Patients with vitiligo treated with oral JAK inhibitors so far

Treatment	No. patients	Type of vitiligo	Administration	Combined treatment	Study type	Duration	Adverse events
Tofacitinib	1	Segmental vitiligo	Tofacitinib 10 mg QD	NB-UVB phototherapy	Case report	1 month	No significant abnormalities on imaging and laboratory examination
Tofacitinib	1	Not specified	Tofacitinib 5 mg BD	No	Case report	Ongoing from 2017	Unknown
Tofacitinib	1	Not specified	Tofacitinib 5 mg BD for the first 19 weeks and 5 mg QD for the rest	No	Case report	5 months–unknown	Gastrointestinal side effects
Tofacitinib	10 (5 male/5 female)	Not specified	5–10 mg QD-BID for an average of 9.9 months	NB-UVB phototherapy in 2 of the patients	Case series	2.5 years	Upper respiratory infection, weight gain, arthralgias, mild elevations of lipids
Tofacitinib	1	Non-segmental progressing vitiligo	Oral tofacitinib 5 mg every other day, after 3 weeks 5 mg QD	No	Case report	> 5 months	Unknown
Tofacitinib	136	Active vitiligo	The experimental group was given tofacitinib 5 mg QD	NB-UVB phototherapy in both groups	Randomized double-blinded clinical trial	6 months	No
Baricitinib	4 (1 female/3 male)	Non-segmental progressing vitiligo	Oral baricitinib	No	Clinical study	3 months	No
Baricitinib	2	Non-segmental vitiligo	Oral baricitinib 2 mg BID	NB-UVB phototherapy	Case report	6–9 months	Unknown
Baricitinib	52 (29 female/23 male)	Non-segmental progressing vitiligo	Oral baricitinib 2 mg BID in the combination group	NB-UVB phototherapy	Clinical study	6 months	Three cases of itchy skin, one erythema, one burning pain intervened by phototherapy
Baricitinib	17	Non-segmental progressing vitiligo	Baricitinib 2 mg QD	NB-UVB phototherapy	Clinical study	4 months	All adverse events were mild
Ritlecitinib	364	Non-segmental progressing vitiligo	Ritlecitinib 50 mg, 30 mg, or 10 mg QD	No	Randomized double-blind, dose-ranging, phase 2 trial study	6 months	Unknown
Ritlecitinib	364	Non-segmental vitiligo	Oral ritlecitinib QD 64-week loading dose or placebo for 24 weeks	Non-responders, received NB-UVB phototherapy	Randomized double-blind, dose-ranging, phase 2 trial study	6 months	Nasopharyngitis, upper respiratory tract infections, headache, infections and infestations, four cases of herpes zoster and two malignancies
Ritlecitinib	187 patients ritlecitinib monotherapy and 43 patients ritlecitinib plus NB-UVB	Non-segmental vitiligo	Ritlecitinib 200 mg for 4 weeks then 50 mg for 20 weeks	NB-UVB phototherapy 2×/week at some of the patients	Randomized double-blind, dose-ranging, phase 2 trial study	6 months	Urinary tract infection, upper respiratory tract infection, headache, nasopharyngitis, pruritus, one uterine leiomyoma, decreased absolute lymphocyte count, hearing loss, increased liver function test, rash, increased blood creatine phosphokinase, photosensitivity reaction, pruritus
Upadacitinib	1	Segmental vitiligo	Upadacitinib 15 mg QD	NB-UVB phototherapy	Case report	4 months	Unknown
Upadacitinib	10 (7 female and 3 male)	Non-segmental vitiligo	Upadacitinib 15 mg QD	6 patients, 308 nm excimer laser therapy twice per week	Case series	4 months–unknown	No
Upadacitinib	1	Slowly progressive vitiligo	Upadacitinib 15 mg QD	No	Case report	12 months	Slight worsening of acne
Upadacitinib	1	Not specified	Upadacitinib 15 mg QD	Crisaborole	Case report	4 months	Unknown
Upadacitinib	185 (115 female/70 male)	Non-segmental vitiligo	Upadacitinib 6 mg, 11 mg, or 22 mg	No	Randomized, double-blind, placebo-controlled, dose-ranging trial	12 months	COVID-19, headache, acne, fatigue, one death of unknown cause, one case of infiltrating lobular breast carcinoma, one coronary artery arteriosclerosis, one non-fatal ischemic stroke
Upadacitinib	10	Non-segmental vitiligo	Upadacitinib 30 mg QD (one 15-year-old patient 15 mg QD)	NB-UVB phototherapy in 1 of the 10 patients	Case series	6 months	No significant or serious adverse event

BID twice a day, NB-UVB narrowband ultraviolet B, QD once a day

Tofacitinib

The oral JAK1/3 inhibitor tofacitinib was approved by the US Food and Drug Administration in 2012 for the treatment of moderate to severe rheumatoid arthritis. It has demonstrated safety and efficacy for the treatment of plaque psoriasis and recently the success of oral tofacitinib in treating alopecia universalis has been reported [9].

Craiglow and King [9] described a female patient in her 50s with widespread and progressive vitiligo, existing for the past year. The increasing involvement of the face and hands was causing the patient significant concern. Treatment with oral tofacitinib was initiated at a dosage of 5 mg every other day. After 3 weeks, the dosage was increased to 5 mg/day (half the approved dosage for rheumatoid arthritis, which is 5 mg twice daily). After 5 months, repigmentation of the forehead and hands was nearly complete and only 5% of the total BSA remained depigmented. The patient tolerated tofacitinib without adverse effects. The fairly rapid response and the repigmentation of the hands, which are often resistant to therapy, are noteworthy.

Guo et al. [10] described the efficacy of tofacitinib combined with NB-UVB phototherapy for the treatment of vitiligo. A total of 136 patients with vitiligo were randomized to phototherapy only (UVB group) or phototherapy combined with tofacitinib (TOF-UVB group). The patients were followed up for 24 weeks. In post-treatment analysis, significantly more patients in the TOF-UVB group (n = 63) showed effective repigmentation compared to the UVB group (n = 61). The TOF-UVB group demonstrated markedly lower Vitiligo Area Severity Index (VASI) (baseline VASI for UVB 5 to post-treatment 4, p < 0.01; baseline VASI for TOF-UVB 5 to post-treatment 3, p < 0.001) and Dermatology Life Quality Index (DLQI) scores than the UVB group at the final visit (baseline DLQI for UVB 16 to post-treatment 11, p < 0.001; baseline DLQI for TOF-UVB 17 to post-treatment 8, p < 0.001). Pronouncedly lower serum levels of inflammatory factors associated with vitiligo, interleukin (IL)-17, IL-23, IFNγ, and IL-6 were observed in both groups, but the TOF-UVB group showed again higher improvement than the UVB group.

Komnitski et al. [11] reported a 40-year-old female patient with comorbid rheumatoid arthritis and vitiligo on her face, neck, elbows, hands, and feet, which had started in 2012. Her brother and mother had a positive history for vitiligo. She was given tofacitinib 5 mg twice a day, resulting in amelioration of the arthritis. After 8 months of tofacitinib use, improvement of the macules and patches with formation of several islets of repigmentation in the hands and face was noted, without the patient being exposed to any source of UV. After 2 years, complete repigmentation of the forehead and perilabial macules were observed, as well as partial repigmentation in the posterior region of the neck and upper chest.

A 56-year-old female patient with stably controlled systemic lupus erythematosus and vitiligo was studied by Lin and colleagues [12]. Initial dermatological examination revealed a white patch on the forehead measuring approximately 2.5 cm × 1.5 cm with clear borders. Reflectance confocal microscopy revealed complete depigmentation of the basal layer of the epidermis. The patient was given 10 mg/day oral tofacitinib. After 30 days, the white macular rash was completely repigmented, the pigment granules in the basal layer of the epidermis returned to normal on reflectance confocal microscopy and no significant abnormalities were found on imaging and laboratory examinations. No recurrence was observed at the 6-month follow-up.

A retrospective cohort study by Hu et al. [13] described the efficacy of oral tofacitinib in 137 patients, whose treatment duration was longer than 3 months. Median pretreatment VASI was 3.79 (1.54–4.0). A total of 58 patients additionally received NB-UVB therapy 2 to 3 times/weekly. After 3 months of oral tofacitinib, the mean total VASI score decreased to 2.68 (1.0–2.92), indicating an overall improvement of 29.3%. Notably, patients also receiving NB-UVB exhibited a significantly higher repigmentation rate (38.78 ± 25.73%), compared to those not undergoing NB-UVB (19.48 ± 11.83%) (p = 0.01). Besides the VASI score, reduction of the Vitiligo Disease Activity Score (VIDA) score was achieved after the 3 months of treatment. Importantly, 59.1% (81/137 patients) acquired disease stabilization, without signs of vitiligo progression. After a 3-month follow-up, 98 patients continued to receive tofacitinib treatment. Patients who received tofacitinib for 6–9 months demonstrated significantly greater improvements than those treated less than 6 months. No statistically significant difference was observed in efficacy among patients treated for more than 9 months. A total of 11 adverse events (AEs) were reported in 19 patients (19/137, 13.8%), the majority of them being mild and not necessitating treatment discontinuation. The most frequently observed AEs, classified as uncommon, included gastrointestinal discomfort (2.9%), acne (2.1%), elevated liver enzymes (2.1%), and palpitations (2.1%).

In another retrospective case series, 10 patients (8 with generalized vitiligo and 2 with primarily acral involvement) were treated with tofacitinib 5–10 mg daily for an average of 9.9 months [14]. A mean decrease of 5.40% BSA was observed in 5/10 patients, while the other 5 did not achieve any repigmentation. Interestingly, in the 5 patients with ameliorated disease, repigmentation occurred only in sun-exposed areas of skin in 3/5, diffusely in a patient undergoing concomitant full-body NB-UVB, and on the hands in another patient that had hand NB-UVB phototherapy. Of the 5 patients who did not experience repigmentation, only one reported significant sunlight exposure, while the others practiced strict photoprotection. The most common AE was upper respiratory infection (2/10 patients), while there were no serious AEs. In this series, JAK inhibitors in combination with either low-dose NB-UVB phototherapy or sun exposure appeared to be more efficacious regarding repigmentation.

A 56-year-old female patient with concomitant Hashimoto thyroiditis presented with vitiligo affecting 30–35% BSA, with lesions primarily on the face, hands, arms, and neck [15]. At baseline she had thyroglobulin antibodies with a concentration of 2 IU/mL, while TSH and free T4 were within normal limits. Within the first month of treatment with tofacitinib (5 mg twice daily) the thyroglobulin antibody levels normalized to 1 IU/mL. Clinical improvement in vitiligo BSA appeared shortly thereafter. At week 19, vitiligo BSA had decreased to 12%, and gastrointestinal side effects prompted a decrease in dosage of tofacitinib to 5 mg once daily.

Baricitinib

Baricitinib primarily targets the JAK1 and JAK2 subunits and is already utilized in dermatology for inflammatory dermatoses driven by JAK/STAT signals.

The initial report on its use for vitiligo was published in 2020 [16]. The patient acquired poor improvement using tofacitinib 5 mg twice daily for 5 months. Then she switched to baricitinib 4 mg daily and almost complete repigmentation was achieved within 8 months.

Dong et al. [17] reported the effectiveness of baricitinib in four patients (one female/three male) with non-segmental progressive vitiligo whose VIDA scores were higher than 4. Baricitinib was used as monotherapy (4 mg daily during the first 4 weeks, then reduced to 2 mg daily for another 8 weeks). Blood tests were obtained before treatment, every 2 weeks in the first 4 weeks of treatment, every 4 weeks during the following 8 weeks, and 3 months after stopping baricitinib. Pigment islets were observed already within 4 weeks of baricitinib treatment, with significant repigmentation in week 12. All four patients tolerated the treatment well and claimed no discomfort, while no obvious AEs were detected in blood tests. At the 3-month follow-up, depigmentation occurred in two patients.

Li et al. reported two further cases treated with baricitinib [18]. A 17-year-old female patient presented with white patches on her trunk and extremities for 3 years. Baricitinib 2 mg twice daily was initiated, combined with 0.1% tacrolimus ointment twice daily and NB-UVB phototherapy twice a week. Repigmentation of the lesions was observed already after 1 month. Eight months after treatment initiation, the hypopigmented patches showed significant repigmentation with good tolerance. The second case, a 56-year-old woman, presented with a 27-year history of vitiligo with a rapid progression in the past year. The hypopigmented patches started on the trunk and then spread to the face and extremities, reaching BSA of about 60%. She was given oral baricitinib 2 mg twice daily, oral ginkgo biloba 80 mg twice daily, as well as 0.1% tacrolimus ointment, mometasone furoate cream, and full-body NB-UVB phototherapy. Repigmentation of more than 75% of the lesions was observed at 6 months follow-up. The drug was well tolerated with no adverse effects in both patients.

In another study, Hu and colleagues employed the combination of baricitinib 2 mg daily and NB-UVB three times a week to treat patients with progressive NSV for 16 weeks, while a control group was treated only with NB-UVB three times a week. Of the 33 patients (mean age 34.1 years; 27.3% women) who completed the study, 12/17 (70.60%) in the combination group and 2/16 (12.50%) in the control group had a Total Body Vitiligo Area Severity Index 50 (T-VASI50) response at week 16. AEs were minor, including erythema, mild blistering after phototherapy, and acne. These results highlight that combination therapy of low-dose baricitinib with NB-UVB phototherapy is effective and well tolerated in adults with progressive NSV [19].

In another report, 52 patients received combination treatment with baricitinib 2 mg twice a day and NB-UVB three times per week for 6 consecutive months in patients suffering from NSV [20]. As a comparative group, 49 patients were treated with oral methylprednisolone mini-pulse therapy (0.5 mg/kg per week on two consecutive days), paired with NB-UVB three times weekly. The improvement in VASI was significantly better in the baricitinib group, irrespective of the months of follow-up. Specifically, improvement of VASI for lesions on the extremities was significantly better at months 4 (p = 0.05), 5 (p = 0.03), and 6 (p = 0.03) in the combination group than in the control group. We further analyzed the overall variations in response rates between the two groups. By month 6, the response rates increased to 86.50% in the combination group and 67.30% in the control group (p = 0.02). These patients also experienced a notable reduction in serum levels of IFNγ and CXCL10. Particularly, IFNγ and CXCL10 levels in the combination group decreased from 38.52 ± 5.98 pg/mL and 976.67 ± 150.57 pg/mL at baseline to 26.46 ± 5.93 pg/mL and 704.14 ± 103.38 pg/mL at 6 months (p < 0.001), respectively. In contrast, no significant decrease in serum levels of IFNγ and CXCL10 were observed in the control group. All patients tolerated the treatment well, without serious AEs and no significant difference in recurrence rates in both groups arose 6 months after the last treatment.

Upadacitinib

Upadacitinib is an oral selective JAK1 inhibitor with a proven efficacy and safety in several immune-mediated conditions. Specifically, it is approved in multiple countries for the treatment of atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spondylarthritis.

Recently, the efficacy and safety of upadacitinib in 185 patients with extensive NSV was studied [21]. Eligible patients were aged 18–65 years and had a F-VASI (Face-Vitiligo Area Scoring Index) ≥ 0.5 and a Total VASI ≥ 5. Patients received upadacitinib 6 mg, upadacitinib 11 mg, upadacitinib 22 mg, or placebo once daily for 24 weeks (preassigned to switch to either 11 or 22 mg upadacitinib in the second part of the study). For weeks 24–52, the probands continued their treatment as randomly assigned initially, while patients on placebo switched to a preassigned dose. The primary endpoint was the percentage change from baseline in F-VASI at week 24, which was met with the higher dosages of 11 mg and 22 mg. Continued repigmentation occurred over the time course of 52 weeks. The safety profile was comparable to that previously reported in other disorders, with the most common treatment-emergent AEs being COVID-19 infection, headache, acne, and fatigue. AEs and drug discontinuation rates were higher for the upadacitinib 22-mg dose.

A 9-year-old child with segmental vitiligo of the face and alopecia areata for 2 months received treatment with upadacitinib 15 mg once daily, in combination with NB-UVB and topical calcineurin inhibitor [22]. The drug was tapered down after 3 months: a weekly decrease of 15 mg was initiated, that is 15 mg/day for 6 days and discontinued for 1 day. After 2 months a further reduction of 15 mg per week was made, with further reductions following thereafter. Within 7 months, the patient had recovered 70% repigmentation of the lesions, while white hair had grown at the alopecia areata areas. Besides a transient increase in creatine kinase, no AEs occurred within 10 months of follow-up.

Magdaleno-Tapial et al. studied 10 patients affected by NSV who were treated with upadacitinib for a maximum of 24 weeks [23]. All received upadacitinib 30 mg daily, except for a 15-year-old patient who received 15 mg/day. None of the patients applied any other topical therapies, while only one had phototherapy sessions at the time of starting upadacitinib. Improvement in the vitiligo extent score (VES) was identified in 90% of the patients, all showed repigmentation at the 12-week follow-up. No serious AEs were reported.

In another study the efficacy of upadacitinib 15 mg daily in 10 patients with stable NSV was evaluated [24]. Six patients received adjuvant treatment with 308 nm excimer laser twice per week. The study participants had great improvement of their disease: the VASI score decreased more than 50% in 6/10 patients, while 4 had a decrease exceeding 75%. Efficacy varied in the different body areas, with best effects on the face and neck, then trunk and finally limbs and extremities. The probands with the combined upadacitinib plus 308 nm excimer laser had the highest (however not statistically significant) lesion response after 16 weeks. None experienced significant AEs.

Pan and colleagues reported a 16-year-old boy with atopic dermatitis (AD) since childhood, who presented with rapidly progressive vitiligo for 4 months [25]. Treatment comprised of upadacitinib 15 mg, combined with crisaborole on both white patches and eczematous lesions. No new white patches appeared after 1 month. Repigmentation reached 90% on his face and neck after 4 months, but only 60% on the chest and was only limited on the extremities. Notably, AD-related pruritus disappeared within 24 h of upadacitinib treatment and lesions almost cleared within 4 months.

Similarly, a 25-year-old female patient with AD since childhood and subsequent onset of slowly progressive vitiligo at the age of 16 (with VASI 0.45) [26] was treated with upadacitinib 15 mg daily. An almost complete remission of vitiligo was achieved at week 28 and was maintained at the 1-year follow-up, with no side effects except for a slight worsening of acne, easily controlled with topical therapies.

Ritlecitinib

Ritlecitinib is an orally bioavailable small molecule that inhibits JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family. It is highly selective for JAK3 and potently inhibits signaling of IL-2 and IL-15, thus being potentially efficacious for the treatment of vitiligo [27].

Ezzedine et al. studied the efficacy of ritlecitinib in a randomized phase 2 clinical trial (NCT03715829) [28], in which 364 probands were treated with different dosages, either receiving loading dosages for 4 weeks or not (total of dose-ranging period, 24 weeks). At week 24, significant differences from placebo in percent change from baseline in F-VASI were observed in all groups; however, these were more pronounced in the group receiving ritlecitinib 50 mg with a loading dose (F-VASI reduction of 21.2 vs 2.1; p < 0.001, compared to F-VASI reduction of 18.5 vs 2.1; p < 0.001 in those not receiving the loading dosage). In the initial dose-ranging period, 66 patients discontinued treatment. In an extension period of additional 24 weeks, patients were either allocated to an open-label brepocitinib group, an open-label ritlecitinib with NB-UVB, or a blinded 200/50 mg ritlecitinib group. An accelerated repigmentation was especially evident for those getting ritlecitinib 200/50 mg in the extension period, with a progressive repigmentation without plateau. In the dose-ranging period, 18% discontinued treatment, while 15.5% discontinued in the extension period (all receiving 200/50 mg ritlecitinib). No dose-dependent trends in AEs or serious AEs were observed across the 48-week clinical trial. Most AEs were mild or moderate (73.10%), while the three most common treatment-emergent AEs comprised nasopharyngitis, upper respiratory tract infections, and headache.

In a phase 2b trial for NSV, 43 patients received ritlecitinib plus NB-UVB and 187 had ritlecitinib as monotherapy over 24 weeks [29]. Both groups had improved facial and total body repigmentation, while the treatment was well tolerated. At week 24, mean percent change from baseline in F-VASI score was 57.0 versus 51.5 (p = 0.158) for ritlecitinib plus NB-UVB and 69.6 versus 55.1 (p = 0.01) for ritlecitinib. Mean percent change from baseline in Total-VASI at week 24 was 29.4 vs 21.2 for ritlecitinib plus NB-UVB (p = 0.04) and 46.8 vs 24.5 for ritlecitinib monotherapy (p < 0.001). Add-on NB-UVB phototherapy appeared to improve ritlecitinib efficacy.

In an exploratory analysis of the NCT03715829 study [28], Yamaguchi et al. reported that ritlecitinib stabilized active lesions and repigmented stable lesions in vitiligo [30]. A total of 364 patients were randomized to daily ritlecitinib 50 mg (with or without a 4-week loading dose); 65 of them agreed to have skin biopsies taken. The authors observed a stabilization of the mean percent change from baseline in depigmentation extent in both active lesions and stable lesions at week 24, with stable lesions having a greater repigmentation rate. The drug also increased expression of melanocyte markers in stable lesions, while Th1/Th2 related and co-stimulatory molecules decreased in all types of lesions. Sera of the probands were also examined, showing decreased levels of inducible T cell co-stimulator (ICOS) and NK cell activation markers.

Other JAK Inhibitors

In 2016, use of oral ruxolitinib was reported in a patient with coexisting vitiligo and alopecia areata [31]. A great improvement in facial vitiligo was achieved after 20 weeks; however, depigmentation occurred after drug withdrawal.

Brepocitinib is an oral TYK2/JAK1 inhibitor used in various autoimmune diseases such as psoriasis, ulcerative colitis, Crohn’s disease, and alopecia areata [32]. A phase 2b study of ritlecitinib and brepocitinib, with or without phototherapy, has been completed in active NSV (NCT03715829). 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 in larger studies.

Povorcitinib (INCB054707) is an oral selective JAK1 inhibitor for hidradenitis suppurativa. A phase 3 clinical trial is ongoing to assess the efficacy and safety of povorcitinib in patients with NSV (NCT06113445, NCT06113471) [32]. In the preceding phase 2 study 171 participants with NSV were assigned to receive either 15 mg, 45 mg, or 75 mg of povorcitinib or placebo for 24 weeks. Subsequently, they continued with either 45 mg or 75 mg povorcitinib during the 28-week extension period. A significant percentage change from baseline in T-VASI at week 24 was demonstrated in the treatment group (NCT04818346), thus the phase III trial followed.

Discussion

Vitiligo is an autoimmune pigmentary disorder characterized by the loss of melanocytes [32]. Recently, novel topical agents targeting the JAK/STAT pathway have emerged, with ruxolitinib 15 mg/g cream representing the first approved for vitiligo therapy. However, unmet needs are still present in patients with vitiligo, since many of them have more than 10% of their body surface affected. In this review we summarize the available evidence on the use of oral JAK inhibitors to treat patients with vitiligo, which appear to be very promising treatment options.

The goals of vitiligo treatment are to slow disease progression, induce repigmentation, and prevent relapses. Compatible with the findings for previous vitiligo treatments, repigmentation initially occurred in the face, whereas acral regions were the most resistant ones. This might be attributable to the lower density of hair follicles at acral sites and the greater exposure of the face to the sun [33].

An interesting point is that concurrent UVB phototherapy appears to improve efficacy of the drugs. Specifically, the proportion of good response in patients who received JAK inhibitors alone was significantly lower compared to who receiving concurrent phototherapy. This has been shown for all JAK inhibitors used so far and is not a new observation for vitiligo treatments, although underlying mechanisms remain unclear. The hypothesis has been established that combined treatment with NB-UVB supports repigmentation by causing immunosuppression and stimulating melanocyte growth [34]. Specifically, photoactivation of melanocytes probably allows them to leave their stem cell niche and populate the epidermis, producing pigment. Meanwhile, the JAK inhibitor suppresses the autoimmune CD8⁺ and IFNγ-dependent responses that attack melanocytes and cause depigmentation [35]. Future studies, both on cellular and clinical level, are required to confirm these findings.

In general, treatment with oral JAK inhibitors for vitiligo appears safe, with no new safety signals arising. Laboratory changes were minimal, and most commonly minor abnormalities in lipid metabolism were identified. Furthermore, there were no cases of new malignancies or reactivation of tuberculosis. It has to be noted that follow-up for available published cases is rather limited and still ongoing. Thus, it is important to emphasize for clinicians using JAK inhibitors that the possibility of serious AEs is still plausible, and that safety profile data for this class of agents in vitiligo is currently under investigation.

Conclusion

Recent studies have shown promising results when using oral JAK inhibitors for treatment of vitiligo. They represent a promising therapeutic strategy for halting disease progression and promoting repigmentation. Combination of JAK inhibitors with phototherapy can improve outcomes and reduce AEs related to systemic JAK inhibitor treatment, by lowering the dose of the drug required for treatment [36]. However, there is a need for further long-term studies to establish specific treatment protocols, optimize combination therapies, and address safety issues.

Author Contributions

Angeliki Panagopoulou: literature search, drafting the manuscript and manuscript revision. Elena Sotiriou: concept and design of the study, writing of the manuscript and manuscript revision. Ilias Papadimitriou: writing of the manuscript and manuscript revision. Anastasios Pavlidis: literature search, writing of the manuscript and manuscript revision. Katerina Bakirtzi: writing of the manuscript and manuscript revision. Aikaterini Tsentemeidou: writing of the manuscript and manuscript revision. Michael Arabatzis: writing of the manuscript and manuscript revision. Efstratios Vakirlis: writing of the manuscript and manuscript revision. Dimitra Kiritsi: concept and design, literature search, writing of the manuscript and manuscript revision.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

All data generated or analyzed during this study are included in this published article.

Declarations

Conflict of Interest

Dimitra Kiritsi is an Editorial Board member of Dermatology and Therapy. Dimitra Kiritsi was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Angeliki Panagopoulou, Elena Sotiriou, Ilias Papadimitriou, Anastasios Pavlidis, Katerina Bakirtzi, Aikaterini Tsentemeidou, Michael Arabatzis and Efstratios Vakirlis have nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.