Oral JAK Inhibitors in Pediatric Generalized Vitiligo Resistant to Conventional Treatment: A Case Series

ABSTRACT

Pediatric generalized vitiligo resistant to conventional therapy remains a major therapeutic challenge. We report four children treated with oral JAK inhibitors achieving marked repigmentation without significant adverse effects. Improvement often began within months, particularly when combined with phototherapy. These findings suggest systemic JAK inhibition as a promising option for refractory pediatric vitiligo.

Abbreviations

JAK

Janus kinase inhibitor

NBUVB

Narrow band UV‐B phototherapy

VASI

vitiligo area severity index

1. Introduction

Vitiligo is a chronic autoimmune depigmenting disorder affecting approximately 1% of the global population [1] with a significant psychosocial impact, particularly in children and adolescents [2]. The disease is driven by an autoimmune response mediated by cytotoxic CD8⁺ T cells that destroy melanocytes through interferon‐γ (IFN‐γ) dependent activation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway [3].

Conventional therapies, including topical corticosteroids, calcineurin inhibitors, narrowband UV‐B phototherapy (NBUVB) have demonstrated repigmentation rates of 54% [4], 55.0% [5], 75% [6] respectively; however, they often fail in extensive or rapidly progressive cases. Oral dexamethasone pulses treatment is reserved for rapidly progressive disease and has been shown to halt progression in up to 88% of patients, although repigmentation rates remain low (27.4%) [7]. JAK inhibitors, by blocking intracellular cytokine signaling, can suppress the inflammatory loop that sustains melanocyte destruction and prevent recruitment of autoreactive T cells. Topical ruxolitinib cream has shown meaningful repigmentation in two 52‐week phase 3 clinical trials conducted primarily in adult populations, in which 52.0% of participants achieved at least 75% improvement in their Facial Vitiligo Area Scoring Index (VASI). Similarly, oral agents such as ritlecitinib and upadacitinib are emerging as promising options for refractory and generalized disease although current evidence is largely limited to adult cohorts [8], with meta‐analyses reporting repigmentation in more than half of treated patients, especially when combined with phototherapy [9]. These advances position JAK inhibition as one of the most promising therapeutic strategies for vitiligo, including the pediatric population.

2. Case Reports

We present a case series of four patients with resistant vitiligo, defined by absent repigmentation despite appropriate conventional therapy, including an adequate course of topical corticosteroids and/or topical calcineurin inhibitors and/or phototherapy administered for at least 6 months [10]. All patients experienced significant repigmentation with oral baricitinib or upadacitinib.

All patients underwent baseline laboratory screening prior to initiation of Janus kinase inhibitor therapy, including complete blood count (CBC) with differential, liver function tests, lipid profile, and screening for hepatitis B and C and tuberculosis. During treatment, laboratory evaluation included repeat CBC, liver enzymes, and lipid profile at regular intervals (every 3 months), in accordance with current dermatology guidelines recommendations.

2.1. Patient 1

A 13‐year‐old girl with a history of atrial septal defect, T‐cell lymphopenia, and generalized vitiligo since age 6 years presented with extensive depigmentation involving the face, trunk, and extremities (VASI 60) (Figure 1). She had previously received multiple therapies including mometasone furoate 0.1% cream twice weekly and tacrolimus 0.1% ointment once daily for 3 years, narrowband ultraviolet B (NBUVB) twice weekly for 2 years, hydroxychloroquine for 6 months, and oral dexamethasone pulse therapy (0.1 mg/kg twice weekly) for 8 months without meaningful repigmentation.

FIGURE 1.

Patient 1 at baseline with multiple achromic coalescent patches on the trunk and extremities (sternal scar from a prior sternotomy after atrial septal defect surgery).

Baricitinib 1 mg/day was initiated with concomitant NBUVB twice weekly. After 4 months, perifollicular repigmentation was observed (VASI 38). The dose was subsequently increased to 2 mg/day to enhance response, resulting in progressive repigmentation (VASI 18 after 18 months) after which improvement plateaued for approximately 14 months. A further dose escalation to 3 mg/day for 1 month was attempted but did not produce additional benefit. Treatment was then switched to upadacitinib 15 mg/day, again in combination with NBUVB twice weekly, leading to near complete repigmentation within 1 year (VASI 7) (Figure 2). Moreover, she has been followed by the Immunology service since the diagnosis of T‐cell lymphopenia and throughout treatment, with no history of infections or infection‐related symptoms, including during baricitinib and upadacitinib therapy.

FIGURE 2.

Patient 1 demonstrating marked repigmentation of vitiligo after 4 years of sequential treatment with baricitinib (for 33 months) and upadacitinib (for 12 months).

2.2. Patient 2

A 7‐year‐old girl with autoimmune hypothyroidism had generalized vitiligo with involvement of the face, trunk, and extremities of 9 months duration with a baseline VASI of 17 (Figure 3). Prior to Janus kinase inhibitor therapy, she had been treated with a 9‐month combination of mometasone furoate 0.1% cream twice weekly, tacrolimus 0.1% ointment once daily, and NBUVB twice weekly, without achieving meaningful repigmentation. Upadacitinib 15 mg (0.68 mg/kg) daily was initiated. At 6 months, marked repigmentation was noted on the extremities (VASI 11), prompting dose escalation to 30 mg (1.36 mg/kg) daily, which resulted in further improvement (VASI 8 after 12 months) (Figure 4). Laboratory monitoring remained normal. Phototherapy was not added due to logistical limitations.

FIGURE 3.

Patient 2 at baseline with multiple achromic patches on lower extremities.

FIGURE 4.

Patient 2 showed marked repigmentation of vitiligo following 1 year of treatment with upadacitinib.

2.3. Patient 3

An 11‐year‐old girl with type 1 diabetes mellitus and juvenile plantar dermatosis presented with generalized vitiligo (VASI 16) involving the face, trunk, and upper and lower extremities. Prior to JAK inhibitor therapy, she had been treated with topical fluticasone propionate 0.05% cream twice weekly and tacrolimus 0.1% ointment once daily for 8 years, hydroxychloroquine for 10 months, and NBUVB twice weekly for 1 year, without achieving sustained repigmentation. Upadacitinib 15 mg (0.47 mg/kg) daily produced early perifollicular repigmentation and resolution of the plantar dermatitis after 2 months of treatment. At 6 months, improvement stabilized (VASI 13), leading to dose escalation to 30 mg (0.94 mg/kg) daily. After 1 year, VASI decreased to 7, with additional repigmentation on the knees and elbows. No adverse events or hematologic abnormalities were observed.

2.4. Patient 4

A 9‐year‐old boy presented with generalized vitiligo affecting face, trunk and extremities (VASI 28) since age 6 years. Before the initiation of oral JAK inhibitor therapy, the patient had previously undergone 1 year of mometasone furoate 0.1% cream twice weekly and tacrolimus ointment 0.1% once daily treatment, 6 months of oral dexamethasone (0.1 mg/kg twice weekly) pulse therapy, and 1 year of NBUVB twice weekly. Baricitinib 2 mg (0.08 mg/kg) daily was started. After 6 months of therapy, partial repigmentation (VASI 18) was achieved, prompting a switch to upadacitinib 15 mg (0.6 mg/kg) daily. Three months later, perifollicular pigmentation was evident, and NBUVB twice weekly was added, accelerating improvement to VASI 9 after 1 year. No adverse events occurred.

3. Discussion

The mechanism of JAKi in vitiligo involves blockade of the IFN‐γ/JAK–STAT pathway, which plays a central role in the crosstalk between keratinocytes and cytotoxic T cells. Inhibition of this signaling cascade interrupts the secretion of CXCL9 and CXCL10 and prevents recruitment of melanocyte‐destructive lymphocytes [11]. Additionally, JAK inhibition may suppress IL‐15–dependent tissue‐resident memory T cells, reducing the risk of relapse [12].

In each patient, perifollicular pigmentation became evident within months of treatment initiation, indicating melanocyte reactivation. These findings align with accumulating evidence supporting the efficacy of JAK inhibition in vitiligo. A comprehensive review assessing JAK and IL‐23 inhibitors in vitiligo in adults showed consistent repigmentation outcomes across multiple agents, including tofacitinib, ruxolitinib, baricitinib, and upadacitinib, together with favorable safety profiles [13]. Randomized controlled trials with selective JAK3/TEC inhibitors have also demonstrated significant improvement in facial and total VASI scores compared with placebo, confirming the clinical efficacy and tolerability of systemic JAK inhibition over extended treatment periods [14]. Furthermore, oral upadacitinib monotherapy has produced meaningful repigmentation responses in adult patients with refractory vitiligo, reinforcing the therapeutic potential of this class of agents [8].

Our experience extends these findings to the pediatric population, in which data remains limited, restricted to a small number of case reports and a single case series. The two published single case reports describe a 16‐year‐old adolescent with rapidly progressive vitiligo and atopic dermatitis who achieved early and marked repigmentation with upadacitinib 15 mg daily, with visible improvement within the first month of treatment [15]; and a 9‐year‐old child with refractory segmental vitiligo and alopecia areata successfully treated with upadacitinib in combination with NBUVB, highlighting the potential synergistic effect of JAK inhibition and phototherapy [16]. The largest pediatric experience to date reported a case series of 13 children with treatment‐resistant vitiligo treated with oral tofacitinib, demonstrating variable but often meaningful repigmentation, particularly in photo‐exposed areas [17].

JAK inhibitors show promising safety and efficacy in children with inflammatory dermatoses, including vitiligo, and a phase 3 trial evaluating the efficacy, safety, and tolerability of ritlecitinib in adults and adolescents is currently ongoing (NCT05583526) [18]. Post‐approval safety data published in 2024 suggest lower reported frequencies of boxed warning adverse events in children compared with adults receiving upadacitinib, abrocitinib, ruxolitinib, or tofacitinib, although detailed event‐specific rates were not provided. Continued pharmacovigilance is therefore warranted to better define long‐term safety in pediatric populations [19]. The absence of hematologic or infectious complications in our cohort aligns with these results and suggests that, under close monitoring and careful patient selection, JAK inhibitors may be used safely in selected pediatric patients with immune‐mediated disorders.

Phototherapy appears to enhance the therapeutic effect of JAK inhibition. Two of our patients who continued NBUVB treatment achieved faster and more extensive repigmentation. This synergistic effect has been confirmed in systematic reviews and meta‐analyses, which demonstrated higher VASI improvement rates when JAK inhibitors were combined with NBUVB compared with monotherapy [9]. The combination likely provides complementary mechanisms: JAK blockade mitigates immune‐mediated melanocyte destruction, while phototherapy stimulates melanocyte proliferation, migration, and melanin synthesis.

Furthermore, our findings suggest a possible dose–response relationship. Patients requiring escalation from baricitinib 1–2 to 3 mg daily, or from upadacitinib 15–30 mg, exhibited renewed repigmentation following dose adjustment. This observation parallels adult trials reporting increased efficacy with higher doses, although optimal pediatric dosing regimens remain to be defined [18].

This study has several limitations. First, the small number of patients included in this case series limits the generalizability of the findings. Second, the descriptive design and absence of a control group prevent any causal inferences regarding the observed outcomes. Finally, the short follow‐up period in some patients may have limited the assessment of long‐term outcomes. These limitations highlight the need for larger, prospective studies to further validate the clinical utility of this approach.

Overall, our real‐world data reinforces that systemic JAK inhibitors can induce robust and durable repigmentation in children with extensive refractory vitiligo (Table 1). The combination with NBUVB appears to enhance outcomes, and the favorable safety profile observed is consistent with the literature.

TABLE 1.

Clinical characteristics of patients.

Patient	Case 1	Case 2	Case 3	Case 4
Sex	F	F	F	M
Age, years	13	7	9	11
Body involvement site	Generalized	Generalized	Generalized	Generalized
Fitzpatrick skin type	III	III	III	VI
Weight, kg	43	22	32	25
Disease duration, years	7	1	8	3
Follow‐up, weeks	180	52	52	84
VASI week 0	60	17	16	28
VASI week 16	38	11	13	18
VASI at the end of the study	7	8	7	9
Baseline VASI/final VASI (%)	88	53	56	68
Treatment received	Baricitinib, upadacitinib	Upadicitinib	Upadacitinib	Baricitinib, upadacitinib
Dose escalation	Baricitinib 1–2 to 3 mg	Upadicitinib 15–30 mg	Upadacitinib 15–30 mg	No
Concomitant treatment	NBUVB	No	No	NBUVB

Abbreviations: F, female; kg, kilogram; M, male; NBUVB, narrowband UV‐B phototherapy; VASI, vitiligo area scoring index.

4. Conclusion

This case series highlights the clinical benefit and potential safety of oral JAK inhibitors in pediatric patients with generalized, treatment‐resistant vitiligo. All four patients achieved substantial and sustained repigmentation, with no laboratory abnormalities. Notably, dose escalation beyond initial dosing was frequently necessary to achieve optimal clinical response, underscoring the importance of individualized dosing strategies in this population.

Author Contributions

Andrés Vidal González: data curation, writing – original draft preparation. Rafael Escudero Tornero and Sergio López Alcázar: conceptualization, methodology. Rocio Maseda Pedrero, Raúl De Lucas Laguna, and Marta Feito Rodríguez: supervision.

Funding

The authors have nothing to report.

Consent

All patients in this manuscript have given written informed consent for participation in the study and the use of their deidentified, anonymized, aggregated data and their case details (including photographs) for publication.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.