Once-daily oral treatment with the JAK inhibitor upadacitinib delivers clinically meaningful facial and total body repigmentation in adults and adolescents with non-segmental vitiligo, according to the phase III Viti-Up 1 and 2 trials.
After 48 weeks of treatment, significantly more participants in the upadacitinib vs the placebo group achieved the coprimary endpoints of a 75-percent improvement on the Facial Vitiligo Scoring Index (F-VASI 75) and a 50-percent improvement on the Total Vitiligo Area Scoring Index (T-VASI 50), reported Prof Thierry Passeron from Côte d’Azur University, Nice, France, and colleagues. [Lancet 2026;408:636-648]
F-VASI 75 rates were 25 percent with upadacitinib vs 6 percent with placebo in Viti-Up 1 and 23 percent vs 7 percent, respectively, in Viti-Up 2 (p<0.001 in both studies). T-VASI 50 rates were 19 percent vs 6 percent in Viti-Up 1 and 21 percent vs 6 percent in Viti-Up 2 (p<0.001 in both studies).
A small percentage of participants in the upadacitinib group met criteria for the coprimary endpoints as early as week 8 (F-VASI 75: 2 percent in both Viti-Up 1 and 2; T-VASI 50: 2 percent in Viti-Up 2)—a finding that Passeron and colleagues found to be notable, given the amount of time it takes for repigmentation to occur in the absence of adjunctive targeted phototherapy.
The Viti-Up trials
Viti-Up 1 and 2 were conducted at 138 institutions across 18 countries in Asia, Europe, North America, and South America. These trials included 614 adults and teens (average age 45 years, 50 percent female, 78 percent White) with nonsegmental vitiligo involving the face and body. They were randomly assigned to receive either upadacitinib (206 in Viti-Up 1 and 205 in Viti-Up 2) or placebo (102 in Viti-Up 1 and 101 in Viti-Up 2) orally once daily.
The Viti-Up populations had a long disease duration (average 16 years), and most participants (62 percent) had active disease at baseline. Mean T-VASI scores were 19.4 in Viti-Up 1 and 16.8 in Viti-Up 2, while mean F-VASI scores were 1.1 in both trials.
Results for secondary endpoints also favoured upadacitinib. Compared with those who received placebo, upadacitinib-treated participants were more likely to achieve F-VASI 50 at week 48 (Viti-Up 1: 48 percent vs 13 percent; Viti-Up 2: 43 percent vs 13 percent) and F-VASI 90 at week 48 (Viti-Up 1: 16 percent vs 2 percent; Viti-Up 2: 12 percent vs 3 percent).
On the Physician's Global Impression of Change, treatment response at week 48 vs baseline was rated as “Much Better (1)” in 17 percent to 20 percent of upadacitinib-treated patients and in 1 percent to 6 percent of placebo-treated patients across the two trials. Similarly, between 16 percent and 18 percent of patients in the upadacitinib group and between 1 percent and 4 percent in the placebo group defined their response as “Much Better (1)” on the Patient's Global Impression of Change.
Safety data were in line with the overall upadacitinib safety profile. There were no reports of adjudicated major adverse cardiovascular events, adjudicated venous thromboembolic events, adjudicated gastrointestinal perforations, active tuberculosis, lymphoma, nonmelanoma skin cancer, or opportunistic infections other than herpes zoster in either Viti-Up 1 or 2.
“As a systemic therapy, upadacitinib provides a therapeutic option for groups in whom vitiligo cannot be addressed by current topical therapies or phototherapy. Such groups might include patients for whom topical therapy or phototherapy use could be challenging, inadequate, or both; patients with active non-segmental vitiligo; and patients with more extensive and/or widespread depigmentation,” Passeron and colleagues noted.
“Based on its ability to systemically treat nonsegmental vitiligo, without limitations to body surface area or the need to reapply and manage frequent topical therapy applications, upadacitinib provides patients with an alternative that can potentially stabilize their disease, provide repigmentation of the face and total body, improve health-related quality of life, and reduce psychosocial burden,” they added.
Looking beyond the endpoints
“As the first large global studies evaluating a systemic therapy for vitiligo, these [Viti-Up] trials mark a defining moment and a major shift from therapeutic scarcity to targeted innovation,” wrote Prof Viktoria Eleftheriadou from the Vitiligo Clinical and Research Centre for Children and Adults, New Cross Hospital, Royal Wolverhampton NHS Trust, Wolverhampton, UK, in a linked commentary. [Lancet 2026;408:580-581]
Eleftheriadou, however, questioned whether the degree of repigmentation achieved was clinically meaningful to patients. “Only around 13 percent to 15 percent of participants who were treated with upadacitinib in Viti-Up rated their vitiligo as ‘A lot less noticeable (4)’ or ‘No longer noticeable (5)’,” she said.
“Nevertheless, these findings should also be interpreted in the context of a 48-week treatment period, and it remains possible that longer treatment duration could yield greater repigmentation over time, considering that therapeutic response in vitiligo generally takes around 12 months or longer to reach satisfactory outcomes,” according to Eleftheriadou.
“Combination approaches might ultimately be required to optimize outcomes, as emerging evidence suggests that combining JAK inhibitor with phototherapy can result in faster and more substantial repigmentation,” she said.
Critical gaps in research
The Lancet, in an accompanying editorial, highlighted critical gaps in vitiligo research, including the Viti-Up trials, that must be addressed before new targeted therapies can achieve meaningful global impact. [Lancet 2026;408:577]
“To translate scientific progress into clinical benefit, dermatology must do more—to enrol the patients who reflect the full range of those affected [ie, those with darker skin for whom the disease is more visible, the contrast starker, and the stigma heavier] and to measure what has often gone unmeasured: stigma, comorbidity, and quality of life, alongside the long-term risks and financial toll for patients across their lifetime,” according to The Lancet.
“Otherwise, the field risks repeating a pattern seen in specialties such as oncology and rheumatology, where positive trials and regulatory-focused endpoints outpace meaningful, durable, and affordable benefits to patients,” they added.