Dual JAK Inhibition Demonstrates Efficacy in Progressive Nonsegmental Vitiligo

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A recent study highlighted the potential of combining oral upadacitinib with topical ruxolitinib cream as a safe and effective therapeutic strategy for patients with progressive nonsegmental vitiligo (NSV). The findings, published in JAAD International, suggest that this dual Janus kinase (JAK) inhibition approach may offer superior repigmentation outcomes compared to existing monotherapies and demonstrate a potent ability to halt disease progression.1

“JAK inhibitors could potentially be a promising therapeutic approach,” according to the authors, who highlight that ruxolitinib cream and oral upadacitinib have separately demonstrated repigmentation activity in prior clinical trials.

Vitiligo is driven in part by interferon gamma activation of the JAK/STAT pathway, making JAK inhibition an area of significant therapeutic interest. Ruxolitinib cream, a selective JAK1/2 inhibitor, is already FDA-approved for NSV, while the oral JAK1 inhibitor upadacitinib has shown efficacy in recent phase 2 studies.2 Investigators evaluated whether dual JAK inhibition could improve outcomes in patients with progressive NSV who are at risk for ongoing pigment loss.1

The single-center trial enrolled 30 patients aged 13 to 60 years with progressive NSV. Participants received oral upadacitinib 15 mg once daily plus 1.5% ruxolitinib cream applied twice daily for 24 weeks. Disease severity was assessed using the Total Vitiligo Area Severity Index (T-VASI) and Facial VASI (F-VASI), along with area-specific measures for extremities and trunk. The results demonstrated a statistically significant improvement in vitiligo severity scores over the course of the study period. The baseline total VASI averaged 2.35 (range, 1-6.65) and decreased to 1.57 (range, 0.57-6.33) at week 12 (P < .0001) and to 1.27 (range, 0.46-6.12) at week 24 (P < .0001). By week 24, one patient achieved T-VASI90, indicating a 90% improvement in total body repigmentation, while 2 patients achieved T-VASI75, and 6 patients achieved T-VASI50.

Facial vitiligo, a highly visible and impactful manifestation of the disease, also showed significant improvement. Among 27 patients with facial vitiligo, the F-VASI at baseline was 0.2 (0.1-0.5) and decreased to 0.135 (0.05-0.27) at week 12 (P < .0001) and 0.1 (0.01-0.20) at week 24 (P < .0001).This represented an average improvement of 36.66% and 56.17%, respectively. Furthermore, at week 24, eight patients achieved F-VASI90, 10 patients achieved F-VASI75, and 15 patients achieved F-VASI50.

Beyond the face, significant improvements were also observed in other challenging areas, including the hands, feet, and trunk. Extremity VASI scores improved significantly in 28 patients (P = .0009 at week 12; P = .0005 at week 24), and trunk scores improved in 24 patients (P < .0001 at week 24). Twenty patients demonstrated significant improvement in their extremities at both 12 weeks (P = .0009) and 24 weeks (P = .0005).

Treatment was generally well tolerated. Four patients (13.3%) reported mild adverse events (AE), with no serious AEs identified. Routine monitoring of liver and kidney function, as well as lipid profiles, did not reveal any clinically meaningful changes over the 24-week period.

Investigators noted that the combination of upadacitinib and ruxolitinib achieved higher repigmentation rates than prior monotherapy trials, with T-VASI50 at 20% and F-VASI75 at 33%, outperforming the phase 2 upadacitinib (11.6% and 19.1%) and phase 3 ruxolitinib cream (29.8% and 30.9%) trials.2,3 This suggests a synergistic effect of the two agents when used in combination.

The introduction of JAK inhibitors has reshaped treatment options for vitiligo, a disease with historically limited options. The current findings highlight the potential of targeted combination approaches to improve repigmentation outcomes in patients with active disease. This research adds momentum for future trials and supports further evaluation of JAK inhibition, particularly in progressive nonsegmental vitiligo that does not respond adequately to monotherapy or standard treatments.

References

  1. Li W, Gao J, Huang H, et al. Efficacy and safety of oral upadacitinib-topical ruxolitinib combination therapy in the treatment of progressive nonsegmental vitiligo. JAAD Int. 2025;22:16-19. doi:10.1016/j.jdin.2025.04.014
  2. Passeron T, Ezzedine K, Hamzavi I, et al. Once-daily upadacitinib versus placebo in adults with extensive non-segmental vitiligo: a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study. EClinicalMedicine. 2024;73:102655. doi:10.1016/j.eclinm.2024.102655
  3. Rosmarin D, Passeron T, Pandya AG, et al; TRuE-V Study Group. Two phase 3, randomized, controlled trials of ruxolitinib cream for vitiligo. N Engl J Med. 2022;387(16):1445-1455. doi:10.1056/NEJMoa2118828

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