The role of JAK inhibitors in dermatology: Focus on vitiligo and atopic dermatitis

Vitiligo

Clinical and economic burden

Vitiligo is a chronic autoimmune depigmenting disorder characterized by immune-mediated destruction of melanocytes, resulting in well-demarcated patches of depigmented skin.¹ The condition is believed to arise from complex interactions between genetic susceptibility and immune dysregulation, with T cell-mediated responses targeting melanocytes. Vitiligo affects approximately 0.5% to 1% of the global population, and patients commonly notice signs before the age of 30 years.² In many patients, the condition persists throughout life, although it may follow a variable course characterized by periods of stability and progression.^1,3

Although vitiligo is not life-threatening, it is associated with a substantial psychosocial burden.³ Because depigmented lesions frequently occur on visible areas such as the face, hands and arms, patients may experience stigmatization, social discomfort and diminished self-esteem. These challenges can contribute to anxiety, depression and overall impairment in quality of life. A 2018 meta-analysis confirmed that patients with vitiligo have a nearly five-fold higher likelihood of developing depression compared to controls (OR, 4.96).⁴

Vitiligo also contributes to healthcare usage and economic burden. Many patients require ongoing dermatology visits, long-term pharmacologic treatment and cosmetic approaches to manage the appearance of lesions. These needs can lead to both direct medical costs and indirect costs associated with reduced work and school productivity. In a retrospective claims database analysis, patients with vitiligo incurred substantially higher medical costs compared with matched controls, with significantly greater all-cause healthcare expenditures (+$7,816) and vitiligo-specific costs (+$3,436), reflecting a meaningful increase in overall healthcare burden (all p-value < 0.0001).⁵ From a therapeutic standpoint, historically available treatment (including topical corticosteroids, topical calcineurin inhibitors and phototherapy) provide varied and often limited efficacy with inconsistent repigmentation and relapse following treatment discontinuation.^3,6 These limitations underscore the need for more effective targeted therapies that can address the underlying immune mechanisms that drive the disease.

Rationale for JAK inhibition in vitiligo

The pathogenesis of vitiligo is closely linked to immune pathways driven by interferon-gamma (IFN-γ), which plays a central role in initiating and sustaining melanocyte destruction.⁷ In vitiligo, IFN-γ signaling activates the JAK-STAT pathway within keratinocytes and immune cells. This activation leads to the production of inflammatory chemokines, including CXCL10, which promote the recruitment and retention of autoreactive CD8+ T cells in the skin. These cytotoxic T cells target and destroy melanocytes, resulting in the characteristic depigmented lesions observed in patients with vitiligo.⁷

Inhibition of the JAK-STAT signaling pathway offers a targeted strategy to interrupt this pathogenic cascade.⁷ By blocking JAK-mediated cytokine signaling, JAK inhibitors reduce downstream production of chemokines induced by IFN-γ, thereby limiting the recruitment of melanocyte-directed T cells to affected skin. Through this mechanism, JAK inhibition may help halt ongoing immune-mediated melanocyte destruction while creating a more favorable environment for melanocyte survival and repopulation. This dual effect — suppressing pathogenic immune activity while supporting repigmentation — provides a strong mechanistic rationale for the use of JAK inhibitors as targeted therapies in vitiligo.

Clinical trial data with ruxolitinib cream

Ruxolitinib cream, 1.5%, is a topical JAK1/JAK2 inhibitor and the first FDA-approved treatment for patients with nonsegmental vitiligo.⁸ In 2022, this approval was supported by results from the phase 3 TRuE-V1 (NCT04052425) and TRuE-V2 (NCT04057573) trials, which collectively enrolled 674 adolescents and adults with nonsegmental vitiligo.⁹ These randomized, double-blind studies evaluated the efficacy and safety of twice-daily ruxolitinib cream, 1.5%, compared with vehicle in patients with depigmented facial lesions. Treatment with ruxolitinib cream demonstrated clinically meaningful repigmentation. At week 24, approximately 30% of treated patients achieved at least a 75% improvement in the Facial Vitiligo Area Scoring Index (F-VASI75) compared with significantly lower response rates in the vehicle group. Continued therapy led to further improvements over time, with roughly half of patients achieving F-VASI75 by week 52. The treatment was generally well tolerated, with the most commonly reported side effects in the TRuE-V1 and TRuE-V2 trials including acne (6.3% and 6.6%, respectively), nasopharyngitis (5.4% and 6.1%) and application-site reactions (5.3% and 5.4%).

Durable repigmentation with ruxolitinib cream: 104-week TRuE-V pooled analysis

Long-term extension data from the phase 3 TRuE-V program provide important insights into the durability of response with ruxolitinib cream in patients with nonsegmental vitiligo.¹⁰ Pooled analyses evaluating outcomes through 104 weeks of continuous treatment demonstrated that repigmentation not only persisted but continued to improve over time.¹⁰

By week 104, clinically meaningful repigmentation outcomes were observed across multiple efficacy end points.¹⁰ Some 72.7% of patients achieved at least a F-VASI75, while 44.1% achieved near-complete facial repigmentation (at least 90% improvement in the F-VASI [F-VASI90]). In addition, 66.5% of patients experienced at least a 50% improvement in Total VASI (T-VASI50). Ruxolitinib cream was well tolerated, with COVID-19 infection (16.9%), nasopharyngitis (8.8%) and acne (7%) the most commonly reported side effects.¹⁰ Collectively, these results suggest that continued treatment with ruxolitinib cream may lead to incremental and durable repigmentation, reinforcing the role of long-term topical JAK inhibition as a disease-modifying approach in vitiligo management.

High repigmentation thresholds in patients with more extensive or progressive disease

Subgroup analyses from the phase 3 TRuE-V1 and TRuE-V2 trials evaluated the efficacy of ruxolitinib cream in patients with more extensive and/or progressive nonsegmental vitiligo.¹¹ These analyses assessed treatment outcomes across disease activity, including a broad range of progressive phenotypes. Patients treated with ruxolitinib cream achieved clinically meaningful repigmentation across diverse subgroups, indicating consistent treatment effects regardless of underlying disease heterogeneity.¹

Notably, approximately 50% of patients who received continuous treatment — even those with more challenging disease profiles — achieved at least a F-VASI75 by week 52.¹¹ These findings suggest that topical JAK inhibition may be effective across a broad spectrum of patients, including those who might not be candidates for systemic therapy.

Clinical trial data with upadacitinib

Upadacitinib is an oral, selective JAK1 inhibitor that has demonstrated robust efficacy and an acceptable safety profile across multiple immune-mediated diseases.¹² It is approved in numerous countries to treat conditions including atopic dermatitis (AD), rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis and non-radiographic axial spondyloarthritis.¹² Upadacitinib is being actively investigated as a systemic treatment option for patients with more extensive vitiligo.¹²

Early-phase clinical data support its potential efficacy in this setting.¹² In a phase 2 randomized trial evaluating multiple dose levels (NCT04927975), percent change from baseline in F-VASI at week 24 (the primary end point) was achieved for the groups given 11 or 22 milligrams (mg) of upadacitinib but not for those given a 6-mg dose.¹² Similar trends were also observed for total-body involvement. Continued therapy was associated with progressive repigmentation through 52 weeks, suggesting that sustained JAK1 inhibition may provide ongoing clinical benefit over time. More recently, topline results from the phase 3 Viti-Up trials (NCT06118411) further supported the efficacy of upadacitinib in adolescents and adults with vitiligo.¹³ In two replicate phase 3 clinical studies, patients given upadacitinib achieved a T-VASI50 and an F-VASI75 at week 48 versus the placebo group. Upadacitinib demonstrated a safety profile consistent with approved indications with no new safety signals; the most common side effects were upper respiratory tract infection, acne and nasopharyngitis.

In addition, emerging evidence suggests that combination approaches, such as using oral upadacitinib with topical ruxolitinib, may enhance repigmentation outcomes and help stabilize disease progression.¹⁴ These findings highlight the evolving role of JAK inhibition, both as monotherapy and in combination strategies, in managing vitiligo.

Atopic Dermatitis

Disease overview and burden

AD is a chronic, relapsing inflammatory skin disorder characterized by intense pruritus, inflamed lesions and recurrent disease flares.¹⁵ The pathogenesis of AD is multifactorial, involving complex interactions between immune dysregulation and impairment of the epidermal barrier.¹⁵ Dysregulated inflammatory signaling — driven by cytokines such as interleukin (IL)-4, IL-13 and other mediators — contributes to cutaneous inflammation and pruritus, while defects in barrier proteins and skin integrity increase susceptibility to environmental triggers and microbial colonization.¹⁵ Together, these processes promote the chronic, fluctuating disease course that is typical of AD.

AD is among the most common inflammatory skin conditions worldwide.¹⁶ The disease affects up to 20% of children and 10% of adults in high-income countries.⁶ Many cases begin in early childhood, yet a substantial proportion of patients continue to experience persistent or recurrent symptoms into adolescence and adulthood.⁶ In some individuals, the disease may also first be noted in adults.¹⁶

Beyond the physical manifestations of the disease, AD is associated with significant impairment in quality of life.¹⁷ Persistent pruritus frequently leads to sleep disruption, fatigue and difficulty concentrating, which can affect academic performance, work productivity and daily functioning.⁷ Patients with moderate to severe disease may also experience psychosocial challenges. A systematic literature review estimated a prevalence of depression of up to 57% and of anxiety of up to 64% in patients with AD.¹⁷ These factors underscore the broad impact of AD that extends beyond dermatologic symptoms alone.

From the healthcare perspective, AD imposes a considerable economic burden. Patients with moderate to severe disease often require frequent medical visits to dermatologists, primary care practitioners, allergists or other medical specialists.¹⁷ These recurring encounters contribute to elevated direct healthcare costs over time. In addition to medical expenditures, AD is linked to meaningful productivity losses, with the literature reporting an average of 68.8 days lost annually due to absenteeism and presenteeism in patients with AD.¹⁷ Decreases in productivity were proportionally related to increasing severity of disease; patients with severe disease lost an average of 26.5 days due to absenteeism and of 92.5 days due to presenteeism. For managed care stakeholders, understanding of the clinical and economic burden of AD is essential when evaluating emerging therapeutic options, including targeted agents such as JAK inhibitors.

Targeted treatment landscape

Traditional management of AD has centered on topical anti-inflammatory therapies and supportive skin care. Common first-line treatments include topical corticosteroids and topical calcineurin inhibitors, with phototherapy sometimes used for patients with more extensive disease.¹⁸ These approaches can be effective for patients with mild disease, but many individuals with moderate to severe AD experience persistent symptoms or frequent flares despite topical therapy and therefore require escalation to systemic treatment.¹⁸

Advances in understanding of AD immunopathology have led to the development of targeted therapies that address key inflammatory pathways underlying disease activity.¹⁸ These include biologic agents that inhibit IL-4 and IL-13 signaling and oral small-molecule JAK inhibitors that disrupt intracellular cytokine signaling involved in type 2 inflammation. By modulating these pathways, targeted therapies reduce cutaneous inflammation, support restoration of skin barrier function and improve symptoms such as pruritus, with some agents demonstrating rapid relief of itch.¹⁵

Role of JAK inhibitors

Oral JAK inhibitors (e.g., upadacitinib, abrocitinib and baricitinib) and the topical JAK inhibitor ruxolitinib inhibit intracellular signaling through the JAK-STAT pathway, which mediates the activity of multiple cytokines implicated in AD pathogenesis, providing a broad mechanism of immune modulation.¹⁸ Clinical trials evaluating these agents in patients with moderate to severe AD have demonstrated significant improvements in disease activity and symptom burden. Treatment with JAK inhibitors has been associated with rapid reductions in pruritus and meaningful improvements in validated measures of eczema severity that are often observed within the first several weeks of therapy.¹⁹ As a result, JAK inhibitors provide an additional systemic treatment option for patients whose disease remains inadequately controlled with topical therapies or who require an alternative to biologic treatments, expanding the therapeutic landscape for moderate to severe AD management.

JAK inhibitor clinical trials in atopic dermatitis

A growing body of clinical evidence supports the use of JAK inhibitors in managing AD.¹⁹ Multiple clinical trials evaluating both oral and topical JAK inhibitors have demonstrated significant improvements in disease severity and symptom burden, ultimately supporting regulatory approvals for these therapies in patients with AD. These studies have helped establish JAK inhibition as a targeted therapeutic strategy that addresses key inflammatory pathways involved in AD pathogenesis.

Ruxolitinib cream was approved by the FDA for the treatment of AD in 2021.¹⁸ Its approval was supported by the phase 3 TRuE-AD1 (NCT03745638) and TRuE-AD2 (NCT03745651) trials in adolescents and adults with mild to moderate disease.²⁰ In these randomized, double-blind studies, ruxolitinib demonstrated higher rates of Investigator’s Global Assessment treatment success (IGA-TS) compared with vehicle at week 8, with more than 50% of patients in the ruxolitinib cream, 1.5%, arm experiencing IGA-TS. Patients treated with ruxolitinib also experienced clinically meaningful reductions in pruritus, with rapid improvements in itch reported during treatment.The therapy was generally well tolerated, and the most frequently reported side effects were mild application-site reactions (0.8%).²⁰

Oral JAK inhibitors have also demonstrated robust efficacy in patients with AD.¹⁹ Approval of upadacitinib for moderate to severe AD was supported by phase 3 trials including Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422) and AD Up (NCT03568318).²¹ Across these studies, once-daily upadacitinib resulted in significantly higher rates of skin clearance and meeting of itch improvement end points compared with placebo, with more than 80% of patients achieving a 75% reduction in Eczema Area and Severity Index score (EASI 75) at 140 weeks. Notably, many patients reported rapid improvements in pruritus within the first week of therapy.

Similarly, the oral JAK1 inhibitor abrocitinib was approved by the FDA in 2022 for moderate to severe AD based on findings from trials including JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871) and JADE COMPARE (NCT03720470) trials, which demonstrated significant improvements in skin lesion severity and itch compared with placebo.^19,22 Abrocitinib also showed strong efficacy when used in combination with topical therapies, further supporting the role of JAK inhibition as an effective treatment option for patients whose disease remains inadequately controlled with conventional topical therapies or biologic agents.^22,23

In summary, clinical trials of JAK inhibitors in AD have consistently demonstrated rapid and robust efficacy across key clinical end points, including improvements in eczema severity (e.g., EASI-75 and IGA) and early reductions in pruritus, often within the first weeks of treatment. Oral agents such as upadacitinib and abrocitinib and the topical formulation ruxolitinib have shown clinically meaningful benefits acrossdiverse patient populations with generally manageable safety profiles. For managed care stakeholders, JAK inhibitors introduce additional considerations related to positioning within treatment algorithms, balancing clinical benefits with safety monitoring requirements and the overall cost of care.

References

1. Renert-Yuval Y, Ezzedine K, Grimes P, et al. Expert recommendations on use of topical therapeutics for vitiligo in pediatric, adolescent, and young adult patients. JAMA Dermatol. 2024;160(4):453-461. doi:10.1001/jamadermatol.2024.0021

2. Ezzedine K, Eleftheriadou V, Whitton M, van Geel N. Vitiligo. Lancet. 2015;386(9988):74-84. doi:10.1016/S0140-6736(14)60763-7

3. Bergqvist C, Ezzedine K. Vitiligo: a review. Dermatology. 2020;236(6):571-592. doi:10.1159/000506103

4. Wang G, Qiu D, Yang H, et al. The prevalence and odds of depression in patients with vitiligo: a meta-analysis. J Eur Acad Dermatol Venereol. 2018;32(8):1343-1351. doi:10.1111/jdv.14739

5.Ezzedine K, Soliman AM, Li C, Camp HS, Pandya AG. Economic burden among patients with vitiligo in the United States: a retrospective database claims study. J Invest Dermatol. 2024;144(3):540-546.e1. doi:10.1016/j.jid.2023.08.025

6. Cavalié M, Ezzedine K, Fontas E, et al. Maintenance therapy of adult vitiligo with 0.1% tacrolimus ointment: a randomized, double blind, placebo-controlled study. J Invest Dermatol. 2015;135(4):970-974. doi:10.1038/jid.2014.527

7.Strassner JP, Harris JE. Understanding mechanisms of autoimmunity through translational research in vitiligo. Curr Opin Immunol. 2016;43:81-88. doi:10.1016/j.coi.2016.09.008

8.Cunningham KN, Rosmarin D. Vitiligo treatments: review of current therapeutic modalities and JAK inhibitors. Am J Clin Dermatol. 2023;24(2):165-186. doi:10.1007/s40257-022-00752-6

9.Rosmarin D, Passeron T, Pandya AG, et al; for the 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

10.Rosmarin D, Sebastian M, Lynde C, et al. Durable repigmentation with ruxolitinib cream in patients with progressive vitiligo: pooled subgroup analysis from the 104-week TRuE-V phase 3 studies. Poster presented at: Maui Derm Hawaii 2026 Annual Meeting; January 25-29, 2026; Maui, HI. Incyte Medical Information. Accessed April 6, 2006. https://www.incytemi.com/document/Poster/Maui%20Derm%202026_Rosmarin_TRuE-V%20Durable%20Repigmentation%20in%20Patients%20with%20Progressive%20Disease.pdf

11. Desai SR, Sturm D, McMichael AJ, Diza X, Ren H, Rosmarin D. Patients with more extensive and/or progressive vitiligo enrolled in TRuE-V1/TRuE-V2 achieved high repigmentation thresholds with ruxolitinib cream. Poster presented at: Maui Derm Hawaii 2026 Annual Meeting; January 25-29, 2026; Maui, HI. Incyte Medical Information. Accessed April 6, 2026. https://www.incytemi.com/document/Poster/Maui%20Derm%202026_Desai_TRuE-V%20High%20Repigmentation%20Thresholds%20in%20Patients%20with%20Progressive%20Disease.pdf

12. 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

13. AbbVie announces positive topline results from phase 3 pivotal studies evaluating upadacitinib (RINVOQ) in adults and adolescents with vitiligo. Press release. AbbVie. October 29, 2025. Accessed March 12, 2026. https://news.abbvie.com/2025-10-29-AbbVie-Announces-Positive-Topline-Results-from-Phase-3-Pivotal-Studies-Evaluating-Upadacitinib-RINVOQ-R-in-Adults-and-Adolescents-with-Vitiligo

14. 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

15. Biliński K, Rakoczy K, Karwowska A, et al. Anti-inflammatory therapies for atopic dermatitis: a new era in targeted treatment. J Clin Med. 2025;14(14):5053. doi:10.3390/jcm14145053

16. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet. 2020;396(10247):345-360. doi:10.1016/S0140-6736(20)31286-1

17. Fasseeh AN, Elezbawy B, Korra N, et al. Burden of atopic dermatitis in adults and adolescents: a systematic literature review. Dermatol Ther (Heidelb). 2022;12(12):2653-2668. doi:10.1007/s13555-022-00819-6

18. Lee HW, Ju YJ, Choi S, Rhew K, Serafin Sevilleno S, Choi MS. Atopic dermatitis management: from conventional therapies to biomarker-driven treatment approaches. Biomol Ther (Seoul). 2025;33(5):813-829. doi:10.4062/biomolther.2025.081

19. Nakashima C, Yanagihara S, Otsuka A. Innovation in the treatment of atopic dermatitis: emerging topical and oral Janus kinase inhibitors. Allergol Int. 2022;71(1):40-46. doi:10.1016/j.alit.2021.10.004

20.Owji S, Caldas SA, Ungar B. Management of atopic dermatitis: clinical utility of ruxolitinib. J Asthma Allergy. 2022;15:1527-1537. doi:10.2147/JAA.S342051

21. Irvine AD, Prajapati VH, Guttman-Yassky E, et al. Efficacy and safety of upadacitinib in patients with moderate-to-severe atopic dermatitis: phase 3 randomized clinical trial results through 140 weeks. Am J Clin Dermatol. 2025;26(6):1003-1016. doi:10.1007/s40257-025-00975-3

22. Gooderham MJ, de Bruin-Weller M, Weidinger S, et al. Practical management of the JAK1 inhibitor abrocitinib for atopic dermatitis in clinical practice: special safety considerations. Dermatol Ther (Heidelb). 2024;14(8):2285-2296. doi:10.1007/s13555-024-01200-5

23. Dogra S, Shah S, Gupta M, Sharma A, Chhabra S. Abrocitinib: a comprehensive review of its efficacy and safety in dermatology. Indian Dermatol Online J. 2024;15(6):930-941. doi:10.4103/idoj.idoj_449_24