Advances in Janus Kinase Inhibitors for Vitiligo Treatment

Abstract

Vitiligo is a cutaneous autoimmune disease characterized by the destruction of epidermal melanocytes leading to white patches with a global prevalence of about 0.5–2%, and patients’ quality of life are greatly affected by the change in appearance and social discrimination caused by the disease. Most of the key cytokines in the pathogenesis of vitiligo act through the Janus kinase/signal transducer and activator of transcription signaling pathway, which is an effective therapeutic target. The first generation Janus kinase inhibitors, i.e., tofacitinib and ruxolitinib, inhibit a variety of Janus kinases, whereas the new generation Janus kinase inhibitors, such as ritlecitinib and upadacitinib, exhibit inhibitory effects only on specific Janus kinases; they are therefore selective as well as safer and more effective. In this review, we aim to provide an up-to-date view of vitiligo pathogenesis at the cellular, molecular, and genetic levels and further to elucidate the relationship between Janus kinase/signal transducer and activator of transcription signaling pathway components and vitiligo. Finally, we summarize currently market-approved and preclinical Janus kinase inhibitors, highlighting the latest advances in their clinical applications.

Keywords

JAK inhibitors - vitiligo - treatment - JAK/STAT signaling pathway - ruxolitinib - tofacitinib - baricitinib - peficitinib - delgocitinib - ritlecitinib - upadacitinib - abrocitinib - ifidancitinib - brepocitinib - cerdulatinib - deucravacitinib

Publication History

Received: 31 May 2025

Accepted after revision: 24 November 2025

Article published online:
05 February 2026

• References

• 1 Bergqvist C, Ezzedine K. Vitiligo: A Review. Dermatology 2020; 236 (06) 571-592
• 2 Montilla AM, Gómez-García F, Gómez-Arias PJ. et al. Scoping review on the use of drugs targeting JAK/STAT pathway in atopic dermatitis, vitiligo, and alopecia areata. Dermatol Ther 2019; 9: 4655-683
• 3 Sheikh A, Rafique W, Owais R, Malik F, Ali E. FDA approves Ruxolitinib (Opzelura) for Vitiligo Therapy: A breakthrough in the field of dermatology. Ann Med Surg 2022; 81
• 4 Liu J-B, Li M, Yang S. et al. Clinical profiles of vitiligo in China: an analysis of 3742 patients. Clin Exp Dermatol 2005; 30: 4327-331
• 5 Iannella G, Greco A, Didona D. et al. Vitiligo: pathogenesis, clinical variants and treatment approaches. Autoimmunity Rev 2016; 15: 4335-343
• 6 Bergqvist C, Ezzedine K. Vitiligo: a focus on pathogenesis and its therapeutic implications. J Dermatol 2021; 48 (03) 252-270
• 7 Barbulescu CC, Goldstein NB, Roop DR, Norris DA, Birlea SA. Harnessing the Power of Regenerative Therapy for Vitiligo and Alopecia Areata. J Investig Dermatol 2020; 140 (01) 29-37
• 8 Frisoli ML, Harris JE. Vitiligo: Mechanistic insights lead to novel treatments. J Allergy Clin Immunol 2017; 140: 3654-662
• 9 Pranić S, Pulumati A, Vuković D. Protocol for a systematic review and meta-analysis on janus kinase inhibitors in the management of vitiligo. Syst Rev 2024; 13 (01) 110
• 10 Frisoli ML, Essien K, Harris JE. Vitiligo: Mechanisms of Pathogenesis and Treatment. Annu Rev Immunol 2020; 38 (01) 621-648
• 11 Cunningham KN, Rosmarin D. Vitiligo treatments: review of current therapeutic modalities and JAK inhibitors. Am J Clin Dermatol 2023; 24 (02) 165186
• 12 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 (04) 453-461
• 13 Mosenson JA, Zloza A, Nieland JD. et al. Mutant HSP70 reverses autoimmune depigmentation in vitiligo. Sci Transl Med 2013; 5: 174
• 14 Chen X, Guo W, Chang Y. et al. Oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to CD8(+) T cells activation via JAK-STAT pathway in vitiligo. Free Radic Biol Med 2019; 139: 80-91
• 15 Scheid J, Cunningham-Bussel A, Kim N. et al. POS0899 FIRST-IN-HUMAN SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS DATA WITH MK-6194, A MODIFIED FORM OF INTERLEUKIN-2, DESIGNED TO SELECTIVELY ACTIVATE REGULATORY T-CELLS – SINGLE ASCENDING DOSE AND MULTIPLE ASCENDING DOSE TRIALS. Ann Rheumatic Dis 2024; 83: 1136-1137
• 16 Custurone P, Di Bartolomeo L, Irrera N. et al. Role of cytokines in vitiligo: pathogenesis and possible targets for old and new treatments. Int J Mol Sci 2021; 22 (21) 11429
• 17 Marchioro HZ, Silva De Castro CC, Fava VM, Sakiyama PH, Dellatorre G, Miot HA. Update on the pathogenesis of vitiligo. An Brasileiros de Dermatol 2022; 97 (04) 478-490
• 18 Martins C, Migayron L, Drullion C. et al. Vitiligo skin T cells are prone to produce type 1 and type 2 cytokines to induce melanocyte dysfunction and epidermal inflammatory response through jak signaling. J Investig Dermatol 2022; 142 (04) 1194-1205.e7
• 19 Yu T, Wu Y, Lu Z. Research progress of vitiligo repigmentation: from oxidative stress toautoimmunity. Cell Mol Biol 2024; 70 (04) 147-151
• 20 Rodrigues M, Ezzedine K, Hamzavi I, Pandya AG, Harris JE. New discoveries in the pathogenesis and classification of vitiligo. J Am Acad Dermatol 2017; 77: 11-13
• 21 Kovacs D, Bastonini E, Briganti S. et al. Altered epidermal proliferation, differentiation, and lipid composition: novel key elements in the vitiligo puzzle. Sci Adv 2022; 8: eabn9299
• 22 Boniface K, Jacquemin C, Darrigade A-S. et al. Vitiligo Skin Is Imprinted with Resident Memory CD8 T Cells Expressing CXCR3. J Investig Dermatol 2018; 138 (02) 355-364
• 23 Rashighi M, Harris JE. Interfering with the IFN-γ/CXCL10 pathway to develop new targeted treatments for vitiligo. Ann Transl Med 2015; 3 (21) 343
• 24 Aulakh S, Goel S, Kaur L. et al. Differential expression of serum CXCL9 and CXCL10 levels in vitiligo patients and their correlation with disease severity and stability: A cross-sectional study. Indian J Dermatol, Venereol Leprol 2024; 91: 1-7
• 25 Yamaguchi HL, Yamaguchi Y, Peeva E. Pathogenesis of alopecia areata and vitiligo: commonalities and differences. Int J Mol Sci 2024; 25 (08) 4409
• 26 Utama A, Wijesinghe R, Thng S. Janus kinase inhibitors and the changing landscape of vitiligo management: a scoping review. Int J Dermatol 2024; 63 (08) 1020-1035
• 27 Fridman JS, Scherle PA, Collins R. et al. Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation. J Investig Dermatol 2011; 131: 91838-1844
• 28 Shang L, Cao J, Zhao S, Zhang J, He Y. TYK2 in immune responses and treatment of psoriasis. J Inflamm Res 2022; 15: 5373-5385
• 29 Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther 2021; 6 (01) 402
• 30 Lin CM, Cooles FA, Isaacs JD. Basic mechanisms of JAK inhibition. Mediterr J Rheumatol 2020; 31: 100 (Suppl. 01)
• 31 Qi F, Liu F, Gao L. Janus Kinase Inhibitors in the Treatment of Vitiligo: A Review. Front Immunol 2021; 12: 790125
• 32 Dragotto M, D’Onghia M, Trovato E, Tognetti L, Rubegni P, Calabrese L. Therapeutic Potential of Targeting the JAK/STAT Pathway in Psoriasis: Focus on TYK2 Inhibition. J Clin Med 2024; 13 (11) 3091
• 33 Tanaka Y, Luo Y, O’Shea JJ, Nakayamada S. Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach. Nat Rev Rheumatol 2022; 18 (03) 133145
• 34 Gadina M. JAK inhibitors: is specificity at all relevant?. SemArthritis Rheumatism 2024; 64: 152327
• 35 Calabrese L, Chiricozzi A, De Simone C, Fossati B, D’Amore A, Peris K. Pharmacodynamics of janus kinase inhibitors for the treatment of atopic dermatitis. Expert Opin Drug Metab Toxicol 2022; 18 (05) 347-355
• 36 Damsky W, King BA. JAK inhibitors in dermatology: the promise of a new drug class. J Am Acad Dermatol 2017; 76 (04) 736-744
• 37 Smith P, Yao W, Shepard S. et al. Developing a JAK inhibitor for targeted local delivery: ruxolitinib cream. Pharmaceutics 2021; 13 (07) 1044
• 38 Rosmarin D, Passeron T, Pandya AG. et al. Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo. N Engl J Med 2022; 387 (16) 1445-1455
• 39 Hamzavi I, Rosmarin D, Harris JE. et al. Efficacy of ruxolitinib cream in vitiligo by patient characteristics and affected body areas: Descriptive subgroup analyses from a phase 2, randomized, double-blind trial. J Am Acad Dermatol 2022; 86 (06) 1398-1401
• 40 Kang C. Ruxolitinib Cream 1.5%: A Review in Non-Segmental Vitiligo. Drugs 2024; 84 (05) 579-586
• 41 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
• 42 Traynor K. FDA approves tofacitinib for rheumatoid arthritis. Am J Health Syst Pharm 2012; 69 (24) 2120-2120
• 43 Craiglow BG, King BA. Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. J Investig Dermatol 2014; 134 (12) 2988-2990
• 44 Xing L, Dai Z, Jabbari A. et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 2014; 20 (09) 1043-1049
• 45 Patel R, Pandya AG, Sikirica V. et al. Prevalence of vitiligo among children and adolescents in the United States. Dermatology 2023; 239 (02) 227-234
• 46 Das A, Chatterjee M. Tofacitinib 2% gel in childhood vitiligo: report of a case of significant improvement. Indian J Dermatol 2023; 68 (06) 705-706
• 47 Biswal A, Agrawal I, Panda M. Use of oral tofacitinib in the treatment of pediatric vitiligo: a case series. Indian J Dermatol 2024; 69 (04) 366
• 48 Liu LY, Strassner JP, Refat MA, Harris JE, King BA. Repigmentation in vitiligo using the janus kinase inhibitor tofacitinib may require concomitant light exposure. J Am Acad Dermatol 2017; 77 (04) 675-682.e1
• 49 Vu M, Heyes C, Robertson SJ, Varigos GA, Ross G. Oral tofacitinib: a promising treatment in atopic dermatitis, alopecia areata and vitiligo. Clin Exp Dermatol 2017; 42 (08) 942-944
• 50 O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013; 368 (02) 161-170
• 51 Mumford BP, Gibson A, Chong AH. Repigmentation of vitiligo with oral baricitinib. Australas J Dermatol 2020; 61 (04) 374-376
• 52 Dong J, Huang X, Ma L-P, Qi F. et al. Baricitinib is effective in treating progressing vitiligo in vivo and in vitro. Dose-Response 2022; 20 (02)
• 53 Li X, Sun Y, Du J, Wang F, Ding X. Excellent repigmentation of generalized vitiligo with oral baricitinib combined with NB-UVB phototherapy. Clin, Cosmetic Invest Dermatol 2023; 16: 635-638
• 54 Samuel C, Cornman H, Kambala A, Kwatra SG. A review on the safety of using JAK inhibitors in dermatology clinical and laboratory monitoring. Dermatol Ther 2023; 13 (03) 729-749
• 55 Doh JY, Rintarhat P, Jung WH, Kim HS. Truncal acne following JAK inhibitor use in vitiligo with rare opportunistic fungal infections: Two case reports. JAAD Case Rep 2023; 37: 123-127
• 56 Jin R, Zhou M, Lin F, Xu W, Xu A. Pathogenic Th2 Cytokine Profile Skewing by IFN-γ-Responding Vitiligo Fibroblasts via CCL2/CCL8. Cells 2023; 12 (02) 217
• 57 Yagi K, Ishida Y, Otsuka A, Kabashima K. Two cases of vitiligo vulgaris treated with topical janus kinase inhibitor delgocitinib. Australas J Dermatol 2021; 62 (03) 433-434
• 58 Ezzedine K, Peeva E, Yamaguchi Y. et al. Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: a randomized phase 2b clinical trial. J Am Acad Dermatol 2023; 88 (02) 395-403
• 59 Ehsan M, Rehman AU, Ayyan M. et al. Efficacy and safety of topical ruxolitinib cream for the treatment of vitiligo: a systematic review and meta-analysis of randomized controlled trials. J Cosmet Dermatol 2024; 23 (01) 350-353
• 60 Xu H, Jesson MI, Seneviratne UI. et al. PF-06651600, a dual JAK3/TEC family kinase inhibitor. ACS Chem Biol 2019; 14 (06) 1235-1242
• 61 Guttman-Yassky E, Del Duca E, Da Rosa JC. et al. Improvements in immune/melanocyte biomarkers with JAK3/TEC family kinase inhibitor ritlecitinib in vitiligo. J Allergy Clin Immunol 2024; 153 (01) 161-172.e8
• 62 Duggan S, Keam SJ. Upadacitinib: First Approval. Drugs 2019; 79 (16) 1819-1828
• 63 Su X, Luo R, Ruan S. et al. Efficacy and tolerability of oral upadacitinib monotherapy in patients with recalcitrant vitiligo. J Am Acad Dermatol 2023; 89 (06) 1257-1259
• 64 Mu Y, Pan T, Chen L. Treatment of refractory segmental vitiligo and alopecia areata in a child with upadacitinib and NB-UVB: a case report. Clin, Cosmet Invest Dermatol 2024; 17: 1789-1792
• 65 Ma R, Li Z, Tang H. et al. NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity. Nat Commun 2025; 16 (01) 989
• 66 Pan T, Mu Y, Shi X, Chen L. Concurrent vitiligo and atopic dermatitis successfully treated with upadacitinib: a case report. J Dermatol Treat 2023; 34 (01) 2200873
• 67 Clément F, Nougarède A, Combe S. et al. Therapeutic siRNAs Targeting the JAK/STAT Signalling Pathway in Inflammatory Bowel Diseases. J Crohn’s Colitis 2022; 16 (02) 286-300
• 68 Samaka RM, Basha MA, Menesy D. Role of janus kinase 1 and signal transducer and activator of transcription 3 in vitiligo. Clin, Cosmet Invest Dermatol 2019; 12: 469-480
• 69 Shan H, Yao S, Ye Y, Yu Q. 3-Deoxy-2β,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi, preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells. Acta Pharmacol Sin 2019; 40 (12) 1578-1586
• 70 Dong Z-y, He M-j, Yu Y-k. et al. Integrative genetics and multiomics analysis reveal mechanisms and therapeutic targets in vitiligo highlighting JAK STAT pathway regulation of CTSS. Sci Rep 2025; 15 (01) 2245