While no definitive cure exists for vitiligo, treatments are available. Treatments for stabilizing rapidly progressive vitiligo include low-dose oral glucocorticoids and phototherapy. Therapeutic alternatives for managing stable, segmental vitiligo include topical therapies like topical corticosteroids and calcineurin inhibitors, targeted phototherapy, and surgical therapy such as tissue and cellular grafts.¹ Recently, many promising therapeutics have emerged, particularly small-molecule inhibitors that target intracellular signaling molecules and biologics that target cytokines.²

JAK inhibitors for vitiligo management

Two of the most prominent treatments target Janus-activated kinase (JAK) signaling.³ Tofacitinib, an FDA-cleared JAK1/3 inhibitor, is safest in its 2% topical form and has demonstrated a mean improvement of 70% in facial vitiligo area scoring index (VASI) when implemented alongside narrow-band ultraviolet B (NB-UVB) therapy.⁴

Ruxolitinib, a JAK1/2 inhibitor, became the first FDA-approved at-home treatment for nonsegmental vitiligo after its 1.5% cream demonstrated safety and effectiveness through 2 clinical trials—after 24 weeks, 30% of patients showcased 75% improvement in facial VASI with the main side effect being application-site acne, which disappeared after discontinuation of treatment.⁵

Stimulation of Wnt/β-catenin signaling as adjuvant therapy

The stimulation of Wnt/β-catenin signaling—which impacts the proliferation, migration, and differentiation of melanocytes—is being considered as an adjuvant therapy for vitiligo treatment.² Both microinjury⁶ and some phenanthridine-derived Wnt-specific agonists binding with the Axin protein⁷ have been shown to activate the Wnt/β-catenin signaling pathway and induce vitiligo repigmentation.

Targets for vitiligo therapy

Since studies suggest that microRNAs (miRNAs) affect gene expression in melanocytes and are associated with genetic polymorphism, immune response, oxidative stress, and melanocyte functions,⁸ miRNAs are targets for vitiligo therapy. Anti-miRNAs, locked-nucleic acids, or antagomiRs have the potential to neutralize the overactivation of miRNA. miRNA replacements that involve the reintroduction of a gene-suppressor miRNA mimic or adeno-associated virus-mediated miRNA gain-of-function can regulate gene expression.⁹

Regulatory T cells (Tregs), which can suppress self-reactive T cell activation and expansion, are another target because a clear lack of Tregs was observed in vitiligo skin.¹⁰ Increasing the number of Tregs through infusing purified populations of Tregs delays depigmentation in mice.¹¹ In addition, 0.1% topical rapamycin increases the abundance of Tregs and is currently being investigated in a phase 2 clinical trial.¹²

Monoclonal antibodies that target cytokines (IFN-γ, CXCL10, CXCR3, HSP70i, IL-15, IL-17/23, TNF) are now part of vitiligo treatment.² Inhibiting IFN-γ especially—the cytokine that impedes melanogenesis, induces melanocyte apoptosis, and recruits T cells to the skin—has been effective. Mice with vitiligo treated with an IFN-γ-neutralizing antibody (XMG-6) at a dose of 100 to 500 μg twice a week demonstrated significant improvements in depigmentation.¹³ Furthermore, 4 patients exhibited repigmentation of the treated area and boundary retreat after receiving intradermal perilesional XMG-6 injections.¹⁴

Looking ahead

With numerous clinical studies underway testing new JAK inhibitors and cytokine-targeted therapies such as IL-15 blockers, there is much to anticipate with emerging treatments to manage vitiligo.

References

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2. Feng Y, Lu Y. Advances in vitiligo: update on therapeutic targets. Front Immunol. 2022;13:986918. doi:10.3389/fimmu.2022.986918
3. Birlea SA, Costin GE, Roop DR, Norris DA. Trends in Regenerative Medicine: Repigmentation in Vitiligo Through Melanocyte Stem Cell Mobilization. Med Res Rev. 2017;37(4):907-935. doi:10.1002/med.21426
4. Mobasher P, Guerra R, Li SJ, Frangos J, Ganesan AK, Huang V. Open-label pilot study of tofacitinib 2% for the treatment of refractory vitiligo. Br J Dermatol. 2020;182(4):1047-1049. doi:10.1111/bjd.18606
5. 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. doi:10.1056/NEJMoa2118828
6. Han X, Chang L, Qiu Z, et al. Micro-injury induces hair regeneration and vitiligo repigmentation through Wnt/β-catenin pathway. Stem Cells Dev. 2022;31(5-6):111-118. doi:10.1089/scd.2021.0276
7. Yang BJ, Fan SR, Zhang XF, et al. Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new anti-vitiligo compounds. Bioorg Chem. 2022;119:105582. doi:10.1016/j.bioorg.2021.105582
8. Li L. The role of microRNAs in vitiligo: regulators and therapeutic targets. Ann Dermatol. 2020;32(6):441-451. doi:10.5021/ad.2020.32.6.441
9. Kwekkeboom RF, Lei Z, Doevendans PA, Musters RJ, Sluijter JP. Targeted delivery of miRNA therapeutics for cardiovascular diseases: opportunities and challenges. Clin Sci (Lond). 2014;127(6):351-365. doi:10.1042/CS20140005
10. Klarquist J, Denman CJ, Hernandez C, et al. Reduced skin homing by functional Treg in vitiligo [published correction appears in Pigment Cell Melanoma Res. 2010 Jun;23(3):477. Wainwright, Derek J [corrected to Wainwright, Derek A]]. Pigment Cell Melanoma Res. 2010;23(2):276-286. doi:10.1111/j.1755-148X.2010.00688.x
11. Mukhatayev Z, Dellacecca ER, Cosgrove C, et al. Antigen Specificity Enhances Disease Control by Tregs in Vitiligo. Front Immunol. 2020;11:581433. doi:10.3389/fimmu.2020.581433
12. Daily topical rapamycin for vitiligo. ClinicalTrials.gov identifier: NCT05342519. clinicaltrials.gov/ct2/show/NCT05342519. Updated August 4, 2022. Accessed June 21, 2023.
13. Harris JE, Harris TH, Weninger W, Wherry EJ, Hunter CA, Turka LA. A mouse model of vitiligo with focused epidermal depigmentation requires IFN-γ for autoreactive CD8⁺ T-cell accumulation in the skin. J Invest Dermatol. 2012;132(7):1869-1876. doi:10.1038/jid.2011.463
14. Skurkovich S, Skurkovich B, Kelly J. Anticytokine therapy, particularly anti-IFN-gamma, in Th1-mediated autoimmune diseases. Expert Rev Clin Immunol. 2005;1(1):11-25. doi:10.1586/1744666X.1.1.11