Povorcitinib

Vitiligo is a common, chronic, immune-mediated disorder characterized by progressive skin depigmentation, often associated with significant psychosocial burden and impaired quality of life. Therapeutic management remains challenging, with limited effective options available. Although topical corticosteroids, calcineurin inhibitors, and narrowband ultraviolet B (NB-UVB) phototherapy constitute the mainstays of treatment, many patients, particularly those with extensive or refractory disease, fail to achieve satisfactory or durable repigmentation. The clinical course is further complicated by high relapse rates and heterogeneous treatment responses across different anatomical sites. Recent advances in the understanding of vitiligo pathogenesis have identified the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway as a central driver of immune-mediated melanocyte destruction. This pathway is activated by key cytokines involved in vitiligo, including interferon gamma (IFN-γ), interleukin 15 (IL-15), among others, which sustain cytotoxic T cell infiltration and melanocyte apoptosis. As a result, JAK inhibitors have emerged as promising targeted therapies for vitiligo. Several topical and JAK inhibitors are currently under clinical investigation, with one topical agent, ruxolitinib cream, already approved for the treatment of vitiligo. Topical ruxolitinib, a JAK1/2 inhibitor, has demonstrated consistent and clinically meaningful repigmentation, particularly in facial lesions, and is already approved for use in both adolescents and adults. Among oral agents, ritlecitinib (a JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor), upadacitinib and povorcitinib (JAK1 inhibitors) have shown the most promising efficacy, either as monotherapy or in combination with NB-UVB phototherapy. Ongoing phase III trials are expected to further define their role in clinical practice. Other agents, including tofacitinib, baricitinib, abrocitinib, among others, are currently under investigation or being used off-label in clinical practice. JAK inhibitors exhibit variable safety profiles depending on selectivity, formulation, and dose. Topical agents are generally well tolerated with minimal systemic absorption, whereas oral JAK inhibitors require monitoring owing to potential risks of infection, hematologic abnormalities, and cardiovascular events. In this article, we review the current evidence on the efficacy and safety of topical and oral JAK inhibitors for vitiligo and contextualize their role within the broader landscape of emerging therapeutic strategies.