Beyond Janus kinases: Targeted Cytokine and Kinase Modulators for Refractory Vitiligo

ABSTRACT Background Refractory vitiligo encompasses disease unresponsive to conventional medical therapies and phototherapy, presenting a significant clinical challenge. Treatment resistance stems from multiple interconnected mechanisms. While JAK inhibitors represented a paradigm shift by targeting interferon‐γ‐driven pathophysiology, substantial limitations persist. This review aims to evaluate emerging therapeutic strategies beyond JAK inhibitors that address the multifaceted pathophysiology of refractory vitiligo. Methods This review covers a broad range of studies, including in vitro and in vivo research, with a focus on therapeutic advancements beyond JAK inhibitors for refractory vitiligo. Results Strategic targeting of immune memory through IL‐15/CD122 blockade, chemokine pathways via CXCL10 and CXCR3 antagonism, epigenetic regulation through BET protein inhibition, and melanocyte regeneration via mTOR modulation, prostaglandin therapy, melanocortin receptor activation, and Wnt pathway agonists represents a paradigm shift from single‐pathway interventions. While most of these novel agents remain in preclinical or early‐phase clinical trials, their mechanistically diverse approaches collectively offer a comprehensive therapeutic framework that addresses both persistent immune‐mediated melanocyte destruction and regenerative insufficiency. Conclusions Among emerging therapies, IL‐15/CD122 blockade shows particular promise by targeting tissue‐resident memory T cells to potentially achieve durable repigmentation. Concurrently, afamelanotide, now in Phase III trials, offers a complementary regenerative approach by stimulating melanocyte proliferation through melanocortin receptor activation. Together, these mechanistically distinct strategies may overcome the immune memory and stem cell depletion that characterizes treatment‐refractory disease. These advances offer exciting new possibilities for patients with refractory vitiligo.