Improvements in immune/melanocyte biomarkers with JAK3/TEC family kinase inhibitor ritlecitinib in vitiligo

Background Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated. Objective This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with non-segmental vitiligo (NSV). Methods 65 adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n=14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n=13), 100/50 mg (n=12), 50 mg (n=11), 30 mg (n=8), or 10 mg (n=6). Skin (lesional and nonlesional) biopsies were taken at baseline, 4, and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular/cellular biomarkers were evaluated by RNA-seq/RT-qPCR/proteomics/flow cytometry. Results Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared with baseline and/or placebo. Significant reductions were seen in CD3+/CD8+ T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50-mg ritlecitinib groups (both P<0.05). There was significant, dose-dependent downregulation in T-cell activation/NK/cytotoxic/regulatory markers in lesional skin (IL-2/IL2-RA/IL-15/CCR7/CD5/ CRTAM/NCR1/XCL1/KIR3DL1/FASLG/KLRD; P<0.05). Th1 and Th2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P<0.05). Changes in immune biomarkers correlated with clinical response. Conclusion Ritlecitinib significantly downregulated pro-inflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response.