34004 Topical ruxolitinib blocks interferon gamma signaling in cutaneous lichen planus

Abstract

Lichen planus (LP) is a chronic inflammatory condition characterized by well-marginated, violaceous, polygonal, pruritic papules and plaques. In the pathogenesis of LP, interferon gamma (IFNG) primes keratinocytes for CD8+ T-cell-mediated cytotoxicity through Janus kinase (JAK)-2/STAT1 signaling. Ruxolitinib selectively inhibits JAK1 and JAK2. We conducted whole transcriptomic analysis on lesional LP (n = 19) and control (n = 10) tissue at baseline, and on responsive (n = 13) and refractory (n = 5) lesional tissue after treatment with ruxolitinib. Our transcriptomic data confirms type I and II IFNs as critical signaling molecules in cutaneous LP. Reactome pathway enrichment analysis identified additional upregulation of cellular regulators of immune response, and phagocytosis. IFNG was elevated at baseline in disease samples and did not change following treatment. Fifty-two interferon stimulated genes (ISGs) were elevated in disease compared with control tissue. Treatment responsive tissue showed reversal of expression patterns of 12 ISGs (TRIM45, IRF9, TRIM14, HLA-DQB1, OAS2, OAS1, GBP1, OAS3, PTAFR, IRF7, OASL, and TRIM17). STAT1, a critical signaling protein in LP and target of topical ruxolitinib, was downregulated in responsive disease post-treatment. Type I MHCs (HLA-A, B, C), whose expression is regulated by pSTAT1 on keratinocytes, were upregulated at pre-treatment and were downregulated in treatment responsive tissue. Taken together, these findings suggest that ruxolitinib abrogated cytotoxic T-cell responses and augmented anti-apoptotic signaling, resulting in the high response rate and rapid improvement that we observed clinically.