High-dimensional cutaneous and systemic immunophenotyping of prurigo nodularis reveals dysregulation of IL-6 family cytokine signaling

Summary: Abstract Body: Prurigo Nodularis (PN) is a chronic inflammatory skin disease characterized by severe pruritus and hyperkeratotic nodules. The role of IL-4, IL-13, and IL-31 emerged in PN, but the involvement of other cytokines in its pathogenesis is unclear. Furthermore, disease endotypes and heterogeneous therapeutic responses highlight the need to investigate immune dysregulation in PN. This study compared the circulating blood immune cells and cytokine profiles between PN patients (n=66; 44% female, 32% African American, severe itch (mean NRS >8/10), mean age 53) and healthy controls (HC) (n=21; 27% female, 14% African American, mean age 49). Immune infiltration and cytokine production were analyzed using flow cytometry (20 markers), plasma cytokine assays, and cutaneous lesional skin analysis via immunohistochemistry and imaging mass cytometry. Monocytes producing IL-6+TNF+ (p<0.0001) and TNF+ (p<0.0001) were elevated in PN vs. HC. M1 macrophages in PN exhibited increased IL-6 (p<0.0001) and IL-6+TNF+ (p<0.001), and plasma IL-6 (p<0.01) and TNF-α (p<0.008) were also higher. Skin biopsies from PN patients showed greater monocyte and M1 macrophage infiltration compared to HC. CD4+ T cells in PN expressed higher IL-31 (p<0.01), OSM (p<0.001), IFN-γ (p<0.05), TNF (p<0.05), and IL-17 (p<0.01). African American patients had higher CD4+ T cells producing IL-31 (p<0.01), TNF (p<0.05), and IL-17 (p<0.01) than Caucasians, contributing to worse outcomes. Dupilumab non-responders showed significantly higher CD4+IL-31+ expression (p<0.01) than responders. These findings highlight the roles of monocytes, M1 macrophages, and IL-6 family cytokines in PN pathogenesis. Targeting these components may improve treatment for various disease endotypes utilizing a precision medicine approach. Kavita Vats¹, Kevin Lee¹, Shahin Shahsavari¹, Louis J. Born¹, Yagiz M. Akiska¹, Davies Gage¹, Thomas Pritchard¹, Madan M. Kwatra^{2, 3}, Shawn Kwatra¹ 1. Department of Dermatology, University of Maryland Baltimore School of Medicine, Baltimore, MD, United States. 2. Department of Anesthesiology, Duke University School of Medicine, Durham, NC, United States. 3. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, United States. Translational Studies: Cell and Molecular Biology