Lam C Tsoi1, Feriel Hacini-Rachinel2, Paul Fogel2, Francois Rousseau2, Xianying Xing3, Matthew T Patrick3, Allison C Billi3, Celine C Berthier4, J Michelle Kahlenberg5, Anne Lazzari2, Henning Wiegmann6, Sonja Ständer6, Christophe Piketty2, Valerie Julia2, Jayendra Kumar Krishnaswamy2, Johann E Gudjonsson7. 1. Department of Dermatology, University of Michigan, Ann Arbor, Mich; Department of Biostatistics, University of Michigan, Ann Arbor, Mich; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Mich. 2. Galderma, La Tour-De-Peilz, Switzerland. 3. Department of Dermatology, University of Michigan, Ann Arbor, Mich. 4. Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Mich. 5. Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Mich; Taubman Medical Research Institute, University of Michigan Medical School, Ann Arbor, Mich. 6. Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Münster, Germany. 7. Department of Dermatology, University of Michigan, Ann Arbor, Mich; Taubman Medical Research Institute, University of Michigan Medical School, Ann Arbor, Mich. Electronic address: johanng@umich.edu.
Abstract
BACKGROUND: Prurigo nodularis (PN) is a debilitating, difficult-to-treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between sensory nerve fibers, immune cells, and the epidermis. It is centered around the neuroimmune cytokine IL-31, driving an intractable itch-scratch cycle. OBJECTIVE: We sought to provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti-IL-31 receptor inhibitor nemolizumab. METHOD: RNA sequencing of biopsy samples obtained from a cohort of patients treated with the anti-IL-31 receptor inhibitor nemolizumab and taken at baseline and week 12. Generation and integration of patient data with RNA-Seq data generated from reconstructed human epidermis stimulated with IL-31 and other proinflammatory cytokines. RESULTS: Our results demonstrate that nemolizumab effectively decreases IL-31 responses in PN skin, leading to effective suppression of downstream inflammatory responses including TH2/IL-13 and TH17/IL-17 responses. This is accompanied by decreased keratinocyte proliferation and normalization of epidermal differentiation and function. Furthermore, our results demonstrate how transcriptomic changes associated with nemolizumab treatment correlate with improvement in lesions, pruritus, stabilization of extracellular matrix remodeling, and processes associated with cutaneous nerve function. CONCLUSION: These data demonstrate a broad response to IL-31 receptor inhibition with nemolizumab and confirm the critical upstream role of IL-31 in PN pathogenesis.
BACKGROUND: Prurigo nodularis (PN) is a debilitating, difficult-to-treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between sensory nerve fibers, immune cells, and the epidermis. It is centered around the neuroimmune cytokine IL-31, driving an intractable itch-scratch cycle. OBJECTIVE: We sought to provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti-IL-31 receptor inhibitor nemolizumab. METHOD: RNA sequencing of biopsy samples obtained from a cohort of patients treated with the anti-IL-31 receptor inhibitor nemolizumab and taken at baseline and week 12. Generation and integration of patient data with RNA-Seq data generated from reconstructed human epidermis stimulated with IL-31 and other proinflammatory cytokines. RESULTS: Our results demonstrate that nemolizumab effectively decreases IL-31 responses in PN skin, leading to effective suppression of downstream inflammatory responses including TH2/IL-13 and TH17/IL-17 responses. This is accompanied by decreased keratinocyte proliferation and normalization of epidermal differentiation and function. Furthermore, our results demonstrate how transcriptomic changes associated with nemolizumab treatment correlate with improvement in lesions, pruritus, stabilization of extracellular matrix remodeling, and processes associated with cutaneous nerve function. CONCLUSION: These data demonstrate a broad response to IL-31 receptor inhibition with nemolizumab and confirm the critical upstream role of IL-31 in PN pathogenesis.
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