Targeting IL-1 controls refractory pityriasis rubra pilaris
Eloi Schmauch, Yannik Severin, Xianying Xing, Aaron R. Mangold, Curdin Conrad, Pål Johannsen, J. Michelle Kahlenberg, Mark Mellett, Alexander A. Navarini, Stefan Nobbe, Mrinal K. Sarkar, Abhigyan Satyam, Lam C. Tsoi, Lars E. French, Jakob Nilsson, Suvi Linna-Kuosmanen, Minna U. Kaikkonen, Berend Snijder, Manolis Kellis, Jóhann E. Guðjónsson, George C. Tsokos, Emmanuel Contassot, Antonios G.A. Kolios
Abstract
Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1β as a key mediator, orchestrating an NF-κB-mediated IL-1β-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1β. With the central role of IL-1β underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1β antagonists in PRP.