Targeting IL-1 controls refractory pityriasis rubra pilaris

• Published in: Science advances 2024-07, Vol.10 (27), p.eado2365
• Main Authors: Schmauch, Eloi, Severin, Yannik, Xing, Xianying, Mangold, Aaron, Conrad, Curdin, Johannsen, Pål, Kahlenberg, J Michelle, Mellett, Mark, Navarini, Alexander, Nobbe, Stefan, Sarkar, Mrinal K, Satyam, Abhigyan, Tsoi, Lam C, French, Lars E, Nilsson, Jakob, Linna-Kuosmanen, Suvi, Kaikkonen, Minna U, Snijder, Berend, Kellis, Manolis, Gudjonsson, Johann E, Tsokos, George C, Contassot, Emmanuel, Kolios, Antonios G A
• Format: Article
• Language: English
• Subjects: Adult; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Biomedicine and Life Sciences; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - metabolism; Female; Guanylate Cyclase - antagonists & inhibitors; Guanylate Cyclase - genetics; Guanylate Cyclase - metabolism; Humans; Immunology; Interleukin 1 Receptor Antagonist Protein - therapeutic use; Interleukin-1 - antagonists & inhibitors; Interleukin-1 - genetics; Interleukin-1 - metabolism; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - metabolism; Keratinocytes - drug effects; Keratinocytes - metabolism; Keratinocytes - pathology; Male; Membrane Proteins; Middle Aged; NF-kappa B - metabolism; Nod2 Signaling Adaptor Protein - antagonists & inhibitors; Nod2 Signaling Adaptor Protein - genetics; Nod2 Signaling Adaptor Protein - metabolism; Pityriasis Rubra Pilaris - drug therapy; Pityriasis Rubra Pilaris - genetics; Pityriasis Rubra Pilaris - pathology; SciAdv r-articles; Signal Transduction - drug effects; Skin - drug effects; Skin - metabolism; Skin - pathology
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.ado2365

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.