Targeting IL-1 controls refractory pityriasis rubra pilaris

Eloi Schmauch; Yannik Severin; Xianying Xing; Aaron Mangold; Curdin Conrad; Pål Johannsen; J Michelle Kahlenberg; Mark Mellett; Alexander 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; Johann E Gudjonsson; George C Tsokos; Emmanuel Contassot; Antonios G A Kolios

doi:10.1126/sciadv.ado2365

Targeting IL-1 controls refractory pityriasis rubra pilaris

Sci Adv. 2024 Jul 5;10(27):eado2365. doi: 10.1126/sciadv.ado2365. Epub 2024 Jul 3.

Authors

Eloi Schmauch^{1

2

3}, Yannik Severin⁴, Xianying Xing⁵, Aaron Mangold⁶, Curdin Conrad⁷, Pål Johannsen⁸, J Michelle Kahlenberg⁵, Mark Mellett⁸, Alexander Navarini⁹, Stefan Nobbe^{8

10}, Mrinal K Sarkar⁵, Abhigyan Satyam¹¹, Lam C Tsoi⁵, Lars E French^{12

13}, Jakob Nilsson¹⁴, Suvi Linna-Kuosmanen^{1

3}, Minna U Kaikkonen³, Berend Snijder⁴, Manolis Kellis^{1

2}, Johann E Gudjonsson^{5

15}, George C Tsokos¹¹, Emmanuel Contassot⁹, Antonios G A Kolios^{8

11

16}

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
⁴ Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, 8049 Zurich, Switzerland.
⁵ Departments of Internal Medicine and Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Department of Dermatology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
⁷ Department of Dermatology, CHUV University Hospital and University of Lausanne (UNIL), Lausanne, Switzerland.
⁸ Department of Dermatology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.
⁹ Department of Biomedicine and Dermatology Department, University Hospital of Basel, Basel, Switzerland.
¹⁰ Department of Dermatology, Cantonal Hospital Frauenfeld, Frauenfeld, Switzerland.
¹¹ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
¹² Department of Dermatology and Allergology, Ludwig Maximilian University of Munich, Munich, Germany.
¹³ Dr. Philip Frost, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA.
¹⁴ Department of Immunology, University Hospital Zurich, Zurich, Switzerland.
¹⁵ Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁶ University of Zurich, Zurich, Switzerland.

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.

MeSH terms

Adult
Antibodies, Monoclonal, Humanized* / pharmacology
Antibodies, Monoclonal, Humanized* / therapeutic use
CARD Signaling Adaptor Proteins / genetics
CARD Signaling Adaptor Proteins / metabolism
Female
Guanylate Cyclase / antagonists & inhibitors
Guanylate Cyclase / genetics
Guanylate Cyclase / metabolism
Humans
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
Signal Transduction / drug effects
Skin / drug effects
Skin / metabolism
Skin / pathology

Substances

Interleukin-1beta
Interleukin 1 Receptor Antagonist Protein
Antibodies, Monoclonal, Humanized
canakinumab
CARD14 protein, human
NF-kappa B
Nod2 Signaling Adaptor Protein
CARD Signaling Adaptor Proteins
Interleukin-1
IL1B protein, human
Guanylate Cyclase
Membrane Proteins