Targeting IL-1 controls refractory pityriasis rubra pilaris-Reference-Cited by-同舟云学术

Targeting IL-1 controls refractory pityriasis rubra pilaris

Published:2024-07-05 Issue:27 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Schmauch Eloi¹²³^ORCID,Severin Yannik⁴^ORCID,Xing Xianying⁵^ORCID,Mangold Aaron⁶^ORCID,Conrad Curdin⁷^ORCID,Johannsen Pål⁸^ORCID,Kahlenberg J. Michelle⁵^ORCID,Mellett Mark⁸^ORCID,Navarini Alexander⁹^ORCID,Nobbe Stefan⁸¹⁰^ORCID,Sarkar Mrinal K.⁵^ORCID,Satyam Abhigyan¹¹^ORCID,Tsoi Lam C.⁵^ORCID,French Lars E.¹²¹³^ORCID,Nilsson Jakob¹⁴^ORCID,Linna-Kuosmanen Suvi¹³^ORCID,Kaikkonen Minna U.³^ORCID,Snijder Berend⁴^ORCID,Kellis Manolis¹²^ORCID,Gudjonsson Johann E.⁵¹⁵^ORCID,Tsokos George C.¹¹^ORCID,Contassot Emmanuel⁹^ORCID,Kolios Antonios G. A.⁸¹¹¹⁶^ORCID

Affiliation:

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.ado2365

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