Pustular psoriasis: Molecular pathways and effects of spesolimab in generalized pustular psoriasis - 05/04/22
, Sudha Visvanathan, PhD b, Sandra Garcet, PhD c, Janine Roy, PhD d, Ramona Schmid, PhD a, Sebastian Bossert, PhD a, Benjamin Lang, MSc a, Hervé Bachelez, MD, PhD e, Robert Bissonnette, MD f, Christian Thoma, MD a, James G. Krueger, MD, PhD cAbstract |
Background |
The IL-36 pathway plays a key role in the pathogenesis of generalized pustular psoriasis (GPP). In a proof-of-concept clinical trial, treatment with spesolimab, an anti–IL-36 receptor antibody, resulted in rapid skin and pustular clearance in patients presenting with GPP flares.
Objective |
We sought to compare the molecular profiles of lesional and nonlesional skin from patients with GPP or palmoplantar pustulosis (PPP) with skin from healthy volunteers, and to investigate the molecular changes after spesolimab treatment in the skin and blood of patients with GPP flares.
Methods |
Pre- and post-treatment skin and blood samples were collected from patients with GPP who participated in a single-arm, phase I study (n = 7). Skin biopsies from patients with PPP (n = 8) and healthy volunteers (n = 16) were obtained for comparison at baseline. Biomarkers were assessed by RNA-sequencing, histopathology, and immunohistochemistry.
Results |
In GPP and PPP lesions, 1287 transcripts were commonly upregulated or downregulated. Selected transcripts from the IL-36 signaling pathway were upregulated in untreated GPP and PPP lesions. In patients with GPP, IL-36 pathway–related signatures, TH1/TH17 and innate inflammation signaling, neutrophilic mediators, and keratinocyte-driven inflammation pathways were downregulated by spesolimab as early as week 1. Spesolimab also decreased related serum biomarkers and cell populations in the skin lesions from patients with GPP, including CD3+ T, CD11c+, and IL-36γ+ cells and lipocalin-2–expressing cells.
Conclusions |
In patients with GPP, spesolimab showed rapid modulation of commonly dysregulated molecular pathways in GPP and PPP, which may be associated with improved clinical outcomes.
El texto completo de este artículo está disponible en PDF.Graphical abstract |
Key words : Spesolimab, BI 655130, biomarkers, IL-36, IL-36R, generalized pustular psoriasis, GPP, palmoplantar pustulosis, PPP
Abbreviations used : DEG, IHC, IL-36R, GPP, PPP, PV, RNA-seq, TNF
Esquema
| This study was funded by Boehringer Ingelheim. Agreements between Boehringer Ingelheim and the authors included confidentiality of the study data. All authors collaborated on the writing of the manuscript and have approved the final manuscript for publication. |
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| Disclosure of potential conflict of interest: P. Baum, R. Schmid, S. Bossert, and B. Lang are employees of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. C. Thoma is an employee of Boehringer Ingelheim International GmbH, Biberach, Germany. S. Visvanathan is an employee of Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Conn. J. Roy is an employee of Staburo GmbH, Munich, Germany, subcontracted by Boehringer Ingelheim for statistical and bioinformatics services. H. Bachelez reports paid consulting activities for AbbVie, Almirall, Biocad, Boehringer Ingelheim, Celgene, Janssen, Kyowa Kirin, LEO Pharma, Lilly, Mylan, Novartis, and UCB, and grant support from Boehringer Ingelheim, Janssen, LEO Pharma, Novartis, and Pfizer. R. Bissonnette reports being an advisory board member, consultant, speaker and/or investigator for, and received honoraria and/or grants from, AbbVie, Almirall, AnaptysBio, Arcutis Biotherapeutics, Aristea Therapeutics, Bausch Health/Valeant, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Dermavant, Eli Lilly, Escalier Biosciences, Janssen, Kineta, Kyowa Kirin, LEO Pharma, Pfizer, Regeneron Pharmaceuticals, Sienna Biopharmaceuticals, and UCB; and is also an employee and shareholder of Innovaderm Research, Montreal, Quebec, Canada. J. G. Krueger reports receiving grants from, and being an investigator for, Boehringer Ingelheim; personal fees from AbbVie, Baxter, Biogen Idec, Delenex Therapeutics, Kineta, Sanofi, Serono, and XenoPort; and grants from Amgen, Bristol Myers Squibb, Dermira, Innovaderm Research, Janssen, Kadmon, Kyowa Hakko Kirin, Eli Lilly, Merck, Novartis, Parexel, and Pfizer. S. Garcet declares no relevant conflicts of interest. |
Vol 149 - N° 4
P. 1402-1412 - avril 2022 Regresar al número
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