Baricitinib-associated changes in global gene expression during a 24-week phase II clinical systemic lupus erythematosus trial implicates a mechanism of action through multiple immune-related pathways.

Autor:	Dörner T; DRFZ Berlin and Department of Rheumatology and Clinical Immunology, Charite University Hospital Berlin, Berlin, Germany thomas.doerner@charite.de., Tanaka Y; The First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu, Japan., Petri MA; Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Smolen JS; Division of Rheumatology, Medical University of Vienna, Wien, Austria., Wallace DJ; Department of Rheumatology, Cedars-Sinai Medical Center, West Hollywood, California, USA., Dow ER; Eli Lilly and Company, Indianapolis, Indiana, USA., Higgs RE; Eli Lilly and Company, Indianapolis, Indiana, USA., Rocha G; Eli Lilly and Company, Indianapolis, Indiana, USA., Crowe B; Eli Lilly and Company, Indianapolis, Indiana, USA., Benschop RJ; Eli Lilly and Company, Indianapolis, Indiana, USA., Byers NL; Eli Lilly and Company, Indianapolis, Indiana, USA., Silk ME; Eli Lilly and Company, Indianapolis, Indiana, USA., de Bono S; Eli Lilly and Company, Indianapolis, Indiana, USA., Fantini D; Eli Lilly and Company, Indianapolis, Indiana, USA., Hoffman RW; Eli Lilly and Company, Indianapolis, Indiana, USA.
Jazyk:	angličtina
Zdroj:	Lupus science & medicine [Lupus Sci Med] 2020 Oct; Vol. 7 (1).
DOI:	10.1136/lupus-2020-000424
Abstrakt:	Objective: To characterise the molecular pathways impacted by the pharmacologic effects of the Janus kinase (JAK) 1 and JAK2 inhibitor baricitinib in SLE. Methods: In a phase II, 24-week, randomised, placebo-controlled, double-blind study (JAHH), RNA was isolated from whole blood in 274 patients and analysed using Affymetrix HTA2.0 array. Serum cytokines were measured using ultrasensitive quantitative assays. Results: Gene expression profiling demonstrated an elevation of STAT1 , STAT2 and multiple interferon (IFN) responsive genes at baseline in patients with SLE. Statistical and gene network analyses demonstrated that baricitinib treatment reduced the mRNA expression of functionally interconnected genes involved in SLE including STAT1 -target, STAT2 -target and STAT4- target genes and multiple IFN responsive genes. At baseline, serum cytokines IFN-α, IFN-γ, interleukin (IL)-12p40 and IL-6 were measurable and elevated above healthy controls. Treatment with baricitinib significantly decreased serum IL-12p40 and IL-6 cytokine levels at week 12, which persisted through week 24. Conclusion: Baricitinib treatment induced significant reduction in the RNA expression of a network of genes associated with the JAK/STAT pathway, cytokine signalling and SLE pathogenesis. Baricitinib consistently reduced serum levels of two key cytokines implicated in SLE pathogenesis, IL-12p40 and IL-6. Competing Interests: Competing interests: TD has received grant support from Chugai, Janssen, Novartis and Sanofi. He has received consultancy support from AbbVie, Celgene, Eli Lilly and Company, Janssen, Novartis, Roche, Samsung and UCB, and speaker bureau fees from Eli Lilly and Company and Roche. YT has received grant support from AbbVie, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, Taisho-Toyama and Takeda. He has received speaker bureau fees from AbbVie, Asahi-kasei, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly and Company, GSK, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, Takeda, UCB and YL Biologics. MP has received consultancy support from Eli Lilly and Company. JS has received grant support from AbbVie, Eli Lilly and Company, Janssen, MSD, Novartis, Pfizer and Roche. He has received consultancy support from AbbVie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Eli Lilly and Company, Gilead, ILTOO, Janssen, Medimmune, MSD, Novartis, Pfizer, Roche, Samsung, Sanofi and UCB. DJW has received consulting support from Amgen, Eli Lilly and Company, EMD Merck Serono and Pfizer. ERD, REH, GR, BC, RJB, NLB, MES, SdB and RWH are employees and stockholders of Eli Lilly and Company. (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu