@article{598c256cb5f441b08e989b6d7a730404,
title = "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",
abstract = "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- 3, 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.",
keywords = "autoimmune diseases, cytokines, lupus erythematosus, systemic, therapeutics",
author = "Thomas D{\"o}rner and Yoshiya Tanaka and Petri, {Michelle A.} and Smolen, {Josef S.} and Wallace, {Daniel J.} and Dow, {Ernst R.} and Higgs, {Richard E.} and Guilherme Rocha and Brenda Crowe and Benschop, {Robert J.} and Byers, {Nicole L.} and Silk, {Maria E.} and {De Bono}, Stephanie and Damiano Fantini and Hoffman, {Robert W.}",
note = "Funding Information: 5Department of Rheumatology, Cedars-Sinai Medical Center, West Hollywood, California, USA 6Eli Lilly and Company, Indianapolis, Indiana, USA Acknowledgements The authors would like to thank the patients and investigators who participated in the study, in addition to Julie Sherman, of Eli Lilly and Company, for assisting with figure development. The authors would also like to thank Adam G. Abel for his contribution on the interferon signature assay. Writing assistance was provided by Katie Crosslin, PhD, of Evidera/PPD, which was funded by Eli Lilly and Company. This work in part has been presented at the following scientific conferences: the 2019 American College of Rheumatology Annual meeting (D{\"o}rner et al, Arthritis Rheumatol. 2019;71 (suppl 10): https:// acrabstracts.org/abstract/molecular-profiling-identifies-immunologic-subgroups-and-informs-mechanism-of-action-of-baricitinib-in-sle/) and the European League Against Rheumatism 2020 Annual Meeting (D{\"o}rner et al., Ann Rheum Dis. 2020;79 (supplement 1): https://congress.eular.org/myUploadData/files/eular_2020_ abstracts_final.pdfhttps://congress.eular.org/myUploadData/files/eular_2020_ abstracts_final.pdfhttps://congress.eular.org/myUploadData/files/eular_2020_ abstracts_final.pdf, page 29). Funding Information: Funding This study and writing support were funded by Eli Lilly and Company. Funding Information: 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. Patient consent for publication Not required. Ethics approval This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by the ethics committee or institutional review board used at each centre. All patients and control subjects provided written informed consent. Full details of the JAHH clinical trial have been published in Wallace et al., 2018. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available in a public, open access repository. Deidentified data will be deposited in GEO. Publisher Copyright: {\textcopyright} ",
year = "2020",
month = oct,
day = "9",
doi = "10.1136/lupus-2020-000424",
language = "English (US)",
volume = "7",
journal = "Lupus Science and Medicine",
issn = "2053-8790",
publisher = "BMJ Publishing Group",
number = "1",
}