Article Text
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-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.
- cytokines
- lupus erythematosus
- systemic
- therapeutics
- autoimmune diseases
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Footnotes
DF and RWH contributed equally.
Contributors All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. TD had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: RJB, ERD, REH, RWH, MAP, MES and YT. Acquisition of data: ERD, RWH and MES. Analysis and interpretation of data: all authors. The authors would also like to thank Adam G Abel for his contribution on the interferon signature assay.
Funding This study and writing support were funded by Eli Lilly and Company.
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.
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