ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1039

Molecular Profiling Identifies Immunologic Subgroups and Informs Mechanism of Action of Baricitinib in SLE

Thomas Dörner1, Yoshiya Tanaka 2, Michelle Petri 3, Josef Smolen 4, Daniel Wallace 5, Ernst Dow 6, Damiano Fantini 6, Richard Higgs 6, Guilherme Rocha 6, Brenda Crowe 6, Robert Benschop 6, Adam Abel 6, Nicole Byers 6, Maria Silk 6, Stephanie de Bono 6 and Robert Hoffman 6, 1Charite Universitätsmedizin Berlin and DRFZ, Berlin, Germany, 2University of Occupational and Environmental Health Japan, Kitakyushu, Japan, 3Johns Hopkins University School of Medicine, Baltimore, MD, 4Medical University of Vienna, Vienna, Austria, 5Cedars-Sinai Medical Center/University California at Los Angeles, Los Angeles, CA, 6Eli Lilly and Company, Indianapolis, IN

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: , , ,

Session Information

Date: Monday, November 11, 2019

Title: SLE – Etiology & Pathogenesis Poster I

Session Type: Poster Session (Monday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Baricitinib is an oral selective Janus kinase (JAK) 1 and JAK2 inhibitor. In the Phase II, 24-week, randomized, placebo-controlled, double-blind study JAHH (NCT02708095), once-daily baricitinib resulted in significant clinical improvements in patients with active SLE receiving standard background therapy, compared with placebo.1 We characterized the molecular and cellular immune pathways impacted by baricitinib in SLE.

Methods: A total of 314 patients were randomized 1:1:1 to receive once-daily placebo, baricitinib 2-mg, or baricitinib 4-mg for 24 weeks in study JAHH. Patients were 18 years of age or older, had a diagnosis of SLE, and had active disease involving skin or joints. Whole blood samples were obtained from patients in JAHH at baseline and weeks 2, 4, 12, and 24, and cellular and serologic immune biomarkers were measured using flow cytometry and immunochemistry assays. RNA was isolated from whole blood and analyzed using Affymetrix HTA2.0 array and quantitative PCR. Data were summarized to transcript level and analyzed using a mixed effects model on a log2 transformed response with multiplicity correction. Clinical and immunologic characteristics were compared between subgroups defined using molecular profiling.

Results: At baseline, the IFN signature negatively correlated with complement (C) 3 and C4, and positively correlated with serum immunoglobulin (Ig) G, anti-dsDNA, anti-Sm, anti-RNP, anti-Ro 52/SSA, anti-Ro 60/SSA, and anti-La/SSB in patients with active SLE. These correlations constituted a distinctive subgroup, or endotype. Serum autoantibodies and complement were not altered by baricitinib treatment, suggesting that the mechanism of action of baricitinib in SLE may be primarily through an anti-inflammatory effect. Gene expression profiling demonstrated that there was an elevation of STAT1, STAT2, and multiple IFN responsive genes at baseline in patients with SLE. Statistical and gene network analysis demonstrated that baricitinib treatment reduced the expression of functionally interconnected genes involved in SLE including STAT1, STAT2, and STAT4, and multiple IFN responsive genes (Figure).

Conclusion: Baricitinib treatment reduced the expression of STAT1, STAT2, and IFN responsive genes in patients with SLE. Gene network analysis revealed that baricitinib treatment reduced the expression of a network of genes associated with JAK/STAT pathways, cytokine signaling, and SLE pathogenesis, suggesting that baricitinib effects may be mediated through pharmacologic impact on multiple immune pathways.

 

1Wallace DJ et al. Lancet. 2018;392:222-231.

Gene network analysis of genes changed based on baricitinib’s inhibition of JAK1 and JAK2 signaling and the most significantly baricitinib-induced changed genes, regardless of mechanism. The analysis includes genes changed with baricitinib 4-mg at week 12 compared with placebo. The genes included were identified by two methods: 1- the 50 genes most significantly changed with baricitinib-treatment and 2- genes that interact with JAK1 or JAK2 via transcriptional regulation or phosphorylation as defined by the curated MetaBase -www.clarivate.com- database and had an adjusted P value < 0.05. In order to graphically show the interactions, these genes, along with STAT1, STAT2, JAK1, JAK2, and TYK2 were queried against the known interactions in MetaBase, and kinases -green-, ligands/receptors -yellow-, and transcription factors -red- with known interactions were connected and displayed using cytoscape -cytoscape.org-; genes that were not directly connected to this network or were in other categories are not shown.

Disclosure: T. Dörner, AbbVie, 5, Celgene, 5, Eli Lilly and Company, 5, 8, GSK, 2, Janssen, 2, 5, Novartis, 2, 5, Novartis Pharma AG, 5, Roche, 5, 8, Samsung, 5, 8, Sanofi, 2, UCB, 5, UCB Pharma, 2, 5; Y. Tanaka, Abbvie, 8, AbbVie, 5, 8, Asahi-kasei, 2, Asahi-Kasei, 2, Asahi-kasei, BMS, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Ono, Pfizer, Sanofi, Takeda, UCB, 2, Astellas, 8, Astellas Pharma, 9, Astellas Pharma, Inc., 2, 3, 5, 8, 9, Astellas, BMS, Chugai, Daiichi-Sankyo, Eli Lilly, Janssen, Mitsubishi-Tanabe, Pfizer, Sanofic, UCB, YL Biologics, 8, BMS, 2, 5, 8, Bristol-Myers, 2, 8, Bristol-Myers Squibb, 2, 8, Chugai, 2, 8, Daiichi-Sankyo, 2, 8, Daiichi-Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, Abbvie, Pfizer, YL Biologics, Bristol-Myers, 8, Eisai, 2, 8, Eli Lilly, 5, 8, Eli Lilly and Company, 8, Genzyme, 5, Glaxo-Smithkline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, Asahi-kasei, 8, Janssen, 8, Mitsubishi-Tanabe, 2, 8, Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, Abbvie, Astellas, Daiichi-Sankyo, Ono, MSD, Taisho-Toyama., 2, Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie, Eisai, 2, Novartis, 8, Ono, 2, Pfizer, 5, 8, Pfizer Inc, 8, Roche, 5, Sanofi, 2, Takeda, 2, 8, Teijin, 8, UCB, 2, YL Biologics, 8; M. Petri, Eli Lilly and Company, 5, Exagen, 2, 5; J. Smolen, AbbVie, 2, 5, 8, Abbvie, 2, 5, Amgen, 5, 8, AstraZeneca, 2, 5, 8, Astra-Zeneca, 5, Astro, 5, 8, BMS, 5, Celgene, 5, 8, Celltrion, 5, Celtrion, 5, 8, Chugai, 5, Eli Lilly and Company, 2, 5, Gilead, 5, GlaxoSmithKline, 5, 8, ILTOO, 5, 8, ILTOO Janssen, 5, Janssen, 2, 5, 8, Lilly, 2, 5, 8, Medimmune, 5, 8, MSD, 2, 5, 8, Novartis, 2, 5, Novartis- Sandoz, 5, Novartis-Sandoz, 2, 5, 8, Pfizer, 2, 5, 8, Pfizer Inc, 5, Roche, 2, 5, Roche;, 2, 5, 8, Samsung, 5, 8, Sanofi, 5, 8, Sanofi-Aventis, 5, UCB, 5, 8; D. Wallace, Amgen, 5, 9, Eli Lilly and Co, 9, Eli Lilly and Company, 5, EMD Merck Serono, 5, EMD Serono, 9, Pfizer, 5, 9; E. Dow, Eli Lilly and Company, 1, 3; D. Fantini, Eli Lilly and Company, 1, 3; R. Higgs, Eli Lilly and Company, 1, 3; G. Rocha, Eli Lilly and Company, 1, 3; B. Crowe, Eli Lilly and Company, 1, 3; R. Benschop, Eli Lilly and Company, 1, 3; A. Abel, Eli Lilly and Company, 1, 3; N. Byers, Eli Lilly and Company, 1, 3; M. Silk, Eli Lilly and Company, 1, 3; S. de Bono, Eli Lilly and Company, 1, 3; R. Hoffman, Eli Lilly and Company, 1, 3.

To cite this abstract in AMA style:

Dörner T, Tanaka Y, Petri M, Smolen J, Wallace D, Dow E, Fantini D, Higgs R, Rocha G, Crowe B, Benschop R, Abel A, Byers N, Silk M, de Bono S, Hoffman R. Molecular Profiling Identifies Immunologic Subgroups and Informs Mechanism of Action of Baricitinib in SLE [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/molecular-profiling-identifies-immunologic-subgroups-and-informs-mechanism-of-action-of-baricitinib-in-sle/. Accessed .

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