{
  "abstract": "Objective Patients with systemic lupus erythematosus (SLE) commonly develop lupus nephritis (LN), the most frequent severe organ manifestation of this systemic autoimmune disease. Using serum and urine samples from a phase 2 trial in LN, we investigated that how the LN metabolome is modulated in response to type I interferon receptor blockade with anifrolumab, an approved treatment for moderate to severe SLE.Methods Patients in TULIP-LN ( NCT02547922) received standard therapy plus intravenous anifrolumab or placebo. Untargeted metabolomics analysis was performed on serum and urine samples from 128 and 119 patients, respectively. Metabolites impacted by anifrolumab and their associations with clinical, serological and kidney measures of LN disease activity were examined. An in vitro model was used to validate the impact of anifrolumab on metabolite-induced inflammation.Results In serum, indoxyl sulfate (IS) and cytosine were the metabolites most modulated by anifrolumab, while baseline levels correlated with measures of kidney damage. In urine, uracil and cytosine were the most modulated by anifrolumab and levels of these metabolites were associated with serological markers of disease activity. Anifrolumab reduced markers of vascular dysfunction and inflammation upregulated by IS in in vitro models. Baseline urine uracil levels predicted response to anifrolumab intensive regimen at Week 52.Conclusion Our findings establish a connection between type I interferon signalling, pyrimidine metabolism and uremic toxins in patients with LN and support the evaluation of urine uracil as a potential biomarker of response to anifrolumab.",
  "authors": [
    {
      "affiliations": [
        "Translational Science and Experimental Medicine, Early Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA"
      ],
      "name": "Patrick G Gavin"
    },
    {
      "affiliations": [
        "Dynamic Omics, Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA"
      ],
      "name": "Erik L Allman"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, UK"
      ],
      "name": "David Jayne"
    },
    {
      "affiliations": [
        "Organización Médica de Investigación, Buenos Aires, Argentina"
      ],
      "name": "Eduardo Mysler"
    },
    {
      "affiliations": [
        "French National Reference Center for SLE, Hôpital La Pitié-Salpêtrière, Sorbonne University, Paris, France"
      ],
      "name": "Zahir Amoura"
    },
    {
      "affiliations": [
        "Dynamic Omics, Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA"
      ],
      "name": "Cristina Di Poto"
    },
    {
      "affiliations": [
        "Dynamic Omics, Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA"
      ],
      "name": "Xiang Tian"
    },
    {
      "affiliations": [
        "Dynamic Omics, Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA"
      ],
      "name": "Sonja Hess"
    },
    {
      "affiliations": [
        "Translational Science and Experimental Medicine, Early Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK"
      ],
      "name": "Eszter Csomor"
    },
    {
      "affiliations": [
        "Translational Science and Experimental Medicine, Early Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA"
      ],
      "name": "Philip Z Brohawn"
    },
    {
      "affiliations": [
        "Translational Science and Experimental Medicine, Early Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden"
      ],
      "name": "Daniel Muthas"
    },
    {
      "affiliations": [
        "Translational Science and Experimental Medicine, Early Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK"
      ],
      "name": "Adam Platt"
    },
    {
      "affiliations": [
        "Late Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK"
      ],
      "name": "Consuelo Anzillotti"
    },
    {
      "affiliations": [
        "Bioscience Renal, Early Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK"
      ],
      "name": "Heena Stone"
    },
    {
      "affiliations": [
        "Bioscience Renal, Early Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK"
      ],
      "name": "Asha Seth"
    },
    {
      "affiliations": [
        "Bioscience Renal, Early Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK"
      ],
      "name": "Kevin Woollard"
    },
    {
      "affiliations": [
        "Late Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK"
      ],
      "name": "Hussein Al-Mossawi"
    },
    {
      "affiliations": [
        "Late Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden"
      ],
      "name": "Catharina Lindholm"
    },
    {
      "affiliations": [
        "Translational Science and Experimental Medicine, Early Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK"
      ],
      "name": "Nicola Ferrari"
    }
  ],
  "title": "Metabolomic profiling of patients with lupus nephritis reveals unique metabolites that are modulated through type I interferon inhibition by anifrolumab treatment in a phase 2 trial",
  "uid": "6c618437-0ae0-55ca-b075-8ee9daedbd1e"
}