{
  "abstract": "Objectives ANA-positive people with non-specific symptoms are at risk of SLE. We aimed to validate interferon (IFN) scores as a biomarker of imminent SLE and analyse a wider range of gene expression scores as well as a cell-specific flow cytometric IFN marker longitudinally to investigate pathogenesis.Methods 176 patients with ANA and new non-specific symptoms were recruited. Progression was defined by 2019 EULAR/ACR SLE criteria. PBMCs were isolated for RNA extraction and flow cytometry analysis. Expression of transcriptomic scores known to be associated with SLE (IFN Score A, IFN Score B, Myeloid, Inflammation, Erythropoiesis and Plasmablast Scores) were calculated using a 96-gene TaqMan array. Cellular abundance and median fluorescence intensity (MFI) of the cell-specific IFN biomarker tetherin (CD317) was measured by flow cytometry gating for B cells, memory B cells, plasmablasts, T cells and monocytes. We compared the odds ratio for progression to SLE utilizing logistic regression models.Results Clinical and demographic variables did not differ between progressors and non-progressors at baseline. In multivariable logistic regression adjusting by age, gender, and ethnicity, IFN Score A (OR=1.507, p-value=0.048) and proportion of memory B cells (OR=0.158, p-value=0.046) were associated with progression. Plasmablast Score was associated with progression in univariable logistic regression (OR=1.698, p-value=0.046). Analysing cell-specific IFN pathway activation, tetherin MFI (divided by 10000) in memory B cell (OR=1.331, p-value=0.044) and T cell (OR=3.120, p-value=0.028) at 6 months were associated with progression in univariable logistic regression . Surprisingly, we observed reduction in expression of most gene expression scores over time in both progressors and non-progressors; change of IFN Score B is shown in figure 1.Abstract S4:05 Figure 1IFN score B of both the progression and non-progression groups at baseline, 6 months, and 12 months. Abbreviations: IFN, interferon; SLE, systemic lupus erythematosus. *: p < 0.05; **: p < 0.01; ***: p < 0.001Conclusions IFN Score A was validated in an independent cohort as a predictor of progression to SLE. Other gene expression signatures known to be elevated in established SLE did not exhibit a decisive role in disease initiation. Flow cytometric IFN analysis suggests that IFN-pathway activation in memory B cells driving plasmablast differentiation is an appropriate set of targets for prevention therapy in high-risk individuals. The reduction in SLE gene expression signatures over time might represent onset of the immune exhaustion known in SLE that, in non-progressors, could be protective.",
  "authors": [
    {
      "affiliations": [
        "University of Leeds – Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK",
        "Linkou Chang Gung Memorial Hospital – Division of Rheumatology, Allergy and Immunology, Taoyuan, * OTHER",
        "Chang Gung University – College of Medicine, Taoyuan, * OTHER"
      ],
      "name": "Han -Hua Yu"
    },
    {
      "affiliations": [
        "University of Leeds – Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK",
        "Leeds Teaching Hospitals NHS Trust – NIHR Leeds Biomedical Research Centre, Leeds, UK"
      ],
      "name": "Jack Arnold"
    },
    {
      "affiliations": [
        "University of Leeds – Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK",
        "Leeds Teaching Hospitals NHS Trust – NIHR Leeds Biomedical Research Centre, Leeds, UK"
      ],
      "name": "Zoe Wigston"
    },
    {
      "affiliations": [
        "University of Leeds – Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK",
        "Leeds Teaching Hospitals NHS Trust – NIHR Leeds Biomedical Research Centre, Leeds, UK"
      ],
      "name": "Lucy Marie Carter"
    },
    {
      "affiliations": [
        "University of Leeds – Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK",
        "Leeds Teaching Hospitals NHS Trust – NIHR Leeds Biomedical Research Centre, Leeds, UK"
      ],
      "name": "Md Yuzaiful Md Yusof"
    },
    {
      "affiliations": [
        "University of Leeds – Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK",
        "Leeds Teaching Hospitals NHS Trust – NIHR Leeds Biomedical Research Centre, Leeds, UK"
      ],
      "name": "Edward M Vital"
    }
  ],
  "title": "S4:05 Pathogenesis and biomarker validation in people at risk of SLE: a transcriptomic and flow cytometric study reveals an increase in B cell interferon-response and differentiation precedes onset of SLE",
  "uid": "23bda32e-0061-5b05-b22a-463bfef3b41f"
}