{
  "abstract": "Objectives Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Significant morbidity and early mortality necessitate early intervention. This study harnessed SLE-associated immune dysregulation to create a Lupus Classification Risk Index (LCRII) and Lupus Disease Activity Immune Index (LDAII) that identified individuals at risk for SLE classification and disease activity.Methods The LCRII was developed from 84 military personnel who developed classified SLE (≥4 American College of Rheumatology criteria) versus matched healthy controls, which was confirmed in 56 lupus blood relatives who developed SLE versus 154 matched unaffected relatives and 77 unrelated controls. The LDAII was informed by SLE patient visits with low (n=132) or active (n=179) disease and 48 matched controls. Data from blood samples assessed for circulating SLE-associated autoantibody specificities and soluble immune mediators informed the LCRII and LDAII. Random forest modelling guided the selection of informative analytes.Results An LCRII informed by 32 or 17 log-transformed/standardised mediators, weighted by their correlation to SLE-associated autoantibodies, differentiated pre-SLE individuals before reaching disease classification (area under the curve (AUC) ≥0.79, p<0.0001; effect size ≥1.1), even before the appearance of clinical criteria (AUC ≥0.74, p<0.0001; effect size ≥0.9). The LCRII-32, LCRII-17 and select mediators, MCP-3/CCL7, TNFRII, stem cell factor (SCF), IL-1α, IP-10/CXCL10 and TGF-β differentiated renal and serositis classification criteria (p<0.05). An LDAII informed by 26 or 13 log-transformed/standardised mediators, weighted by their correlation to SLE-associated autoantibodies or disease activity (hybrid Systemic Lupus Erythematosus Disease Activity Index; hSLEDAI), differentiated SLE patients with low (hSLEDAI <4) or active (hSLEDAI ≥4) disease (AUC >0.6, p ≤ 0.002, effect size ≥0.4), including clinical/serologic active versus quiescent disease (AUC ≥0.7, p<0.0001, effect size ≥0.6). The LDAII-26, LDAII-13 and select mediators MCP-1/CCL2, TNFRII, SCF, IL-2Rα, IL-10 and TGF-β differentiated renal and serositis manifestations.Conclusions We have conceptualised two immune mediator-informed indexes, the LCRII that predicts SLE from months to years before clinical presentation, and the LDAII that analogously predicts active disease in SLE to distinguish patients who would benefit from early intervention.",
  "authors": [
    {
      "affiliations": [
        "Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA"
      ],
      "name": "Melissa E Munroe"
    },
    {
      "affiliations": [
        "Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA"
      ],
      "name": "Kendra Young"
    },
    {
      "affiliations": [
        "Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA",
        "Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"
      ],
      "name": "Rufei Lu"
    },
    {
      "affiliations": [
        "Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA"
      ],
      "name": "Joel M Guthridge"
    },
    {
      "affiliations": [
        "Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA"
      ],
      "name": "Diane L Kamen"
    },
    {
      "affiliations": [
        "Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA"
      ],
      "name": "Gary S Gilkeson"
    },
    {
      "affiliations": [
        "Division of Rheumatology, Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA"
      ],
      "name": "Michael H Weisman"
    },
    {
      "affiliations": [
        "Division of Rheumatology, Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA"
      ],
      "name": "Mariko L Ishimori"
    },
    {
      "affiliations": [
        "Division of Rheumatology, Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA"
      ],
      "name": "Daniel J Wallace"
    },
    {
      "affiliations": [
        "Division of Rheumatic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA"
      ],
      "name": "David R Karp"
    },
    {
      "affiliations": [
        "Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "George C Tsokos"
    },
    {
      "affiliations": [
        "Walter Reed National Military Medical Center, Bethesda, Maryland, USA"
      ],
      "name": "Michael P Keith"
    },
    {
      "affiliations": [
        "US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA",
        "Cincinnati Education and Research for Veterans Foundation, Cincinnati, Ohio, USA"
      ],
      "name": "John B Harley"
    },
    {
      "affiliations": [
        "Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA"
      ],
      "name": "Jill M Norris"
    },
    {
      "affiliations": [
        "Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA",
        "Departments of Pathology and Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"
      ],
      "name": "Judith A James"
    }
  ],
  "title": "Dysregulated soluble immune mediators and lupus-associated autoantibody specificities inform the development of immune indexes that characterise classified SLE transition and SLE disease activity",
  "uid": "e7504fb8-44b2-5074-afb6-7ca1efa04377"
}