Development of Immune Mediator Based Blood Tests that Inform Concurrent and Future Clinical Disease Activity in Systemic Lupus Erythematosus (SLE)

PROJECT SUMMARY/ABSTRACTSystemic lupus erythematosus (SLE) is a multifaceted autoimmune disease characterized by immune dysregulation, disabling symptoms and progressive organ damage. Recognition and early treatment to prevent tissue and organ damage is challenging, as signs and symptoms of high disease activity and clinical disease flare are captured after their occurrence. Despite clinical instruments of disease activity and improved treatment regimens to temper chronic inflammation, SLE patients may experience an average of 1.8 disease flares annually. Current treatment for ongoing heightened clinical disease activity and disease flares, which must be done in reactive, rather than proactive, fashion, typically relies on rapidly acting, toxic agents such as steroids. Earlier identification and proactive treatment of heightened clinical disease activity and imminent disease flare might prevent significant organ damage and improve the quality of life for patients with SLE.Our scientific premise is that alterations in SLE-associated immune pathways underlie ongoing clinical disease activity and future disease flare. Traditional biomarkers incorporated in clinical disease activity measures are not necessarily the earliest, nor sufficient, biologic signals of worsening disease. Using a multi- analyte approach, we initially determined that lupus patients, prior to disease flare, have additional immune dysregulation of multiple and varied immune pathways. This information was transformed into a Lupus Flare Prediction Index (LFPI) that reflects the pre-flare immune status in lupus patients who go on to flare. Lupus patients with ongoing heightened clinical disease activity are also at risk for permanent organ damage. We therefore leveraged our initial studies to evaluate immune dysregulation in lupus patients with current low disease activity vs. active clinical disease. Again, we observed alterations in multiple and varied immune pathways, but in a different manner than what occurred prior to disease flare. This led us to design a Lupus Disease Activity Immune Index (LDAII) that correlates well with clinical disease activity measures.Our proposed research in Phase I/Aim 1 will focus on determining a distinct subset of SLE-associated mediators that best inform this novel LDAII, with validation of the LDAII during Phase II/Aim 2 in SLE patients with concurrent low vs. active clinical disease activity from ethnically diverse patient cohorts. Access to these SLE cohorts will also allow for the validation of our innovative LFPI in Phase II/Aim 3 in SLE patients with pre- flare vs. nonflare periods based on their future clinical disease activity. A successful outcome of this proposal will be optimized, validated LDAII and LFPI tests that are a game-changer in the lupus space by allowing proactive, rather than reactive, disease management. This study will also allow Progentec to transition these tests to a clinical lab certified by the College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA), procure codes for reimbursement, and launch clinical trials in Phase III.PROJECT NARRATIVE Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease which causes significant morbidity and early mortality, especially in young minority women. SLE patients are at risk for ongoing heightened clinical disease activity and disease flares that often result in end-organ damage, and are only identified after clinical signs and symptoms have occurred. We propose to measure a select panel of blood proteins that are known to activate or regulate the immune system and feed the results into innovative mathematical algorithms that assign a single, immune system-informed and clinically actionable disease activity or flare prediction score to provide proactive information as to which SLE patients are likely to have heightened clinical disease activity or who are at risk of imminent disease flare (positive score) for early intervention, organ damage prevention, and reduced need for treatments that carry damaging side effects.