Systemic Lupus Erythematosus (SLE) is a systemic, autoimmune connective tissue disease affecting multiple organ systems, marked by arthritis, dermatitis, nephritis (LN) as well as neurological involvement. The prevalence of LN varies depending on age, sex, and ethnicity, and is estimated to be 40–70%. Despite advancements in the understanding of the pathophysiology of end-organ involvement in lupus, and novel therapeutics, only 50–70% of patients achieve remission. There is clearly a need for identifying easily measurable biomarkers for diagnosing and monitoring this autoimmune disease, predicting response to therapy and prognosticating long term outcome in lupus. Our project focuses on identifying proteins in body fluids that may help identify and subset lupus more effectively. In the past cycle of funding, we have reported serum biomarkers for systemic disease in lupus, cerebrospinal fluid proteins for neuropsychiatric lupus, as well as excreted proteins for renal disease, using a variety of different proteomic approaches. In this renewal proposal, we will focus on ten proteins that have been independently validated across multiple patient cohorts, using orthogonal approaches, as being highly reflective of disease activity in lupus. Together, these 10 proteins constitute LN-10-plex. We will perform extended clinical validation of the LN-10-plex proteins in larger patient cohorts of different ethnic origins to confirm their association and correlation with clinical disease activity, using training and validation cohorts. Using longitudinal cohorts, we will examine if the LN-10-plex proteins at baseline can be used to predict oncoming disease flares. In lupus patients undergoing induction therapy, we will ascertain if baseline levels of LN-10-plex proteins can predict response to therapy. We will also assess if easily measurable biomarkers can be used to track tissue pathology, as this will avoid the need for repeat biopsies. Thus, the broad, over-arching goal of our research is to be able to identify easily measurable biomarkers of disease in lupus, and harness them for improved clinical utility.