PROJECT SUMMARY We propose to extend the California Lupus Epidemiology Study (CLUES), which has established a racially and ethnically diverse cohort of over 450 individuals with systemic lupus erythematosus (SLE). The CLUES cohort was launched from the successful California Lupus Surveillance Project, which established the incidence and prevalence of SLE in San Francisco County. Individuals identified through the surveillance effort were invited to participate in the longitudinal CLUES cohort. The study currently includes i) extensive clinical data, including physician-assessed measures of SLE disease activity, medical history, SLE manifestations, and outcomes such as damage; ii) biologic specimens and data, including genetic, epigenetic, gene expression and environmental exposure information; and iii) data from structured interviews with participants covering sociodemographics, healthcare access and gaps, symptoms, disability, and a wide variety of patient-reported outcomes. This exceptionally broad and deep data collection has catalyzed a wide spectrum of SLE research studies, ranging from the examination of clinical and patient-reported outcomes in SLE to studies of DNA methylation and gene transcription across racially and ethnically diverse populations. Through data collection, analyses and dissemination, the overarching aim of the CLUES cohort is to advance our understanding of the epidemiology, biology, natural history, and outcomes of SLE, particularly among diverse racial, ethnic and socioeconomic groups. In the renewal period, our aims are 1) to continue longitudinal data collection on CLUES participants, including comprehensive patient-reported data, 2) to enhance and maintain a state-of-the-art biospecimen repository and provide access to this valuable resource to investigators, and 3) to conduct two special projects, one examining the metabolome during and after flares to gain insight into mechanisms of SLE disease activity, and one examining the natural history of disability across the activity spectrum, including how flares may affect disability trajectories. The overall project leverages outstanding institutional resources and builds on the proven track-record of the investigators in building a successful administrative and management infrastructure for CLUES, developing and maintaining longitudinal cohort studies, and creating effective systems for sharing clinical data and biospecimens. CLUES is unique because there are very few population-based studies of Asians or Hispanic-Americans with SLE, two groups that are disproportionately affected by the disease and who comprise a significant and growing proportion of the U.S. population. In addition, we continue to address disease flares, an area that is ripe for research and central to advancing knowledge about the natural history, outcomes, biologic mechanisms of SLE and related health disparities.