This application addresses the broad Challenge Area of comparative effectiveness (05) and specific Challenge Topic of Comparative Effectiveness of Biologics in Autoimmune Rheumatic and Skin Diseases (05-AR-101). We propose to build upon our experience in meta-analysis, large-scale epidemiology, and cost-effectiveness research in rheumatoid arthritis (RA) using three large RA registries, a systematic literature review, and computerized simulation modeling to study clinical and cost-effectiveness of biologics to determine the best therapy for individual patients. RA is the most common systemic autoimmune disease and affects approximately 1% of the general population. RA represents a chronic, progressive, and destructive joint disease associated with systemic inflammation, often leading to substantial disability and premature mortality. Biologics are very efficacious in treating RA, but are also very costly. This combination of marked benefits and high costs brings a challenging dilemma in appropriately allocating limited resources and determining the best therapy for individual patients. An accurate understanding of the comparative clinical and cost-effectiveness of biologics in RA is an important step in determining the best therapy for individual patients. In this study, we will perform a systematic literature review and analyze three large RA registries (National Data Bank for Rheumatic Diseases [n=25,977]), Swedish RA registry [n=40,000], and RA Investigational Network [n=2,000]) to compare the clinical effectiveness of alternative biologic agents. Our outcomes include effects on disease activity, quality of life, termination rate, remission rates, radiologic outcomes, and major adverse event rates (i.e. mortality, cardiovascular outcomes, malignancy, and infection). We will determine the clinical effectiveness of biologic agents among subpopulations defined by age, gender, disease duration, history of disease modifying anti-rheumatic drug (DMARD) use, and comorbidities. Furthermore, we will estimate the long-term cost-effectiveness of alternative biologic agents from a US societal perspective and determine the cost-effectiveness of biologic agents among these subpopulations. Lastly, we will perform a probabilistic analysis to characterize the uncertainty associated with comparative cost- effectiveness of biologics in RA and to establish the value of additional information. These specific aims will comprehensively characterize the comparative clinical and cost-effectiveness of biologics to help determine the best therapy for individual RA patients. This project will provide comprehensive information that has important implications for clinical care, public health, and future research funding allocations on this crucial topic in a highly cost-efficient design. PUBLIC HEALTH RELEVANCE: The proposed study will build upon our experience in meta-analysis, large-scale epidemiology, and cost-effectiveness research in rheumatoid arthritis (RA), using three large RA registries, a systematic literature review, and computerized projection modeling to study the clinical and cost-effectiveness of biologics to determine the best therapy for individual patients. This project will provide comprehensive information that has important implications for clinical care, public health, and future research funding allocations on this crucial topic, in a highly cost-efficient design.