Asthma affects 8.4% of the United States population and 4.3% of the worldwide population and leads to significant morbidity and mortality. Identification of clinically relevant endotypes, such as high T2 (T helper cell, type) asthma, led to the development of targeted therapeutics and improved outcome. However, despite these advances, there remains 5-10% of asthma patients who are refractory to conventional treatment and have limited therapeutic options. We propose to meet this need by utilizing precision medicine techniques to define a unique asthma phenotype that we have described which are likely influenced by the generation of autoimmune antibodies. My preliminary data identified a population of asthma patients at risk for the development of autoimmune disease through the generation of autoantibodies specific for rheumatoid arthritis (RA). In our preliminary data I found that 15% of asthma subjects had clinically positive levels of RA specific autoantibodies (antibodies to citrullinated peptide antigens (ACPA)) in serum and 92% in sputum (n=42) compared to 5.6% in a normal population (p=<0.01 for both). In our preliminary data, higher ACPA levels were correlated (via Spearman's method) with lower Asthma Quality of Life Questionnaire scores (rho=-0.42, p=0.02) and worse pulmonary function as measured by forces expiratory volume in 1 second (rho=-.32, p=0.03). My preliminary data describes a cohort of asthma patients who develop clinically positive serum ACPA, which is associated with increased risk for the development of RA (specificity of positive ACPA assay is 90.4% for the development of RA) and associated with worse asthma-specific disease metrics. The central hypothesis for this study is that asthma patients who generate ACPA represent a specific clinical endotype which can be further characterized using precision medicine techniques. Our long-term goal is to develop biologic and genetic insights into the mechanism of ACPA development in asthma to generate future therapeutic targets for interventional study designs.