Rheumatoid Arthritis and Respiratory Outcomes in Prospective Cohorts

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 DESCRIPTION (provided by applicant): Candidate: Dr. Sparks is an Instructor of Medicine in the Section of Clinical Sciences (SCS), Division of Rheumatology, Immunology and Allergy at Brigham and Women's Hospital (BWH) where he has 88% of his full-time professional effort committed to his research projects. He has 12% of his time devoted to clinical care at BWH and teaching at Harvard Medical School (HMS). He has received a Master of Medical Sciences degree in patient-oriented research from HMS, and a career development award from the Rheumatology Research Foundation. His dedication to clinical investigation is evident by 9 total and 6 first-author original research publications, presentations at national and international scientific meetings, and service on scientific committees. He has an experienced team of senior mentors and strong institutional support in an environment that fosters training in patient-oriented research. In line with his career development plan for this award, his immediate career goals are to expand his prior findings on increased risk of respiratory mortality for patients with rheumatoid arthritis (RA) using two prospective cohorts that will serve as the foundation for future independent research endeavors linking RA pathogenesis with subsequent respiratory outcomes. With the assistance of his expert mentoring team, led by Dr. Elizabeth Karlson, he will obtain training in advanced statistical methods in outcomes research, pulmonary evaluation and phenotyping, and integration of biomarkers in his studies to complete the aims of this proposal. The research training, mentorship, and results that arise from this project will lay the groundwork so that he can achieve his long-term goal to become an independent scientist in the field of RA epidemiology. Ultimately, he plans to develop interventions that prevent or decrease the respiratory burden of RA patients while informing the pathogenesis of respiratory diseases. Environment: Dr. Sparks has a commitment from his Department and Division at BWH that ensures at least 75% protected time for the research and career development activities detailed in this K23 proposal. He has institutional support from a recruitment package as well as supplemental salary support though his primary mentor's funding. He has access to subjects with RA for recruitment in the Brigham RA Sequential Study (BRASS), an ongoing 13-year longitudinal cohort, as well as >2,500 RA patients seen annually at the BWH Arthritis Center. Since BWH is a leading academic hospital for rheumatic and pulmonary diseases, he will have access to recruit adequate numbers of subjects for this project and future studies. He will obtain training in pulmonary phenotyping at the BWH Pulmonary Physiology Center and RA/Interstitial Lung Disease Clinic. In addition, he has full access to data in the Nurses' Health Study (NHS), through the BWH Channing Division of Network Medicine. The NHS is composed of 121,700 women followed since 1976 with data on RA, respiratory outcomes, and covariates such as smoking. He has access to data on biomarkers from banked samples in a subset of women in the NHS who later developed RA. He has full access to data already collected and biospecimens in BRASS through the Division and SCS at BWH. Translational and patient-oriented research expertise is available at HMS, the Harvard Clinical and Translational Science Center, and the Harvard T.H. Chan School of Public Health. At the latter, he will take courses in causal inference, programming, biomarkers, and longitudinal analysis to acquire skills for this proposal. Dr. Sparks will have access to the larger BWH and Harvard research communities for presentations and feedback. In addition to protected time and financial support, Dr. Sparks has an office, computer with word processing and statistical software, telephone, copy/fax machine, and administrative support provided by the Division and SCS that will be extended during this award. Research: The overall hypothesis of this project is that inflammation and autoimmunity contribute to the respiratory burden of RA. This hypothesis is based on prior data demonstrating increased respiratory mortality among women with seropositive RA independent of smoking. In addition, preliminary data suggest that serum inflammatory markers and anti-citrullinated protein antibodies are associated with increased respiratory burden among patients with RA. In this K23 proposal, Dr. Sparks will build upon these findings using two prospective cohorts, the NHS and BRASS. He will utilize the strengths of both cohorts to examine complementary hypotheses. The NHS is comprised of detailed and lengthy data on a large cohort of women in the United States. Follow-up data before and after RA diagnosis in the NHS are available for examining how pre-RA factors affect outcomes occurring after RA diagnosis. BRASS has detailed data on clinical and RA-specific measures including disease activity, medications, and functional status in a large cohort of RA patients. First, this proposal will determine whether women with RA in the NHS are at increased risk for asthma, chronic obstructive pulmonary disease, and respiratory mortality. Second, this proposal will examine whether inflammatory biomarkers are associated with dyspnea and pulmonary comorbidities in BRASS. In this aim, the candidate will recruit subjects to prospectively receive additional respiratory measures. Finally, this proposal will examine whether anti-citrullinated protein antibodies are associated with respiratory outcomes when measured in the pre-clinical RA phase and patients with RA. By investigating the roles of inflammation and autoimmunity in respiratory outcomes in RA, Dr. Sparks will obtain training in statistical analysis, recruitment, pulmonary phenotyping, and biomarkers that position him to become a leader in clinical investigation.