The candidate is a junior investigator in rheumatology with advanced training in clinical epidemiology and a focus on patient-oriented research in chronic rheumatic diseases. He has a long history of clinical work within the Philadelphia VA and has recently been appointed here as clinical faculty. Throughout his training he has shown dedication to the care of veterans and proposes to develop his career within the VA. The candidate proposes a comprehensive interdisciplinary career development plan that will provide him with the skills and experience for his development into an independent clinical investigator. His co-mentors are NIH K24-funded senior investigators from the UPENN and VA, who have expertise in bone and joint health in varied chronic diseases. His multidisciplinary team includes additional NIH-funded leaders in biostatistics, epidemiology, bone metabolism, body composition, and rheumatic disease, each of whom is dedicated to a coordinated effort to ward the success of his career. He will draw on outstanding resources, including the VA Rheumatoid Arthritis national registry as well as the CTSA-supported Center for Clinical and Translational Research, and the Center for Clinical Epidemiology and Biostatistics at nearby UPENN. He will also complete additional formal didactic training in methods relevant to this proposal. The proposed project will build on his epidemiology training and prior research experience to promote his transition to independence. His long-term goals are to conduct clinical trials to improve body composition, bone health, and related outcomes in rheumatoid arthritis (RA). The study proposed here is the necessary first step to inform these trials. Osteoporotic fractures and joint damage account for significant morbidity in RA, resulting in billions of dollars in national costs.1 Recent studies suggest a greater prevalence and severity of arthritis in US veterans, compared with non-veterans.2 Furthermore, the VA identified arthritis, pain, obesity, and osteoporosis as priority conditions in women;each of these is addressed in this application. Low body weight has been associated with many adverse outcomes in RA, including fractures, joint damage, and death. However, the dynamic effect of the disease itself on BMI has not been characterized nor have the effects of altered body composition on RA outcomes. The long-term effects of this chronic inflammatory disease on body weight have not been clarified and may help explain these associations. Similarly, low BMI is associated with low lean mass. The applicant demonstrated that low lean mass and greater fat mass are associated with cortical thinning of bone among healthy adults. Given that 1) rheumatoid cachexia is characterized by reduced lean mass with normal or increased fat mass and 2) low lean mass is associated with thinning of cortical bone, loss of lean mass in RA likely contributes to the excess fracture risk in this population. The critical knowledge gaps are 1) whether associations between bone and BMI are related to confounding by long-term effects of disease and 2) to what extent altered lean and fat mass (rather than BMI) account for bone deficits. Taken further, the positive effects of lean mass on cortical bone may be important for prevention of invasion of inflammatory pannus, and integral to the health of overlying cartilage. Interventions to reverse lean mass deficits in RA could therefore have a valuable impact on disease outcomes through mechanical effects on cortical bone or production of muscle- derived factors. The applicant aims to 1) quantify alterations in bone structure and body composition in RA, compared with controls, and to evaluate associations with growth factors, cytokines and structural joint damage within RA participants at baseline, 2) identify baseline disease characteristics, physical function, serologic measures, and body composition measures associated with longitudinal deteriorations in ALM, bone density and structure, joint damage and disability over 2 years, and 3) To determine if lower disease activity is associated with greater increases in BMI, independent of glucocorticoid therapy in VARA participants.
The applicant is a junior investigator with an appointment at the Philadelphia VA and advanced training in clinical epidemiology and biostatistics. He aims to develop his career within the VA, utilizing the mentorship, resources, and support he has gained through the master's program at UPENN. The disease of interest, Rheumatoid Arthritis, is the most common inflammatory joint disease at the VA (67,000 patients) and causes significant disability- particularly among veterans, in whom the severity of disease is often greater. Epidemiology research has demonstrated that low body weight is associated with increased risk of disability, fracture, and joint damage in RA. However, the long-term effects of disease on weight have not been clarified nor have the direct effects of low lean mass (muscle) on bone structure, and an increased long-term risk of osteoporosis and joint damage. Understanding these associations in RA and the underlying mechanisms could result in use of novel therapies to directly affect muscle and improve these long-term outcomes.
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