This proposal describes a detailed 5-year training program for the development of an academic career in rheumatology, with a special focus in geriatrics. This principal investigator has shown her firm commitment to an academic career in her specific field of study, and is perfectly poised to establish herself as an independently funded clinical investigator in geriatric rheumatology. She has completed all required coursework for the Masters in Clinical Research at UCLA. She has also completed her written thesis and is preparing for the oral presentation her thesis to her Advisory Committee. The training activities as outlined in this proposal will build upon a foundation of clinical/research skills and allow her to develop into an independent scientist capable of performing translational studies (biomarker discovery and development) in the field of geriatric rheumatology. Through formal coursework and informal training over the 5-year award, she will gain expertise in aging, basic immunology, building/managing large biomarker databases, and advanced multivariate statistical analyses. Drs. Theodore Hahn, Harold Paulus and Dr. Daniel Furst, are nationally and internationally recognized researches in the field of geriatrics and rheumatoid arthritis clinical trials;they will jointly mentor the scientific development of this principal investigator. A Mentorship Advisory Committee, consisting of three successful biostatistical/laboratory researchers will advise the candidate by providing scientific and career guidance (Drs. Elaine Reed, Betty Tsao, and David Elashoff). Despite significant advances in rheumatoid arthritis (RA) treatment options, clinicians still face challenges in treating the complex older RA patient with comorbid conditions. Up to 1/3 of RA patients treated with a TNF inhibitor have minimal to no improvement;this causes unnecessary time spent on a costly immunosuppressive agent with the potential for toxicity. Consequently, the earlier a clinician can determine if a patient will respond to therapy, the sooner one can arrive at the optimal therapeutic regimen. We hypothesize that the early assessment of biomarkers when starting a TNF inhibitor in older RA patients can aid in predicting response to therapy. We will test our hypothesis by evaluating the utility of 1) a T-cell immune response assay, 2) a readily available multiplex protein profile array, 3) a targeted set of promising markers and 4) clinical characteristics specific to the older RA patient, for early prediction of therapeutic response. In a cohort of 150 older RA patients initiating a new TNF inhibitor we will: 1) Determine the association of biomarkers with both 'status'and 'response'short-term (initial 3 months) RA outcome measures, 2) Examine the association between biomarkers (at baseline, 1 month, and 3 months) and long-term RA patients'clinical disease status at 6, 12, and 24 months (DAS28/ESR, HAQ-DI, and radiographic progression), 3) Determine the clinical characteristics specific to the older RA population (comorbidity measures, age, polypharmacy) that predict whether or not he/she will achieve minimal disease activity (MDA;DAS28/ESR<2.85) criteria over the 2-year study, and 4) Develop a statistical model using both clinical markers and biomarkers to predict therapeutic response (EULAR and ACR Response) in the older RA patient. Our central contention is that there is a great need to develop and evaluate biomarkers for early identification of therapeutic response in RA, especially for older RA patients. We anticipate that the results of this 5-year study, utilizing a combination of clinical and biomarker data will improve the rheumatologists'ability to more rapidly select the optimal therapeutic regimen in each older RA patient, in the clinical setting.
TO PUBLIC HEALTH Our central contention is that there is a great need to develop and evaluate biomarkers/clinical markers for early identification of therapeutic response in RA, especially for older RA patients. We anticipate that the results of this 5-year study, utilizing a combination of clinical data as well as the T-cell immune response assay, cytokine profiling, a targeted set of biomarkers, and clinical characteristics will improve the rheumatologists'ability to manage older RA patients in the clinical setting.
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