Eight separate projects related to outcomes of patients with rheumatic diseases are included in this report. The first project, Genetic determinants of ankylosing spondylitis severity, is a prospective observational study of 1000 subjects with ankylosing spondylitis (AS) that seeks to identify genetic determinants of AS susceptibility and severity. This project will test genotype-phenotype correlations in a large sample. Over 900 subjects have been enrolled, and genetic testing and data analysis is underway. Radiographic data and HLA data have been finalized on 789 patients. Findings include identification of immunogenetic markers associated with more hip arthritis, hip arthritis has larger impact on physical functioning than spinal damage, and characterization of the typical pattern of radiographic involvment. Additional studies have identified depression and learned helplessness as factors that influence patient-reported AS symptoms. Collaborators include Drs. J. Reveille, M. Weisman, J. Davis, T. Learch, and J. Malley. In a related genome wide association study, we identified ERAP1, IL23R, IL1R2, ANTRX2, TRADD, and STAT3 as associated with the susceptibility to AS, along with areas on 2 chromosomes not known to contain genes. Recent work has identified an interaction between HLA-B27 and ERAP1 in risk of susceptibility to AS. We are also testing associations of these markers with measures of functional and radiographic severity, and will similarly test associations with several candidate genes involved in bone formation and regulation. The second project, Progression of spinal fusion in ankylosing spondylitis, is a pilot study to develop a measure of spinal fusion in AS based on quantification of calcification of the lumbar intervertebral discs by computed tomography. Thirty-seven subjects have been enrolled, and 31 have completed follow-up scans at 1 and 2 years. Nineteen subjects have completed follow-up radiographs at 4 years. Eight subjects completed studies testing the short-term reliability of measurements. Computer-based semi-automatic algorithms for determing syndesmophyte volume and height have been optimized to maximize reliabiilty, with less than 1% error on repeat scans. We have also developed this method to measure vertebral body height and disk height, which may be useful for precise measurement of vertebral fractures and disk disease Collaborators on this project are Drs. J. Flynn, L. Yao, Y. Yao, and S. Tan. The third project, Clinically important changes in rheumatoid arthritis, is a prospective observational study of clinically important changes in rheumatoid arthritis (RA) activity. Current criteria for improvement in RA have not emphasized the patients perspective. The goals of this project are to identify benchmarks of important improvement in pain, functioning, and global arthritis status in RA based on the self-assessment by patients of changes in their symptoms. A secondary goal is to examine the measurement properties of preference measures. To date, 231 patients have been enrolled. Initial results indicate patients are somewhat consistent in the degree of improvement necessary to be appreciated as an important change, and that clinical trial measures of improvement, such as the ACR20, are sensitive measures of improvement. The fourth project, Measurement of physical functioning, uses secondary analysis of clinical trial and observational data to understand what aspects of functioning are being measured in commonly used self-report instruments. We have found that performance measures are neither sensitive nor specific indicators of self-reported functional limitations. We have also found that, contrary to much previous literature, women and men have similar levels of self-reported functional limitations. In addition, we found no racial/ethnic differences in functional limitations after adjustment for measures of disease burden, although large differences by socioeconomic status remained despite adjustment for disease burden. The fifth project, Malignancy in patients with rheumatoid arthritis, uses the Medicare-SEER database to compare the incidence and survival from cancer between patients with RA and those without RA. Rheumatoid arthritis may modify the risk of malignancy, increasing the risk of certain types of cancer (lymphoma, lung) and decreasing the risk of other types of cancer (colorectal). However, risks of malignancy are not well defined in patients with RA, nor is it known if the outcomes of cancer are similar between patients with RA and those without RA. The Medicare-SEER database is a large population-based linked database that combines clinical information from Medicare billing records with cancer data from SEER locations. Patients with RA are identified from Medicare records, while cancer incidence is obtained from SEER. Data analysis is currently underway. The sixth project, Treatment-related outcomes in rheumatoid arthritis, uses primary data to examine if particular disease-modifying medications are associated with higher- or lower-than- expected risks of mortality, using advanced statistical methods to account for differential prescribing of more serious medications to sicker patients. We have found that methotrexate is associated with a substantial survival benefit, not attributable to channeling or selective medication use. We are also testing if differential access by patients of higher socioeconomic status to more effective anti-rheumatic medications over the past 25 years has resulted widening of socioeconomic disparites in health over time. The goals of the seventh project, Clinical epidemiology of systemic lupus erythematosus, are to investigate health disparities among patients with SLE, and to identify clinical features and health care practices that are associated with mortality. We are beginning a study of quality of care indicators for hospitalized patients with systemic lupus erythematosus. The eighth project, Outcomes in Orthopedics, has a goal of investigating associations between processes and outcomes of orthopedic care. Initial studies have focused on time trends in the incidence of subtrochanteric fractures, using secondary data. Increases in incidence over time in the U.S. have paralleled increased use of bisphosphonate. Based on these observations, we have begun an observational study of 900 subjects to examine the association between chronic bisphosphonate use and subtrochanteric beaking, the radiographic precursor of subtrochanteric fracture.
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