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 900 subjects with ankylosing spondylitis (AS) that seeks to identify genetic determinants of ankylosing spondylitis severity. The severity of AS varies widely among patients, but the reasons for this variation are unknown. Because the susceptibility to AS is largely genetically determined, it is possible that the severity of AS may also be largely genetically determined. This project will test genotype-phenotype correlations in a large sample, stratified by duration of AS to capture inflammatory signs in early duration subjects and the degree of fusion and functional impairment in late duration subjects. Over 800 subjects have been enrolled, and genetic testing and data analysis is underway. Radiographic data and HLA data have been finalized on 769 patients. Recent findings have included identification of immunogenetic markers associated with more hip arthritis, the finding that hip arthritis has larger impact on physical functioning than spinal damage, and characterization of the typical pattern of radiographic involvment of different joint areas. Additional studies have identified depression and learned helplessness as factors that influence patient-reported AS activity and functional limitations. 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. Current work investigates interactions among these susceptibility markers. 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 feasibility study with a goal to develop and test a measure of spinal fusion in AS based on quantification of calcification of the lumbar intervertebral discs by computed tomography. Thirty-six subjects have been enrolled, and 23 have completed follow-up scans at 1 and 2 years. Seventeen subjects have completed follow-up radiographs at 4 years. Eight subjects completed studies testing the short-term reliability of measurements. Computer-based algorithms for determing incremental changes in bone volumes are being optimized to maximize reliabiilty. Collaborators on this project are Drs. J. Flynn, L. Yao, Y. Yao, S. Tan, and R. Summers. 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. It is also not known if patients rate changes in their symptoms and signs of RA similarly as their physicians, or if different patients are concordant in their judgments of how much of an improvement in symptoms represents an important improvement. 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, 197 patients have been enrolled. We recently expanded inclusion criteria to allow enrollment of Spanish-speaking patients, and have started a dedicated RA clinic to screen patients for eligibility for this protocol. In an initial study, we found that a new method of measuring patient global asessment, using a rating scale with marker states, was no more valid than the traditionally used visual analog scale. 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. One focus is to study the relationship between measures of physical performance and measures of self-reported functional limitations. 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. We are extending these observations to examine changes in population levels of functional limitations over the past 30 years, and to test if epidemiologic measures of depression assess not only affect but functional limitations. 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. SEER is the nation's primary cancer epidemiology program, operated by the National Cancer Institute. 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 are planning to investigate associations between anti-rheumatic medication use and blood glucose levels using secondary data from BTRIS. 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. Administrative data have been used to identify socioeconomic differences in the incidence of end-stage renal disease due to lupus nephritis, and further studies showed these differences are related to access to care. 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 bisphosphonates.
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