Outcomes in Rheumatic Diseases

本报告包括八个与风湿病患者预后相关的独立项目。第一个项目，强直性脊柱炎严重程度的遗传决定因素，是一项对强直性脊柱炎（AS）患者的前瞻性观察研究，旨在确定AS易感性和严重程度的遗传决定因素。该项目将在大样本中测试基因型-表型相关性。包括NIH临床中心在内的5个中心已经招募了1200多名受试者，基因检测和数据分析正在进行中。对801例患者的影像学资料进行了分析。研究结果包括26个与AS易感性相关的新基因，HLA-B27和ERAP1在AS风险中的基因-基因相互作用，骨代谢候选基因与影像学严重程度缺乏相关性，髋关节关节炎对身体功能的影响，影像学损伤与功能损害之间的相关性随着AS的延长而减弱，ESR和CRP与轴向损伤的相关性。合作者包括博士。J. Reveille， M. Brown， M. Weisman， J. Davis， T. Learch，和J. Malley。正在进行的工作将在更大的样本中测试精细的定位和额外的易感性标记。

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 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 1200 subjects have been enrolled at five centers including the NIH Clinical Center, and genetic testing and data analysis are underway. Radiographic data have been analyzed on 801 patients. Findings include 26 new genes associated with susceptibility to AS, gene-gene interaction between HLA-B27 and ERAP1 in risk of AS, lack of association of bone metabolism candidate genes with radiographic severity, impact of hip arthritis on physical functioning, lessening of association between radiographic damage and functional impairment with more prolonged AS, and association of ESR and CRP with axial impairments. Collaborators include Drs. J. Reveille, M. Brown, M. Weisman, J. Davis, T. Learch, and J. Malley. Ongoing work will test fine mapping and additional susceptibility markers in larger samples. The second project, Progression of spinal fusion in ankylosing spondylitis, is a developmental study to test a measure of spinal fusion in AS based on quantification of calcification of the lumbar intervertebral discs by computed tomography. Thirty-eight subjects have been enrolled, and 33 have completed follow-up scans at 1 and 2 years. Computerized semi-automatic algorithms for measuring syndesmophyte volume and height have been optimized to maximize reliability. Based on the three-dimensional information provided by these scans, we have discovered that syndesmophytes are preferentially formed at the posteriolateral vertebral rim. This localization coincides with areas of high mechanical stress and suggests that biomechanics are likely under-recognized factors in syndesmophyte development. We have tested this hypothesis using finite element analysis on longitudinal data. Collaborators on this project are Drs. J. Flynn, L. Yao, Y. Yao, S. Tan and T. Keaveny. 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. Based on longitudinal data on 250 patients, we developed criteria for improvement have been determined for pain, physical functioning, patient global assessment, and four composite measures of RA activity, as well as for SF-36 scales. We also determined that clinical trial response criteria, such as the ACR20, are quite sensitive, but not specific, measures of improvement. Additional studies of determinants of patient global assessments and patient-physician discrepancies are underway. The fourth project, Outcomes in patients with RA, uses secondary data to examine risks of mortality, malignancy and cardiovascular disease between patients with RA and those without RA. We have found the perioperative risk of cardiovascular events and mortality not to be increased among persons with rheumatoid arthritis. We are planning a study of trends in risk of colorectal cancer and lymphoma in patients with rheumatoid arthritis, which may vary with changes in the treatments used over time. The goals of the fifth 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 health outcomes. We have completed a systematic literature review and Bayesian meta-analysis of risk of end-stage renal disease in patients with lupus nephritis, which document improved outcomes between 1970 and 1995, but no subsequent improvement in risk of end-stage renal disease, along with a slight increase recently. The goal of the sixth project, Outcomes in Orthopedics, is to investigate associations between processes and outcomes of orthopedic care. Initial studies have focused on time trends in the incidence of subtrochanteric fractures, using secondary data. Risk of atypical hip fractures was associated with degree of compliance with bisphosphonate treatment among Medicare beneficiaries. In an observational study we found no difference in subtrochanteric beaking and chronic bisphosphonate use, indicating that this bone change is not an inevitable consequence of bisphosphnate treatment. The seventh project examines the frequency and complications of orthopedic procedures among Medicare beneficiaries. Specifically we will investigate: 1) rates of joint arthroplasty from 1996 to 2010 among patients with RA and AS, and if these rates differ by treatment with TNF inhibitors; 2) infection and other complications following surgery in patients with RA by use of TNF inhibitors; 3) regional variations in surgeries for low back pain and knee or hip arthroplasty, and their relationship to variations in risk factors for osteoarthritis; 4) postoperative complications associated with either warfarin or heparinoid anticoagulation; 5) outcomes of treatment of femoral neck fractures with either hemiarthroplasty or total hip replacement. The goal of the eight project is to test whether patients with RA in clinical remission can safely be withdrawn from treatment with TNF inhibitors without having relapse of their arthritis. We have initiated a multicenter double-blind placebo-controlled withdrawal trial to test this hypothesis in 300 patients with RA in remission. This study will also provide data on clinical, imaging (joint ultrasound and magnetic resonance imaging), and immunological predictors of relapse.