Outcomes in Rheumatic Diseases

本报告包括与风湿病患者预后相关的9个独立项目。第一个项目，强直性脊柱炎（AS）严重程度的遗传决定因素，是一项前瞻性观察性研究，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。包括美国国立卫生研究院临床中心在内的五个中心已招募了1200多名受试者，数据分析正在进行中。先前的研究结果包括鉴定与AS易感性相关的新基因，AS风险中HLA- b27和ERAP1之间的基因相互作用，骨代谢候选基因与影像学严重程度缺乏关联，HLA与AS易感性相关。目前的工作是研究肿瘤坏死因子α抑制剂治疗与影像学脊柱融合进展的变化之间的关系，以及AS诊断的多基因预测。正在进行的工作将测试精细制图和其他易感性标记。

Nine separate projects related to outcomes of patients with rheumatic diseases are included in this report. The first project, Genetic determinants of ankylosing spondylitis (AS) severity, is a prospective observational study of subjects with 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 data analysis is proceeding. Previous findings include identification of 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, and HLA associations with AS susceptibility. Current work examines the association between treatment with tumor necrosis factor alpha inhibitors and changes in the progression of radiographic spine fusion, and multigene prediction of AS diagnosis. Ongoing work will test fine mapping and additional susceptibility markers. The second project, Progression of spinal fusion in AS, is a developmental study to test a measure of spinal fusion in AS based on quantification of syndesmophytes in the intervertebral discs by computed tomography. Sixty-one subjects have been enrolled. 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 recently extended the imaging to include the thoracic spine. We are currently examining the dynamics of syndesmophyte growth within different regions of the disc space, and have found relative sparing of syndesmophyte development on the vertebral rim next to the aorta. We are planning a study of the association of vertebral bone mineral density and syndesmophyte development, and a scanning protocol using less radiation exposure. The third project, Clinically important changes in rheumatoid arthritis, is a prospective observational study of clinically important changes in rheumatoid arthritis (RA) activity. Based on longitudinal data on 250 patients, 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 sensitive but not specific measures of improvement. We have also determined that correlates of the patient global assessment differ with the level of RA activity, and that patient-physician discrepancies are due in part to use of different standards of comparison. We have used these data to validate the health transition question, and found that generic transition questions are as valid as domain-specific transition questions. We have recently developed statistical equivalences between changes in composite RA activity measures for use in the planning and interpretation of clinical trials. We have also estimated the minimal clinically important improvement in the RAPID3 measure. This project is completed. The fourth project, Outcomes in patients with RA, uses administrative data to examine risks of mortality and comorbid diseases between patients with RA and those without RA. We have determined that the risks of post-operative infections and mortality were not related to pre-operative withholding of infliximab. 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 end-stage renal disease risk 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. We recently used the same methodological approach to study trends in mortality among patients with SLE over time. Our results indicate that there has been no improvement in survival in patients with SLE since the early 1990s. We have also determined that, among patients with end-stage renal disease, the "survival advantage" of blacks on dialysis relative to whites on dialysis is due to differential use of transplantation and withdrawal of dialysis. We have shown inter-hospital differences in mortality among hospitalized patients with SLE and sepsis. We have participated in an international effort to develop treatment recommendations for adults with antiphospholipid syndrome. We are currently working on a systematic review of the treatment of cardiovascular complications in patients with SLE. The goal of the sixth project, Outcomes in Orthopedics, is to investigate associations between processes and outcomes of orthopedic care. Risk of atypical hip fractures was associated with degree of compliance with bisphosphonate treatment among Medicare beneficiaries. We also reported an association between media reports of the association between bisphosphonate use and atypical fractures and a subsequent decline in these fractures. We also reported that only one-half of Medicare beneficiaries with osteoporosis were treated with anti-resorptive medications. This project is complete. The seventh project examines the frequency and complications of orthopedic procedures among Medicare beneficiaries. We have found that patients with AS not only have higher rates of total hip arthroplasty than patients without AS, but also have higher rates of total knee arthroplasty. Risk of knee arthroplasty was higher among patients who also had hip arthroplasty, suggesting that altered biomechanics may have a role in knee damage. We have found that the frequency of complications of total hip arthroplasty is no higher in patients with AS than those without AS. We have documented large regional differences across the U.S. in rates of total knee arthroplasty, even when adjusted for patient clinical risk factors, and that use of conservative treatments is lower in areas with high rates of total knee arthroplasty. The goal of the eighth project is to test whether patients with RA in clinical remission can safely be withdrawn from treatment with TNF inhibitors without relapse of their arthritis. We have initiated a multicenter double-blind placebo-controlled withdrawal trial to test this hypothesis in 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. This trial was stopped after the first planned interim analysis showed a substantially higher risk of relapse among participants randomized to TNF withdrawal. Data analysis is ongoing. The ninth project is a study of the etiology of melorheostosis, a progressive bone-forming disease, which is testing the hypothesis that somatic mutations in affected bone are responsible for the condition. Genetic analyses of bone, skin and blood indicate that a somatic mutation in MAP2K1 is responsible for the disease in one-half of patients.