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Outcomes in Rheumatic Diseases

风湿性疾病的治疗结果

基本信息

批准号：
10265851
负责人：
Michael Ward
金额：
$ 67.76万
依托单位：
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10265851
关键词：
3-Dimensional Adult Affect Ankylosing spondylitis Antiphospholipid Syndrome Aorta Area Arthritis Biomechanics Blood Bone Density Candidate Disease Gene Cardiovascular system Caring Characteristics Chest Clinical Clinical Treatment Clinical Trials Data Data Analyses Degenerative polyarthritis Development Diagnosis Diagnostic radiologic examination Dialysis procedure Disease Disease remission Double-Blind Method End stage renal failure Enrollment Etiology Fracture Frequencies Genes Genetic Genetic Determinism Genetic study Genotype Goals Growth HLA-B27 Antigen Health Health Personnel Health Services Accessibility Health Transition Healthcare Height Hip Fractures Hospitals Image Immunologics Infection International Intervertebral disc structure Joints Knee Lupus Lupus Nephritis MAP2K1 gene Magnetic Resonance Imaging Measures Mechanical Stress Medicare Melorheostosis Meta-Analysis Methodology Methods Observational Study Orthopedic Procedures Orthopedic Surgery procedures Orthopedics Osteoporosis Outcome Outcome Measure Pain Participant Patient-Focused Outcomes Patients Pharmaceutical Preparations Phenotype Physical Function Physicians Placebos Postoperative Period Predisposition Process Protocols documentation Provider Radiation exposure Randomized Recommendation Relapse Reporting Research Review Literature Rheumatism Rheumatoid Arthritis Risk Risk Factors Role SF-36 Sampling Scanning Sepsis Severities Skin Somatic Mutation Spinal Fusion Structure Study Subject Symptoms Systemic Lupus Erythematosus TNF gene Techniques Testing Time Transplantation Ultrasonography United States National Institutes of Health Variant Vertebral Bone Vertebral column Withdrawal Work X-Ray Computed Tomography automated algorithm base beneficiary bisphosphonate bone bone metabolism clinical center clinical epidemiology clinical remission clinical risk comorbidity computerized disorder risk gene interaction genetic analysis health disparity high risk hip replacement arthroplasty improved outcome infliximab inhibitor/antagonist knee replacement arthroplasty mortality mortality risk prospective regional difference relapse prediction relapse risk response social spine bone structure systematic review tool trend tumor necrosis factor-alpha inhibitor

项目摘要

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.

本报告包含九个与风湿病患者结局相关的独立项目。第一个项目是强直性脊柱炎 (AS) 严重程度的遗传决定因素，是一项针对强直性脊柱炎受试者的前瞻性观察性研究，旨在确定强直性脊柱炎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 个中心已招募了超过 1200 名受试者，数据分析正在进行中。先前的研究结果包括与 AS 易感性相关的新基因的鉴定、AS 风险中 HLA-B27 和 ERAP1 之间的基因-基因相互作用、骨代谢候选基因与放射学严重程度之间缺乏关联，以及 HLA 与 AS 易感性之间的关联。目前的工作研究了肿瘤坏死因子α抑制剂治疗与放射学脊柱融合进展变化以及AS诊断的多基因预测之间的关联。正在进行的工作将测试精细绘图和其他易感性标记。第二个项目是 AS 脊柱融合的进展，是一项开发性研究，旨在通过计算机断层扫描对椎间盘中的韧带骨赘进行量化，测试 AS 脊柱融合的测量结果。已招收六十一名受试者。用于测量韧带骨赘体积和高度的计算机半自动算法已经过优化，以最大限度地提高可靠性。根据这些扫描提供的三维信息，我们发现韧带骨赘优先形成于后外侧椎骨边缘。这种定位与高机械应力区域一致，表明生物力学可能是韧带骨赘发育中未被充分认识的因素。我们最近将成像范围扩展到包括胸椎。我们目前正在研究椎间盘空间不同区域内韧带骨赘生长的动态，并发现主动脉旁边的椎缘上韧带骨赘发育相对较少。我们正在计划研究椎骨矿物质密度与韧带骨赘发育之间的关系，以及使用较少辐射暴露的扫描方案。第三个项目“类风湿性关节炎的临床重要变化”是一项针对类风湿性关节炎（RA）活动的临床重要变化的前瞻性观察研究。根据 250 名患者的纵向数据，确定了疼痛、身体功能、患者整体评估、RA 活动的四项综合测量以及 SF-36 量表的改善标准。我们还确定临床试验反应标准（例如 ACR20）是敏感的，但不是具体的改善措施。我们还确定，患者总体评估的相关性与 RA 活动水平不同，患者与医生之间的差异部分是由于使用了不同的比较标准造成的。我们使用这些数据来验证健康转换问题，并发现通用转换问题与特定领域的转换问题一样有效。我们最近开发了复合 RA 活动指标变化之间的统计等价性，用于临床试验的规划和解释。我们还估计了 RAPID3 测量中具有临床意义的最小改善。该项目已完成。第四个项目是 RA 患者的结果，使用管理数据来检查 RA 患者和非 RA 患者之间的死亡率和合并症风险。我们已经确定，术后感染和死亡的风险与术前停用英夫利昔单抗无关。第五个项目“系统性红斑狼疮的临床流行病学”的目标是调查 SLE 患者的健康差异，并确定与健康结果相关的临床特征和医疗保健实践。我们已经完成了对狼疮性肾炎患者终末期肾病风险的系统文献综述和贝叶斯荟萃分析，记录了 1970 年至 1995 年间结局的改善，但终末期肾病风险随后没有改善，而且最近略有增加。我们最近使用相同的方法来研究 SLE 患者死亡率随时间的变化趋势。我们的结果表明，自 20 世纪 90 年代初以来，SLE 患者的生存率没有改善。我们还确定，在终末期肾病患者中，接受透析的黑人相对于接受透析的白人的“生存优势”是由于移植和退出透析的区别使用。我们已经显示了 SLE 和脓毒症住院患者的死亡率存在医院间差异。我们参与了一项国际努力，为成人抗磷脂综合征制定治疗建议。我们目前正在对 SLE 患者心血管并发症的治疗进行系统评价。第六个项目“骨科成果”的目标是调查骨科护理过程和结果之间的关联。非典型髋部骨折的风险与医疗保险受益人对双磷酸盐治疗的依从程度相关。我们还报道了媒体报道的双磷酸盐使用与非典型骨折之间的关联以及随后这些骨折的减少。我们还报告说，只有一半患有骨质疏松症的医疗保险受益人接受了抗骨吸收药物治疗。该项目已完成。第七个项目检查医疗保险受益人中骨科手术的频率和并发症。我们发现，AS患者不仅比非AS患者的全髋关节置换率更高，而且全膝关节置换率也更高。同时进行髋关节置换术的患者进行膝关节置换术的风险较高，这表明生物力学的改变可能在膝关节损伤中发挥作用。我们发现，AS患者的全髋关节置换术并发症发生率并不高于非AS患者。我们记录了美国各地全膝关节置换术率存在巨大的地区差异，即使根据患者临床风险因素进行调整，并且在全膝关节置换术率高的地区，保守治疗的使用率较低。第八个项目的目标是测试临床缓解的 RA 患者是否可以安全地退出 TNF 抑制剂治疗而不会复发关节炎。我们启动了一项多中心双盲安慰剂对照戒断试验，以在缓解期 RA 患者中检验这一假设。这项研究还将提供有关复发的临床、影像（联合超声和磁共振成像）和免疫学预测因素的数据。在第一次计划的中期分析显示随机接受 TNF 戒断的参与者复发风险显着较高后，该试验被停止。数据分析正在进行中。第九个项目是对骨质增生症（一种进行性骨形成疾病）病因学的研究，该项目正在检验受影响骨骼中的体细胞突变导致该病的假设。对骨骼、皮肤和血液的遗传分析表明，MAP2K1 的体细胞突变是导致一半患者患病的原因。