RHEUMATOID ARTHRITIS ASSOCIATED AUTOIMMUNITY IN HIGH RISK POPULATIONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项研究将观察类风湿性关节炎患者及其家人，他们患相同或其他自身免疫性疾病的风险可能会增加。希望这将增加我们对类风湿关节炎免疫发病机制的理解。 我们认为，在临床未受影响的个体中，确定遗传风险、流行病学暴露和RA相关自身免疫之间的关系的第一步对于增加我们目前对RA免疫发病机制的理解是重要的。此外，这项研究还有助于为在无症状的RA高危人群中进行前瞻性研究奠定基础。这两种类型的研究对于我们的长期目标至关重要，即制定战略，选择临床上未受影响的携带高危HLA等位基因并表现出RA相关自身抗体的个体，这些抗体将成为预防策略或非常早期的治疗干预的候选对象。 在这方面，尽管这样的策略在RA或任何自身免疫性疾病中可能被认为是不切实际的，但科罗拉多大学健康科学中心和其他地方在1型糖尿病方面的广泛经验已经证明，这种方法是合理的，具有实质性的科学相关性和治疗潜力。在丹佛的一项名为DAISY(青少年糖尿病和自身免疫研究)的特定研究中，通过对25,000名新生儿进行群体筛查，确定了患有1型DM的高危儿童，其定义是存在与疾病相关的DR4和DR3等位基因，然后登记进入前瞻性跟踪队列，目前持续时间长达10年。这些儿童和由1型糖尿病患者的健康FDR组成的其他队列中的儿童正在被前瞻性地跟踪研究胰岛特异性自身免疫的发展。与我们的长期目标相关的是，在丹佛和其他地方，患有高度预测性1型糖尿病相关自身抗体的儿童已经被随机纳入预防试验，然后才出现临床明显的疾病。尽管预防策略并不成功，但证明处于危险中的人群可以被识别并进行临床试验，这使得人们对开发新的方法来治疗这种自身免疫性疾病和其他自身免疫性疾病产生了极大的兴趣，这些疾病处于自身抗体阳性但临床无症状的时期。 这项研究的长期目标是在疾病的临床前阶段识别那些有足够高风险患类风湿性关节炎(RA)的健康个体，以便采取合理的初级预防策略。我们的第一个目标是确定健康受试者中是否存在RA相关自身抗体。其次，我们将前瞻性地跟踪那些携带自身抗体的受试者，以确定他们是否预测RA的未来发展。最后，我们将筛选可能与RA相关自身抗体的出现相关的环境因素。由于这些自身抗体的筛查试验最近只在已知的类风湿关节炎患者中开发和测试，它们在健康人群中的临床相关性尚未确定。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study will observe subjects with Rheumatoid Arthritis and their families who may have an increased risk for developing the same or other autoimmune diseases. Hopefully this will increase our understanding of the immunopathogenesis of RA. We believe that this first step toward defining the relationship between genetic risk, epidemiologic exposures and RA related autoimmunity in clinically unaffected individuals is important to increasing our current understanding of the immunopathogenesis of RA. In addition, this study can help to lay the groundwork for the performance of prospective studies in sub-groups of asymptomatic individuals at especially high risk for developing RA. Both types of studies are essential to our long term goal of developing strategies for the selection of clinically unaffected individuals who carry high risk HLA alleles and exhibit RA related autoantibodies that would be candidates for prevention strategies or very early therapeutic interventions. In this regard, although such a strategy in RA, or indeed any autoimmune disease, may be thought to be impractical, extensive experience at the University of Colorado Health Sciences Center and elsewhere in Type 1 DM has demonstrated that this approach is rational and has substantial scientific relevance as well as therapeutic potential. In one particular study in Denver, termed DAISY (Diabetes and Autoimmunity Study in the Young) children at high risk for the development of Type 1 DM as defined by the presence of disease-associated DR4 and DR3 HLA alleles have been identified during a population screen of >25,000 newborns and then enrolled into a prospectively followed cohort with a current duration of up to ten years. These children and those from other cohort composed of healthy FDRs of individuals affected with Type 1 DM are being followed prospectively for the development of islet-specific autoimmunity. Relevant to our long-term goals, children in Denver and elsewhere who develop highly predictive Type 1 DM related autoantibodies have already been randomized into prevention trials prior to the development of clinically apparent disease. Although the prevention strategies were not successful, the demonstration that a population at risk could be identified and undergo a clinical trial has led to substantial interest in developing new ways to treat this and other autoimmune disease in the auto antibody positive but clinically asymptomatic period. The long-term goal of the study is to identify, during the pre-clinical phase of disease, those healthy individuals who are at sufficiently high risk for developing Rheumatoid Arthritis (RA) so that a rational primary prevention strategy can be employed. Our first objective will be to determine if RA-related autoantibodies are present in healthy subjects. Secondly, we will follow those subjects with autoantibodies prospectively in order to determine if they predict the future development of RA. Finally, we will screen for environmental factors which may be associated with the appearance of RA-related autoantibodies. Since the screening tests for these autoantibodies have been recently developed and tested only in patients with known RA, their clinical relevance in a healthy population has not yet been determined.