RHEUMATOID ARTHRITIS ASSOCIATED AUTOIMMUNITY IN HIGH RISK POPULATIONS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 本研究将观察风湿性关节炎受试者及其家庭，他们可能具有发生相同或其他自身免疫性疾病的风险增加。 希望这将增加我们对RA免疫发病机制的理解。 我们认为，这是确定遗传风险，流行病学暴露和RA相关的自身免疫性在临床上未受影响的个人之间的关系的第一步，是很重要的，以增加我们目前的理解免疫发病机制的RA。 此外，这项研究可以帮助奠定基础的前瞻性研究的性能在亚组的无症状的个人在特别高的风险发展为RA。 这两种类型的研究是必不可少的，我们的长期目标是制定战略，选择临床上未受影响的个人谁携带高风险的HLA等位基因和表现出RA相关的自身抗体，将是预防策略或非常早期的治疗干预的候选人。 在这方面，虽然这种策略在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型糖尿病中的广泛经验已经证明这种方法是合理的，并且具有实质性的科学相关性和治疗潜力。 在丹佛的一项称为DAISY（年轻人糖尿病和自身免疫研究）的特定研究中，在> 25，000名新生儿的群体筛查期间鉴定了具有发展1型DM的高风险（如通过疾病相关的DR 4和DR 3 HLA等位基因的存在所定义的）的儿童，然后将其招募到当前持续时间长达10年的前瞻性随访队列中。 这些儿童和来自其他队列的受1型DM影响的个体的健康FDR的儿童正在前瞻性地随访胰岛特异性自身免疫的发展。 与我们的长期目标相关的是，丹佛和其他地方发展高度预测性1型糖尿病相关自身抗体的儿童在临床明显疾病发展之前已经随机进入预防试验。 虽然预防策略并不成功，但可以识别风险人群并进行临床试验的证明已经引起了人们对开发新方法以治疗这种自身抗体阳性但临床无症状的自身免疫性疾病的极大兴趣。 该研究的长期目标是在疾病的临床前阶段，确定那些健康的人谁是在足够高的风险发展风湿性关节炎（RA），以便可以采用合理的一级预防策略。 我们的第一个目标是确定RA相关的自身抗体是否存在于健康受试者中。 其次，我们将前瞻性地随访那些有自身抗体的受试者，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相关自身抗体出现相关的环境因素。 由于这些自身抗体的筛查试验最近才开发出来，并且仅在已知的RA患者中进行了测试，因此尚未确定其在健康人群中的临床相关性。

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.