RA-Related Autoantibodies in Healthy FDR of RA Patients

描述(申请人提供)：类风湿性关节炎(RA)是一种自身免疫性疾病，影响关节和关节外部位，导致关节破坏，显著发病率和死亡率增加。对另一种自身免疫性疾病-1型糖尿病(DM)的分析表明，大多数最终受该疾病影响的人表现出三个疾病进展阶段：1)主要通过人类白细胞抗原关联携带遗传风险，2)临床上沉默的自身抗体的存在至少几年，以及3)临床明显的高血糖。我们认为，类风湿性关节炎也表现出这些阶段的疾病，与1型糖尿病类似，分析遗传高危、自身抗体阳性但临床无症状的未受影响的个体人群中的流行病学关联将为这种疾病的发病机制提供重要的见解。先前对受RA影响的个体的分析已经建立了在某些HLADR4和DR1等位基因中携带的“共享表位”与RA的遗传风险和严重程度之间的显著关系。在受影响的个体中RA的存在与被称为抗环瓜氨酸肽(CCP)抗体的高度特异的RA相关自身抗体之间也存在新的联系。一些研究还表明，抗CCP和其他RA相关自身抗体可能在临床疾病发病前几年就存在了。然而，除了我们最近开发的初步数据外，对于任何具有遗传风险但尚未受RA影响的人群中高危等位基因与RA相关抗体的存在之间的关联，我们知之甚少。此外，吸烟、咖啡、雌激素、怀孕、感染和环境毒素(如二氧化硅)与RA相关自身抗体的存在之间的联系也鲜为人知。从以前的人群研究中，我们知道，受RA影响的个人的一级亲属(FDR)表现出显著增加的疾病风险，可能是由于遗传和环境因素。我们建议鉴定和研究RA患者的FDR群体，以解决以下特定目标：特定目标1：在RA患者的未受影响的FDR中，确定携带高危HLA等位基因与存在RA相关自身抗体之间的关联。具体目标2：在未受影响的FDR人群中，确定流行病学暴露与RA相关自身抗体存在之间的关联。我们认为，确定这些因素之间的关系对于增加对RA免疫发病机制的理解以及潜在地制定选择临床未受影响的个体的策略是重要的，这些个体可能是预防方式或非常早期的治疗干预的候选对象。

DESCRIPTION (provided by applicant): Rheumatoid Arthritis (RA) is an autoimmune disease that affects joints and extra-articular sites, leading to joint destruction, significant morbidity and increased mortality. Analysis of another autoimmune disease, Type 1 Diabetes Mellitus (DM), has shown that the majority of individuals ultimately affected with that particular disease exhibit 3 phases of disease progression: 1) Carriage of genetic risk primarily through HLA associations, 2) Presence of clinically silent autoantibodies for at least several years, and 3) Clinically apparent hyperglycemia. We propose that RA also exhibits these phases of disease and that, in a similar manner as Type 1 DM, analysis of epidemiologic associations within the genetically at-risk, autoantibody positive but clinically asymptomatic population of unaffected individuals will provide important insights into the pathogenesis of this disease. Previous analyses of individuals affected with RA has established a significant relationship of the "shared epitope" that is carried within certain HLA DR4 and DR1 alleles to both the genetic risk and severity of RA. There is also a newly-established relationship between the presence of RA in affected individuals and highly specific RA-related autoantibodies designated anti-cyclic citrullinated peptide (CCP) antibodies. Several studies have also demonstrated that anti-CCP and other RA-related autoantibodies may be present several years prior to the onset of clinical disease. However, with the exception of preliminary data we have recently developed, little is known about the association of high-risk HLA alleles and the presence of RA-related antibodies in any population that is genetically at-risk but not yet affected by RA. In addition, associations between exposures such as smoking, coffee, estrogens, pregnancy, infections, and environmental toxins such as silica and the presence of RA-related autoantibodies are also poorly understood. From previous population studies we know that first degree relatives (FDRs) of individuals affected with RA exhibit a substantially increased risk of developing disease, likely due to both genetic and environmental factors. We propose to identify and study a population of FDRs of individuals with RA in order to address the following specific aims: Specific Aim #1: In unaffected FDRs of individuals with RA, determine the association between the carriage of high risk HLA alleles and the presence of RA-related autoantibodies. Specific Aim #2: In this population of unaffected FDRs, determine the association between epidemiologic exposures and the presence of RA-related autoantibodies. We believe that defining the relationship between these factors is important to increasing the understanding of the immunopathogenesis of RA as well as potentially developing strategies for the selection of clinically unaffected individuals who would be candidates for prevention modalities or very early therapeutic interventions.