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Rheumatoid Arthritis-Related Autoantibodies, Articular Inflammation, and RA-Associated Interstitial Lung Disease

类风湿关节炎相关自身抗体、关节炎症和 RA 相关间质性肺病

基本信息

批准号：
10207955
负责人：
Jeffrey Andrew Sparks
金额：
$ 81.44万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-27 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10207955
关键词：
Acetaldehyde Adult Affect Ants Autoantibodies Autoimmunity Award Chest Clinical Colorado Complication Cyprinus carpio Data Data Set Derivation procedure Development Disease Enrollment Etiology Excess Mortality Exposure to Fibrosis Foundations Funding General Hospitals Genetic Genotype Goals High Resolution Computed Tomography Hospitals Image Inflammation Inflammatory Arthritis Inhalant dose form Interstitial Lung Diseases Investigation Joints Lead Life Style Link Lung MUC5B gene Malondialdehyde Massachusetts Measures Medicine Michigan Mission Morbidity - disease rate Mucous Membrane National Institute of Arthritis and Musculoskeletal and Skin Diseases Nested Case-Control Study Observational Study Outcome Pain Pathogenesis Patient Recruitments Patients Performance Phenotype Post-Translational Protein Processing Predisposition Prevention strategy Process Production Prospective cohort Protein-arginine deiminase Proteins Pulmonary Inflammation Registries Research Research Personnel Rheumatoid Arthritis Rheumatoid Factor Risk Risk Factors Role Scanning Serum Site Smoker Smoking Smoking History Surface Sushi Domain Symptoms Testing United States National Institutes of Health Universities Variant Woman X-Ray Computed Tomography biobank chest computed tomography chronic autoimmune disease chronic pain clinical risk cohort cyclic citrullinated peptide disability disease phenotype disorder risk high risk improved insight lung injury medical schools mortality neoantigens patient registry patient stratification predictive modeling prevent professor promoter prospective screening seropositive systemic autoimmune disease systemic inflammatory response

项目摘要

PROJECT SUMMARY Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting nearly 1% of adults causing a painful, destructive inflammatory arthritis with serious long-term consequences including chronic pain, disability, accumulation of morbidities, and excess mortality. Patients with RA are susceptible to developing interstitial lung disease (ILD), a devastating complication with high morbidity and mortality. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (ant-CCP) autoantibodies are elevated in the serum of two-thirds of patients with RA. Seropositive RA patients are more likely to develop RA-ILD. Previous studies suggest that mucosal surfaces of the lung may be an initiating site for RA, after smoking or exposure to other inhalants, where RF, anti-CCP, and other autoantibodies may be formed years before joint symptoms develop. Aberrant post- translational modifications (PTM) to proteins may serve as neoantigens forming local inflammation in the lungs and production of autoantibodies related to PTM. This site of lung injury may later manifest clinically as RA-ILD and articular inflammation may impact risk for subclinical RA-ILD through systemic inflammation. Therefore, RA-related autoantibodies, articular inflammation, and RA-ILD may be linked throughout the disease course of RA. These investigations will study whether RA-related autoantibodies and articular inflammation predict subclinical and clinically-apparent RA-ILD. In the first aim, we will perform a nested case-control study using a derivation dataset in the Brigham RA Sequential Study (BRASS) and a replication dataset in the Partners Biobank. BRASS and the Partners Biobank are patient registries for research. We have identified RA-ILD cases as well as controls with RA but no ILD in these research registries and propose to measure clinical and PTM RA- related autoantibodies. In the second aim, we will perform a multi-site prospective observational study of patients with new-onset RA who will undergo serial measures of articular inflammation and chest high- resolution computed tomography imaging to evaluate whether the burden of articular inflammation in early RA reflects risk for subclinical RA-ILD. In the third aim, we will analyze whether smokers in COPDGene with elevation of RA-related autoantibodies without articular RA are more likely to have subclinical ILD. COPDGene is a large US nationwide observational study that has already been phenotyped for presence or absence of ILA on chest computed tomography imaging. Dr. Jeffrey Sparks (the PI) is an Assistant Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School. He is an early-stage investigator previously funded by NIAMS through K23 and R03 awards to investigate the role of the lung in RA etiology and outcomes. These proposed studies will interrogate the overarching hypothesis that RA autoimmunity, articular inflammation, and ILD are intrinsically linked across the disease course of RA (pre-RA, early RA, established RA). These studies have high potential for impactful results that will elucidate the pathogenesis of both RA and RA-ILD and may ultimately provide the evidence basis for RA-ILD screening and prevention strategies for this devastating complication.

项目总结