R01AR077607

Rheumatoid Arthritis-Related Autoantibodies, Articular Inflammation, and RA-Associated Interstitial Lung Disease - 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. These consequences include 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 (anti-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 the mucosal surfaces of the lung may be an initiating site for RA, after smoking or exposure to other inhalants. It is believed that 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 the 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.

The investigations proposed in this study will examine whether RA-related autoantibodies and articular inflammation predict subclinical and clinically-apparent RA-ILD. In the first aim, a nested case-control study will be performed 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. RA-ILD cases and controls with RA but no ILD have been identified in these research registries, and the study aims to measure clinical and PTM RA-related autoantibodies.

In the second aim, a multi-site prospective observational study will be conducted on patients with new-onset RA. These patients 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 the risk for subclinical RA-ILD.

In the third aim, the study 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 the presence or absence of ILA on chest computed tomography imaging.

Dr. Jeffrey Sparks, the principal investigator, 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. Ultimately, they may provide the evidence basis for RA-ILD screening and prevention strategies for this devastating complication.

Brigham & Womens Hospital

THE NATIONAL INSTITUTE OF AND MUSCULOSKELETAL AND SKIN DISEASES (NIAMS) MISSION IS TO SUPPORT RESEARCH INTO THE CAUSES, TREATMENT, AND PREVENTION OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES, TRAINING OF BASIC AND CLINICAL SCIENTISTS TO CARRY OUT THIS RESEARCH, AND DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN THESE DISEASES. THE EXTRAMURAL PROGRAM PROMOTES AND SUPPORTS BASIC, TRANSLATIONAL, AND CLINICAL STUDIES OF SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES, SKIN BIOLOGY AND DISEASES, BONE BIOLOGY AND DISEASES, MUSCLE BIOLOGY AND DISEASES, AND JOINT BIOLOGY AND DISEASES AND ORTHOPAEDICS. NIAMS SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES PROGRAMS ADDRESS BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS AND OBSERVATIONAL AND MECHANISTIC STUDIES, FOCUSED ON IMMUNE-MEDIATED ARTHRITIS AND AUTOIMMUNE-RELATED ACUTE AND CHRONIC DISORDERS IN ADULTS AND CHILDREN. NIAMS SKIN BIOLOGY AND DISEASES PROGRAMS SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN SKIN, INCLUDING BOTH COMMON AND RARE SKIN DISEASES. THESE PROGRAMS INCLUDE INVESTIGATIONS OF THE BASIC MOLECULAR, CELLULAR, AND DEVELOPMENTAL BIOLOGY OF SKIN, AS WELL AS STUDIES OF SKIN AS AN IMMUNE, SENSORY, ENDOCRINE, AND METABOLIC ORGAN. NIAMS BONE BIOLOGY AND DISEASES PROGRAMS SUPPORT RESEARCH ON THE CONTROL OF BONE FORMATION, RESORPTION, AND MINERALIZATION AS WELL AS THE EFFECTS OF SIGNALING MOLECULES ON BONE CELLS. THEY SUPPORT CLINICAL STUDIES OF INTERVENTIONS TO PREVENT FRACTURES ASSOCIATED WITH OSTEOPOROSIS AND RESEARCH INTO LESS COMMON BONE DISEASES. NIAMS MUSCLE BIOLOGY AND DISEASES PROGRAMS ENCOURAGE RESEARCH ON MUSCLE DEVELOPMENTAL BIOLOGY, GROWTH, MAINTENANCE, AND HYPERTROPHY, PHYSIOLOGY OF CONTRACTION, STRUCTURAL BIOLOGY OF THE CONTRACTILE APPARATUS, DISEASE MECHANISMS, BIOMARKERS AND OUTCOME MEASURES, AND DEVELOPMENT AND CLINICAL TESTING OF THERAPIES FOR CONDITIONS INCLUDING THE MUSCULAR DYSTROPHIES. NIAMS JOINT BIOLOGY, DISEASES, AND ORTHOPAEDICS PROGRAMS SUPPORT A BROAD SPECTRUM OF RESEARCH CENTERED ON THE INTERPLAY AMONG THE BODY'S MUSCLES, BONES, AND CONNECTIVE TISSUES. THEY ENCOURAGE TISSUE ENGINEERING AND REGENERATIVE MEDICINE RESEARCH, MOLECULAR BIOLOGY, IMAGING, AND CLINICAL RESEARCH, AND THE TREATMENT AND PREVENTION OF ORTHOPAEDIC CONDITIONS. NIAMS PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.846 - Arthritis, Musculoskeletal and Skin Diseases Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

Boston, Massachusetts 021156110 United States

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NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 353% from $814,364 to $3,692,582.