ORCID ID

0000-0002-9649-3588

Graduation Date

Fall 12-20-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Ted R. Mikuls, MD, MSPH

Second Advisor

Geoffrey M. Thiele, PhD

Third Advisor

Fang Yu, PhD

Fourth Advisor

Shinobu Watanabe-Galloway, PhD

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease that predisposes afflicted individuals to reduced quality of life, physical disability, and premature mortality. While joint involvement is the primary manifestation of RA, extra-articular features including lung disease are responsible for a significant portion of the excess mortality. In this dissertation I demonstrate the contribution of chronic lung diseases to premature mortality in RA, contrasting with the more widely recognized comorbidity in RA of cardiovascular disease. Then, I establish that a novel serum biomarker, anti-malondialdehyde-acetaldehyde adduct (MAA) antibody, is associated with the presence of interstitial lung disease (ILD) in RA subjects. Further implicating its role in the pathogenesis of RA-ILD, I will demonstrate the presence of MAA as well as the co-localization of MAA with RA autoantigens and immune effectors cells in the lungs of RA-ILD subjects. Finally, I describe how biomedical informatics algorithms that incorporate multiple ILD diagnosis codes, provider specialty, and diagnostic testing can accurately classify ILD status in RA subjects. Together, these studies advance our ability to identify RA-associated lung diseases across the spectrum of clinical and translational research. These results will pave the way for future clinical and translational research studies to compose biomarker panels that aid in the screening of RA subjects for lung disease, identify pathways that could be targeted for novel therapeutics in RA-ILD, and facilitate the completion of comparative effectiveness and outcomes research studies using real-world data.

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