Research Objective: The objective of our proposed research is to identify patients with rheumatoid arthritis associated interstitial lung disease (RA-ILD) that are at the highest risk for progressive disease and may potentially benefit from more targeted, and potentially less harmful, treatment. Unmet Health Need: Deaths from RA-ILD are not improving despite an overall decline in RA mortality. Novel, noninvasive methods are urgently needed to identify those with progressive RA-ILD so that interventions can delay the development of end-stage lung disease. Rationale: RA-ILD is a heterogeneous condition and the majority will experience disease progression resulting in lung transplantation and/or death. Despite the heterogeneity of RA-ILD, all RA-ILD is treated the same without taking in to account the known heterogeneity of this disease. This immunosuppressive-based treatment approach has led to unpredictable natural histories, inconsistent responses to treatment, and ultimately irreversible fibrosis leading to increased symptom burden, worse quality of life, and ultimately death. Hypothesis: Our overall hypothesis is that novel quantitative imaging and specific blood markers will be associated with a progressive phenotype in RA-ILD. Aims: We will evaluate the role of novel quantitative imaging (Specific Aim 1), peripheral blood telomere length (Specific Aim 2) and peripheral blood mononuclear cell (PBMC) gene expression (Specific Aim 3) in predicting progressive RA-ILD as defined by 12-month change in FVC% predicted. We will also explore the overlap and additive strength of each of these predictors in a composite profile (Specific Aim 4). Approach: To achieve the proposed aims, we will recruit 364 subjects with RA-ILD at the time of ILD diagnosis by an ILD pulmonologist and prior to treatment with lung-specific immunosuppression. Recruitment will occur at 4 expert ILD centers across the country with longitudinal collection of clinical, physiologic, and radiologic data with collection of serial biospecimens. The overall goal of this proposal is to identify the subset of RA-ILD patients that are at highest risk for disease progression following diagnosis by using novel imaging and specific blood markers. This risk stratification will help us determine whether or not immunosuppression should be started on an RA-ILD patient at the time of diagnosis. This knowledge will ultimately lead to less harm to patients with RA-ILD by decreasing exposure to immunosuppression in the subset that is most vulnerable. This proposal will lead to future precision-medicine based investigations for RA-ILD treatment and will lay the foundation to perform clinical trials that will determine the role of additional treatment pathways (e.g., observation, antifibrotic therapy, novel therapeutics and/or combination therapy) in RA-ILD, leading to reduction in harm and delaying the development of end- stage lung disease.

Project Narrative/Public health relevance: The mortality associated with rheumatoid arthritis associated interstitial lung disease (RA-ILD) is unacceptably high and clinicians are unable to accurately predict prognosis for a disease that is markedly heterogeneous. The overall goal of the proposed research is to identify patients with RA-ILD that are at the highest risk for progressive disease and may potentially benefit from more targeted, and potentially less harmful, treatment. Our proposed research focuses on a critical unmet public health need in RA-ILD by contributing to the fundamental understanding of identification of clinically meaningful disease phenotypes.