Functional Response Biomarkers for Systemic Sclerosis-Associated Interstitial Lung Disease

Interstitial lung disease (ILD) is a leading cause of systemic sclerosis (SSc)-related death in the United States and the World. ILD occurs in the majority of patients with SSc and progresses the most rapidly early in the disease course. We have demonstrated that patients who experience SSc-ILD progression within the first two years of their disease have an increased risk of premature mortality. Therefore, modifying the course of SSc- ILD at this early disease stage through therapeutic intervention can improve outcomes for patients. However, no reliable treatment response biomarkers exist for SSc-ILD to personalize therapy. Clinicians struggle to determine whether a patient is responding to a specific therapy using existing response tools that rely on clinical, physiologic and radiologic assessments, which are imperfect in their ability to categorize patients who are and are not benefiting from therapy. Further, measurable changes in the existing response tools only occur after a substantial amount of time (1 year or more) and lung damage has occurred from ILD. Response biomarkers that signal therapeutic efficacy early in the course of treatment are greatly needed. With the expansion of treatment options for SSc-ILD, reliable response biomarkers could guide clinicians to stop administering an ineffective agent and start an alternative agent before the patient experiences irreversible lung damage. Our group has demonstrated that specific circulating biomarkers, such as C-reactive protein, interleukin-6, and chemokine (C-X-C motif) ligand 4, chemokine ligand 18 and Krebs von den Lungen 6, decrease in response to treatment with mycophenolate mofetil (MMF) in the context of a clinical trial. A greater decline in these biomarkers at 1 year was associated with future improvement in lung function at 2 years. We herein propose to validate the aforementioned response biomarkers in an observational cohort of patients with SSc-ILD and determine whether early changes (at 3, 6 months) in these and other circulating biomarkers predict progressive pulmonary fibrosis (PPF) at 1 year. We also propose to study a novel response biomarker for SSc-ILD: Positron emission tomography (PET) with a tracer that targets fibroblast activation protein (FAP). Through measuring the change in pulmonary 68Ga-FAPi-46 uptake, we aim to track the evolution of fibrotic remodeling activity in the lungs and link these changes to changes in circulating biomarkers. We hypothesize that a panel of circulating biomarkers will predict changes in 68Ga-FAPi-46 uptake, as well as PPF at 1 year. To test this hypothesis, we will perform biochemical and functional imaging biomarker assessments early in the treatment course and evaluate patients for PPF at 1 year. This work will: (1) Identify circulating response biomarkers for SSc-ILD; (2) Determine whether functional imaging plays a role in monitoring treatment response in SSc-ILD; (3) Understand how 68Ga-FAPi-46 uptake correlates with radiologic features of ILD (e.g., fibrosis, ground glass, honeycombing); (4) Reveal biological pathways linked to fibrotic remodeling activity on PET imaging. This work is not only relevant for SSc, but also for other rheumatic diseases associated with ILD. Project Number: 1R01HL174555-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Elizabeth Volkmann | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $693,558 | Activity Code: R01 | Study Section: Clinical Translational Imaging Science Study Section[CTIS] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17455501A1