Thursday, May 1, 2025
5/1/2025
Type I interferon Impacts Treatment Response in Rheumatoid Arthritis - Rheumatoid arthritis (RA) is a common multisystem inflammatory condition. Delay in effective treatment results in increased morbidity and mortality, and a heavy economic burden. Current treatment strategies are empiric because we have no markers to suggest which therapy is best for an individual. Tumor necrosis factor inhibitors (TNFi) are the most common initial biologic treatment in RA. Responses are variable, with approximately 30% not responding and another 30% having only partial response. We have shown in test and validation cohorts that pre-treatment circulating type I IFN (T1IFN) predicts non-response to TNFi. Pre-treatment IFN-β to IFN-α activity ratio >1.3 was strongly predictive of non-response to TNFi (specificity=77% in the validation cohort). No patient with a ratio >1.3 achieved remission or low disease activity. We used single cell analysis to study blood monocyte (Mo) gene expression in RA patients with high vs. low IFN-β-to-α activity ratio and found major differences between the groups, supporting downstream effects upon a critical effector cell population. Presence or absence of JAK1 expression strongly aligned with IFN-β-to-α ratio. In RA, blood Mo invade synovium, and local stimuli drive expansion of inflammatory macrophage (Mφ) populations. It is not known whether the circulating IFN ratio in RA reflects T1IFN levels and pathway activation in the synovium, and this will be examined in Aim 1. The relative contributions of blood vs. synovial signals in the diapedesis and differentiation of Mo to inflammatory Mo/Mφs is not known. This will be explored in Aim 2 using a novel perfusable organ-on-a-chip system. HYPOTHESIS: RA TNFi non-responders have increased blood and synovial IFN-β/α ratio that results in altered expression of JAK1 and IFN-stimulated genes, increased diapedesis and differentiation of Mo into inflammatory Mφs. I will explore this overarching hypothesis in 2 Specific Aims: (1) Detect differences in T1IFN, pathway activation, and histopathology in synovium of RA patients who have a EULAR good response or no response to TNFi. (2) Determine the impact of IFN-α and IFN-β on RA Mo, Mo-derived Mφ, and fibroblast-like synoviocytes. I will gain new skills biased and unbiased analyses, data architecture/artificial intelligence, and in use of a bioengineered microphysiological system to interrogate human RA biology, which I need to successfully launch and establish myself as an independent investigator advancing precision medicine in RA. Results will provide fertile ground for future directions. Select coursework will complement my research and fortify my skills. Presenting, publishing, and submitting grants will sharpen my abilities. I aim to use cell biology, immunology, and contemporary approaches to understand differences among RA patients and allow for prognostication and a treatment approach tailored to an individual’s disease and personal immunology. NYU is heavily invested with the resources and infrastructure to promote basic, clinical and translational research. The density of high caliber scientists and collegial environment is ideal for an ESI transitioning to independence. Support from a K08 is vital in my efforts to expand my research skills and empower my independent career.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).