Interrogation of STAT3 activation in patients with polyarticular juvenile arthritis

Abstract

Abstract Juvenile idiopathic arthritis (JIA) can cause pain and disability, but early disease control improves outcomes. The polyarticular JIA (polyJIA) subset is clinically similar to adult rheumatoid arthritis (RA), yet its pathogenesis remains incompletely understood. A pathway of interest in polyJIA is STAT3 signaling. STAT3 is a transcription factor critical to development of inflammatory Th17 cells and modulation of regulatory T cells. Elevated Th17s and activated STAT3 have been shown in RA. We aimed to profile T cell subsets and STAT3 activation in polyJIA. Blood from 13 patients with polyJIA was collected at initial diagnosis and serially until remission. Peripheral blood mononuclear cells were isolated and T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Regulatory T cells from patients with polyJIA were found at similar levels as pediatric controls. However, treatment naïve polyJIA patients had increased Th17s compared to pediatric controls (0.15% v 0.44%, p=0.037). We identified IL-17 and IFN-γ dual+ helper T cells (non-classical Th1s) appearing in post-treatment samples from polyJIA patients. After stimulation (IL-6, IL-27 or IFN-α), a subset of polyJIA patients had highly activated STAT3, but not STAT1 or STAT5, in CD3+CD4+ T cells. A better understanding of the mechanisms underlying polyJIA is needed for more efficient and effective clinical care. Although multiple therapeutics to treat JIA exist, a biomarker-driven approach to treatment does not. Patients with polyJIA have increased Th17s and a subset have highly activated STAT3. These immunologic features may help identify patients that would benefit from upfront, tailored treatment with therapeutics targeting this pathway.