Background/Purpose: A better understanding of the pathogenesis of polyJIA is necessary to guide more effective clinical care, such as the development of data-driven approaches to guide selection of the ideal therapeutic agent for an individual patient. One inflammatory pathway of interest is the JAK-STAT signaling cascade. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s), as well as influencing T regulatory cell (Tregs) development. Previous studies have demonstrated elevated Th17 cells and activated STAT3 in adult patients with rheumatoid arthritis, but less is known about T cell subsets and STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls.

Methods: Blood from 17 patients with polyJIA was collected at initial diagnosis (treatment-naïve) and after remission was achieved. Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4+ T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry.

Results: Treatment naïve polyJIA patients had increased Th17 cells (CD3+CD4+interleukin(IL)-17+) compared to controls (0.15% v 0.44%, p=0.0371), but, Tregs (CD3+CD4+CD25+FOXP3+) from patients with polyJIA did not differ from controls. We identified dual IL-17+ and interferon (IFN)-gamma+ expressing CD4+ T cells (Th17/1s) in patients, but not controls. Further, both Th17/1s and ex-Th17s (CD3+CD4+CCR6+CD161+IFN-gamma+IL-17neg) were increased in patients post-treatment (0.065% v 0.29%, p=0.0117 and 1.42% v 2.26%, p=0.0195, respectively). The patients with the highest Th17/1 cells post-treatment remained therapy-bound, but other patients were successfully weaned off medications following remission. Ex vivo stimulation of CD4+ T cells (using IL-6 or IFN-alpha) from treatment-naïve patients compared to controls demonstrated smaller changes in STAT3 phosphorylation between stimulated and unstimulated cells.

Conclusion: Patients with polyJIA have increased baseline Th17 cells and are less responsive to inflammatory cytokine stimulation ex vivo , possibly reflecting higher tonic STAT3 activation in vivo . These quantifiable immune markers may diagnostically identify patients that would benefit from upfront, pathway-focused anti-cytokine biologic therapeutics. Our data also suggest that Th17/1s, a subset not detected in controls but increased in samples from treated patients, should be further evaluated as a prognostic tool to stratify patients in clinical remission on medication. Future work will explore both these proposed diagnostic and prognostic biomarkers.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interrogation-of-stat3-activation-in-patients-with-polyarticular-juvenile-arthritis-polyjia/