Synovial Tissue‐Guided Interleukin‐17A Inhibition for Refractory Arthritis in a Patient With Systemic Juvenile Idiopathic Arthritis

Objective The objective of this study was to characterize the clinical, immunologic, and synovial tissue features of a patient with a systemic juvenile idiopathic arthritis (sJIA) who carries a novel heterozygous STAT5B loss‐of‐function variant (p.Gln139Ter) and whose arthritis responded markedly to interleukin‐17A (IL‐17A) inhibition. Methods Patient blood was compared with blood from healthy donors (n = 5) for immunoblotting, phospho‐flow cytometry and immune cell profiling. Patient synovial fluid was compared with synovial fluid from seronegative oligoarticular or polyarticular juvenile idiopathic arthritis (oligo/poly JIA) (n = 5–6) for immune cell profiling. Patient synovial tissue was compared with synovial tissue from children with oligo/poly JIA (n = 11) using Xenium spatial transcriptomics. Results CD4 + T cells from the patient exhibited impaired STAT5 phosphorylation ( z score = ‐11.1). Synovial fluid CD4 + T cells showed markedly increased IL‐17A production (z score = 34.5) and reduced FOXP3 expression ( z score = ‐2.25) in regulatory T cells. Spatial transcriptomics revealed T helper 17 (Th17) cells distributed diffusely throughout the patient's synovium, in contrast to JIA controls in which Th17 cells were largely restricted to tertiary lymphoid structures (TLS) ( z score = 3.08). The patient's severe arthritis, previously refractory to IL‐1 and IL‐6 blockade, improved markedly after IL‐17A inhibition. Conclusion STAT5B haploinsufficiency may contribute to an sJIA phenotype characterized by Th17/IL‐17 dysregulation and an altered distribution of Th17 cells outside TLS. Integrated genetic, functional, and spatial tissue analyses may help identify therapeutic targets in refractory pediatric arthritis.