Predictive molecular signatures for successful tapering of canakinumab in systemic juvenile idiopathic arthritis.

OBJECTIVES: Canakinumab induces clinical remission in a substantial proportion of patients with systemic juvenile idiopathic arthritis (sJIA), although not all achieve a complete response. However, tapering and withdrawal frequently lead to disease flares. This study aimed to identify serum and transcriptomic biomarkers that predict successful or unsuccessful tapering of canakinumab in sJIA. METHODS: Seventy-nine patients with sJIA in remission on canakinumab enrolled in a randomised withdrawal study were analysed; 71 had samples available for gene expression profiling. Serum biomarkers were quantified using Luminex assays. Whole-blood RNA was assessed by RNA sequencing (RNA-Seq) and a targeted 67-gene NanoString panel informed by exploratory analyses. Differential expression, hierarchical clustering, and enrichment analyses were performed. Biomarkers and gene signatures were compared between patients who later successfully withdrew canakinumab and those who experienced unsuccessful tapering. RESULTS: Lower serum levels of sCD163, CXCL9, interleukin (IL)-1RA, and IL-18 were associated with successful tapering. RNA-Seq showed marked differences between active and inactive sJIA and revealed that future nonresponders exhibited lower expression of type I IFN-induced and higher expression of erythopoiesis-related genes. NanoString profiling identified 9 genes (ATF6, BCL6, FAS, IL1B, MAPK1, PPARG, SLC25A37, TNFAIP3, and UBE2D1) overexpressed in patients with unsuccessful tapering, reflecting persistent inflammation and cellular stress. A composite score of these genes discriminated successful from unsuccessful discontinuation (area under curve, AUC, 0.71). CONCLUSIONS: Serum inflammatory markers and targeted gene expression signatures identify patients with sJIA at higher risk of flare during canakinumab tapering. Combined molecular biomarker profiling may enable individualised tapering strategies and support precision medicine approaches for Still's disease.