Transcriptional immune programs underlying inadequate response to tumor necrosis factor inhibitors in ankylosing spondylitis.

Inadequate response to tumor necrosis factor inhibitors (TNFi) in ankylosing spondylitis (AS) remains common. As the immunoregulatory and immunometabolic alterations across TNFi inadequate responder (TNFi-IR) subsets remain unexplored, we characterized molecular profiles across distinct immune subsets in TNFi-IRs and identified signatures linked to TNFi-IR. We compared subset-specific expression in 16 TNFi-IRs and 13 TNFi responders (TNFi-Rs). Gene expression demonstrated fair-good discriminative power (area under the curve: 0.70-0.87). TNFi-IRs displayed distinct transcriptomic profiles and aberrant transcription factor activity amplifying inflammatory responses across immune subsets. Pathway analysis revealed synergistic association between immune subsets and inadequate response, with recurrent alterations in mitochondrial respiration accompanied by metabolic reprogramming exacerbating immune activation. Altered cell-cell communication hinted at impaired IL-10 and IL-19 regulatory signaling. We identified candidates with repurposing potential for TNFi-IRs. These findings reveal crucial therapeutic targets spanning genes, transcription factors, pathways, metabolites, and cell-cell communication signaling for bench-to-bedside investigation.