Why Do Some Therapies Work While Others Fail? Mechanisms of Response and Emerging Treatments in axial Spondyloarthritis: 2026 SPARTAN Annual Meeting Proceedings.

PURPOSE OF REVIEW: This review summarizes recent advances in the pathogenesis of axial spondyloarthritis (axSpA), examines why TNF, IL-17, and JAK inhibition is effective whereas IL-23 blockade has not demonstrated clinical efficacy, and highlights emerging therapeutic targets.

RECENT FINDINGS: TNF, IL-17 A, and IL-17 F are key drivers of inflammation in axSpA and may also contribute to pathological new bone formation. HLA-B27 can present peptides to CD8+ T cells, potentially expanding pathogenic T-cell populations, including TRBV9+ (V9 T cell receptor beta chain) cells, that produce TNF and IL-17. Although antigen-presenting cell (APC)-derived IL-23 can promote IL-17 production, its contribution may be limited once inflammation is established, potentially explaining the lack of efficacy of IL-23 blockade in axSpA. In addition, a type I interferon (IFN) signature has been associated with anti-TNF/IL-17-refractory disease. Emerging therapeutic targets include TRBV9, macrophage migration inhibitory factor (MIF), and hypoxia-inducible factor-1α (HIF-1α). Current evidence validates TNF, IL-17, and JAK inhibition over IL-23 blockade. Type I IFN, TRBV9, MIF, and HIF-1α represent novel targets for future therapies.