From IL-23/IL-17 to GM-CSF: how is the immuno-inflammatory continuum reshaped in spondyloarthritis?

Abstract

Spondyloarthritis (SpA) encompasses axial SpA/ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and inflammatory bowel disease-associated arthritis, unified by entheseal inflammation, extra-musculoskeletal manifestations, and a strong but atypical genetic signature. Although SpA lacks the highly specific autoantibodies and immune-complex pathology typical of prototypic autoimmune rheumatic diseases, adaptive immune participation is evident, positioning SpA along an immuno-inflammatory continuum bridging autoimmunity and autoinflammation. The IL-23/IL-17 axis has provided a powerful framework linking barrier perturbation and tissue stress to neutrophil-rich inflammation and to therapeutic efficacy of cytokine blockade. However, IL-17 is increasingly best viewed as an “ecosystem” output generated by multiple lymphocyte lineages, including innate-like cells, under tissue-specific constraints, with partial uncoupling from continuous IL-23 dependence in selected sites and disease stages. These features expose the limits of a linear IL-23/IL-17 model and help explain therapeutic heterogeneity and the imperfect coupling between inflammation control and osteoproliferative outcomes. In parallel, granulocyte-macrophage colony-stimulating factor (GM-CSF) is emerging as a myeloid amplifier that links lymphocyte activation to durable monocyte and macrophage effector programs, reinforcing cytokine redundancy, including TNF and IL-1 family circuits, and promoting inflammatory “lock-in”. We propose a “stage × tissue” model in which early IL-23/IL-17 licensing transitions toward a GM-CSF-licensed, IL-17-dominant, partially IL-23-uncoupled, myeloid lock-in phase. We also discuss biomarker strategies integrating cytokine-module readouts with imaging to support precision trials.