Type 1 interferon signature and allograft inflammatory factor-1 contribute to refractoriness to TNF inhibition in ankylosing spondylitis

Introduction

Spondyloarthritis (SpA) is an inflammatory disease affecting the axial skeleton and peripheral joints^{1, 2–3}. It is characterized by enthesitis, inflammation at the sites where tendons and ligaments attach to the bone⁴. SpA encompasses several subtypes, including ankylosing spondylitis (AS), a chronic inflammatory condition characterized by inflammation in the spine along with extra-articular manifestations, such as uveitis, psoriasis, inflammatory bowel disease, and aortitis⁵. However, the mechanisms by which pathological immune cells are aberrantly activated in patients with AS remain unclear. Effective disease-modifying treatments for AS became available with the advent of TNF inhibitors (TNFi)^{6, 7–8}. Nearly half of active patients with AS do not experience significant improvement with initial NSAID treatment⁹ and are candidates for treatment with TNFi. However, only 50-60% of TNFi users achieve >50% improvement in disease activity^6,7. Considering the limited response rate, high cost, and safety issues associated with prolonged TNFi use^10,11, risk stratification is required based on the mechanisms of TNFi failure rather than the current ‘try-and-fail’ approach.

The role of monocytes in AS and their responses to TNFα and TNFi treatment have been of particular interest. TNFα has been shown to induce significant changes in monocyte differentiation and function, promoting an inflammatory phenotype characterized by increased production of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNFα^12,13. In addition, TNFα can induce a state of tolerance in monocytes, in which pre-exposure to TNFα reduces their sensitivity to subsequent stimulation with this cytokine^14,15. Conversely, TNFi treatment has been reported to suppress these inflammatory pathways¹². However, the impact of TNFi on monocyte subsets and their role in mediating the response or non-response to treatment in patients with AS remains poorly understood.

Recent research has highlighted the role of IL-17-producing CD4⁺ T cells, known as T helper 17 (Th17) cells, in the pathogenesis of AS. The therapeutic efficacy of IL-17A inhibitor (IL-17i) highlights the importance of the Th17 axis in AS^16,17. Previous studies have shown that TNF promotes Th17 differentiation by stimulating monocytes to produce IL-6 and IL-1β¹⁸, whereas TNFi suppresses Th17 cell functions¹⁹. However, the clinical response to TNFi is heterogeneous among patients with rheumatoid arthritis (RA)...