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

Woogil Song, Eunyoung Emily Lee, Seongwan Park, Baekgyu Choi, Min-Gang Kim, Seo Yoon Ban, Se Rim Choi, Jeong Yeon Kim, Seon Uk Kim, Jong-Il Kim, Eui-Cheol Shin, Inkyung Jung (), Jeong Seok Lee () and Eun Young Lee ()
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Woogil Song: Korea Advanced Institute of Science and Technology (KAIST)
Eunyoung Emily Lee: Korea Institute of Radiological and Medical Sciences
Seongwan Park: Korea Advanced Institute of Science and Technology (KAIST)
Baekgyu Choi: Korea Advanced Institute of Science and Technology (KAIST)
Min-Gang Kim: Seoul National University College of Medicine
Seo Yoon Ban: Seoul National University College of Medicine
Se Rim Choi: Hanyang University Hospital for Rheumatic Diseases
Jeong Yeon Kim: Seoul National University College of Medicine
Seon Uk Kim: Seoul National University College of Medicine
Jong-Il Kim: Seoul National University College of Medicine
Eui-Cheol Shin: Korea Advanced Institute of Science and Technology (KAIST)
Inkyung Jung: Korea Advanced Institute of Science and Technology (KAIST)
Jeong Seok Lee: Korea Advanced Institute of Science and Technology (KAIST)
Eun Young Lee: Seoul National University College of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that primarily affects the enthesis and may culminate in bony ankylosis of the spine. Despite TNF inhibitor (TNFi) being foundational in managing active inflammation, 30-40% of patients with AS remain non-responsive. Through longitudinal and multi-omics profiling of peripheral blood mononuclear cells from TNFi-receiving patients with AS, here we reveal that elevated type I IFN signatures at baseline are associated with poor TNFi response, leading to a paradoxical enhancement of IFN signatures and Th17 responses following TNFi therapy. Among type I IFN-related genes, we identify and validate AIF-1 as a predictive biomarker reflecting the inherent IFN signature that differentiates responders from non-responders. AIF-1 also contributes to an inflammatory cycle by increasing IFNα receptor expression and Th17 responses. In summary, our findings advocate for a personalized approach to managing AS by considering individual variations in AIF-1 levels and IFN signatures.

Date: 2025
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DOI: 10.1038/s41467-025-60445-6

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