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Background <p>IL-17&#xa0;A plays a role in the pathology of spondyloarthritis (SpA), as evidenced by the clinical efficacy of IL-17&#xa0;A inhibitors (IL-17Ai). Nevertheless, the exact role of IL-17&#xa0;A in driving synovial inflammation and pathological remodeling remains unknown. In this study, we investigated the molecular pathways affected by IL-17Ai in SpA synovitis to determine whether this response is tissue- and/or treatment-specific.</p> Methods <p>Synovial biopsies from 12 peripheral SpA (pSpA) patients before and after 12 weeks of IL-17Ai treatment were analyzed by RNA-sequencing and qPCRs. The synovial tissue response to IL-17Ai in 7 psoriatic arthritis (PsA) patients was compared to open-source gene expression data of skin biopsies from 15 psoriasis (PsO) patients treated with IL-17Ai, and synovial biopsies from 7 PsA patients receiving IL-12p40/IL-23p40 blockade.</p> Results <p>Compared to baseline, IL-17Ai significantly modulated the expression of 1255 genes (549 upregulated and 706 downregulated, FDR &lt; 0.1) in the synovium at week 12. The downregulated genes were predominantly associated with inflammatory processes and stromal functions. Comprehensive analysis revealed that IL-17Ai-mediated suppression of bone remodeling is independent of its inhibition of inflammatory pathways. While IL-17Ai consistently attenuated inflammation-related pathways in both psoriatic joints and skin, its effect on bone remodeling pathways was specific to the synovium. This distinguishes IL-17Ai from IL-12p40/IL-23p40 inhibitors, which, while mitigating synovial inflammation, did not affect tissue remodeling.</p> Conclusions <p>Our findings provide new insights into the molecular mechanisms of IL-17&#xa0;A blockade in pSpA, underscoring its unique role in selectively targeting bone-remodeling processes specific to the joints of individuals with SpA.</p>

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Dual impact of interleukin-17 A blockade on inflammatory and stromal pathways in peripheral spondyloarthritis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月5日

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  • Ihsan Hammoura,
  • Renée H. Fiechter,
  • Leonieke J. J. van Mens,
  • Henriëtte M. Y. de Jong,
  • Inka A. Fluri,
  • Sander W. Tas,
  • Dominique L.P. Baeten,
  • Marleen G.H. van de Sande,
  • Nataliya G. Yeremenko

摘要

Background

IL-17 A plays a role in the pathology of spondyloarthritis (SpA), as evidenced by the clinical efficacy of IL-17 A inhibitors (IL-17Ai). Nevertheless, the exact role of IL-17 A in driving synovial inflammation and pathological remodeling remains unknown. In this study, we investigated the molecular pathways affected by IL-17Ai in SpA synovitis to determine whether this response is tissue- and/or treatment-specific.

Methods

Synovial biopsies from 12 peripheral SpA (pSpA) patients before and after 12 weeks of IL-17Ai treatment were analyzed by RNA-sequencing and qPCRs. The synovial tissue response to IL-17Ai in 7 psoriatic arthritis (PsA) patients was compared to open-source gene expression data of skin biopsies from 15 psoriasis (PsO) patients treated with IL-17Ai, and synovial biopsies from 7 PsA patients receiving IL-12p40/IL-23p40 blockade.

Results

Compared to baseline, IL-17Ai significantly modulated the expression of 1255 genes (549 upregulated and 706 downregulated, FDR < 0.1) in the synovium at week 12. The downregulated genes were predominantly associated with inflammatory processes and stromal functions. Comprehensive analysis revealed that IL-17Ai-mediated suppression of bone remodeling is independent of its inhibition of inflammatory pathways. While IL-17Ai consistently attenuated inflammation-related pathways in both psoriatic joints and skin, its effect on bone remodeling pathways was specific to the synovium. This distinguishes IL-17Ai from IL-12p40/IL-23p40 inhibitors, which, while mitigating synovial inflammation, did not affect tissue remodeling.

Conclusions

Our findings provide new insights into the molecular mechanisms of IL-17 A blockade in pSpA, underscoring its unique role in selectively targeting bone-remodeling processes specific to the joints of individuals with SpA.