Background/Purpose: Enthesitis is an early event in the course of psoriatic arthritis (PsA) and a hallmark feature of the disease. Currently, much of the understanding of enthesitis relies on clinical assessment and imaging techniques such as MRI and ultrasound, which complicates detailed molecular analysis due to the difficulty in acquiring high-quality entheseal tissues. Previous pre-clinical studies and surgical data indicate that interleukin-17 (IL-17) plays a pivotal role in the pathogenesis of enthesitis, supported by the efficacy of IL-17 blockers in clinical settings. However, molecular insights on how IL-17 blockade affects enthesitis in humans remain limited. This study aims to investigate the immune and non-immune compartments in active enthesitis of PsA patients and their alterations following IL-17A inhibition.

Methods: We performed minimally invasive ultrasound-guided biopsies of the lateral epicondyle on ten biologic-naïve PsA patients with active elbow enthesitis before and after six months of treatment with secukinumab. One patient did not undergo the second biopsy. Tissue samples underwent conventional histological staining, second harmonic generation (SHG) for morphological assessment, Hyperion imaging mass cytometry (IMC) for protein expression, scRNAseq and GeoMx spatial transcriptomic technology for RNA expression analysis.

Results: Eleven patients with active psoriatic arthritis (PsA) and lateral epicondyle enthesitis were screened, resulting in ten enrollments, where 40% were female. The mean Disease Activity in Psoriatic Arthritis (DAPSA) score at screening was 22.8 ± 12.6, indicating moderate disease activity, with an average of 9.6 ± 6.8 tender joints and a SPARCC entheseal score of 4.30 ± 2.75. Nine patients had previously failed conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Following treatment with secukinumab, PD signals significantly decreased six months later (P = 0.0156), and notable improvements were observed in DAPSA (11.8 ± 10.5; P = 0.0078) and SPARCC scores (1.4 ± 2.5; P = 0.0039). Adverse events were mild and managed well. Total IL-17A+ cell counts decreased substantially, contributing to the therapeutic response as assessed by Imaging mass cytometry. Spatial transcriptomics highlighted a significant shift towards DKK3 and CD200 positive fibroblasts following IL-17A inhibition, indicating a transition to a pro-resolving phenotype in the entheseal tissue. Furthermore, pathways related to osteoblast differentiation were significantly reduced upon treatment with secukinumab, indicating a decreased transcriptional activity associated with osteoblasts post-treatment.

Conclusion: Here we show a full picture of cellular changes in the microarchitecture of inflamed entheses upon anti-IL-17A treatment. Resolving entheseal inflammation is not only associated with reduction of IL-17-producing cells but also with DKK3/CD200+ fibroblast / ILC2 activation and osteoblast control.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-il-17a-inhibition-on-entheseal-osteoblast-and-fibroblast-dynamics-in-psoriatic-arthritis-insights-from-the-ebio-biopsy-study/