Background/Purpose: Enthesitis is considered to be an early event in psoriatic arthritis (PsA) course, representing a hallmark feature of the disease. So far, most of the data on enthesitis in PsA are based on clinical assessment as well as MRI or ultrasound examinations, due to the challenge in retrieving good quality entheseal tissue for molecular analysis. However, pre-clinical studies as well as surgical invasive approaches on spondylarthritis patients showed that interleukin-17 (IL-17) is a key molecule in enthesitis pathogenesis, as also confirmed by the high clinical efficacy of IL-17 blockers in patients with this manifestation. Up to date, there are no molecular data assessing how IL-17 blockade ameliorates enthesitis in human. Therefore, deep omics analysis of these ultra-specialized tissues might expand our insights on PsA pathogenesis as well as provide information on treatment response. The aim of the study is to investigate the immune and the non-immune compartment in active enthesitis of PsA patients and their changes upon IL-17A neutralization.

Methods: Methods:

Minimal-invasive ultrasound-guided biopsy of the lateral epicondyle was performed, as previously described¹, on 10 PsA patients with active elbow enthesitis before and after at least 3 months of treatment with secukinumab. All patients were biologic naïve at time of inclusion. Only one patient did not receive the second biopsy. Once harvested, the samples were fixed and conventional histology staining as well as second harmonic generation (SHG) were performed for morphologic evaluation and entheseal region identification¹. Further slides were used for protein expression, through Hyperion imaging mass cytometry (IMC) and for RNA expression, through GeoMx spatial transcriptomic technology.

Results: 40% of the patients included into the study were female with an average age of 54 (± 9 SD). At the time of screening DAPSA, LEI and SPARCC were (mean ± SD) 23 ± 12, 2 ± 1 and 4 ± 3, respectively and by the end of the study (week 28), 11 ± 10, 1 ± 1, 1 ± 1, respectively. Entheseal region within the biopsies was identified by SHG. Neutrophils, CD4+T cells and ILC significantly decreased upon IL-17 blockade (p=0.017, 0.017, 0.021, respectively), with particular respect to the IL-17A positive fractions of each cell type. Beside quantitative reduction of IL-17-producing immune cells, major effects have been observed on transcriptional states of resident entheseal cells.

Spatial deconvolution analysis revealed a significant increase in the abundance of pro-resolving CD200+ fibroblasts² and ILC2 cells following treatment (p=0.055, 0.049, respectively). Moreover, these cells were found to spatially colocalize together and with MERTK+ macrophages (CD200+ R=0.57 p=0.0041, ILC2 R=0.39 p=0.063), while dissociating with CD4+ T cells (CD200+ R=-0.74 p=0.000, ILC2 R=-0.64 p=0.001).

Conclusion: Here we show for the first time a full picture of cellular changes in the microarchitecture of inflamed entheses upon anti-IL-17 treatment. Resolving entheseal inflammation was not only associated with a reduction of the cellular load of IL-17-producing cells but also with tissue intrinsic modulations towards a pro-resolving microenvironment upon treatment with IL-17 inhibitors.

« Back to ACR Convergence 2024

ACR Meeting Abstracts - https://acrabstracts.org/abstract/results-from-the-biopsy-driven-ebio-study-entheseal-tissue-signature-in-response-to-il-17-blockade-in-psoriatic-arthritis/