Pôle de pathologies rhumatismales systémiques et inflammatoires, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
Service d'Hématologie, Oncologie et Rhumatologie pédiatrique, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Front Immunol. 2021 Aug 30;12:724895. doi: 10.3389/fimmu.2021.724895. eCollection 2021.
Our goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab.
Synovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3, CD20, and CD68 cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR.
Gene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders.
We provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.
评估阿巴西普对 RA 滑膜的组织学和转录组学影响，并将其与之前发表的来自另外四种 DMARDs（托珠单抗、利妥昔单抗、甲氨蝶呤和阿达木单抗）的四项研究数据进行比较。
使用超声引导下的活检技术，从 14 例接受每周皮下注射 125mg 阿巴西普治疗的患者的受累关节中获取滑膜组织。对石蜡切片进行 CD3、CD20 和 CD68 细胞浸润的染色和评分。使用 GeneChip Human Genome U133 Plus 2.0 阵列（Affymetrix）进行转录谱分析，并在 Genespring GX（Agilent）上进行分析。在 Genespring GX、Metascape 和 EnrichR 上进行通路分析。
基因表达分析鉴定出 304 个在滑膜组织中被阿巴西普调节的转录本。下调的基因在免疫过程中显著富集，与我们在其他治疗方法中的发现强烈重叠。将这些研究的数据进行汇总，发现被 DMARDs 下调的基因显著富集 T 细胞和髓样白细胞激活途径。有趣的是，DMARDs 似乎对这两条途径有协同作用，与中度和非应答者相比，对治疗的良好应答者的影响更强。
我们提供的证据表明，五种 DMARDs 对 RA 滑膜的作用最终都集中在相同的途径上。这证实了之前的研究表明，DMARDs 的下游存在共同的介质，而与它们的主要靶点无关。
