Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue

Abstract

ObjectivesOur 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.MethodsSynovial 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.ResultsGene 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.ConclusionWe 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.

Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis

“…Somewhat in contrast with these observations, we previously reported that different disease-modifying antirheumatic drugs (DMARDs) downregulate a robust set of genes in common, notwithstanding their direct targets or mechanisms of action 6. This would suggest a high degree of interdependence between the different cell populations and processes in the synovium that therefore exert knock-on effects on each other.…”

A Mechanistic Cellular Atlas of the Rheumatic Joint

“…dataset section) between the paired post-and pretreatment samples as an overlay to identify enriched signalling pathways from the fibroblast map in RA patients after treatment with abatacept compared to untreated RA patients. The list of DEG was downloaded from the supplementary materials of the associated publication (Triaille et al, 2021). Results of the GSE analysis for the upregulated genes are shown in Figure 7.…”

Repolarization of Unbalanced Macrophages: Unmet Medical Need in Chronic Inflammation and Cancer

“…Abatacept (ABA) is a fusion protein (extracellular domain of cytotoxic-T-lymphocyte antigen 4 (CTLA-4) protein and Fc region of an IgG1) designed to disrupt the interaction between T cells and antigen presenting cells. When assessed in synovium of treated patients, it does not seem to reduce immune infiltration but this observation has to be interpreted considering synovia pathotypes [92]. ABA indirectly downregulates the activation of MP by T cells and subsequently IL6, TNF, IL1β, IL12p70, and TGFβ by RA synovial MP and monocyte-derived MP in co-culture experiments [93,94].…”

“…However, despite not directly targeting MP, in treated patients, RTX alters monocyte-derived MP functions with an increase in B cell activating factor (BAFF), IL10, and CD86 expression, as well as a decrease in TNF secretion [97]. It should be noted that RTX, ABA, TCZ, and adalimumab (a TNFi) share a common transcriptomic downregulation of genes involved in both T cell and myeloid leukocyte activation pathways, such as LCK, STAT1, STAT3, JAK2, and JAK3, irrespective of the primary drug's target [92].…”