Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
The advances in understanding of the molecular nature of immune cell receptors enabled to offer new oral, targeted therapies. Tofacitinib (TOF) is the first selective kinase inhibitor to be approved to treat rheumatoid arthritis (RA). TOF inhibits Janus kinase (JAK) 1, JAK3 and, to a lesser extent, JAK2, which is known to lead inhibition of cytokine signaling including interleukin (IL)-6. Tocilizumab (TCZ), an anti-IL6 receptor monoclonal antibody, also block IL-6 signaling by preventing IL-6 from binding to both membrane-bound and soluble receptors. IL-6 is known to have a wide range of biological activities including B cell and T cell differentiation. As Spleen tyrosine kinase (SYK) participates in the activation of B cells and T cells, a Syk kinase inhibitor, fostamatinib (FOS) have been a candidate for RA treatment. Although the targets of these three treatments are specific, the downstream biological activities seem to be wide. In order to investigate whether the effect of these treatments share common biological process or are disparate, we conducted transcriptome analysis with using next-generation sequencing.
The study includes a total of 30 RA patients treated by these three medications (TOF 6-20mg/d:15, FOS 100-200mg/d:4, TCZ 8mg/kg/4w:11). Peripheral blood was drawn at just before (pre) and 3 months after (post) these treatments. Total RNAs were then extracted with using PAXgene miRNA kit. After constructing single-stranded, strand-specific libraries (length 50bp), multiplex sequencing was done. After quantifying the expressions of transcripts, hierarchical clustering analysis was performed. And then, differentialy expressed genes (DEGs) were selected by paired comparison (post vs. pre), setting thresholds at 2-fold change up/down and less than P=0.05 in corrected paired T-test.
In total, 57571 genes/transcripts including 976 newly predicted genes were quantified. By a hierarchical clustering analysis, the pre and the post of FOS or TOF treatment were segregated each other while those of TCZ treatment were nearest neighbors, indicating that TCZ has the least influence over the transcriptome. The 118, 344 and 121 genes were selected as DEGs from the comparison of post vs. pre treatment of TOF, FOS or TCZ, respectively. Disparate gene ontology (GO) terms were enriched in each DEGs group. Terms relevant to immunity including ‘JAK-STAT cascade’ were enriched in the down-regulated genes in the TOF group. Of 344 DEGs from the FOS group, 30 were related to “ribosomal proteins” and 29 of them were up-regulated. In the TCZ group, terms related to “extra cellular matrix”, such as “extracellular matrix binding” and “wound healing” were detected.
Although some of downstream biological cascade for JAK, SYK or IL-6 appear to share, the influence of these treatments over the transcriptome in the peripheral blood seems to be disparate. The hierarchical clustering shows TCZ treatment has the least influence on transcriptome. On the other hand, it is noteworthy that FOS treatment seems to have much greater influence upon transcriptome as compare with others. Enrichment analysis using GO terms indicated that different biological processes were involved in the effect of each treatment.
Eli Lilly Japan Inc,
Meiji Seika Pharma Inc,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-il-6-jak-or-syk-an-analysis-of-transcriptome-alteration-in-peripheral-blood-by-ra-treatments/