Background/Purpose: Inhibition of IL-6 signaling is one of the most established strategies for RA treatment. Tocilizumab (TCZ) is the pioneer which blocks IL-6 signaling by preventing IL-6 from binding to its receptors. Tofacitinib (TOF) inhibits Janus kinase (JAK) 1, JAK3 and, to a lesser extent, JAK2. Recently, Baricitinib (BAR), JAK 1 and JAK2 selective kinase inhibitor, were also approved to treat RA. These JAK inhibitors are known to inhibit cytokine signaling IL-6. It is very important to know whether these treatments affect common biological processes or disparate, because it will provide a rationale for switching each other if one of these treatments resulted in lack of efficacy. In this study, we investigate the gene-expression modification profiles among TOF, BAR and TCZ treatments.

Methods: Total of 38 RA cases were analyzed, including TOF (n=15), BAR (n=10:) and TCZ (n=13) treatment groups. 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 quantifying the expressions of transcripts by multiplex sequencing, differentially expressed genes (DEGs) were selected by paired comparison (post vs. pre) with using paired T-test. And then, hierarchical clustering analysis and enrichment analysis using gene ontology (GO) terms were performed.

Results: From the comparison of post- vs. pre-treatment of TOF, BAR and TCZ, the 120, 62 and 193 genes were selected as DEGs respectively. It seems to be discrete depending on the treatment, because overlapped genes were only 1.0% in up-regulated and 5.7% in down-regulated genes. The hierarchical clustering with expression profiles of these DEGs showed major 4 clusters. 92.3％ of TCZ and 70% of BAR cases were segregated into 1st and 3rd clusters respectively, while those of TOF cases fell into 2nd and 4th clusters. Disparate GO terms were enriched in each DEGs group. For example, genes relevant to viral defense including ‘response to type I interferon (IFN)’ were suppressed in TOF group. Meanwhile, down regulation of genes involved in phosphorylation process including ‘IL-7 signaling’ seemed to be significant in BAR group. It is noteworthy that terms related to wound healing such as ‘platelet activation’ were enriched in the down-regulated genes of TCZ group.

Conclusion: It is speculated that the downstream biological cascade for TOF, BAR and TCZ treatment might be shared, as IL-6 signaling is mediated by JAK1/JAK2/TYK2 activation. However, the influence of these treatments over the transcriptome in the peripheral blood seems to be disparate. Enrichment analysis using GO terms also indicated that different biological processes were involved in the effect of each treatment. Our findings will support a rationale for switching each other if one of these treatments resulted in lack of efficacy. An increased risk of herpes zoster by a treatment with JAK inhibitors has been well recognized. It makes sense because IFN signaling is also mediated by JAK/STAT pathway. On the other hand, we have experienced a case with exacerbation of skin ulcer during TCZ treatment despite the activity of RA was absolutely under control. It is accounted for by the suppression of genes involved in wound healing after TCZ treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-to-il-6-or-specific-jaks-for-ra-treatment-seeking-a-rationale-for-switching-each-other-if-one-of-these-treatments-resulted-in-lack-of-efficacy/