AB0466 IDENTIFICATION OF POTENTIAL BLOOD BIOMARKERS FOR JAK INHIBITOR TREATMENT-RELATED PATHWAYS THROUGH BULK RNA SEQUENCING ANALYSIS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background

Targeted small molecule therapy that inhibits receptor-mediated signaling via Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathways has become an established strategy for the treatment of rheumatoid arthritis (RA). The rationale for using these inhibitors is that JAKs have critical roles in specific pathological mechanisms and thus their targeted inhibition can lead to effective disease control. Despite JAK inhibitors (JAKi) having been approved for the treatment of RA and other systemic or organ-specific autoimmune diseases, the DAS28 response to JAKi is highly variable, emphasizing the need for reliable biomarkers.

Objectives

To reveal the potential impact of JAKi on treating RA patients, we aim to identify the biomarkers related to the responses of JAKi from blood bulk RNA-seq.

Methods

To better understand the molecular mechanisms of JAKi, we analyzed the global transcriptomics profile (using bulk RNA-seq) in peripheral blood mononuclear cells (PBMCs) that were collected from three RA patients before and after the treatment of JAKi.

Results

Comparing the responder and non-responder groups, we identified 1366 upregulated differentially expressed genes (DEGs) and 1366 upregulated differentially expressed genes (DEGs), and 1630 DEGs. To reveal further insight into the biological roles of the DEGs, we performed GO pathway analysis. Compared with responders, we found that the non-responders have a higher inflammation rate. In addition, non-responders have higher expression of genes that are involved in the JAKs signaling pathway. Specifically, gene profiling of non-responder represents higher Type I and II interferon pathway. In contrast, gene profiling of the responder represents a higher IL-12 pathway.

Conclusion

These changes were accompanied by changes in broader immune cell composition, based on the deconvolution of bulk RNA-sequencing data. In summary, our study revealed several phenotypic and cellular changes that underlie the clinical improvement with JAKi.

Reference

[1]Henkel M DF, Jones DM, Wilkerson ER, Horne W, Kolls JK, et al. RNA transcripts from peripheral blood mononuclear cells as predictors of clinical responsiveness in rheumatoid arthritis subjects treated with abatacept. Arthritis and rheumatism. 2013;65 Suppl 10:1485.

Acknowledgements:

NIL.

Disclosure of Interests

None Declared.