Candidate pharmacogenetic signals at CCL2 and ITPA associated with JAK inhibitor response in Taiwanese rheumatoid arthritis.

OBJECTIVES

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent synovial inflammation. Janus kinase inhibitors (JAKi) are effective targeted therapies for RA, yet clinical responses vary. We aimed to identify genetic predictors of JAKi effectiveness in Taiwanese patients with RA.

METHODS

In this retrospective study, 275 RA patients treated with tofacitinib, baricitinib, or upadacitinib in the Taiwan Precision Medicine Initiative (TPMI) were recruited and classified as Effective or Non-effective. Fifty-eight candidate single-nucleotide polymorphisms (SNPs) were evaluated using existing Taiwan Biobank v2 array data. We integrated cell-type-specific eQTL resources (scQTLbase) and single-cell RNA sequencing (scRNA-seq) to support gene-level associations.

RESULTS

In this cohort (Effective, n=217; Non-effective, n=58), CCL2 rs1024611/rs4586 and ITPA rs1127354 were the top nominal candidates (all p<0.05). In scQTLbase (GRCh38), rs1024611 associated with higher CCL2 in dendritic cells, and rs1127354 with higher ITPA in CD14+ monocytes. scRNA-seq showed higher CCL2 in Non-effective patients (p<0.001), predominantly across M0/M1/M2 monocytes. ITPA was higher in Effective patients (p=0.018), most notably in M2 monocytes (p<0.001), with elevated ITPA also observed in M1 monocytes of Non-effective patients (p 0.004).

CONCLUSIONS

Our data prioritise CCL2 and ITPA as candidate pharmacogenetic signals for JAKi response. Given the use of a persistence-based effectiveness endpoint and the exploratory nature of secondary EULAR-based outcome assessments, independent replication using standardised ACR/EULAR outcomes is warranted.