Exploratory single-cell multiomics suggests naive CD4+ T cell dysregulation in treatment refractory rheumatoid arthritis

Around 20% of patients with rheumatoid arthritis (RA) have disease that remains refractory to multiple targeted treatments, highlighting a major clinical challenge. We determine single-nucleus transcriptional and chromatin landscapes (10x Genomics Epi Multiome) on 14,625 primary CD4 + T-cells isolated from treatment-naive early and refractory (defined as per the EULAR definition of difficult-to-treat) patients with RA. We systematically analyze circulating regulatory profiles to reveal potential mechanisms and therapeutic targets that may contribute to the difficult-to-treat phenotype. We highlight disease-stage-specific alterations in naive and Th1-like memory CD4 + T-cells. In particular, refractory naive cells show signatures of heightened activation, upregulation of pathways aligning with T cell anergy, diminished regulation at regulatory loci (e.g., FOXP1, ICOS) and blunted stimulation responses; consistent with a more desensitized or exhausted state. Genes such as LGALS3, ZBTB7B and FOXO4 emerge as potential candidate regulators of the difficult-to-treat state. Finally, through RA GWAS integration, we prioritize putative causal variants in cis-regulatory elements.