Abstract
<jats:p>Objective In the first year after onset of the autoimmune disease RA (RA), 40-60% do not achieve remission on conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). To understand how autoreactive T cells may contribute to unstable or non-remission, we studied CD4+ T cells, including those recognising citrullinated (Cit) vimentin in participants with RA. Methods Two cohorts of drug-naive new-onset participants with RA were treated with csDMARDs. Disease activity score (DAS28-CRP) and peripheral blood (PB) mononuclear cells were collected longitudinally. In HLA-DR-shared epitope+ cohort 1 (n=21), T cells were assessed with a 17-marker spectral flow panel, incorporating HLA-DRB1*04:01/01:01-VimentinCit64(59-71) or HLA-DRB1*04:04-VimentinCit71(66-78) tetramers. T cell subset changes over time were assessed in remitting and non-remitting participants using a generalized linear mixed model with a negative binomial distribution. In cohort 2 (n=26), the transcriptome of disaggregated synovial tissue (ST) and PB CD4+ T cells was analysed at baseline, and ST biopsy spatial proteomics at baseline and 6 months. Results CD4+CXCR5-PD1+ peripheral helper T cells (Tph), including Cit-vimentin-reactive Tph, CD4+CCR7+CXCR5-PD1+ stem-like Tph and TIGIT+PD1+ Tph were increased with moderate/high DAS28-CRP at any time point. Remission outcome was associated with low CD4+ follicular helper T cell (Tfh) and Cit-vimentin-reactive Tfh through year one. In non-remitting participants, Tph/fh infiltrated germinal-centre-like ST aggregates. This decreased in remission. Circulating TIGIT+ Tph genes reflected B lymphoid activation and lymph node egress, while in ST they reflected local differentiation. Conclusion Persistently high circulating TIGIT+ Tph and Tfh, including Cit-vimentin specificities, reflect antigen-presenting B-cell interactions, and reduced response to csDMARDs in recent-onset RA.</jats:p>