Background/Purpose: Clinical outcomes in Rheumatoid arthritis (RA) have improved with the introduction of biological and targeted synthetic disease modifying anti-rheumatic drugs (b & tsDMARDs). Abatacept (CTLA4-Ig), modulates T cell co-stimulation by interacting with CD80/86 expressed on antigen-presenting cells (APC) and has the potential to interfere both with proinflammatory amplification pathways and autoimmunity. In the Phase IV Inhibition of co-stimulation in RA (ICosRA) trial, we aimed to determine the impact of Abatacept on the peripheral frequencies and phenotypes of citrulline specific T cells in seropositive and shared epitope HLA-DR*04 positive RA patients.

Methods: HLA-DRB1*04:01 or *04:04 ACPA⁺ RA patients were recruited into a 24-week open label study (n= 25). Peripheral blood mononuclear cells were harvested at baseline, 12 weeks, and 24 weeks after abatacept treatment. A panel of 18 markers expressed on various T-cell subsets and 12 known citrullinated epitope specific HLA class II tetramers was employed to investigate citrulline specific and broad T-cell responses, using spectral flow-cytometry. One-way Anova or Friedman test, with post-hoc tests were used for testing statistical significance.

Results: Evaluation of the global CD4⁺ T cell compartment revealed that abatacept treatment significantly decreased CD4⁺CD69⁺ recently activated T cells (p = 0.03), CD4⁺HLA-DR⁺ T cells (p = 0.005) and CXCR3^–CCR6⁺CD4⁺ Th17 cells (p = 0.05). Abatacept treatment also significantly decreased CD4⁺CD25⁺CD127^– regulatory T cells (p= 0.03). This was accompanied by a significant decrease in expression of HLA-DR (p = 0.0004), CD137 (p = 0.003), CD95 (p = 0.0004) and CD38 (p = 0.03), but not PD1. Characterization of the citrulline specific T cell compartment, demonstrated that citrullinated Tenascin C specific T cells dominated the autoreactive TCR fine-specificities (p< 0.05). Moreover, the frequencies of citrulline specific T cells decreased significantly over time (p= 0.003). Patients responding to therapy showed significantly higher baseline number of citrulline specific T cells than non-responders (p= 0.05). TCR sequencing of in-vitro expanded cit-Tenascin C specific T cells from 4 patients at baseline and subsequent follow up, revealed persistence of autoreactive TCR clones.

Conclusion: Abatacept decreases both global and citrulline specific T cell populations. Notably, prior to treatment there were higher numbers of autoreactive T cells in those patients that respond; suggesting that not only do these individuals potentially have a stronger autoimmune disease component but are also more receptive to therapeutic intervention targeting inhibition of co-stimulation. Finally, the persistence of citrulline specific T cell clones underscores the notion that abatacept does not fully abrogate the T cell compartment’s propensity to drive autoimmunity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abatacept-modulates-both-global-and-citrulline-specific-t-cell-signatures-results-from-inhibition-of-co-simulation-in-rheumatoid-arthritis-phase-iv-trial/