1318: Abatacept Modulates Both Global and Citrulline Specific T Cell Signatures: Results from Inhibition of Co-Simulation in Rheumatoid Arthritis Phase IV Trial

Ravi Kumar Sharma¹, Aysin Tulunay Virlan², Louise Bennett³, John Cole³, Sam McAllister², Sara Turcinov⁴, Samantha Miller³, Fraser Morton³, Ashley Gilmour³, Sean Kerrigan³, Anatoly Dubnovitsky¹, Leonid Padyukov⁵, Caron Paterson³, William Kwok⁶, René Toes⁷, Lars Klareskog⁸, Arthur Pratt⁹, John Isaacs¹⁰, Sean Connolly¹¹, Duncan Porter³, Stefan Siebert¹², Iain McInnes³, Vivianne Malmström⁸ and Carl Goodyear³, ¹Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, ²University of Glasgow - School of Infection & Immunity, Glasgow, United Kingdom, ³University of Glasgow, Glasgow, United Kingdom, ⁴Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet. Theme of Inflammation and Ageing, Medical Unit Gastro, Derma, Rheuma, Karolinska University Hospital, Stockholm, Sweden, ⁵Karolinska Institutet, Solna, Sweden, ⁶Benaroya Research Institute at Virginia Mason, Seattle, WA, ⁷Leiden University Medical Center, Leiden, Netherlands, ⁸Karolinska Institutet, Stockholm, Sweden, ⁹Immunity and Inflammation Theme, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom, ¹⁰Translational and Clinical Research Institute, Newcastle University and Musculoskeletal Unit, Newcastle Hospitals, Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom, ¹¹Bristol Myers Squibb, Princeton, NJ, ¹²School of Infection and Immunity, University of Glasgow, Glasgow, United Kingdom

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.


R. Kumar Sharma: None; A. Virlan: None; L. Bennett: None; J. Cole: None; S. McAllister: None; S. Turcinov: None; S. Miller: None; F. Morton: None; A. Gilmour: None; S. Kerrigan: None; A. Dubnovitsky: None; L. Padyukov: None; C. Paterson: None; W. Kwok: None; R. Toes: Bristol-Myers Squibb(BMS), 5; L. Klareskog: None; A. Pratt: Gilead, 5, GlaxoSmithKlein(GSK), 5, Pfizer, 5; J. Isaacs: AbbVie/Abbott, 6, AnaptysBio, 2, Annexon, 2, AstraZeneca, 2, Bristol-Myers Squibb(BMS), 2, Eli Lilly, 1, Galapagos, 2, Gilead, 1, GSK, 5, Istesso, 2, Janssen, 5, Kira Biotech, 2, Ono Pharma, 2, Pfizer, 5, Revelo, 2, Sonoma Biotherapeutics, 2, Teijin Ltd, 2; S. Connolly: Bristol Myers Squibb, 3, 11; D. Porter: None; S. Siebert: AbbVie, 6, Amgen, 5, 6, AstraZeneca, 6, Boehringer-Ingelheim, 5, Bristol-Myers Squibb(BMS), 5, Eli Lilly, 5, 6, GlaxoSmithKlein(GSK), 5, 6, Janssen, 5, 6, UCB, 5, 6; I. McInnes: AbbVie, 2, Amgen, 2, AstraZeneca, 2, Bristol Myers Squibb, 2, 5, Cabaletta, 2, 11, Causeway Therapeutics, 2, 11, Celgene, 2, 5, Compugen, 2, 11, Dextera, 11, Eli Lilly, 2, EveloBio, 1, 2, 4, 11, Gilead, 2, Janssen, 2, 5, Moonlake, 2, NHS GGC, 4, Novartis, 2, 5, Pfizer, 2, Sanofi, 2, UCB, 2, 5, Versus Arthritis, 12, Trustee Status; V. Malmström: Eli Lilly, 1, Janssen, 5, ONO, 1, Pfizer, 5; C. Goodyear: Abbvie, 6, AstraZeneca, 2, 5, Bristol-Myers Squibb(BMS), 2, 5, Celgene, 5, Eli Lilly, 5, Galvani, 2, 5, GlaxoSmithKlein(GSK), 5, Istesso, 5, Janssen, 5, MedAnnex, 2, 5, Medincell, 2, MiroBio, 5, Revolo, 5, UCB, 5, 6.