OP0150 DRUG-FREE REMISSION IS CHARACTERISED BY EXPANSION OF CITRULLINATED VIMENTIN-REACTIVE IMMUNE-REGULATORY CD4+CD39+TIGIThi T CELLS IN ACPA+ RHEUMATOID ARTHRITIS

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Background: There is a need for immunotherapy that sustains symptom remission without ongoing need for disease modifying drugs (DMARDs). In a phase 1b trial of antigen-specific tolerising immunotherapy in ACPA+ RA patients, expansion of peripheral blood CD4+ T cells recognising either collagen II 259-273 or vimentinCit64 59-71 was associated with reduced DAS28, suggesting that expanding autoreactive T cells may regulate RA under tolerogenic conditions [1]. In the BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (BIO-FLARE) study [2], 50% of patients who stop conventional synthetic (cs)DMARDs maintain "drug-free remission" (DFR) for at least 6 months, potentially also reflecting a state of immune tolerance. Objectives: The current study compared the frequency and phenotype of peripheral blood CD4+ T cells recognising citrullinated (cit) vimentin in ACPA+ HLA-DRB1*04:01, *01:01 or *04:04+ RA patients who flared or remained in DFR 6 months after stopping csDMARDs with the aim to characterise the antigen-specific T cells in DFR. Methods: Individuals with RA receiving methotrexate, sulfasalazine and hydroxychloroquine, singly or in combination (csDMARDs), and in clinician-defined remission (DAS28-CRP <2.4) were recruited into the BIO-FLARE study. Treatment was stopped and participants monitored over 24 weeks. Flare was defined as DAS28-CRP ≥3.2 at any visit or DAS28-CRP ≥2.4 twice within 14 days. PBMC were analysed using a 32 marker spectral flow panel, incorporating HLA-DRB1*04:01/01:01-VimentinCit64 59-71 or HLA-DRB1*04:04-VimentinCit71 66-78 tetramers. Data were analysed using Wilcoxon signed-rank tests. Results: Nineteen flaring patients were compared with 17 patients remaining in DFR 24 weeks after stopping therapy. At baseline the number and phenotype of cit-vimentin-specific CD4+ T cells was comparable in both groups, except that CD38 expression was higher in the group subsequently maintaining DFR. In each group, cit-vimentin-specific CD25 + CD127 - Treg increased and expression of CD55 decreased over time (Figure 1A). At flare or the preceding time point a lower proportion of cit-vimentin-specific CD4+ T cells expressed CD161, fewer were naïve, and CXCR3 expression was reduced. In the DFR group, cit-vimentin-specific CD4+ T cells expanded, the proportion expressing CD39 increased, whilst expression of TIGIT increased and CCR6 decreased (Figure 1B-D). Conclusion: Together these data suggest that, in patients achieving DFR, there is ongoing cit-vimentin autoantigen presentation and T cell activation under tolerogenic conditions, expanding antigen-specific CD4+ T cells expressing markers of immune regulation and anergy. Reduced circulating CD161+CXCR3hi antigen-specific T cells during flare suggests migration of effector memory autoreactive T cells to synovial inflammatory sites. REFERENCES: [1] Sonigra A et al. JCI Insight 2022. [2] Rayner F et al. BMC Rheumatol. 2021. Acknowledgements: NIL . Disclosure of Interests: Amy E. Anderson: None declared, Henrique Lemos: None declared, Hendrik Nel: None declared, Sofia Sorbet Santiago: None declared, Jia Yi Hee: None declared, Fiona Rayner: None declared, Abbie Degnan: None declared, Imogen Wilson: None declared, Julie Diboll: None declared, Jasmine Sim: None declared, Andrew Melville: None declared, Stefan Siebert AbbVie, Amgen, AstraZeneca, Janssen, Novartis, Pfizer, Syncona, Teijin Pharma and UCB, BMS, Boehringer-Ingelheim, Eli Lilly, GSK, Janssen and UCB, Iain B. McInnes: None declared, Carl S Goodyear: None declared, Catharien Hilkens: None declared, Andrew Filer: None declared, Karim Raza: None declared, Christopher D Buckley: None declared, Hugh Reid: None declared, Kenneth F Baker Modern Biosciences, Pfizer and Genentech, Arthur Pratt: None declared, Jamie Rossjohn: None declared, Ranjeny Thomas: None declared, John D Isaacs: None declared. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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