OP0069 SEQUENTIAL B CELL/T CELL THERAPY TO RE-INDUCE HUMORAL IMMUNE TOLERANCE IN ACPA-POSITIVE RHEUMATOID ARTHRITIS (TOLERA): FIRST RESULTS FROM PHASE 2, OPEN LABEL, RANDOMIZED CONTROLLED TRIAL COMPARING RITUXIMAB AND ABATACEPT WITH RITUXIMAB ALONE
Authors: A. Kleyer, D. Simon, S. Bayat, K. Tascilar, G. Corte, F. Fagni, A. Wilhelm, R. Pfeifle, F. Hartmann, A. Hueber, G. Schett, G. Krönke
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Anti-citrullinated protein antibodies (ACPA), are associated with a more severe course of rheumatoid arthritis (RA).[1] There are currently no therapies to efficiently halt autoantibody production and restore immune tolerance in these patients. Both B cell-targeting therapy (Rituximab) and T cell-targeting therapy (Abatacept) have been shown to reduce ACPA levels and occasionally induce seroconversion.[2] We hypothesized that sequentially combining Rituximab (RTX) and Abatacept (ABA) will enhance the tolerogenic potential of these drugs, by eliminating autoantibody production and leading to seroconversion with the aim to achieve "deep" immunological remission" and re-induce immune tolerance. <h3>Objectives:</h3> To evaluate the effect of a sequential RTX/ABA treatment to lower ACPA titers, eliminate auto-antibody production and attenuate disease activity in RA patients in comparison to RTX alone. <h3>Methods:</h3> The TOLERA Trial ((EudraCT: 2018-003877-91) is a phase 2 randomized-controlled open-label clinical study, aiming to evaluate sequential RTX/ABA therapy in ACPA+ RA patients with active. Main inclusion criteria were CCP2 positivity (≥20RE/ml) and inadequate response or intolerance to MTX, anti-TNF or IL-6 blockade. Participants received two initial RTX infusions of 1000 mg after which they were randomized 1:1 to receive ABA sc 125 mg/week (ABA) or enter a watch-and-wait phase (control). The primary outcome was number of pts with anti-CCP2 antibody seroconversion (&lt;5U/ml) at wk 52, comparing RTX/ABA to RTX/best medical care. Secondary outcomes included changes in anti-CCP2 AB levels, IgG subclasses, AB glycosylation profiles, CCP2-specific B-cell numbers, DAS28, SDAI, CDAI. Between-group comparisons for primary analysis were conducted on the intention-to-treat population. Analyses were conducted using Fisher's exact test and linear mixed effects regression with BL adjustment, using all post-baseline data. Flare-free survival was compared with log-rank test. We herein report results on the primary outcome, anti-CCP2 AB levels, disease activity and flares at 52 wks. <h3>Results:</h3> 20 patients received RTX treatment, followed by 1:1 randomization. 10 pts were allocated to each group: RTX/ABA (4 females, age 57 [16], disease duration 10[11] years); control arm (5 females, age 49 [11], disease duration 5 [4] years).18 patients completed the trial. Patients in the RTX/ABA arm were older, had higher anti-CCP2 AB, and a longer disease duration at BL (Table 1). The primary outcome, seroconversion, occurred in none of the participants. Anti-CCP2 antibody levels were higher at 52 wks in the RTX/ABA group, compared to the control group as it was at BL (ABA:374.47 [441.64] U/ml, Control: 54.12 [51.98], Figure 1A), the mean between-group difference at 52 wks after adjustment for BL levels was -2.49 (-144.31 to 139.34, p=0.97) indicating no significant difference. The overall disease activity was moderate (DAS-28 ESR: 4.8 (1.4)) at BL and did not show a significant difference between groups at 52 wks (RTX/ABA: 3.21 [1.30], Control: 3.32 [0.88], Figure 1B) with an adjusted mean difference (95%CI) of -0.07 (-1.13 to 0.99, p=0.90). 9 patients in the RTX/ABA arm and 6 patients in the control arm remained flare-free (log-rank p=0.086, Figure-1C). There were 6 SAEs (5/6 in the control group). <h3>Conclusion:</h3> Sequential treatment with RTX, followed by ABA did not lead to loss of anti-CCP AB and did not reduce the antibody levels in comparison to RTX alone. Interestingly we did not observe a significant difference in terms of disease activity or excess serious adverse events. Limitations of our study were the open-label design and the small sample size. The latter was intended to detect a large effect that would justify further pursuit of research on sequential treatment in case of a positive finding. <h3>REFERENCES:</h3> [1] McInnes, I.B. and G. Schett, <i>The pathogenesis of rheumatoid arthritis.</i> N Engl J Med, 2011. <b>365</b>(23): p. 2205-19. [2] Wunderlich, C., et al., <i>Effects of DMARDs on citrullinated peptide autoantibody levels in RA patients-A longitudinal analysis.</i> Semin Arthritis Rheum, 2017. <b>46</b>(6): p. 709-714. <h3>Acknowledgements:</h3> Mr Schuster/Dr. Dagmar Werner for assisting the trial - BMS for providing Abatacept/This study was supported by German Research Foundation (DFG) PANDORA FOR 2886, CRC1181, Leibniz Award to G.S. <h3>Disclosure of Interests:</h3> Arnd Kleyer Abbvie, Lilly, MSD, Novartis, BMS, UCB, Alexion, Medac, Lilly, Lilly, Medac, Novartis, David Simon: None declared, Sara Bayat: None declared, Koray Tascilar: None declared, Giulia Corte: None declared, Filippo Fagni: None declared, Artur Wilhelm: None declared, Rene Pfeifle: None declared, Fabian Hartmann: None declared, Axel Hueber: None declared, Georg Schett: None declared, Gerhard Krönke BMS.