ABATACEPT TO SILENCE ANTI-CITRULLINATED PROTEIN ANTIBODY-EXPRESSING B CELLS IN RHEUMATOID ARTHRITIS: THE ASCARA TRIAL

N. Blomberg, J. Kwekkeboom, S. Böhringer, T. Huizinga, R. Toes, H. U. SchererLeiden University Medical Center (LUMC), Rheumatology, Leiden, Netherlands Leiden University Medical Center (LUMC), Biomedical Data Sciences, Leiden, Netherlands  Background Rheumatoid arthritis (RA) is one of the most prevalent systemic autoimmune diseases. Despite clinically effective drugs, RA remains a chronic disease with frequent disease flares upon drug tapering. Patients harbouring anti-citrullinated protein antibodies (ACPA) most frequently relapse and rarely achieve drug-free remission. We observed that in established RA, ACPA-expressing memory B cells (mBC) are highly activated, proliferate, secrete pro-inflammatory cytokines and differentiate into plasmablasts [1]. This phenotype points to continuous, T helper cell-driven stimulation of the ACPA B cell response and persists in patients in clinical remission induced by conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), suggesting ongoing immunological disease activity (IDA) despite clinically quiescent disease. Persistent IDA may be responsible for disease flares, making immunological remission a potential treatment target required for cure. Objectives To test the hypothesis that CTLA4-Ig (abatacept), a biological DMARD that blocks co-stimulatory signals such as those provided by helper T cells to B cells, can impact on IDA, as evidenced by the induction of a silent, non-proliferative phenotype of ACPA-expressing mBC. Methods We conducted a single-center, randomized, open-label clinical trial in which patients with newly diagnosed, untreated RA (n=42) were treated with either methotrexate (MTX, n=21) or abatacept/MTX (ABA/MTX) combination therapy (n=21) for 6 months. Frequency and phenotypic characteristics of peripheral blood ACPA-expressing B cells were assessed directly ex-vivo by flow-cytometry at baseline (BL), 3 months (V2) and 6 months (V3). The expression of Ki-67 (primary endpoint), CD80, CD86 and HLA-DR were used to determine the activation state of the B cells in either group, next to B cell lineage and differentiation markers. Tetanus-toxoid (TT) specific B cells served as antigen-specific controls. Clinical disease characteristics as well as serum parameters were assessed in parallel. Differences between treatment groups were statistically analyzed using a mixed effect model with random slope and intercept. Results Of patients receiving treatment, n=14 in the ABA/MTX and n=16 in the MTX monotherapy arm harboured ACPA-expressing mBC in the circulation at sufficient frequency for phenotypic analysis. Patients with untreated RA exhibited a highly active ACPA mBC response, in line with previous results [1]. Both MTX and ABA/MTX reduced clinical disease activity at 6 months to a similar extent (p=0.33). The frequency of circulating ACPA-expressing mBC remained unaffected in either group. However, while ACPA-expressing mBC maintained their highly active phenotype in the MTX group, ABA/MTX impacted on the ACPA mBC response by significantly reducing the expression of Ki-67, CD86 and CD80. The expression of HLA-DR did not change upon treatment. Figure 1. Image/graph: Conclusion The ASCARA study provides first evidence that the activation of ACPA-expressing mBC can be therapeutically modulated towards a phenotype compatible with immunological remission. ABA/MTX, but not MTX alone had this modulatory effect, indicating that potentially important immunological drivers of RA disease processes are resistant to MTX-mediated effects. Interestingly, the phenotype induced by ABA/MTX resembles that observed in patients in sustained drug-free remission as well as in individuals with clinically suspect arthralgia that do not convert to RA (long-term non-converters, (1)). Follow-up analysis of the ASCARA study with ABA discontinuation beyond V3 will elucidate the stability of this effect and its relation to clinical disease characteristics. Reference [1] Kristyanto et al., Sci Transl Med. 2020 Nov 18;12(570):eaaz5327 Acknowledgements This study was financially supported by Bristol Myers Squibb within the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (IMI2-JU) project RTCure. Disclosure of Interests Nienke Blomberg: None declared, Joanneke Kwekkeboom: None declared, Stefan Böhringer: None declared, Thomas Huizinga Speakers bureau: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb, Rene Toes Grant/research support from: Bristol Myers Squibb, Hans Ulrich Scherer Speakers bureau: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb. Keywords: Rheumatoid arthritis, Randomized control trial, Biomarkers DOI: 10.1136/annrheumdis-2023-eular.4607Citation: , volume 82, supplement 1, year 2023, page 11Session: Adaptive immunity (T cells and B cells) in rheumatic diseases (Oral Presentations)