ANTIDRUG ANTIBODIES ARE NEGATIVELY ASSOCIATED WITH RESPONSE TO BIOLOGICAL DRUGS IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS OF THE ABIRISK STUDY

S. Bitoun, S. Hässler, D. Ternant, N. Szely, A. Gleizes, S. Hacein Bey, C. Richez, M. Soubrier, J. Avouac, O. Brocq, J. Sellam, N. De Vries, T. Huizinga, E. Jury, J. Manson, C. Mauri, A. Matucci, D. Mulleman, M. Pallardy, P. Bröet, X. MarietteUniversité Paris-Saclay, INSERM U1184, Hôpitaux Universitaires Paris Saclay, APHP, FHU CARE, Rheumatology, Le Kremin Bicêtre, France INSERM U1018, Université Paris Saclay, CESP, Villejuif, France University of Tours, CNRS 7292, Tours, France Faculty of Pharmacy, Paris-Saclay University, INSERM UMR 996, Orsay, France Hôpital Bicêtre AP-HP, Université Paris Saclay, Laboratoire d’immunolgie, Le Kremin Bicêtre, France Hôpital Bicêtre AP-HP, Université Paris Saclay, Laboratoire d’immunolgie, Le Kremin Bicêtre, France CHU de Bordeaux-GHPellegrin, Rheumatology Department, Bordeaux, France CHU Gabriel-Montpied, Rheumatology Department, Clermont-Ferrand, France Hôpital Cochin, AP-HP.Centre- Université de Paris Cité, Rheumatology Department, Paris, France Hôpital Princesse Grâce de Monaco, Rheumatology Department, Monaco, Monaco Hopital St Antoine, APHP, Paris Sorbonne university, Rheumatology Department, Paris, France Amsterdam UMC | AMC, University of Amsterdam, Rheumatology & Clinical Immunology, Amsterdam, Netherlands Leiden University Medical Center, Rheumatology Department, Leiden, Netherlands University College London, Centre for Rheumatology Research, London, United Kingdom University College London Hospital, Rheumatology Department, London, United Kingdom University College London, Division of Infection, Immunity and Transplantation, London, United Kingdom Azienda Ospedaliero Universitaria Careggi, Department of immunology, Florence, Italy University of Tours, CNRS 7292, Tours, France Université Paris-Saclay INSERM U1184, Hopital Bicêtre AP-HP, Rheumatology Department, Le Kremin Bicêtre, France  Background Anti-drug antibodies (ADAb) may be involved in loss of response or primary failure of bDMARDs in rheumatoid arthritis (RA). However, evidence in prospective clinical studies of diminished response to treatment in presence of ADAb is rare and restricted to monoclonal anti-TNF antibodies[1]. Objectives In this analysis of the prospective European trial ABIRISK we aimed to analyze how ADAb might influence response to several bDMARDs in RA. Methods RA patients resistant to methotrexate and starting a bDMARD (anti TNF, anti IL-6 R and anti CD20) were included in 4 countries (ABIRA, NCT02116504). They had a clinical assessment and ADAb quantification at 6, 12, and 15 to 18 months. ADAb were detected using mesoscale discovery (MSD) technology. They were defined as transient if they were negative after a positive time point and persistent positive if they were positive at two sequential visits without negative timepoints afterwards. ADAb positivity was defined as having been ADA positive at least in one visit in the first 12 months. The primary endpoint was the EULAR response at 12 months. Association with ADAb was analyzed using univariate logistic regression. Patients withdrawing for side effects or for inefficacy were considered as non-responders. We also performed a univariate and a multivariate analysis through a generalized estimating equation (GEE) model that analyzes the EULAR response and ADAb status for each visit starting at 6 months. This allows taking advantage of all the data available in the study. The effect of methotrexate on ADAb was also studied. Finally, we performed drug concentration measurements for anti-TNF drugs. Results 230 patients were included treated with: adalimumab or infliximab = monoclonal TNFi (mTNFi, N=68); etanercept (ETN, N=82), rituximab (RTX N=30) or tocilizumab (TCZ N=50). ADAb were positive in 38,2% of the mTNFi-treated patients, 50% of the RTX-treated and 20% of the TCZ-treated patients. ADAb positivity was negatively associated with EULAR response at 12 months for all drugs OR=0.20 [0.10-0.42]. Only persistent and not transient ADAb were negatively associated with EULAR response at 12 months (persistent ADAb vs ADAb negative OR 0,17 [0.06-0.43] transient ADAb vs ADAb negative, p=0.57). This was also the case for mTNFi alone (persistent ADAb vs ADAb negative OR 0,1; p=0,0051; transient ADAb vs ADAb negative, p=0,99). 6% of ETN patients presented ADAb, always transient. In the GEE longitudinal analysis there was a negative association between ADAb positivity and response to all treatments (OR 0,36 [0.20-0.64]) and individually for TCZ (OR=0.18 [0.04-0.83]) and mTNFi (OR 0,44; p=0,097 trend). In the multivariate analysis, the ADAb status remained independently associated with non-response to treatment (Figure 1). Methotrexate co treatment at baseline was negatively associated with ADAb (OR=0.5 [0.25-1.00]). There was a significantly lower concentration of adalimumab and infliximab in ADAb positive patients compared to ADAb negative. There was a significantly higher concentration of adalimumab and etanercept in EULAR responder patients compared to EULAR non-responders. Conclusion This prospective multicenter study demonstrates that ADAb are frequently detected and associated with non-response to bDMARDs in RA. It is the first study demonstrating the association between ADAb and non-response to TCZ. Monitoring of ADAb should be considered in the personalized management of RA patients particularly in non-responder patients. Image/graph:Figure 1. Multivariate analysis of parameters associated with EULAR response in the GEE analysis from M6 onwards. Reference [1]Syversen SW, Jørgensen KK, Goll GL, et al. Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. JAMA 2021;326:2375. doi:10.1001/jama.2021.21316 Acknowledgements Financial support: ABIRISK was funded by the European Union thru the Innovative Medicine Initiative Joint Undertaking under grant agreement no.[115303], resourcesofwhich arecomposed of financial contributionfrom theEuropean Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ inkind contribution. Disclosure of Interests None Declared. Keywords: Prognostic factors, bDMARD, Rheumatoid arthritis DOI: 10.1136/annrheumdis-2023-eular.251Citation: , volume 82, supplement 1, year 2023, page 590Session: Rheumatoid arthritis - biological DMARDs (Poster View)