OP0269 BIOMARKERS TO PREDICT RISK OF VENOUS THROMBOEMBOLISM IN PATIENTS WITH RHEUMATOID ARTHRITIS RECEIVING TOFACITINIB OR TUMOUR NECROSIS FACTOR INHIBITORS
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BackgroundIn the ORAL Surveillance study of patients (pts) aged ≥50 yrs with moderate to severe rheumatoid arthritis (RA) and ≥1 additional cardiovascular risk factor (NCT02092467), the incidence of pulmonary embolism was higher with tofacitinib than with tumour necrosis factor inhibitors (TNFi).1ObjectivesTo explore whether biomarkers explained the associations of tofacitinib vs TNFi with venous thromboembolism (VTE) in ORAL Surveillance.MethodsORAL Surveillance was a prospective, open-label, event-driven, noninferiority, post-authorisation safety study. Pts were randomised 1:1:1 to receive tofacitinib 5 or 10 mg twice daily or a TNFi (adalimumab 40 mg every 2 weeks or etanercept 50 mg once weekly). For this exploratory post hoc analysis, 294 soluble, proteomic, genetic and antibody biomarkers were assessed (of which 79 have a known role in inflammation, coagulation, vascular biology and/or Janus kinase signalling). Biomarkers were quantified in serum collected at baseline (BL) and Month (M)12 in VTE cases and 4:1 matched controls. D-dimer was analysed with a larger control group (all eligible pts without VTE) and final adjudicated data from BL, M12 and study end.ResultsOf the 4362 randomised and treated pts, D-dimer was quantified in 3732 pts (54 with VTE; 3678 without) and the remaining biomarkers were analysed in 285 pts (57 VTE cases; 228 matched controls). BL characteristics were generally similar in those with or without VTE and between treatment groups. At BL, D-dimer levels were ≥2×upper limit of normal for ~50% of controls and 67% of VTE cases. Mean D-dimer levels decreased from BL to M12 in controls across treatment groups (Figure 1). Key findings from the biomarker analyses are shown in the Table 1. No biomarker showed a clear mechanistic association with the increased risk of VTE for tofacitinib vs TNFi, or demonstrated adequate performance for prognostic use in pts with RA.Table 1.Summary of results from biomarker analysesBiomarkerKey resultsTier 1C-reactive protein•No association with VTE in any treatment arm at BL or M12D-dimer Thrombopoietin•Higher M12 levels were prospectively associated with greater risk of subsequent VTE with tofacitinib 10 mg BID ◦ For D-dimer, the same effect was observed with tofacitinib 5 mg BID •Treatment specificity of effects could not be establishedTier 2Factor VIII Thrombin–antithrombin complex Tissue factor pathway inhibitor Plasminogen activator inhibitor-1 Protein C Antithrombin Apolipoprotein C-III Leptin•No clinically meaningful differences across treatment armsTiers 3 & 4Exploratory proteomic assays (276 markers from multiplex panels)•Two biomarkers with no known relationship to VTE (angiogenin and TNFSF13B) showed significant associations with pulmonary embolism in the tofacitinib 10 mg BID arm ◦ Treatment specificity of effects could not be established for either analyteGenetic biomarkersFactor V Leiden R506Q, prothrombin G20210A and JAK2 V617F mutations•Factor V Leiden and prothrombin risk alleles, individually or combined, were associated with increased incidence of VTE but did not explain excess events with tofacitinib •No VTE cases or matched controls had the JAK2 mutationAntibody biomarkersACA IgG and IgM, anti-β2GP1 IgG and IgM•No statistical differences were observed between treatment arms or between VTE cases and matched controlsACA, anticardiolipin antibody; β2GP1, beta-2-glycoprotein 1; IgG, immunoglobulin G; IgM, immunoglobulin M; JAK2, Janus kinase 2; TNFSF13B, tumour necrosis factor ligand superfamily member 13BConclusionThis post hoc exploratory analysis did not identify biomarkers at BL or M12 that explain the increased VTE risk for tofacitinib vs TNFi. Notably, ORAL Surveillance was neither designed nor powered to compare the risk of VTE across treatments or to identify biomarkers with a mechanistic relationship to VTE. Individual VTE risk should be considered when making decisions about initiation or maintenance of tofacitinib treatment.References[1]Ytterberg et al. N Engl J Med 2022; 386: 316-326.AcknowledgementsStudy sponsored by Pfizer Inc. Medical writing support was provided by Julia King, CMC Connect, and funded by Pfizer Inc.Disclosure of InterestsZoltán Szekanecz Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Paid instructor for: AbbVie, Eli Lilly, Gedeon Richter, Novartis, Pfizer Inc and Roche, Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Grant/research support from: Pfizer Inc, Christina Charles-Schoeman Consultant of: AbbVie, Gilead Sciences, Pfizer Inc and Sanofi-Regeneron, Grant/research support from: AbbVie, Bristol-Myers Squibb and Pfizer Inc, Ivana Vranic Shareholder of: Pfizer Inc, Employee of: Pfizer Ltd, Burak Sahin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sara A Paciga Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Zhenyu Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Craig Hyde Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, David Martin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Jeffrey I Weitz Speakers bureau: Anthos, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Ionis, Janssen, Novartis, Pfizer Inc, PhaseBio, Portola and Servier Pharmaceuticals, Grant/research support from: Bayer AG and Boehringer Ingelheim
