Biomarkers to predict risk of venous thromboembolism in patients with rheumatoid arthritis receiving tofacitinib or tumour necrosis factor inhibitors

Abstract

Objective: In the ORAL (Oral Rheumatoid Arthritis triaL) Surveillance study of patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor, incidence of pulmonary embolism was higher with tofacitinib 10 mg two times per day than with tumour necrosis factor inhibitors (TNFi). This exploratory post hoc analysis examined whether biomarkers explained the associations of tofacitinib versus TNFi with venous thromboembolism (VTE).

Methods: ORAL Surveillance was a prospective, open-label, event-driven, non-inferiority, postauthorisation safety study. Patients were randomised 1:1:1 to receive tofacitinib 5 mg or 10 mg two times per day or a TNFi. For this analysis, 294 soluble, proteomic, genetic and antibody biomarkers (of which 79 had a known role in inflammation, coagulation, vascular biology or Janus kinase signalling) were quantified in serum collected at baseline, month 12 and study end.

Results: Overall, 4362 patients were randomised and treated. The exploratory biomarker data set included 285 patients (57 VTE cases; 228 matched controls). D-dimer was quantified in 3732 patients (54 VTE cases; 3678 controls). No biomarker demonstrated a clear mechanistic association with the increased risk of VTE for tofacitinib versus TNFi. Month 12 D-dimer levels were positively associated with risk of a subsequent VTE within the tofacitinib 5 mg and 10 mg two times per day arms.

Conclusions: Overall, this post hoc analysis did not identify biomarkers that explained the increased VTE risk for tofacitinib versus TNFi. Individual VTE risk should be considered when making decisions about initiation or maintenance of tofacitinib treatment.

Trial registration number: NCT02092467; ClinicalTrials.gov.

Keywords: antirheumatic agents; arthritis, rheumatoid; cardiovascular diseases.

Conflict of interest statement

Competing interests: JIW received honoraria from Anthos, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Ionis, Janssen, Novartis, Pfizer, PhaseBio, Portola and Servier Pharmaceuticals, and institutional grants from Bayer AG and Boehringer Ingelheim. ZS has received consulting fees and honoraria from AbbVie, Amgen, BMS, Gedeon Richter, Lilly, MSD, Pfizer, Roche, Sanofi and UCB. CC-S has received consulting fees, research grants and/or honoraria from AbbVie, Amgen, BMS, Gilead, Octapharma, Pfizer and Sanofi/Regeneron. IV, BS, SAP, ZW, CH and DAM are employees and/or shareholders of Pfizer Inc.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

(A) CRP levels at baseline and (B) changes from baseline in CRP levels at month 12 by treatment arm in controls and VTE cases (full clinical data set). Normal assay range:

Figure 2

D-dimer levels at baseline, month 12 and end of study by treatment arm in controls and VTE cases (D-dimer data set). Normal assay range:

Figure 3

(A) TPO levels at baseline and changes from baseline in TPO levels at month 12; (B) exploratory biomarker data set; (C) changes from baseline in platelet counts at month 12 (full clinical data set) in controls and VTE cases. For patients assigned to receive tofacitinib at a dose of 10 mg two times per day who had their dose reduced to 5 mg two times per day, the data collected after patients had been switched to 5 mg two times per day were counted in the arm receiving 10 mg two times per day. BID, twice daily; CI, confidence interval; ln, natural logarithm; LS, least squares; TNFi, tumour necrosis factor inhibitor; TPO, thrombopoietin; VTE, venous thromboembolism.