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

Abstract

ObjectiveIn 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).MethodsORAL 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.ResultsOverall, 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.ConclusionsOverall, 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 numberNCT02092467; ClinicalTrials.gov.

Proteomics in orthopedic research: Recent studies and their translational implications

“…Patients with autoimmune disorders such as RA are in a hypercoagulable state as evidenced by both inflammatory and coagulation biomarkers 53 . Weitz 54 and colleagues investigated if serum biomarkers in RA patients on different therapies explained differing rates of VTE. The study followed patients with RA that were over 50 years old with 1 or more cardiovascular risk factors.…”

Cardiovascular Risk Management in Patients Treated With Janus Kinase Inhibitors

“…One group found D-dimer levels to be associated with subsequent VTE risk in a post-hoc analysis of ORAL Surveillance; however, its low specificity and variability in inflammatory states deem it unreliable as a marker for VTE in patients on JAKi who are already in a hyperinflammatory state. 58 Most of the evidence thus far supports a multiple-hit hypothesis, wherein CV risk increases with a combination of traditional CV risk factors and use of JAKi. Thus, we recommend that patients undergo an initial comprehensive CV history and laboratory evaluation to identify patients who would benefit from serious consideration of alternative treatment modalities, if available, and CV risk mitigation strategies if JAKi therapy is initiated (Fig.…”

“…One group found D-dimer levels to be associated with subsequent VTE risk in a post-hoc analysis of ORAL Surveillance; however, its low specificity and variability in inflammatory states deem it unreliable as a marker for VTE in patients on JAKi who are already in a hyperinflammatory state. 58…”

Navigating Comorbidities in Chronic Inflammatory Rheumatic Diseases: Insight and Strategies

“…40 This risk seems notable in older individuals, smokers, and those with a history of coronary artery disease. 40,52,53 In return, some comorbidities may decrease the efficacy of some antirheumatic drugs. For instance, smoking may reduce the effectiveness of MTX, TNFi and abatacept, while it does not affect the response to rituximab and JAKi.…”