Article Text

Download PDFPDF

  1. F. Montastruc1,
  2. C. Flumian2,
  3. Y. Degboe3,
  4. A. Constantin3,
  5. A. Ruyssen-Witrand4
  1. 1Toulouse University Hospital, Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Centre d’Investigation Clinique 1436, Team PEPSS « Pharmacologie En Population cohorteS et biobanqueS », Toulouse, France
  2. 2Toulouse University Hospital, Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse, France
  3. 3Toulouse University Hospital, Rheumatology Center, Inserm UMR Infinity, Paul Sabatier University, Toulouse, France
  4. 4Toulouse University Hospital, Rheumatology Department, Centre d’Investigation Clinique 1436, Team PEPSS « Pharmacologie En Population cohorteS et biobanqueS », Toulouse University Hospital, Toulouse, France


Background Recently, awareness has raised regarding JAK inhibitor safety in rheumatoid arthritis (RA), in particular with tofacitinib. Indeed, in a trial involving more than 4,000 patients (ORAL Surveillance), a numerically higher number of major cardiovascular events (MACEs) in patients treated with tofacitinib compared to anti-TNF (1), and a higher risk of venous thromboembolic events (VTE) in patients treated with tofacitinib 10mg twice a day compared to patients treated with tofacitinib 5mg twice a day or anti-TNF was observed. This increased risk of MACEs was also suspected in another study performed on American Health databases (2). Recently, the FDA extended warnings and use’s recommendations to other JAK-inhibitor drugs (3).

Objectives To corroborate these safety warnings, we compared the reporting MACEs and VTEs with JAK inhibitors versus anti-TNF alpha drugs from the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database (VigiBase).

Methods We selected reports in Vigibase of patients aged between 18 and 75 years, between 01/01/2011 and 12/31/2020, with JAK inhibitors (tofacitinib, baricitinib, upadacitinib, filgotinib) or anti-TNF (etanercept, adalimumab, infliximab, certolizumab pegol, golimumab) with a diagnosis of RA. In these reports we selected MACEs including myocardial infarction, strokes and cardiovascular deaths and VTE including deep venous thromboses (DVT) and pulmonary embolisms (PE). Characteristics of reports including age of patients, country of declaration, drug involved, co-reported drugs, and type of event were described. The reporting risk was investigated using disproportionality analyses and expressed as Reporting Odds Ratios (ROR) with 95% Confidence Interval (95%CI). A sensibility analysis was performed stratifying by age category (≥ 65 years, ≥ 50 years), and by sex.

Results Of the 11,455,891 reports in patients aged between 18 and 75 years in the period of interest, 39,097 of reports were for a JAK-inhibitor in RA (mean age 60.6 years, SD:16.3) and 231,860 of reports were for an anti-TNF in RA (mean age: 57.2 years, SD: 13.0). Most of the reports came from USA and Canada (respectively 77.4% and 12.5% for JAK-inhibitor and 86.4% and 2,6% for anti-TNF). Among the reports, 611 (1.6%) in JAK-inhibitor treated patients and 3240 (1.4%) in anti-TNF treated patients were MACEs while 341 (0.9%) in JAK-inhibitors and 571 (0.2%) in anti-TNF treated patients were VTE. Disproportionality analyses identified an increased risk of reporting VTE events in JAK-inhibitors compared to anti-TNF (DVT: ROR = 3.99 [95%CI: 3.15-5.04], PE: ROR = 3.47 [2.90-4.13], Figure 1). This risk was not modified after stratification by age or sex. No increased ROR for MACE was found.

Conclusion Based on real-world data, the analysis did not identify an increase of declaration of MACEs with JAK-inhibitor compared to anti-TNF whereas we could observe more than three times declarations of VTE in Vigibase with JAK-inhibitors compared to anti-TNF.

References [1]Ytterberg SR, Bhatt DL, Mikuls TR, Koch GG, Fleischmann R, Rivas JL, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386(4):316-26.

[2]Khosrow-Khavar F, Kim SC, Lee H, Lee SB, Desai RJ. Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study. Ann Rheum Dis. 2022.

[3]FDA. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. https://wwwfdagov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death. 2021.

Disclosure of Interests None declared

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.