Managing Cardiovascular and Cancer Risk Associated with JAK Inhibitors

Drug Saf. 2023 Nov;46(11):1049-1071. doi: 10.1007/s40264-023-01333-0. Epub 2023 Jul 25.


Janus kinase inhibitors (JAKi) have enormous appeal as immune-modulating therapies across many chronic inflammatory diseases, but recently this promise has been overshadowed by questions regarding associated cardiovascular and cancer risk emerging from the ORAL Surveillance phase 3b/4 post-marketing requirement randomized controlled trial. In that study of patients with rheumatoid arthritis with existing cardiovascular risk, tofacitinib, the first JAKi registered for chronic inflammatory disease, failed to meet non-inferiority thresholds when compared with tumor necrosis factor inhibitors for both incident major adverse cardiovascular events and incident cancer. While this result was unexpected by many, subsequently published observational data have also supported this finding. Notably, however, such a risk has largely not yet been demonstrated in patients outside the specific clinical situation examined in the trial, even in the face of many studies examining this. Nevertheless, this signal has practically re-aligned approaches to both tofacitinib and other JAKi to varying extents, in other patient populations and contexts: within rheumatoid arthritis, but also in psoriatic arthritis, axial spondyloarthritis, inflammatory bowel disease, atopic dermatitis, and beyond. Application to individual patients can be more challenging but remains important to harness the substantive potential of JAKi to the maximum extent safely possible. This review not only explores the evolution of the regulatory response to the signal, its informing data, biological plausibility, and its impact on guidelines, but also the many factors that clinicians must consider in navigating cardiovascular and cancer risk for their patients considering JAKi as immune-modulating therapy.

Publication types

  • Review

MeSH terms

  • Antirheumatic Agents* / adverse effects
  • Arthritis, Psoriatic* / drug therapy
  • Arthritis, Rheumatoid* / complications
  • Arthritis, Rheumatoid* / drug therapy
  • Clinical Trials, Phase III as Topic
  • Humans
  • Inflammatory Bowel Diseases* / drug therapy
  • Janus Kinase Inhibitors* / adverse effects
  • Neoplasms* / chemically induced
  • Neoplasms* / drug therapy
  • Neoplasms* / epidemiology
  • Randomized Controlled Trials as Topic


  • Janus Kinase Inhibitors
  • Antirheumatic Agents