Tofacitinib Use Associated with Cardiovascular and Cancer Risk: Results of the ORAL Surveillance Trial

Results of the ORAL Surveillance study were recently published in the NEJM in late January 2022.  ORAL Surveillance was a randomized, Phase 3b-4 post-marketing non-inferiority trial evaluating safety and efficacy of tofacitinib compared to TNF inhibitor in patients with rheumatoid arthritis (RA) [1].  As noted in the paper, the FDA required a head-to-head safety trial of tofacitinib compared to TNF inhibitors, after increases in serum lipid levels and incidence of cancers were observed.

The study randomized patients 1:1:1 to receive either tofacitinib 5mg twice daily, 10mg twice daily, or a subcutaneous TNF inhibitor (adalimumab or etanercept).  Patients enrolled were 50 years of age or older and had at least one additional cardiovascular risk factor.  The cardiovascular risk factors included current smoking, hypertension, history of coronary artery disease, diabetes mellitus; cancers (other than treated nonmelanoma skin cancers) were excluded.  Over 4,300 patients with RA were enrolled in this international study and followed for 4 years.  The co-primary endpoints included MACE or major adverse cardiac events (i.e. death from cardiovascular causes, non-fatal myocardial infarction or stroke) and cancers, excluding nonmelanoma skin cancer.

Ultimately, the study found a higher incidence of both major adverse cardiac events amongst the tofacitinib group compared to TNF inhibitors (3.4% vs 2.5%) and higher incidence of malignancy in the tofacitinib group vs TNFi (4.2% vs 2.9%).  Based on the results of increased risk of MACE, malignancy, thrombosis and mortality with tofacitinib compared to TNF inhibitors in the surveillance data, the FDA placed a Box Warning on tofacitinib, baricitinib, and upadacitinib.  Interestingly the data was extrapolated from the study, only evaluating tofacitinib, and extended to all classes of JAK inhibitors, with the FDA citing a similar mechanism of action [2].  Given tofacitinib is a pan-JAK inhibitor, it is theoretically possible that these adverse events with tofacitinib will not necessarily be observed across the more selective JAK inhibitors.

There are several unanswered questions from this study.  First, there were no other control groups in ORAL Surveillance; thus, the incidence of MACE and cancer risk could not be compared with other treatments in RA such as conventional synthetic DMARDs and other biologics.  Given previous data has demonstrated a role of immunosuppressive therapy, such as TNF inhibitors, in decreasing cardiovascular risk among patients with rheumatoid arthritis [3], it is notable that tofacitinib does not have a similar effect.  It is also important to note that adalimumab was used in the North American trial participants versus etanercept for the rest of the world; it is possible the relative risk differed between the two agents.

As a result of this study, indications for use of tofacitinib, upadacitinib, and baracitinib were adjusted by the FDA and are now limited to use in those with inadequate response or intolerance to one or more TNF inhibitors.  The American College of Rheumatology (ACR) released a statement (updated January 28, 2022) recommending shared decision making between patient and provider regarding ongoing use and risk/benefit of JAK inhibitors [2].  The results of ORAL Surveillance suggest taking careful consideration regarding whether to continue JAK inhibitors particularly in the highest risk patients, including those who are smokers, men, over 65 years of age, or those with prior cardiac events, stroke, or prior malignancy other than a successfully treated nonmelanoma skin cancer.


[1] Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. The New England Journal of Medicine 2022;386(4):316-26.

[2] Snow M, Beall A, Goodman S, et al.  Janus Kinase Inhibitor Boxed Warning Statement from the American College of Rheumatology Updated: January 28, 2022.  Accessed:

[3] Barnabe C, Martin BJ, Ghali WA. Systematic review and meta-analysis: anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis. Arthritis care & research 2011;63(4):522-9.