Analysis Offers Insight into Patients Most Likely to Derive Benefit from Tofacitinib


An analysis of the ORAL Surveillance trial details the efficacy of tofacitinib relative to TNF inhibition based on history of ASCVD and baseline cardiovascular risk.

George Karpouzas, MD | Credit: Lundquist Institute

George Karpouzas, MD
Credit: Lundquist Institute

A new analysis of data from the ORAL Surveillance trial provides further insight into patient profiles most likely to benefit from use of tofacitinib.

Presented at the European Congress of Rheumatology (EULAR) 2023 annual meeting, the analysis of ORAL Surveillance data indicates the efficacy of tofacitinib is “at least as good” as TNF inhibition with comparable risk of MACE in patients with no history of cardiovascular disease.1

“In patients who do not have ASCVD risk, the use of tofacitinib is much more likely to produce clinical remission compared to TNF inhibition. There is a Blackbox Warning that's in place now stating that patients at high risk should not be taking this, but it's not as monolithic as that,” said study investigator George Karpouzas, MD, professor of Medicine at the David Geffen School of Medicine at UCLA and chief of the Division of Rheumatology at Harbor-UCLA Medical Center, in an interview with HCPLive at EULAR 2023. “If you exclude actual patients who suffered a cardiovascular event, as opposed to the rest of the patients with high to moderate risk, the patients at high to moderate risk actually had better clinical responses to tofacitinib versus TNF inhibitors and, more importantly, did not have a safety signal.”

A randomized, open-label, noninferiority, postauthorization, safety end-point trial, the ORAL Surveillance trial enrolled patients 4362 patients and randomized them in a 1:1:1 ratio to 5 mg tofacitinib twice daily,10 mg tofacitinib twice daily, and 1451 received a TNF inhibitor. Initial results published in the New England Journal of Medicine suggested use of tofacitinib was associated with increased incidence of major adverse cardiovascular events (MACE) and cancers.2

At the American College of Rheumatology 2022 annual meeting, an analysis of the trial using an 8-point MACE endpoint suggested there did not appear to be a difference in incidence between the tofacitinib and TNF inhibitor groups. This analysis also indicated risk was numerically higher in patients with a history of atherosclerotic cardiovascular disease (ASCVD).3

ORs for Remission vs TNFi


Tofacitinib 5 mg: 0.89 (95% CI, 0.46-1.70)

Tofacitinib 10 mg: 1.48 (95% CI, 0.82-2.65)

Without ASCVD

Tofacitinib 5 mg: 1.40 (95% CI, 1.08-1.82)

Tofacitinib 10 mg: 1.48 (95% CI, 1.14-1.92)

In the EULAR 2023 study, Karpouzas and investigators sought to further explore the benefit-risk profile of tofacitinib based on history of ASCVD. Of the 4362 patients included in the trial, 640 had a history of ASCVD and 3722 had no history of ASCVD. Investigators pointed out 3672 of the 3722 had baseline cardiovascular risk score data available.1

Upon analysis, results suggested the odds ratios (ORs) for achieving remission or low disease activity were greater for those receiving tofacitinib relative to their counterparts receiving TNF inhibitors among the overall study populations. Investigators pointed a similar trend was observed for those with no history of ASCVD while the ORs for achieving remission with tofacitinib among those with a history of ASCVD were comparable to those seen with TNF inhibitor use.1

“In the United States, it can be a bit jarring for the physician to sort of forego this massive block of a Blackbox Warning, but I think it's really important to understand that this Blackbox Warning is a highly nonselective block and we need to really redefine what is the actual population that incurred the risk,” Karpouzas explained. “There could still be people that you've inadvertently, and platform, put into this box that could benefit much more from this modality without presenting a danger signal.”


  1. Buch MH, Mortezavi M, Giles J, et al. IMPACT OF CARDIOVASCULAR COMORBIDITIES ON EFFICACY OF TOFACITINIB VS TNFI IN RHEUMATOID ARTHRITIS. Paper presented at: European Congress of Rheumatology (EULAR) 2023. Milan, Italy. May 31 – June 3, 2023.
  2. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927
  3. Campbell P. Examining drivers of cardiovascular risk with tofacitinib, with Deepak Bhatt, MD, MPH. HCP Live. November 15, 2022. Accessed June 8, 2023.
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