Studies Reveal Nuances in Efficacy, MACE Risk Between JAKi and TNFi

Cristina Ferrario

June 07, 2023

Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the European Alliance of Associations for Rheumatology (EULAR) 2023 Annual Meeting.

Tofacitinib vs TNFi Efficacy With or Without History of Atherosclerotic CVD

The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.

Dr Maya Buch

Given that a prior "post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib vs TNFi, depending on the personal history of atherosclerotic cardiovascular disease," Buch and co-authors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4362 patients, 640 (14.7%) had a positive history of ASCVD, while 3722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.

The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs TNFi.

Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. "Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA," she concluded.

Dr Kim Lauper

Kim Lauper, of the division of rheumatology at Geneva University Hospitals, Geneva, Switzerland, who was not involved in the study, commented to Medscape Medical News on the importance of this data: "These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs."

A Real-World Perspective

Dr Romain Aymon

MACE occurred at similar rates between JAKi vs TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals, Geneva, Switzerland. But a sub-analysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs TNFi and OMA vs TNFi.

Aymon said that the analysis is still ongoing, with additional registries being included.

Lauper, who is the principal investigator of the study presented by Aymon, noted that "the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients."

The Dutch Perspective

Merel Opdam, MSc

In line with the the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two sub-analyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA's Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.

"Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi," Opdam said.

Dr Anja Strangfeld

"Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs," commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin, Berlin, Germany. She said that registries have a pivotal role in this regard.

Buch reports serving on a speakers' bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Aymon and Opdam report no relevant financial relationships.

European Alliance of Associations for Rheumatology (EULAR) 2023 Annual Meeting:

Abstract OP0043. Presented May 31, 2023.

Abstract OP0219. Presented June 2, 2023.

Abstract OP0221. Presented June 2, 2023.

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