Dr. Roy Fleischmann discusses the clinical context of JAK versus TNF inhibitor safety in the ORAL Surveillance study, including best practices for how and in whom he uses JAK inhibitors.
Roy Fleischmann, MD, MACR, is Clinical Professor of Medicine at the University of Texas Southwestern Medical Center, and Co-Medical Director of the Metroplex Clinical Research Center Clinical Professor of Medicine, Dallas, Texas
“The ORAL Surveillance study has been misinterpreted, or not quite interpreted correctly, exaggerated, or minimized by several observers. Let me explain my thoughts on the results of the study,” said Roy Fleischmann, MD, MACR.
The NEJM study1 compared cardiovascular and cancer risk with Janus kinase (JAK) inhibitor tofacitinib (Xeljanz, Pfizer) to a tumor necrosis factor (TNF) inhibitor in rheumatoid arthritis.
“In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of major adverse cardiovascular events [MACE] and cancers were higher with tofacitinib and did not meet noninferiority criteria. Several adverse events were more common with tofacitinib.”
But the study’s true interpretation is in the details, said Dr. Fleischmann, a rheumatologist with 15 years’ experience in the use of JAK inhibitors in practice and has published extensively on JAK inhibitor use, efficacy, and safety.
“ORAL surveillance was designed as a safety study for the FDA after tofacitinib was approved in June 2012. The FDA was concerned with the increase in lipids observed with all the JAK inhibitors. Additionally, in the early development program of tofacitinib there were lymphomas observed when tofacitinib was used in high dose.”
ORAL Surveillance examined the safety of tofacitinib, 5 mg BID or 10 mg BID, versus a TNF inhibitor with respect to the development of MACE and malignancies. The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor.
In this event-driven study for MACE and malignancy, there had to be a certain number of MACE and a certain number of malignancies before the study was concluded.
During a median 4-year follow-up, 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor, according to the study.
“The upper limit of the 95% confidence interval for both MACE and malignancy for tofacitinib, both 5 and 10 mg BID, was higher than 1.8 and therefore non-inferiority was not found. One cannot conclude that tofacitinib is inferior to the TNF inhibitors but rather only that tofacitinib was not found to be non-inferior to TNF inhibitors,” said Dr. Fleischmann.
Safety In Perspective
Incidence rates for MACE, malignancy, serious infections, mortality, and venous thrombotic episodes were very low for tofacitinib, as well as for the TNF inhibitor, said Dr. Fleischmann.
“This is the only head-to-head powered safety study, and what you can conclude is that there were numerically small increases in the rates of MACE, malignancy, venous thrombosis events, mortality, and serious infections with tofacitinib at 5 or 10 mg BID versus the TNF inhibitor.”
“However, if you evaluate the number needed to harm, one can assess how strong is this signal. The number needed to harm was 575 for MACE. This means that one would have to treat 575 more patients with tofacitinib to get one more MACE event than would occur with the TNF inhibitor. For malignancy, it was about 250. One would have to treat 250 more patients with tofacitinib to have one more malignancy than would occur with the TNF inhibitor,” he said.
Without a control group (which would have been unethical in a population of people with active rheumatoid arthritis treated for so long) it’s impossible to know whether tofacitinib reduced the rate of these adverse events as well, but perhaps not as well as a TNF inhibitor, according to Dr. Fleischmann.
“I believe that is exactly what occurred.”
Enter The FDA
Based on this study, the FDA has said to limit to use of tofacitinib to TNF failures in rheumatoid arthritis, according to Dr. Fleischmann.
“The FDA extended the Black Box warning to all JAK inhibitors for all diseases.2 Should that be the case? The answer is probably yes. The integrated safety databases of all JAK inhibitors show that the incidences of MACE, malignancy, venous thrombotic events, and serious infection are almost identical.”
In clinical context, Dr. Fleishmann has his preferences for how and in whom to use JAK inhibitors.
“Given my druthers, I would use JAK inhibitors before methotrexate JAKs are more effective than methotrexate. But methotrexate is cheaper and is relatively safe, so it is very reasonable to use JAK inhibitors after methotrexate,” said Dr. Fleischmann.
Given the choice, Dr. Fleischmann might also use a JAK inhibitor before a TNF inhibitor, especially if a patient was unwilling to take a TNF inhibitor or for some reason couldn’t, he said.
However, Dr. Fleischmann said he would not likely prescribe a JAK inhibitor to patients with a high cardiovascular disease risk or at risk for venous thrombotic events (VTEs).
“The way we utilize JAK inhibitors now is in any patient after a TNF inhibitor, as long as they don’t have the signals of high cardiovascular risk and haven’t had a VTE previously. But I have to point out that I wouldn’t use a TNF inhibitor in those patients either because the TNF inhibitors in this study also were more likely to have a VTE if the patient had a prior VTE and were more likely to have a MACE if they had a high cardiovascular risk.”
“If the label didn’t state that I had to use JAK inhibitors after TNF inhibitors I would probably use them more than TNF inhibitors but would still be concerned about patients at higher risk,” said Dr. Fleischmann.
A Need for Drug Monitoring
“JAK inhibitors are relatively safe, but there is drug monitoring that has to be done,” said Dr. Fleischmann.
“The JAK inhibitor labels point out potential anemia, leukopenia, and lymphopenia. This [is] laboratory monitoring that should be done every three months or so. JAKs can also elevate lipids. If a patient does not have elevated lipids before you start the JAK inhibitor, check the lipids six or eight weeks later. If the lipids are elevated, then the patient needs a lipid-lowering agent.”
Disclosures
Dr. Fleischmann is a consultant with AbbVie, Amgen, and Pfizer.
References
- 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.
- 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. FDA.gov. December 2021 Update. Accessed March 23, 2022. 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 | FDA
