The mean age of the population was 61 years, and the median age was 60 (range 50–88 years). Most patients were female (78%) and white (77%). The noninferiority criterion was not met for the comparison of the combined tofacitinib regimens to TNF blockers for the endpoints of MACE and malignancies because the upper limit of the 95% confidence intervals (CI) for these hazard ratios exceeded the prespecified noninferiority criterion of 1.8. For MACE, the estimated hazard ratio and 95% CI associated with the combined tofacitinib regimens relative to TNF blockers were 1.33 (0.91, 1.94). For malignancies excluding NMSC, the estimated hazard ratio and 95% CI associated with the combined tofacitinib regimens relative to TNF blockers were 1.48 (1.04, 2.09).
There was an increased risk of death, MACE, malignancies and thrombosis associated with both regimens of tofacitinib. The data showed evidence of a dose-dependent increased risk for MACE, all-cause mortality, and thrombosis at both doses of tofacitinib when compared with treatment with TNF blockers. Additionally, the data showed evidence of a non-dose-dependent increased risk for malignancy excluding NMSC at both doses of tofacitinib when compared with TNF blockers. Lymphomas and lung cancers were observed at a higher rate in patients treated at both doses of tofacitinib compared with those treated with TNF blockers. In particular, a higher rate of lung cancers was observed in current or past smokers treated with tofacitinib. Current or past smokers had an additional increased risk of overall cancers.
The FDA is also requiring new and updated warnings for two other JAK inhibitors, baricitinib and upadacitinib. Baricitinib and upadacitinib have not been studied in trials similar to the large safety clinical trial with tofacitinib, so the risks have not been adequately evaluated. However, because they share mechanisms of action with tofacitinib, the FDA considers that these medicines may have similar risks as seen in the tofacitinib safety trial.
Note: Two other JAK inhibitors, Jakafi (ruxolitinib) and Inrebic (fedratinib), are not indicated for the treatment of arthritis and other inflammatory conditions and so are not a part of the updates currently being required.
Impact
Ethan Craig, MD, MHS, an assistant professor of clinical medicine with the Division of Rheumatology at the University of Pennsylvania, Philadelphia, a rheumatologist at the Corporal Michael J. Crescenz VA Medical Center and an associate editor of The Rheumatologist, says he doesn’t think this decision will have much of a clinical impact on practices because many insurance plans already require a TNF first approach to treatment. “For most indications, JAK inhibitors as second line to TNF inhibitors is probably appropriate based on data we have at this point. Although this may not change my habits considerably, this is a big deal,” he says.
