JAK inhibitors tied to increased CV, cancer risk in RA: 'But is it clinically meaningful?'
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Janus kinase inhibitors are associated with numerical, but not statistically significant, risks for adverse cardiovascular events and malignancy, according to a presenter at the 2021 Congress of Clinical Rheumatology-West.
“When we talk about [JAK inhibitors], you have to remember that they affect multiple cytokines,” Roy M. Fleischmann, MD, clinical professor in the Department of Internal Medicine at the University of Texas Southwestern Medical Center and in private practice at Rheumatology Associates in Dallas, Texas. “When you impact so many cytokines, you could get safety outcomes that you would not get with a TNF inhibitor.”
Fleischmann briefly addressed the known risks associated with JAK inhibitors, namely herpes zoster. “The herpes zoster risk was of real concern to us before,” he said, adding that this risk has remained consistent.
Turning to malignancy risk, Fleischmann suggested that the data are ambiguous. While lung cancer and lymphoma incidence have been shown to be elevated in rheumatoid arthritis patients treated with JAK inhibitors, certain bowel cancers and “female organ cancers” are lower, he said.
Similarly, creatine phosphokinase (CPK) levels may also be elevated in patients treated with these drugs. However, the implications of this elevation are uncertain. “It is a lab abnormality, but it is not clinically meaningful,” Fleischmann said.
Turning to thromboembolic event risks, Fleischmann noted that venous thromboemboli (VTE) are more likely to occur in RA populations overall compared with the general population. In addition, patients with higher RA disease activity were more likely to experience these events compared with other RA patients.
In clinical trial programs, while JAK inhibitors yielded elevated VTE event rates, methotrexate, adalimumab (Humira, Abbvie) and other therapies were also associated with increases in these events. “We also do not know if one JAK inhibitor is more likely to produce a VTE than another,” Fleischmann said.
The FDA made headlines with a warning of cardiovascular outcomes associated with JAK inhibitors. However, Fleischmann drew an important distinction. “This is a warning, this is not the label,” he said. “Numerically, it is correct. Statistically, if you look at the P values, it is not.”
Fleischmann spent significant time discussing results of Pfizer’s 1133 study, which investigated 5 mg and 10 mg doses of the JAK inhibitor tofacitinib (Xeljanz, Pfizer) compared with a TNF inhibitor in RA patients older than 50 years and with a history of at least one additional cardiovascular risk factor. Results showed that risk of major adverse cardiovascular outcomes (MACE) were elevated in these patients who were older than 65 years and ever smokers, but the findings were ambiguous for other populations.
“The noninferiority of Pfizer 1133 was not met,” Fleischmann said. He noted that the incidence rate of MACE overall was 0.91 per 100 person-years for tofacitinib and 0.73 per 100 person-years for TNF. “The study failed because it did not meet the upper limit of confidence interval. But these are very low incidence rates.”
For patients who are older than 65 years, former or current smokers or who have other cardiovascular risks, the drugs could elevate risk. In other populations, it is not so certain.
Fleischmann suggested that these findings raise a key question for practitioners. “There is a small increase in risk,” he said. “But is it clinically meaningful?”
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Fleischmann RM. Safety of Jakinibs in Rheumatoid Arthritis. Presented at: Congress of Clinical Rheumatology-West annual symposium; September 18-21, 2021 (hybrid meeting).
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