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JAK inhibition’s cardiovascular, malignancy risks are a ‘moving target’


December 01, 2022

3 min read

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Giles J. Abstract 14M135. Presented at: ACR Convergence 2022; Nov. 11-14, 2022; Philadelphia (hybrid meeting).

Disclosures:
Giles reports consulting for Abbvie, Bristol Myers Squibb, Eli Lilly & Co., Gilead Sciences, Novartis and Pfizer.

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PHILADELPHIA — Making sense of real-world data and black-box warnings associated with Janus kinase inhibitors can be challenging for rheumatologists hoping to prescribe these medications, according to a presenter at ACR Convergence 2022.

“It is not my intention to render a verdict today,” Jon Giles, MD, MPH, associate professor of medicine at Columbia University, told attendees.

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“Screening and risk mitigation consistent with regulatory warnings is advisable,” Jon Giles, MD, MPH, told attendees. Source: Adobe Stock

Rather, Giles aimed to raise some questions for rheumatologists to consider as they sort through the data and try to optimize the use of JAK inhibition in their patients.

Jon Giles

Currently approved JAK inhibitors include tofacitinib (Xeljanz, Pfizer), baricitinib (Olumiant, Eli Lilly) and upadacitinib (Rinvoq, Abbvie), with indications in rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, juvenile idiopathic arthritis and ankylosing spondylitis.

At the center of the discussion is the ORAL Surveillance trial, which suggested that JAK inhibitors carry elevated risks for cardiovascular events and malignancy that have led to black-box warnings for tofacitinib in patients with RA. For Giles, there are three questions to consider from these results.

The first is whether the results apply to other JAK inhibitors in RA. The second is whether the risks apply to other diseases. The third is whether, and how, to switch drug classes in potentially high-risk patients.

According to Giles, the obvious place to look for an answer to the first question is comparison trials. Unfortunately, rheumatologists have few options in this regard.

“There are actually very few head-to-head trials of a JAK against another biologic,” Giles said.

However, he noted a handful of trials examining a JAK inhibitor vs. adalimumab (Humira, Abbvie).

“To various degrees, the ACR50 responses are larger for the JAK groups,” Giles said. “We can conclude that they are at least as good in their efficacy as the other alternatives that you might choose at that point, which is to put them on a TNF inhibitor.”

Regarding the risks, Giles suggested that upadacitinib appears to have “similar” cardiovascular outcomes as tofacitinib, both in terms of incidence rates and how it compares with other biologics.

In addition, the FDA has mandated a phase 4 safety study of baricitinib to explore similar endpoints.

“Two trials are happening now,” Giles said.

Meanwhile, the picture is less certain for the second and third questions. “There are no data that are rigorous” in answering those questions, according to Giles.

Looking closer at malignancy risk in ORAL Surveillance, Giles highlighted that the rates were 1.13 per 100 patient-years for both the 5 mg and 10 mg doses of tofacitinib, compared with 0.77 per 100 patient-years for TNF inhibition. However, age, higher baseline malignancy risk and smoking were also found to be risk factors for malignancy.

There is another reason to be careful in interpreting these results, according to Giles.

“The numbers are still very, very small,” he said.

Putting these risks aside, it is important to remember that JAK inhibitors have been in use in the rheumatology space for more than a decade, Giles added.

“They have efficacy and effectiveness,” he said.

According to Giles, a good way to stay ahead of cardiovascular and malignancy outcomes is to inform patients of the risks associated with these drugs.

“This should include an assessment of the magnitude of the risk,” he said. “That is an important part of the conversation. Screening and risk mitigation consistent with regulatory warnings is advisable.”

Giles counseled that rheumatologists and patients should have a plan in place if something goes wrong with one of these drugs.

“If you stop the JAK inhibitor, what are you going to put them on?” he said.

Meanwhile, yet another issue is that there is no clear plan for additional medications to reduce potential cardiovascular and malignancy risks with JAK inhibition.

“We do not have any evidence yet that any medication we use to use to reduce risk will actually reduce risk,” Giles said.

However, despite these issues, Giles remains dedicated to finding answers and sharing them with his colleagues.

“It is a moving target, but it is one I am happy to follow over time,” he said.



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