“Based on these studies, the JAK inhibitors have a benign safety profile that wouldn’t put our patients at a particular risk—except for herpes zoster, which we can manage these days by vaccination,” Dr. Schulze-Koops remarked. However, we all now know about the ORAL surveillance study, which has changed things.”
The ORAL surveillance study was published in the New England Journal of Medicine in January 2022. This was a “randomized, open-label, noninferiority, post-authorization, safety end-point trial involving patients with active RA despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor.”13
Dr. Schulze-Koops explained, “The ORAL investigators intentionally looked at an ‘at-risk population.’ And all of a sudden it appeared there was an increased risk of MACE and malignancy compared with TNFα inhibitors.”
Shortly after the publication of ORAL, another study (STAR-RA) showed similar results.14 STAR-RA looked at two cohorts of RA patients initiating therapy with tofacitinib or a TNFα inhibitors: “a real-world evidence cohort consisting of routine care patients, and an RCT-duplicate cohort mimicking inclusion and exclusion criteria from the ORAL surveillance trial to calibrate results against the trial findings.”
“The real-world experience cohort had no increased risk for cardiovascular outcomes,” explained Dr. Schulze-Koops, “similar to our RABBIT register data.” However, tofacitinib was associated with an increased risk of cardiovascular outcomes, although not statistically significant, in patients with RA with cardiovascular risk factors. “There appears to only be a difference in risk in the ‘at-risk’ group, just like ORAL,” he said.
Data from ORAL induced medical warnings for different JAK inhibitors across the world.15,16 So are they safe and should we prescribe them for our patients or not? “Because of safety concerns, only use a JAK inhibitor if you explicitly consider the potential side effects for every patient,” said Dr. Schulze-Koops. “In at-risk populations, I think we should wait until we have conclusive evidence as to why these increased risks happen before we close the book.
Promise 4: Simple Mechanism of Action
On a biochemical level, what do JAK inhibitors do? A kinase is an enzyme that transfers a phosphate residue to a substrate, and JAK inhibitors prevent this from occurring. However, the human body has 518 protein kinases. “In essence, the mechanism of action of JAK inhibitors is simple,” said Dr. Schulze-Koops. “But if we try to inhibit just one kinase, we must accept that this will never be 100% selective or specific in any given life situation. We need to learn more to understand how exactly JAK inhibitors work, and how they put particular patient populations at particular risk.”
In Sum
Dr. Schulze-Koops concluded his talk on a positive note. “Overall, I think that JAK inhibitors are wonderful and a perfect addition to our treatment armamentarium. However, there may be something [about JAK inhibitors] that’s as dark as this room is without the lights on, and I’m looking forward to seeing that data. Only then will we be able to determine if all JAK inhibitor promises have been fulfilled.”
