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Safety and JAK Inhibitors


Experts share clinical insights boxed warning for the JAK inhibitor drug class.

Raj Chovatiya, MD, PhD: We were waxing poetic about efficacy. By no means does that mean I need to shortchange the safety argument because that’s the other half of this coin. Both providers and patients think a lot about safety with JAK inhibition. Just to make sure everyone is at the same place, when we think about JAK inhibitors as a class, all contain very similar wording—what people sometimes call black-box warning—highlighting concerns…when it comes to therapy.

Here’s a little brief history lesson on where all this comes from and why we got to this point. There was a long-term study done after the initial launch of tofacitinib. This was a medication that was a more broad JAK inhibitor—JAK1 and JAK3—that was used to treat individuals with rheumatoid arthritis. Over a decade ago, when the results of these phase 2 trials were released, the drug was approved. Then the FDA decided that it wanted to see more data on some signals that seemed to be apparent related to mortality, major adverse cardiovascular events, renal thrombotic events, malignancy, and infections. Over the next decade after launch, there was the ORAL Surveillance study, which looked at a couple of different doses of tofacitinib compared with individuals getting standard of care with TNF [tumor necrosis factor]-alpha inhibitors for their rheumatoid arthritis.

It’s worth noting that in this long-term study, people were over age 50 and had at least 1 cardiovascular risk factor. In this group, some of these signals were observed in the original studies. It’s also worth noting that as part of standard of care, all these patients were on methotrexate concurrently, and more than half of patients were on oral steroids as well. In case you’re thinking about it, we don’t think about these many agents all at once. But this is normal in rheumatoid arthritis when you’re trying to get control of disease.

Once the data from this study finally read out, there were slightly increased signals as far as incidents or potential risk in those categories that I mentioned: overall mortality, major adverse cardiovascular events, renal thrombotic events, malignancies—particularly nonmelanoma skin cancers and solid organ malignancies and lymphomas—and infections. From that point forward, there was wording added, whether for a topical JAK inhibitor or an oral JAK inhibitor, to a box warning to reflect what was seen in those studies.

We face a question in dermatology all the time is. We have safety results from all our medications and dermatologic studies, and we have this boxed warning given to highlight some of the things we’re seeing based on studies. How do we bring it all together, in the context of what’s come out about topical ruxolitinib, abrocitinib, and upadacitinib? I’ll flip it back to you for a second, Lisa. How do you contextualize all this together?

Lisa Swanson, MD, FAAD: I have a lot of thoughts on this matter. I’ll start with topical ruxolitinib. When I explain topical ruxolitinib and the black-box warning to my patients, I say, “This medicine is a member of a family called JAK inhibitors. Most of the members of this family are pills. Because of a study on 1 of these pills, the FDA put a black-box warning on all JAK inhibitors. Even though topical ruxolitinib is topical, it got the warning too.” I explain that topical ruxolitinib is like Kendall Jenner. She’s low drama, but she’s in the same family as Kim, Khloé, and Kourtney Kardashian and Kylie Jenner, who are higher drama. That seems to resonate with a lot of folks. They completely understand what’s going on when I use that analogy.

Raj Chovatiya, MD, PhD: The trashy TV analogy works well, doesn’t it?

Lisa Swanson, MD, FAAD: It always works. Everybody knows the Kardashians. With regard to the oral JAK inhibitors abrocitinib and upadacitinib, that’s more of a challenging conversation. I struggled for the first several months thinking about how I’m going to thoroughly and effectively explain this warning to my patients. I’m thinking about how to do my job in an efficient manner in a busy clinic. I also need to explain it in a not-so-scary way. There are a lot of ways you could explain this warning that wouldn’t get anybody to take these medicines.

Raj Chovatiya, MD, PhD: So true.

Lisa Swanson, MD, FAAD: It’s all in the delivery. It’s all in the way you communicate what this warning is all about. Honestly, that took me some time and practice to get down. To communicate it to my patients now, I explain the origin of the warning with the studies on tofacitinib. I say that this warning involves the risk of rare but serious adverse effects with this class of medications. For that reason, we have to do a little blood work, and we might want to think about HSV [herpes simplex virus] suppression. We might want to think about zoster vaccination. We might want to think about whether you’re planning on becoming pregnant. I ask about smoking history. I ask about history of blood clots.

Most of my patients classify as a lower risk for some of these black-box warning concerns. I mention that to them. There was a fantastic letter to the editor, in response to an editorial, in the JAD [Journal of the American Academy of Dermatology] in August from Brett King and Brittany Craiglow about the JAK inhibitors and their black-box warning. It really resonated with me because everybody is intimidated by this warning. Everybody wants to do the best for their patients and to practice good medicine. The black-box warning has put a cloud over these novel and fantastic medicines.

The point in their article was not to be afraid of the black-box warning. Embrace it, and learn everything you can about it. Learn how to communicate about it with your patients. But don’t forget the wellness that can be provided by these medicines. Don’t be so focused on, “Oh gosh, but there’s a black-box warning.” Embrace it. Get to know it. Get comfortable with it. Talk to your patients about it, and see these medicines for what they can be.

Transcript edited for clarity

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