Management of Type 2 Inflammation in Atopic Dermatitis - Episode 10

Atopic Dermatitis: Breaking Down the AE Profile of JAK Inhibitors

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Drs. Lio, Feldman and Jain reflect on the adverse event profile of JAK inhibitor therapy in atopic dermatitis and consider when these agents are appropriate for use.


Peter A. Lio, MD: Let’s talk about the effects. What’s remarkable about this class of JAK inhibitors is that for better or worse—I can see both sides of this argument, and I say that not to sound diplomatic—they’re often grouped together as 1 class. That’s important, especially in the early days, but it can start to hinder us later. A good example is tacrolimus topically, which got slapped with a black-box warning in 2005. It was talked about as if it were a systemic agent. After more than a decade of work, we understand that those risks probably aren’t real in real-life patients.

Amy Paller et al just published a beautiful 10-year trial of children with atopic dermatitis using topical tacrolimus, and they didn’t see a signal. I don’t know how we beat that. But the black-box warning persists as a theoretical risk. That’s what we see in our topical JAK inhibitor. We see everything that’s been in the class. Of course, the class data have been affected. It’s widely known that there was a delay of these 2 oral agents. The third 1 that was abrocitinib [Cibinqo], which hasn’t even come out. It may not. I don’t know. I have no insider knowledge on this because the FDA is still deliberating.

Some of the data that came out regarding another JAK inhibitor, tofacitinib [Xeljanz], a pan-JAK inhibitor that’s used in rheumatoid arthritis. They got some more safety data, and the FDA took some time to parse that out. Now we’re seeing it in the labels of these drugs—another agent in the class and its risks in a very particular study. This is what’s fascinating. The study that was done was on patients with rheumatoid arthritis who were over 65 or over 60. They were older, and they all had a cardiovascular risk factor.

It’s important work. I don’t mean to undermine the work, but it seems strange to talk about some of the safety signals that came up in this enriched population and then apply it to somebody putting a cream on their antecubital fossa. Are we doing more harm than good? I truly don’t know. But it makes our job hard as a clinician because when I’m writing topical ruxolitinib, I have to say, “There’s a black-box warning that talks about blood clots, malignancy, and adverse cardiovascular events. This is a big deal.

Thankfully, we don’t have to do lab monitoring with the topicals, but we have to do lab monitoring, both baseline and monitoring labs for our oral agents. Generally speaking, for a baseline, we’re doing a complete blood count [CBC], a complete metabolic panel. We’re doing lipids because they can affect lipids as well. Hyperlipidemia has been described. We’re also doing a hepatitis panel, a tuberculosis panel, and some people are even doing HIV. These things are reasonable to do. We’re doing them annually, and then every month or 2, maybe every quarter, checking in on some of those same labs—especially the lipids, because we know that’s an issue, and the CBC, because we know there can be low hematocrit and low platelets. All of these are things we have to keep an eye on.

That makes it much harder to use. Many dermatologists and many allergists who might use an agent for atopic dermatitis are going to be a little more cautious. Our patients are cautious too. For the right patient, it’s a slam dunk, but it’s a harder sell for a patient who’s on the fence about these agents. Have you guys had much experience?

Neal Jain, MD: This is 1 of our last-resort therapies when you fail other things. I’m curious to know if you use this in patients who have 80% control with dupilumab [Dupixent] but who have severe flares at times. Do you use it to cool them down in those severe flares for short periods of time if you can get it approved? Access becomes another question, but we don’t know what the long-term are going to be. I see myself using it in that manner.

One question I often ask—and I hear it when I go to these conferences and we talk to our colleagues about patients who don’t seem to respond to anti–IL-4/13 therapies or other systemic therapies—is are we treating the right disease? Is this undiagnosed ACD [allergic contact dermatitis]? Is this some other condition? Is that why you see this response from these somewhat promiscuous drugs that have this effect on various inflammatory pathways? It’s an interesting question. I don’t know the answer.

Matt Feldman, MD: I agree. Dr Lio, not to bring up an NF1, but from a safety analysis or discussion, we have to disclose that in the pivotal clinical trial phase 3 for upadacitinib [Rinvoq], there was a pneumonia death in a 40-year-old who was otherwise healthy. Talk about interferon responses that are suppressed.

So I’d have a frank discussion with these patients: we don’t know what we don’t know. What we do know is that if the patient in front of us is asking for help and willing to take that risk, these are FDA-approved therapies that have gone through rigorous safety analyses, and they’ve been approved. I don’t think there’s a reason to completely discount these therapies or shy away from them in every situation.

On the flip side, we have to disclose that we don’t know a lot about long-term safety. Some significant safety signals need to be closely monitored, but there are patients who can do phenomenally well in these therapies and can be helped. This is the perfect example of how getting buy-in, having a good relationship with your patient, and doing appropriate shared decision-making can make a difference.

Peter A. Lio, MD: I love it. I completely agree. If we’re doing good patient selection, everybody wins because for the right patient who needs this, this is going to change them. I’ve seen it. I have patients whose lives have changed. They failed everything else. They were miserable. This is the 1 thing that’s helped. For us, it’s going to be good too because we finally have a new tool in our toolbox. But [we have to] have a frank discussion with shared decision-making and education, because with any tool, there are negatives as well as positives. The sword cuts both ways, so we have to be careful. These powerful medicines potentially have some powerful adverse effects.

It may be that they’ll sequence a little later. I feel as if I have to talk about the biologics and, ideally, even try the biologics before we go there for many of these patients. But what if they’re mostly better but having a flare-up because these agents work so quickly? Could we use them more intermittently? Would that be a way to hedge our bets in terms of safety? Maybe use them for a month or 2. We’ll do all our lab monitoring be careful but then be able to come on and off. The truth is, we don’t know. They’re not studied that way, but that may be a niche that could still be filled. Maybe, in time, we’ll say, “This is a nice way to use it for some patients,” as opposed to chronic care.

Although as you said, they’ve passed their FDA trials and have beautiful longitudinal data that seem to be quite durable. We’re going to see lots of patients’ needs being met with this big palette that we can now draw from.

Transcript edited for clarity.