JAK inhibitors for the Management of Atopic Dermatitis (AD) - Episode 9
Drs Alexandra K. Golant, Raj J. Chovatiya, Linda Stein Gold, and Eric Simpson comment on clinical implications of boxed warnings for the utilization of JAK inhibitors when treating atopic dermatitis.
Linda Stein Gold, MD: The elephant in the room is the boxed warning. Can you just talk to us a little bit about how that came about? What are your thoughts behind it? How do you deal with it in actual clinical practice?
Alexandra Golant, MD: As dermatologists, we aren't new to boxed warnings. All of our systemic immunosuppressants before the JAK inhibitors have boxed warnings. Many of our other dermatology biologics have boxed warnings, so this is something to understand but not to shy away from. The more comfortable you become with the safety data, including the boxed warning language, the more confidently you can present it to your patients and counsel them. Ultimately, that's the goal. You want every patient to leave feeling comfortable with safety. The JAK inhibitors are immunosuppressive to some extent. You do get standard warning language of infection and malignancy. There were some thromboembolic events in the trials. The warning language was kind of enhanced by JAK inhibitors at the time, not for use in atopic dermatitis, but from oral surveillance studies with different JAK inhibitors in a different disease state where there were some signals for cardiovascular events for sudden cardiovascular death or overall adverse events that did get added to the label. This has complicated things a little bit—just differentiating what events came from that drug in atopic dermatitis versus the JAK inhibitor class in general and for overall all disease states. That's where the conversation becomes very nuanced. When I counsel patients on this, sometimes I will do a deep dive, saying, this is what came from the label in an atopic dermatitis population, which is so different from populations like rheumatoid arthritis. It tends to be younger and healthier, so I want them to come away with incidents of these adverse events, which can feel scary as a patient when you're reading them for this population and this drug in particular. Going step-by-step in terms of what is the warning language they're going to see, it is weird that shared decision-making comes into play so strongly because taking a strong history, knowing your patient, knowing their comorbidities or their lack of comorbidities, lets you then personalize the conversation and say, based on what you've told me, I still think that you are a very appropriate candidate, or I feel very comfortable with the safety of this medication in your circumstance, and this is why. That will create more confidence in this drug than just saying, this is a warning. You interpret it on your own and are not giving that guidance as to why this medication still remains appropriate for that patient.
Linda Stein Gold, MD: That was a great overview of the boxed warnings. It's not just our patients, but our colleagues who don't always understand that we're referencing another study, but as you explained, this study was done in rheumatoid arthritis patients. They are all 50 years or over, and they all had at least 1 cardiovascular comorbidity—a very different population from most of our atopic dermatitis patients.
Alexandra Golant, MD: Exactly. That makes it so difficult even for the average provider to extrapolate and say, how is this relevant to a younger, healthier patient population without that preexisting risk factor? Let's be clear, the JAK inhibitor that was used or that was the topic of the oral surveillance study was a less selective JAK inhibitor that carries its own bias in terms of the incidence of these adverse effects that were seen in the trial. It becomes very difficult for providers to interpret and then for patients to understand. I like to state this on a broad level that yes, some of these risks came from upadacitinib or came from abrocitinib in an atopic dermatitis population. There were ‘X’ number of clots, for example, in the trial for atopic dermatitis. Other language on the label was baggage from and then gives some context from the oral surveillance study. I would be curious to know how my colleagues are doing it.
Linda Stein Gold, MD: This is a conversation that our colleagues are going to wonder, how much do I have to discuss this with my patients? Raj, do you go into depth about it, or do you just kind of give them an overview about where it comes from, what the main risks are, and why you're comfortable prescribing a particular medication? We also see the boxed warning. I would like you to comment on the topical JAK ruxolitinib. Do you talk to those patients as well?
Raj Chovatiya, MD, PhD: Great question. A real-world, applicable one because you don't want to run into that circumstance where maybe you haven't given it your due diligence, they go home and they're like, what in the world did you just prescribe? There's a list of things here. “You're crazy. I'm never coming back to see you again. You're trying to kill me.” Because that's literally what we all want to avoid here. There's just so much context that goes into the discussion that largely, number 1, if you determine that it is a JAK inhibitor, whether in topical form or if oral is going to be the right therapy for your patient, it behooves you to know it ahead of time. Something I tell my residents is to download that prescribing information. I want you to read it. Read it, think about it, and ruminate on it because it's going to be up to you to come up with a way that you can break that down and add context, much like Ale beautifully articulated. That will make people feel comfortable. You're not going to have time to sit there and read it word-for-word and to interpret it. You'll need an entire other degree to do that. Getting across those high-level points is what you want once you start figuring out what the patient is interested in hearing. We talked about older patients that want you to be a little more paternalistic and that younger, extremely well-educated, well-researched Manhattan patients that want to sort of know everything. It starts to break itself down into what detail you need to go into for your patients as well. The 1 thing I like to remind folks is that the black box warning is not a game of absolutes. There isn't anything either saying you absolutely do not do this or you absolutely do not do that. It's trying to highlight some high-level points that you want to think about when you're considering prescribing that medication, because we have great examples in dermatology previously of other medications that have black box warnings that maybe never materialized. Tacrolimus is 1 great example in terms of lymphoma. We have others—such as in the case of warnings on adalimumab for psoriasis—where we find out that this has a lot to do with the many different indications of this class of medications, and it probably applies slightly differently across those with skin disease, joint disease, gut disease, and things like that.
Linda Stein Gold, MD: That's an important point—that often on the label, we have a class labeling, and so if any drug within the class has this particular adverse effect or warning, it will be carried to the other drugs within that same class. Eric, you have the luxury of having 30-minute appointments. How do you approach it? How much do you give?
Eric Simpson, MD, MCR: It's great to hear from my colleagues. I'm similar, actually. I love the approaches outlined here. I probably provide too much detail sometimes, but I just feel like that understanding and explaining where the black box came from, and understanding that that was a different population, and a 5-year study in a high-risk population may not apply. I sometimes say, that's the worst-case scenario situation because it's a pan-JAK. I'll explain that to the patient, but it blocks all JAKs, and it's in older patient population, so there's a reason to believe that the risk can be much lower. Then, I actually quote some of those frequencies. After 5 years, they got this black box warning because, for example, let's say cancer. If you look and they say, that's elevated, then it's definitely elevated in that pan-JAK inhibitor, but the frequencies are low. You're talking 2% versus 1% after 5 years. I'm still working on my delivery, obviously, but I think sometimes it's showing patients that these are really rare events—super rare events. To Raj's point or to your point, I think about the black box warning signaling kind of high level, that's true, and it helps us pick the right patients with the questions that we ask, as Ale was explaining. We have to spend more time just making sure there's not a clotting history in the patient or in the family. How many cardiovascular risk factors do they have? Do they have adequate renal and hepatic function? Have they had serious infections in the past? Do they have a strong cancer, either in themselves or in their family? Those are maybe additional questions that we don't ask as much in our biologic patients, but we have to do our due diligence with that history for our patients.
Linda Stein Gold, MD: I agree with you. I think we have to figure out who is not a good patient and who is a great patient for a JAK inhibitor.
Transcript Edited for Clarity