In part 4 of this Frontline Forum, Raj Chovatiya, MD, PhD; Neal D. Bhatia, MD; Alexandra K. Golant, MD; and Brett King, MD, PhD, discuss the rapidly changing use for JAK inhibitors and other agents for atopic dermatitis.
Chovatiya: Can I ask you to follow up? Is there any concern you have, since we’ve talked a lot about steroids with JAK inhibitors that are similar to topical oral corticosteroids?
Bhatia: Again, it goes back to what’s under the hood, right? We check their labs upfront, we check their risk of [tuberculosis], [their] history of hepatitis: again, good medicine. And there’s nothing wrong with that. At 4 weeks in I would say, “OK, I don’t need to necessarily even see you back, but just get your blood work in and let’s see it. And then I would probably see them again in 3 months. Let’s check your lipids and then off you go.” Because anything that’s bad, probably would have happened by now. I even have them take the first dose in front of me. I mean, fortunately, all the companies have been very generous with their samples. So I sit there with whichever one they’re going to take: I say, here’s a glass of water, take your first pill, and you’ll sit here for half an hour. And they [ask] why. [My answer is], you see all these things you’re worried about? After 30 minutes, we’ll know that none of them are going to happen. And essentially, then they leave the office like, OK, maybe not so bad. I mean, it’s a little bit quirky, but you have to do it, because again, that gets them off the ledge, but it also gets everybody with the understanding like, OK, angioedema and anaphylaxis would have happened by now. And it didn’t happen.
Chovatiya: Yes. And I think that for years, in many ways, we [have deluded] ourselves thinking that there’s zero risk for corticosteroids, whether topical or oral. And I think we have some of the best data that in fact, chronic corticosteroids do a lot of things even beyond just HPA axis suppression.
Bhatia: Dermatologists don’t see avascular necrosis of the hip. We don’t see the insulin resistance and everything [else that may happen]. We’re not the recipient of the problems, [but] we may be the cause of the problems.
Chovatiya: That’s exactly right. As we continue to gain more data over time, there will be a big interest in long-term extension data, particularly for safety. The argument would be, well, many of these events that you may see at low rates that are on the boxed warning could potentially accrue over time. Now, I think that the short preview would be in the studies…that are reading out so far, that are getting presented to congresses, we’re not seeing it. Do you have any thoughts about long-term [use] or safety concerns?
King: No. Actually, for me, the oral surveillance study in particular has been really useful for me in the way I think about long-term use, and also in the conversations that I have with patients. The data about the numbers of patients in the oral surveillance study was a study in which risk of bad events were optimized—it was a study designed to optimize the rate of bad events. And so, when you actually communicate the numbers of patients—4500 patients in those clinical trials, patients observed for years—[you see that] the rate of bad events was tiny. And mind you, that was a study in which everybody was on methotrexate, 57% of patients were on prednisone, the average BMI [body mass index] was 30, and they were smokers and had hypertension, hyperlipidemia, a history of premature coronary artery disease. And therefore, I feel really comfortable with [patient X]—[say], a 30-year-old with AD without those other factors—taking this medicine for a long period of time. I have no concern, actually.
Chovatiya: Isn’t it funny how that subtle point about the methotrexate and prednisone seems to be lost on everybody all the time whenever that study comes up?
King: Right.…Partly it’s because you have to go to the [study] supplement. Anytime you have to dig into the supplement to find something, nobody’s going to know—but [in this case] it’s really, really important. Truly, the average BMI was 30, 57% of patients were taking prednisone. I mean, these are all the things that we’re talking about that we hate doing. As Allie pointed out at the start, that is the study that gave us all of the boxed warnings—for JAK inhibitors in alopecia areata, for topical ruxolitinib, in vitiligo and in AD. It’s just crazy.
Bhatia: The paradox is that methotrexate has 17 black box warnings, and yet everybody uses it like [there’s] no tomorrow, because it’s cheap and easy. And that actually is the fundamental paradox of how we do things.
Chovatiya: I could not agree with you … more on that.
[Let’s] transition … to something, obviously in my clinical practice and that I love thinking about, research-wise and treatment-wise, is itch, as we think about it as an important symptom. Often, [it’s] the overriding reason patients are coming to see us. It’s really exciting to think about the revolution in JAK inhibition therapy in the context of disease, but specifically in the context of symptomatic resolution. And we’ve begun to understand exactly how it just signaled over the past handful of years. We still don‘t understand much; it’s largely a big black box warning in terms of cutaneous sensations of itch and pain. But we do know that there are, generally speaking, histaminergic and nonhistaminergic IgE pathways. And for a long time, everyone thought histamine is itch. And that’s why [physicians] to this day still give antihistamines as monotherapy unnecessarily to patients who don’t have allergies. They say, “Oh, you’re itchy, use the antihistamine.” And we know from our clinical experience, antihistamine monotherapy really won’t do much for the itch of somebody with AD, largely because most of the itch is driven by nonhistaminergic pathways. Those pathways actually are directly influenced by the neuroimmune axis, and the actual binding of many of those cytokines, we think about how it directly relates to cutaneous afferents and nerve terminals. So in many ways, the nerves in the skin are like their own little macrophages in the immune system, organizing inflammation locally and sensation. A lot of those things we talked about in the case of IL-31, IL-4, IL-13, TSLP, actually can bind directly to neurons, and all of these cytokines, as we mentioned before, utilize the JAK stat signaling pathway.
So, it’s probably very easy to understand when I say that to understand why there’s such broad applicability and really fast action on itch when we think about this disease state, along with stuff that’s happening in the epidermal barrier, and the actual immune system itself. We are beginning to get to a point where we realize that it’s not all just about an EASI score or an IgE. [It’s about] really thinking about clinically meaningful or—something that I’ve really loved in the past couple of years—deep responses in terms of how we can get people itch-free or very, very close to itch-free. That is really the excitement. And so, Neal, I might ask you, as somebody who does a lot of clinical studies, what does it mean to you as an important end point? And what have been some of the cool data we’ve seen with responses to topical and oral JAK inhibition?
Bhatia: [We see response in] eczema and psoriasis and the redness of rosacea, And yet, the funny thing is steroids inherently and mechanistically don’t have anti-itch as a property. They don’t do anything to histamine, or to the brain, or to serotonin, [or to] any of the other pathways. It’s truly anti-inflammatory in its mechanism. Whereas here, we talked about direct inhibition of signals that make cytokines for itching, correct? And here we talked about what are we seeing quickly in terms of the fossa being turned off? This is why the patients are getting better within 3 days. But from a standpoint of clinical improvement, if you break that itch/scratch cycle quickly, all of that is going to improve these, this score is going to prove everything you see objectively. And then all of a sudden, you see your leveling of the playing field. Again, you’re not saying anything disparaging about biologics or anything else. It’s just that we’re trying to break that cycle quickly, so that the patients can get some relief. And then their experience is like, oh, I’m better. I’m feeling different. I can sleep, I can concentrate at work, I can drive the car without stopping at the intersection to scratch, or my kids are sleeping and my spouse is sleeping. All of those are things we take for granted in quality of life. So I think the inherent part of stopping itch is, again, stopping what we know is the manifestation of the disease that they see. And then we take the objective part of it, and then we follow it.
Chovatiya: I think that’s an interesting point: The question always comes up is rapid onset, which is really important. And we can all debate that. But we know that for our patients sometimes it’s a lot of work, a lot of months to years,…to try to convince them that a systemic option might be a good choice. We don’t have that much time to waste to really make sure we get buy-in, and hopefully adherence, on the fact that they need something to control their disease. I think that is one of the most important [points] when you’re thinking about time to some type of clinical response.
Bhatia: The other missing link is, again, the patient experience of what’s going to happen next. We’ll talk to them about, OK, here’s the next couple of weeks. And a lot of us don’t even see these patients back, because we don’t want to hear like, OK, what do I do now? And it’s like, no, stick with this for a while. And let’s see where this goes.
Chovatiya: It’s the whole “come back in 3 months” thing, right?
Bhatia: Exactly. But we’ve all talked about [how] these long-term extension trials are proof of safety. They measure efficacy and long-term outcomes, but the reality is, we wouldn’t run these trials if they weren’t safe drugs. And that’s why I think we have to talk to patients about [our plan, saying], I’m giving you a year’s worth of refills, because I want you to stay better, I don’t want you to just get better…The cheerleading that comes with it, again, is about the talking points that we all have to have in the office. Not just the physicians, but everybody in the office—the ones who would answer the calls, the ones who fight for prescriptions, all of us—has to have those talking points ready.
Chovatiya: And from a nerdy aspect, we look at itch a lot of different ways when it comes to our trials. And often, based on what has been studied, it is what the FDA has deemed clinically meaningful. We can debate this, too. A 4-point improvement on that numerical rating scale of 0 through 10 for measuring itch that we often will use in practice, which is a validated scale, has been determined to be clinically meaningful—even though, when we first started off, going from 10 to even 7 actually matters for somebody who is really, really itchy. That is an improvement. So, there are different ways to look at this. But based on the way you cut the data, whether you’re looking at abrocitinib, upadacitinib, or even topical ruxolitinib—the 3 approved JAK inhibitors in the United States—you’re talking about responses in days. Sometimes—in the case of just looking at raw change in the actual NRS score itself—it’s even hours…The most exciting thing for me has been that a lot of itchy people come in to see me on a weekly basis, and I can actually make claims about some of these response times and see it play out in real life with my patients.
Bhatia: And to be fair, I mean, in the trials, this was all monotherapy. They didn’t have anything extra for itch. They didn’t have any adjuncts that they could use. So in the real world, we can say, look, this is how good it was, just on the medicine alone. Now we can, obviously, build a whole program for stopping the process. So, to your point, Raj, it’s like, this is the template. Now let’s see how much better we can do from what we did in the research world.
Chovatiya: Yes. And, from the case of topical vs oral, what has been some of your experience in terms of rapidity of onset for your patients with AD, particularly as it relates to itch?
King: It’s really remarkable. My first experience with this was years ago when I was using tofacitinib off-label in AD. I always remember [when] a patient came back and said, 6 hours after taking the first dose, I felt better than I have felt in my life. This was a man in his 30s who had had bad AD for all of his life—and that has stuck with me. Now, in a world where we can use these much more easily, I’ve had that experience, again. And for sure it is not everybody, not at all. But you only have to use these medicines a few times to have somebody come back and tell you that story.
Chovatiya: Isn’t that remarkable?
King: It is incredible that we can intervene so effectively in a disease that really is quite awful, which, again, is part of why we’re here. But…again, I feel like we’ve done a relatively poor job of educating ourselves about JAK inhibitors and risk. And I think also, still too often, we diminish the effect of itch on quality of life. And for sure, when I was a resident, I heard multiple times from my mentors, “Don’t scratch.”
Bhatia: How helpful.
King: I get it: “You’re itchy, but don’t scratch.” It’s like telling somebody in chronic pain, “Don’t have pain.” …You are itchy,…. and it’s awful. And we really have to appreciate that …we own this. If we don’t own this, for sure, nobody else will. We really have to…stop diminishing it and stop telling patients just to not scratch or to not itch, like somehow you can magically turn it off. And we need to think really carefully about how to make it better. JAK inhibitors are really an amazing opportunity to affect this really horrible symptom.
Golant: The first time you use a JAK inhibitor, it’s almost like nothing else we’ve had in dermatology in terms of the onset, the rapidity of action. We’ve all had patients come back and say, “A day in, I felt 50% better. By day 2, it was even better.” It almost is hard to believe, the first type of couple times you hear it. And that is what makes them, I think, such powerful tools. In practical knowledge, when you’re counseling on these medications, to be able to tell a patient that as early as day 2 in the trials, there were many patients reporting significant introduction by week 1. To contextualize it, I think, gives them a lot of hope. [Generating this] feeling that “I’ve lived this with for so long [and it] may go away and may go away quickly” has been really powerful and quite an effective talking point in the exam room.
[Edited for space and clarity]