In part 2 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: Thinking about those transitions to therapy, can we visit the JAK inhibitors a little more in detail to understand the circumstances in which these might be good choices for patients when they’re not having well-controlled disease? [I’ll be] brief since I don’t want to put everyone to sleep. The reason we’re so excited about JAK inhibitors is the very mechanism by which …. they work. So, very broadly, we think about Janus kinases and their associated STAT protein signal transducers and activators of transcription. Essentially, this is the important downstream conserved signal transduction pathway across a number of different cytokines in the immune system. In the case of AD, we know that cytokines are … like the currency of the immune system. [We need to know] whether you have things like IL[interleukin]-4 and IL-13, which are really important for a lot of overarching roles in type 2 inflammation; IL-31, which tends to modulate itch directly on neurons; IL-5, which is important for other accessory roles in IG and eosinophils; IL-22, thickening of skin; alarmins like TSLP [thymic stromal lymphopoietin] and IL-33…you name it. They all kind of go through this pathway.
These Janus kinase proteins—by virtue of their name, the Roman god of duality—occur in pairs on the intracellular portion of these receptors. When you have a cytokine on the outside of the cell, binding to a receptor causes a confirmational activation and phosphorylation of JAK proteins, which causes activation of STAT proteins and a whole …relay race that begins all the way down to the nucleus where you have transcription and then subsequent translation of a lot of the different proinflammatory programs we think about when it comes to AD. So with that … preamble in mind, you could understand why JAK inhibitors are so exciting, because with the biologic therapy, maybe you can send a signal [to] shut off 2 specific cytokines, but with JAK inhibitors, you can actually hit a protein that’s involved in many different aspects of the pathophysiology of your disease. [You can] actually work across various symptoms and signs in a particularly rapid and efficient manner we think about in the case of a small molecule as opposed to a biologic therapy. So with that being said, can I ask you what really makes JAK inhibitors different than what else is out there for AD?
King: …[B]uilding on what you said, these molecules modulate myriad cytokines that are important in disease...I think it’s important to note that they modulate these multiple cytokines, but they don’t block them. And this gets [back to what we were] saying earlier about patients’ fear and our misunderstanding of this class of medicines. JAK inhibitors don’t block 25 cytokines. If they blocked 25 cytokines, indeed they would be dangerous molecules. But they modulate the behavior or the activity of multiple cytokines as opposed to blocking the activity of certain cytokines with the monoclonal or a potent monoclonal antibody.
…[T]he fact that these small molecules do this means that we can formulate them as topicals and we can ingest them orally, which are 2 of the treatment modalities that we ….prize—topical in particular. We are skin doctors, and so being able to apply a therapy, a highly effective therapy, topically is amazing for us. But, again, they also offer an opportunity and …, I would say, our first opportunity in AD to effectively treat this disease with an oral therapy. So …[their] mechanism of action is really hugely important and has … expanded [dramatically] our toolbox in AD….
Chovatiya: That’s a good way to think about it, particularly in the case of the oral agents, where largely before we were all using relatively broadly acting immunosuppressive drugs that worked at very high points in the immune system. And that was one of the reasons why we had a lot of baggage with them, whether it was cyclosporine, methotrexate, azathioprine, you name it—things we’ve all used and still use but nothing we want to use when we have better options available.
Bhatia: It’s funny because…everybody hit it on the head in saying, “This is talking about modulation,” because the 2 things that are not happening are depletion of cytagon[ph] population and anything that poisons the cells. And yet to get that into patients’ heads, about suppressing the immune system, is a big challenge. Or even [into the head of] average-Joe dermatologist, who is just thinking, “I don’t want to deal with these dangerous drugs.” [You want to say], “How is this dangerous when all this is doing is turning off signals?”
King: Part of it, I think, is that we haven’t done a good job of messaging among ourselves. I don’t think that it is necessarily that people have failed to understand. Maybe we haven’t done a good job in educating ourselves about this class of medicines and how this class of medicines works compared with the other things that we have done historically. I think it’s just a matter of education.
Bhatia: Oh, totally. [Again, it’s,] “Who’s afraid of the big black box?” That they are why are we not writing these drugs should probably be more the narrative of why you should write these drugs.
Chovatiya: Thinking about just the aspect of how we [should] communicate better, Al, you’re going to fix that for us here. Can you talk a bit about the safety profile of JAK inhibitors in patients, particularly those with AD? How do you conceptualize all of this? How can you communicate this pretty easily and efficiently to make sure that there’s a good balance and understanding of how this goes alongside all the great stuff that we’ve heard about around the table?
Golant: Sure. Knowing that these medications have a boxed warning, and knowing that any patient you’ve prescribed this to is going to see this at the pharmacy or read about it online, it’s really important to preempt. [Although] it does take a little bit of time in the exam room, let them know that this medication has a boxed warning. As we know, a lot of the language in the boxed warning came from the oral surveillance trial, which was not [done in] an AD population and was not the type of JAK or the specific JAKs we use currently to treat AD. So I like to contextualize that: I let patients know that some of the major risks in the label were related to a different disease state, and a different patient population, with a different type of medication in the same class. I think it’s important to quantify the risks for specific patients, so for an AD patient, I go through what the risks are, but I say, “In the trials, there are the same risks that exist in the general population in patients not taking any medication” and “The risks in AD population were elevated very minimally, if at all, for some of these in AD patients.” So it’s important to acknowledge the risks, but also important to give context on the magnitude of the risks, which are very low. I always like to end by saying, “This is a medication I would give to a family member. I think this is a medication that is safe for you.” That conversation works best, of course, after you’ve taken their history and made sure there are no major risk factors; then, you can further personalize that dialogue.
Chovatiya: I like that. Patients ask all the time, “OK, doc, what are the highest risks I should be thinking about?” I tell them, “Not getting treated for your chronic disease is the highest risk I worry about. Everything else is [far, far] secondary to that.” And I feel that that does serve to put this in context for people who are on the fence for any particular reason, and, like you mentioned, there wasn’t really necessarily class-wide box labeling until we had the results read out from the 10-year oral surveillance study. That took a look at tofacitinib in rheumatoid arthritis patients based on some of the trial findings that had been seen a decade ago, and that’s where a lot of this wording [came] in across topical and oral medications. You’ll notice a lot of consistent wording about certain risks, major cardiovascular AEs, venothrombolic events, malignancy, infections. That’s what scares people. Death, even, and you can’t get scarier than that—but you’ve got to actually take a closer look and read [exactly] what it says, then think about why exactly did this happen, and then what does this look like for AD patients? One of the tough things that we all have to face is that, whether you’re using a topical JAK inhibitor or an oral, it’s largely a lot of the same wording on there, even though those risks don’t necessarily reflect what was actually seen in the AD trials and even in the long-term extensions of those trials. Some thoughts, Neal?
Bhatia: I was just thinking that we’re so quick to throw tofacitinib under the bus, and yet it was the pioneer. It was the first of its kind. We didn’t even get to use it a lot in dermatology without taking some risks, and yet now—how many, 5 to 10 years later?— we’re thinking, “Oh, now we have safety in 12-year-olds. We have safety in 18-year-olds.” That’s fine, because, again, treating 50-year-olds with comorbidities who were smokers, who had multiple pharmacy issues, who were in the hospital, they are going to generate black box warnings…[and] AEs. And that’s unfortunate, but that doesn’t have to apply to the young kids who need treatment. That doesn’t need to be an obstacle for what we need to do today for healthy patients who actually need something that will put their foot on the gas. So I think, again, it comes back to the idea of playing defense from what was. Again, we talk about tofacitinib like it was a bad molecule. It was a great molecule, but it was, again, the pioneer of what we have got to build on. So we just have to understand what [the situation] was, and now where we are sitting in this class of drugs.
Chovatiya: When you really take some time to go through that treatment, the AE tables and the prescribing information, and just get familiarized with each of these drugs—which I encourage all my residents and everyone to do—you see the stuff on there. Nasopharyngitis is at the top of every table, then things like headache. In certain cases, [such as] abrocitinib, nausea is up there. With upadacitinib, acne is up there. In the case of topical ruxolitinib, actually, sort of a lot of stuff related … to its topical treatment more than anything else. Not much.
Bhatia: And that’s the funny thing, because the 5 black box warnings are like, “OK, here we are. Let’s watch serious infections, MACE [major adverse cardiovascular events], malignancy, everything else, and then look at the incidence in the trials.” So I tell everybody, “There’s a difference between what everybody sees on the internet and what actually happened in research.” You have to have those talking points ready, because we’re constantly playing defense in discussing these drugs with patients.
Chovatiya: I like that point that you make. … [P]robably everyone has been successful in terms of talking to their patients …, once you familiarize yourself, understand your talking points and your dialogue of how you’re … going to work this. It’s not [a situation in which you can] just go in half-blind and … try to explain, because there’s a lot of user dependence understanding in that discussion. We probably haven’t done an amazing job communicating a lot of this, among even ourselves as physicians; therefore, there’s so much heterogeneity of that message, even in that we’re not delivering it in the right way. … When would you recommend using a JAK inhibitor and what kind of patients with AD would be best suited for them? And … does disease severity take a role here? Do you think about certain special populations? Take me through your thoughts.
King: Because we have a topical JAK inhibitor in addition to oral JAK inhibitors to think about, that question is fairly broad. [In] my approach, I … don’t think about disease severity in AD as one of mild, moderate, and severe. I think of disease severity as being whether somebody has disease that can be addressed topically, or does it need to be addressed systemically? And so, is it limited BSA? And even limited BSA is not always amenable to topical therapy if the patient has multifocal disease, [especially] multifocal always-changing disease. That’s a patient who you’re going to have a hard time chasing after with topical therapy, and so that’s a patient who then would graduate to systemic therapy considerations. And so a topical JAK inhibitor will be for the patient [who is] always in need of therapy. And I don’t feel comfortable giving clobetasol, 60-g tube with 6 refills, to anybody.
Chovatiya: Yet we do that all too often, don’t we?
King: Yes. And for me, a topical JAK inhibitor is ideal for that patient because I don’t have concern—going back to the [previous] conversation— about the black box warning. …I’m quite dismissive of the black box warning associated [with] topical ruxolitinib.. And…when I think about systemic JAK inhibitors or oral JAK inhibitors, it really is for the patient who …. [has failed] dupilumab. Here, [though], I want to be clear: Failure of dupilumab doesn’t mean that dupilumab did not work. It means that the [patient] did not get clear or almost clear. Again, it goes back to the earlier conversation. I [believe] we should be thinking more deeply about AD, and that we should all be striving for clear or almost clear. And so when dupilumab does not get a patient there, and when dupilumab does not get a patient to an itch score of 0, 1, or 2, we should be thinking about an oral JAK inhibitor. For the rare patient who—due to work schedule and travel or for whatever reason—doesn’t want to take or can’t take a needle, an oral JAK inhibitor is appropriate. And then there’s the other group of patients, who are common in my practice—I don’t know… [whether] they’re common in general—who have multiple autoimmune or inflammatory comorbidities. I think that oral JAK inhibitors are an amazing option for these patients because oral JAK inhibitors are showing efficacy literally from rheumatology to gastroenterology to dermatology. [They’re p]robably going to have a role in pulmonology. And for that patient,…we should reach for an oral JAK inhibitor… before dupilumab.
[Edited for space and clarity].