JAK Inhibitors in Treating Atopic Dermatitis

In this interview, Dr Song explains the unique mechanisms of JAK inhibitors compared to traditional immunosuppressants in atopic dermatitis treatment. He highlights their targeted action, superior efficacy, and rapid symptom relief, while discussing potential safety concerns, patient suitability, and the promising future of JAK inhibitors in dermatological care.

Eingun James Song, MD, FAAD, is the director of clinical research and serves as the co-chief medical officer for Frontier Dermatology. He’s also a clinical instructor at the University of Washington in Everett, WA.

Transcription:

1. How do JAK inhibitors differ from traditional immunosuppressant treatments for atopic dermatitis?

So as our understanding of a disease continues to evolve and get more advanced, it lets us develop therapies that are much more targeted in treating the disease. And the advantage of that is that we get better efficacy potentially, but more so from the safety side.

I think that is where we get a clear advantage if we're more targeted. With our older medications, we know that they've worked in certain individuals because these are what we call kind of broad-acting traditional immunosuppressant agent. So they would knock out multiple different cell lines, whether it's B cells, T cells, and even within the T cells, there are multiple different subsets, but these older medicines that we use, they kind of blocked everything almost indiscriminately, which is why it didn't work for everyone, and we did see certain side effects that happen if you use these medicines long enough.

With the JAK inhibitors, it really was a product of our understanding of this disease and kind of leveraging that and developing therapies to really get at the underlying kind of root cause of what that inflammation is triggered by, which, the case of atopic dermatitis, we call it type-2 inflammation. So these are the cytokines that belong to a certain family that we know can cause a multitude of different types of conditions such as atopic dermatitis. Now, the biggest difference between the JAK inhibitors vs some of the biologic agents that we have is that JAK inhibitors work intracellularly. They work inside the cells whereas the biologics are more kind of blocking our cytokines directly or the receptor blockers and so one’s an extracellular target, another is an intracellular target. And there are pros and cons of each of these as well.

2. How do JAK inhibitors target the underlying causes of atopic dermatitis? Can you describe the specific pathways that JAK inhibitors affect in the immune response related to atopic dermatitis?

So in order to treat a disease effectively, we have to understand which immune access is involved in causing that disease. And so you could start at the top, which cytokines are responsible for a disease, and then which JAK proteins do those cytokines signal through.

So in order to treat that disease, you could either block it at the cytokine level. That's what a biologic would do. Or you could block it intracellularly. That's what a small molecule protein like a JAK inhibitor would do. We know that in atopic dermatitis, there's a multitude of different cytokines that are at play. Unlike psoriasis, which we think is much more homogenous, in AD, it's a really is a much more kind of mixed population, depending on whether you're Black, Asian, White, whether you had AD as a child or as an adult, whether you have other type-2 comorbidities, your cytokine profile will look quite different. And because of that, sometimes we can't just be blocking a single cytokine or 2, which is what our biologics are doing. So of course, IL-4 and -13, those are 2 very important cytokines in atopic dermatitis, but that is not all. We know that there are other cytokines like IL-31, IL-22, and interferon, which also contribute to atopic dermatitis, but may not be inhibited by a biologic like a JAK inhibitor would.

The key thing that all of those cytokines have in common is that in order for them to signal, they have the signal through these JAK proteins. And depending on the pair of JAK proteins, that will determine which cytokines it will signal through. And what you’re seeing is that, there are over 50 different cytokines that signal through those just 4 JAK proteins. So there’s a lot of redundancy built in here. What we know, is that the key cytokines that drive atopic dermatitis signal through JAK 1. Which is why we want to target JAK 1 and leave alone the other members of the JAK family, like JAK 2, JAK 3 or TYK2, because those JAK members also serve important functions that we don't necessarily want to be blocking, whether it's metapoesis or lipid metabolism, fighting off viruses, anti-tumors or galens. There's a lot of different functions. And so ideally, we get very selective with our JAK inhibitors too, which poses another question, how are JAK inhibitor, are they all the same? Are they different? And are older JAK inhibitors, we call these first-generation JAK are going to be more pan-JAKs, meaning they are blocking JAK 1, JAK 2, JAK 3, TYK2 less discriminately. So tofacitinib is an example of that. Baricitinib is more of a JAK 1, JAK 2. So it's a little bit more broader acting. But now our kind of second-generation JAK inhibitors or our designer JAK inhibitors, these are more selective, right? And no JAK inhibitors is 100 % selective, but it's relatively more selective for JAK 1 versus JAK 2, JAK 3, and TYK2. And the 2 oral JAK inhibitors that we have approved in atopic dermatitis, at least in the U.S., okay, Abrocitinib and Upadacitinib are JAK 1 selective. And that's the rationale, why it was developed that way.

3. What have clinical trials revealed about the efficacy of JAK inhibitors in treating moderate to severe atopic dermatitis? How quickly can patients expect to see improvement in their symptoms after starting treatment with a JAK inhibitor?

So the 2 JAK inhibitors, The oral JAK inhibitors that we have in the U.S. are Upadacitinib and Abrocitinib. They both conducted randomized placebo-controlled studies showing that JAK inhibitors were superior to just using nothing, so placebo or people who are using steroids in the background. Some of the numbers that we've seen in these studies were nothing short of extraordinary.

These are some of the highest numbers that we've seen with any therapies for atopic dermatitis, talking for some studies, the IGA -01, getting there about two-thirds at a time with monotherapy. We're talking about itch reduction happening not just within days or weeks, but sometimes hours or minutes. We also are starting to see that JAK inhibitors are able to push what we think is possible when it comes to skin clearance, but also it's reduction.

So we're not even looking at itch improvement. We're starting to measure what percentage of patients will have no itch now or trace itch, that is what we call NRS-01 and that wasn’t even something we talked about with the biologics. But now with the JAK inhibitors, getting to a completely itch-free state is possible. We actually also have a number of what we call network meta-analysis where we indirectly compare drugs against each other. It’s not a perfect way to do it but it’s better than just looking at numbers just kinda head-on. And what we consistently see is that JAK inhibitors, they come to the top when we look at efficacy. Where it’s EASI-90 clear to almost clear, NRS-01. It's the same 3 JAK inhibitors that are coming top to both doses of Upadacitinib and a higher dose of Abrocitinib are consistently doing better. In addition, and we talk a little bit about some of the head-to-head studies now that have been done with oral JAK inhibitors and then dupilumab, which, you know, is still probably the number one prescribed systemic therapy for atopic dermatitis, most people's first-line therapy within good reason, right? And what we see is that when you compare these drugs, the JAK inhibitors are going to outperform dupilumab, especially at the more stringent endpoints. And so like EASI-75, both dupilumab and the JAK inhibitors, they're fairly comparable.

But when you look at EASI-90, EASI-100, and NRS-01, that's clearly where you see the advantage goes to the JAK inhibitors, as well as the speed of onset. We're seeing the JAK inhibitors work very, very quickly. And that's not to say that dupilumab is slow, it’s actually a pretty rapid-acting drug as well, but JAK inhibitors are that much faster. Which I think is really important in a disease like atopic dermatitis where these patients are so much more miserable, they want to get better immediately. 

4. Are there any long-term safety concerns that dermatologists should be aware of when prescribing JAK inhibitors? How do you monitor and manage potential side effects in patients on JAK inhibitors?

We can't talk about safety of JAK inhibitors without talking about the box warning, right? I think that's what a lot of people kind of fixate on. And I'm going to start with that first. Okay, we call these the adverse of special interest, because these are the ones that we like to kind of follow, as some of our listeners may know, that box warning comes from a different JAK inhibitor. It's called a Tofacitinib. This is a pan-JAK inhibitor, and we talk a little bit about why pan-JAK inhibitors maybe are less advantageous than our selective JAK inhibitors. And it was studied in a high-risk rheumatoid arthritis population. It is a different patient population. And the reason it was done this way is because if they study this drug in just regular rheumatoid arthritis patients, this study would have taken decades to complete because these things just don't happen that often. So they have to pick patients where this is more likely to happen.

So in other words, they kind of have to cherry-pick or enrich that patient population where this is more likely to happen. So these patients were on average 60 years old. They had moderate to severe RA. All of these patients were on methotrexate. Just under 60% of those patients were on systemic steroids. So that’s the patient population we’re talking about, which looks, on average, a lot different than we as dermatologists see. And those patients were then compared to TNF inhibitors. So that was kind of the gold standard in RA at that time, and it still probably is.  

And then we followed these patients out for 5 years. And at the end of that study, what we found was that some of these things like blood clots, cancers, heart attack, strokes, they happen in both groups. They happen with the TNF inhibitor. They happen with the JAK inhibitor too. The rates were actually low for both groups, but the relative risk was a little bit higher with the JAK inhibitor versus the TNF inhibitor, which is where those boxed warnings comes from right so it's a relative risk although the absolute risk is low.

But there's a couple key things that we need to point out here is that first there wasn't a placebo group here so we don't actually know what would have happened if those patients didn't get treated with anything we actually know that rheumatoid arthritis patients are more likely to get cancer, heart attacks, strokes, blood clots even if you don't treat them with anything because of that underlying inflammation which can cause problems too. The other thing is TNF inhibitors are actually helpful in reducing the rates of heart attacks and strokes. It's not a fair comparison, right? And the third is, of course, this is a different patient population. This isn't the same population that we're studying. So there's a lot of question mark that this study has kind of led to that we still probably won't know for some time. But what we can say is that, in the real world, when we try to copy that study or replicate this oral surveillance study, we did not see the same results. The risk of these things were actually very comparable in both people who take TNF inhibitors versus people who take JAK inhibitors. We've seen that in the U.S. registries. We've seen that in the Denmark registry, excuse me, the German registries, whether that's for RA whether that's in psoriatic arthritis as well, so we were able to replicate these.

And I forgot to mention, even when you looked at those raw numbers from that safety study, they were still low. We're talking 1 to 4 percent will get some of these things. And this is kind of your worst-case scenario. When you pick the worst of the worst patients, it's still 1 to 4 percent. So that's kind of the way I talk about to my patients.

Now, in dermatology, of course, we have less data because it hasn't been out in dermatology for more than a couple of years. I believe 2021 was when we first came out, at least the oral JAK inhibitors. And we now have, I want to say 5 years worth of data for Upadacitinib in atopic dermatitis and 4 years worth of data with Abrocitinib in atopic dermatitis.

And what we've seen is that these adverse effect of interest, heart attack, strokes, blood clots, cancer, serious infections, death, they really aren't that much different than what we see in the general population. Can it happen? Sure, it can happen. But can it also happen to people who also have atopic dermatitis, who have the same severity, but don't take a JAK inhibitor? Yes, it happens in them too.

And that's where that real-world data comes in. it’s kind of giving us a reference point of what's the general rate of these things happening in the background. And what's the likelihood that this is going to happen to people who take JAK inhibitors? And when I showed the data, right, between the background rate and the people in the studies, there wasn't that much of a difference. Now, this is not to say these things can't ever happen, but these things generally happen in people who have risk factors. Okay, we're not talking about 18-year-old, healthy junior olympians that all of a sudden dropped dead from a heart attack or stroke, those things just don't happen.

These are happening in people who have a bunch of risk factors. So that leads me to the second point is that we need to do our best to control or modify some of those risk factors. So if someone smokes, has high blood pressure, they have diabetes, they're overweight. It doesn't mean they're not a candidate for a JAK inhibitor. And truthfully, I probably would start with a biologic first, just because it's simpler that way. But if they fail that, the JAK inhibitor is not off the table.

It does mean that we have to be very intentional about how we're counseling these patients, what we're telling them what they need to do. You know, you've got to control your diabetes, your blood pressure, you have to get your cancer screening, try to minimize or cut down your smoking. These are things that we can control. And I have certainly used JAK inhibitors in patients who've had all of these risk factors, okay? And I don't mean to say that flippantly. We obviously had a very serious conversation about what we need to do, the mixture for you to reduce their risks, right? But we've been able to do that very successfully in a lot of my patients. What have I seen, though, like in the real world of using JAK inhibitors and hundreds of patients, I've seen some lab abnormalities, okay? Lipid elevations is probably the most common things that I've seen and rarely has this led to a scenario where I had to stop the medication or put someone on like a stent. Rarely have I seen liver function bumps, but if they do happen, they're temporary. They come back down.

And the big thing that we talk about a lot is shingles. And certainly shingles is at risk with the entire JAK inhibitor class. I probably had two patients that had shingles. When you look at the studies, the vast majority of those patients are not vaccinated for shingles. If you vaccinate them, chances are that shingles rate goes even further down, but it's something we need to be aware of, and counsel our patients on, but truthfully, not something that I am seeing all that often.

5. What criteria do you use to determine if a patient with atopic dermatitis is a good candidate for JAK inhibitors? How do you determine when to prescribe a JAK inhibitor versus other treatment options?

I think the first step is trying to decide whether that patient is a topical patients or a systemic patient. And once you get past that, then you have more options, right? But for me, if a patient has tried an intensive regimen of topical steroids and they can’t get better, it's time to at least consider a systemic agent.

Now, more times than not, a biologic and a JAK inhibitor are going to be both very good options and you leave it up to the patient. Some do prefer a shot that they can do every two weeks and they don't even have to worry about much else, right? The safety of our biologics are so good. You don't even have to check labs. Some people just feel better with that. Whereas other patients want a pill once a day and from an efficacy standpoint, it probably will work better for some people. and so some people prefer that as well.

Of course, the medical history is important. So if they have a lot of those risk factors like I just talked about, not to say that it's a contraindication, but it might make more sense to start with a biologic first. And if that doesn't get them to that treatment goal, then go to the JAK inhibitor.

But there might be certain clinical scenarios where it makes more sense to start with a JAK inhibitors. So I kind of talked about patients who have this predominant head and neck eczema. So the rest of the body clears or on the biologic, then maybe that's the leftover area or that's just the main presentation they have.

In those patients, JAK inhibitors may actually work better. And there's a number of studies showing why that might be the case. But one theory is that these patients who have a predominant head and neck dermatitis might have a lot of other things that are going on like contact dermatitis, for example, in addition to their atopic dermatitis, and we know that biologics don't work quite as well for contact dermatitis as JAK inhibitors do.

And there's actually another study that I kind of mentioned where they show that there is a higher expression of IL-22 in patients with head and neck dermatitis. And as I mentioned earlier on, we talked about the MOA of JAK inhibitors. JAKs are able to inhibit a broader range of cytokines, not just IL -4 and -13, but IL-22 as well. I've also found that patients who kind of have like this hybrid between eczema and psoriasis, which sometimes it's hard to tell, especially when it's on the hands and feet. JAK inhibitors work better because it hits both the psoriasis, as well as at atopic dermatitis.

And on that note, we are starting to see a lot more report to people who started off with psoriasis and they developed eczema when they started their biologic or vice versa. They start with eczema and they develop psoriasis. Or they just happen to have both diseases in the same person, which historically we didn't think were possible. We're like, these are 2 completely different disorders on 2 completely polar opposite ends of the immune spectrum. So you can't have them in the same individual. Actually, you can. We're starting to see that a lot more.

And that might be because our therapy is now, are so targeted, you block 1 thing really well and kind of shifts your immune access to the other way. But in those patients, JAK inhibitors might, I think JAK inhibitors actually better than biologics. And that's kind of what I'm reaching for at most.

Also patients who have predominant itch, let's say they're very, very itchy, but their skin doesn't look as bad. Maybe their body surface area is pretty low, low EASI scores, if you do an EASI. But their itch score is really high. We call those itch-predominant atopic dermatitis patients. And I found that the JAK inhibitors works very very well more so than biologics.

And lastly, I have a patient that wants the flexibility of being able to start and stop a drug. The JAK inhibitors have a clear advantage there. Biologics by nature are large proteins that your body will see and if you start and stop a biologic, in theory, you could develop antibodies that are neutralizing it and lowering the efficacy of the drug. Whereas a JAK inhibitor, a small molecule protein that works inside the cell, you shouldn’t develop antibodies and one of the studies that I share in that presentation is called JADE DARE study where you take people on Abrocitinib, 200 milligrams. You get them to clear or almost clear, and then you stop Abrocitinib, and then you wait to see how long it took for those patients to flare.

And when they flared, you were able to rescue them again with Abrocitinib. And the vast majority of those patients, over 90% got right back to where they were. And so I think the concept of intermittent dosing, some people really like.

And if they want that, especially those people who have seasonal flares, maybe they get worse in the wintertime or the summertime, but the rest of the year they're good, JAK inhibitors make more sense for them as well.

6. How do JAK inhibitors fit into the overall treatment strategy for atopic dermatitis? Can JAK inhibitors be used in combination with other treatments, and if so, which ones?

The JAK inhibitors are legitimate, bonafide, fist-line systemic agents for atopic dermatitis. Actually, the American Academy of Dermatology came up with some recent guidelines ranked or ranged our systemic therapies and they gave 5 agents the strongest recommendations. So it was 2 biologics: Dupilumab and Tralokinumab and 3 oral JAK inhibitors; Baricitinib, which is not approved in the US but it is approved in Japan for AD, and then Abrocitinib and Upadacitinib. So from that standpoint, biologics and JAK inhibitors are in parity from the strength of recommendation standpoint. Now for the label, for JAK inhibitors, you have to have tried a systemic therapy first before you bow to the JAK. That could be something as simple as a course of systemic steroids whereas in the biologics, you could go straight onto a biologic that is maybe an advantage there. But these are both really good options.

And going back to what I was saying before, it's going to just come down to patient preference. Now, as far as can you combine JAK inhibitors with other types of treatments? it depends. So topical corticosteroid, topical calcineurin inhibitors, absolutely, right? In the studies, actually, for both Abrocitinib and Upadacitinib, some of the studies did allow for concomitant use of topical corticosteroid and topical calcineurin inhibitors.

The challenge will be what topical JAK inhibitors. We have 1 right now. That topical JAK inhibitor does have the same warning label as the oral JAK inhibitor saying that you shouldn't combine JAKs with biologics or JAKs to JAKs. So technically you're not allowed to, even though that's not based on any type of medical information. It's really just a labeling thing. What should become more interesting is as we start to get new non-steroidal topicals that are getting approved, we got one that recently got approved with Roflumilast 0.15 % cream, and then we'll get Tapinarof 1% cream probably sometime later this year.

Can you use those therapies together with our JAK inhibitors? And there's no medical reason why you cannot. Some of that may be payer or insurance company driven, but purely from a medical standpoint, there's no reason you can't combine them.

Now, as far as systemic therapies, yes, it does say that you shouldn't combine oral JAK inhibitors with other systemic immunosuppressants. And keep in our atopic dermatitis studies, you can't combine systemic therapies ever, right? It's never a combo study. But we use JAK inhibitors in RA, in PsA, and IBD, and not uncommonly in those patient studies, they are using it with other immunosuppressants, mainly methotrexate, but also the rufinamide and sulfasalazine.

So we do have data from non-atopic dermatitis cohorts that you can safely use these things together. And I'm quite just being complete transparent here. I combine oral JAK inhibitors with other medicines like methotrexate, not in frequently in certain patient types, even though technically per the label you're not supposed to.

7. Can you discuss the long-term management of patients on JAK inhibitors?

So atopic dermatitis, like a lot of our chronic Indian diseases, are long-term, right? So I always try to set the expectation that this is not something that we're going to just treat in the next couple weeks or months, but we're probably looking at atleast the next couple of years. We do know that in atopic dermatitis there are some patients that may grow out of it, although that’s not as common as you think. The vast majority will have some form of atopic dermatitis in their adult life. Now it’s just a matter of how severe is it. Some might just have mild AD like on their hands and feet and for others, it might get worse over time, and we're still not great at predicting who those patients are. But I said expectation, this is long term. Having said that, I'm not opposed for someone to start spacing out their medication and saying, can they come out of it if they've been well controlled for a reasonable amount of time.

And this isn't just true with JAK inhibitors, but this is true for biologics as well, is that if someone has low levels of disease activity, so they're well controlled for, I'd say a year, then I would say, okay, maybe we can start spacing your dosing out a little bit. So if you're like a higher dose of a JAK inhibitor, first drop it to the lower dose, and then maybe try to go every other day with a biologic I might just start spacing the dose out. But it's the same concept here is that if you are going to try tapering the dose or even stopping therapy, you want to be under good control for a long period of time.

8. What advancements or ongoing research in JAK inhibitors are you most excited about? How do you see the role of JAK inhibitors evolving in the treatment of atopic dermatitis over the next few years?

What I'm most excited about for JAK inhibitors, particularly in atopic dermatitis is just getting more people comfortable with this class of medication. The efficacy has proven itself, it's the most effective class that we currently have right now, but I think it’s the safety that keeps people from using this medication. We’ll get more data with time, but that going to take time, we’ve got 5 years worth of data with 1 of the JAK inhibitors, 4 with the other. But I’m really looking forward to the day where we can all really feel comfortable using these medications in the right patients. And we're not going to have to use it as a last resort where we scaled everything else and this is going to be kind of last thing. We'll feel comfortable enough to use these medications early on in our treatment sequence in the right individual.

And it will be much more comfortable having these nuanced conversations with people so that, you know, we as the experts could really contextualize, now what is the efficacy of these drugs, but more importantly, what's safe, right? Because if we just tell a patient, hey, read up on the medicine, let me know if you want it or not. I don't think we're doing patients any service there, right? We need to be the ones that are the experts and that could explain it to them and contextualize it to them in such a way that they could truly make an informed decision when it comes to benefits versus risks.