JAK Inhibitors in Atopic Dermatitis Treatment

© 2025 HMP Global. All Rights Reserved.
Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of The Dermatologist or HMP Global, their employees, and affiliates.

In this interview, Dr Eingun James Song explains the unique mechanisms of Janus kinase (JAK) inhibitors in atopic dermatitis (AD) treatment, highlighting their targeted action, superior efficacy, and rapid symptom relief and discussing potential safety concerns and patient suitability.

The Dermatologist: How do JAK inhibitors differ from traditional immunosuppressant treatments for AD?

Dr Song: 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 is that we get better efficacy potentially, but more so from the safety side. With our older medications, we know that they have worked in certain individuals because these are what we call broad-acting traditional immunosuppressant agents. They would knock out multiple different cell lines, blocking everything almost indiscriminately, which is why they did not work for everyone, and we did see certain negative side effects happen if you use these medicines long enough.

With JAK inhibitors, we really get at the underlying root cause of what the inflammation is triggered by. In the case of AD, we call it type 2 inflammation. These are the cytokines belonging to a certain family that we know can cause a multitude of different types of conditions such as AD. The biggest difference between the JAK inhibitors vs some of the biologic agents we have is that JAK inhibitors work intracellularly, whereas the biologics are extracellular, blocking our cytokines directly or acting as receptor blockers. There are pros and cons of each of these as well.

The Dermatologist: Can you describe the specific pathways that JAK inhibitors affect in the immune response related to AD?

Dr Song: To treat a disease effectively, we must understand which immune access is involved in causing that disease. You could start at the top, which cytokines are responsible for a disease, and then which JAK proteins do those cytokines signal through. To treat that disease, you could either block it at the cytokine level, which is what a biologic would do, or you could block it intracellularly, which is what a small molecule protein like a JAK inhibitor would do. We know that in AD, there is a multitude of different cytokines at play. Unlike psoriasis, which we think is much more homogenous, in AD it is a much more a mixed population. Depending on whether you are Black, Asian, or White; whether you had AD as a child or as an adult; and whether you have other type 2 comorbidities, your cytokine profile will look quite different. And because of that, sometimes we cannot just be blocking a single cytokine or 2, which is what our biologics are doing. Of course, IL-4 and IL-13 are 2 very important cytokines in AD, but that is not all. We know that there are other cytokines, such as IL-31, IL-22, and interferon, which also contribute to AD, but may not be inhibited by a biologic like a JAK inhibitor would.

The key thing that all those cytokines have in common is they have to signal through these JAK proteins. There are over 50 different cytokines that signal through just 4 JAK proteins, so there is a lot of redundancy built in here. What we know is that the key cytokines driving AD 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 do not necessarily want to be blocking, such as lipid metabolism and fighting off viruses. Ideally, we get very selective with our JAK inhibitors too, which poses another question: Are JAK inhibitors all the same? Are they different? And what about the older first-generation JAK inhibitors that block JAK 1, JAK 2, JAK 3, and TYK2 less discriminately? Our second-generation JAK inhibitors are relatively more selective for JAK 1, but no JAK inhibitor is 100% selective.

The Dermatologist: What have clinical trials revealed about the efficacy of JAK inhibitors in treating moderate-to-severe AD?

Dr Song: Randomized placebo-controlled studies were conducted for the oral JAK inhibitors that we have in the United States, upadacitinib and abrocitinib, showing that JAK inhibitors were superior to just using nothing, a placebo, or people using steroids in the background. Some of the numbers that we have seen in these studies were nothing short of extraordinary. We are talking about itch reduction happening not just within days or weeks, but sometimes hours or minutes. We are also starting to see that JAK inhibitors can push what we think is possible when it comes to skin clearance, and we are starting to measure what percentage of patients will have no itch or trace itch. With the JAK inhibitors, getting to a completely itch-free state is possible.

What we consistently see is that JAK inhibitors come to the top when we look at efficacy. When you compare oral JAK inhibitors with dupilumab, which is still probably the number one prescribed systemic therapy for AD, the JAK inhibitors are going to outperform dupilumab, especially at the more stringent endpoints. For Eczema Area and Severity Index (EASI)-75, both dupilumab and the JAK inhibitors are fairly comparable, but when you look at EASI-90, EASI-100, and achieving a numerical rating scale score of 1, that is clearly where you see the advantage goes to the JAK inhibitors, as well as the speed of onset. We are seeing the JAK inhibitors work very quickly and this is not to say dupilumab is slow, it is 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 AD where these patients are so much more miserable, they want to get better immediately.

The Dermatologist: Are there any long-term safety concerns that dermatologists should be aware of when prescribing JAK inhibitors?

Dr Song: We cannot talk about the safety of JAK inhibitors without talking about the box warning, which comes from a different JAK inhibitor called tofacitinib that was studied in a high-risk rheumatoid arthritis (RA) population. This is a pan-JAK inhibitor, which maybe are less advantageous than our selective JAK inhibitors, and it was studied in a different patient population. These patients were on average 60 years old and they had moderate-to-severe RA. All of them were on methotrexate and just under 60% were on systemic steroids. This patient population looks on average a lot different than the patients we as dermatologists see. And those patients were then compared to tumor necrosis factor (TNF) inhibitors. At the end of the 5-year study, what we found was that some of the adverse events, such as blood clots, cancer, heart attack, and stroke, happened in both groups, with the TNF inhibitor and the JAK inhibitor. The rates were actually low for both groups, but the relative risk was a little bit higher with the JAK inhibitor vs the TNF inhibitor, which is where the box warning comes from. Even when you look at the raw numbers from that safety study, they were still low. We are talking 1% to 4% will get some of these things and this is your worst-case scenario. When you pick the worst of the worst patients, it is still 1% to 4%. That is the way I talk about the box warning with my patients.

There are a few key things that we need to point out here. First, there was not a placebo group, so we do not actually know what would have happened if those patients did not get treated with anything. We know that patients with RA are more likely to experience cancer, heart attack, stroke, and blood clots, even if they are not treated with anything because of the underlying inflammation. Second is that TNF inhibitors are helpful in reducing the rates of heart attack and stroke, so it is not a fair comparison. And the third thing is, of course, that this is a different patient population. This is not the same population we are studying. There is a question this study has led to that we still probably will not know the answer to for some time. In dermatology, we have less data: 5 years’ worth for upadacitinib in AD and 4 years’ worth for abrocitinib in AD. What we have seen is that these adverse events of interest (heart attack, stroke, blood clots, cancer, serious infections, and death) really are not 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 have AD but do not take a JAK inhibitor? Yes, it happens in them too.

This is where real-world data come in to give us a reference point of the general rate of these things happening in the background and what the likelihood is that they are going to happen to people who take JAK inhibitors. These things generally happen in people who have risk factors, so we need to do our best to control or modify some of those risk factors. If someone smokes, has high blood pressure and diabetes, and they are overweight, it does not mean they are not a candidate for a JAK inhibitor, but it does mean that we must be very intentional about how we are counseling these patients. We must have a very serious conversation about what they need to do to reduce their risks, which we have been able to do successfully in a lot of my patients. In the real world of using JAK inhibitors with hundreds of patients, I have seen some lab abnormalities such as lipid elevations but rarely has this led to a scenario where I had to stop the medication. Rarely I have seen liver function bumps, but if they do happen, they are temporary and they come back down. And the big thing that we talk about a lot is shingles as a risk with the entire JAK inhibitor class. Truthfully, this is not something I am seeing all that often; I have probably had 2 patients who had shingles. When you look at the studies, most of those patients are not vaccinated for shingles. If you vaccinate them, chances are that the shingles rate goes even further down, but it is something we need to be aware of and counsel our patients on.

The Dermatologist: What criteria do you use to determine if a patient with AD is a good candidate for JAK inhibitors?

Dr Song: For me, if a patient has tried an intensive regimen of topical steroids and they cannot get better, it is time to at least consider a systemic agent. Now, more times than not, a biologic and a JAK inhibitor are going to both be very good options and you leave it up to the patient. Some do prefer a shot that they can do every 2 weeks, and they do not have to worry about much else. The safety of our biologics is so good, you do not 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 patient’s medical history is important. If they have a lot of risk factors it might make more sense to start with a biologic first. And if that does not get them to the 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 inhibitor. For example, patients who have predominant head and neck eczema. The rest of their body clears on the biologic, and maybe that is the leftover area, or it is just the main presentation they have. In those patients, JAK inhibitors may actually work better. There are several studies showing why this might be the case. One theory is that these patients who have predominant head and neck dermatitis might have a lot of other things going on like contact dermatitis, for example, in addition to their AD, and we know biologics do not work quite as well for contact dermatitis as JAK inhibitors do. There is another study where JAK inhibitors can inhibit a broader range of cytokines, not just IL-4 and IL-13, but IL-22 as well. I have also found that for patients who have a hybrid between eczema and psoriasis, a JAK inhibitor works better because it hits both the psoriasis and the AD. Also, for patients who have itch-predominant AD, I have found that JAK inhibitors work better than biologics.

Lastly, if I have a patient who 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 with a JAK inhibitor, a small molecule protein that works inside the cell, you should not develop antibodies. One of the studies that I share is called the JADE DARE study in which patients took abrocitinib 200 mg until they were clear or almost clear, and then they stopped the abrocitinib and waited to see how long it took for them to flare. And when they flared, over 90% of the patients got right back to where they were when they started abrocitinib again. I think some people really like the concept of intermittent dosing. For a patient who has seasonal flares, maybe they get worse in the wintertime or the summertime, but the rest of the year they are good, JAK inhibitors make more sense for them as well.

The Dermatologist: How do JAK inhibitors fit into the overall treatment strategy for AD?

Dr Song: JAK inhibitors are legitimate, bona fide, first-line systemic agents for AD. The American Academy of Dermatology recently ranked or ranged our systemic therapies and they gave 5 agents the strongest recommendations: 2 biologics (dupilumab and tralokinumab) and 3 oral JAK inhibitors (baricitinib, which is not approved in the United States, but it is approved in Japan for AD; abrocitinib; and upadacitinib). Biologics and JAK inhibitors are in parity from the strength of recommendation standpoint. Now for the label, you have to have tried a systemic therapy first before you go to the JAK inhibitor. That could be something as simple as a course of systemic steroids. Patients can go straight onto a biologic, so that is maybe an advantage there. It is going to come down to patient preference.

Can you combine JAK inhibitors with other types of treatments? It depends. Topical corticosteroids and topical calcineurin inhibitors, absolutely. Some of the studies for both abrocitinib and upadacitinib did allow for concomitant use of topical corticosteroids and topical calcineurin inhibitors. The challenge will be with topical JAK inhibitors. The approved topical JAK inhibitor does have the same warning label as the oral JAK inhibitors saying that you should not combine JAK inhibitors with biologics or with other JAK inhibitors. So technically you are not allowed to, even though that is not based on any type of medical information. As we start to get new nonsteroidal topicals approved, it should become more interesting. Can you use those therapies together with our JAK inhibitors? Purely from a medical standpoint, there is no reason why you cannot combine them.

Now, as far as systemic therapies, yes, it does say that you should not combine oral JAK inhibitors with other systemic immunosuppressants. In our AD studies, you cannot combine systemic therapies ever; it is never a combo study. But we use JAK inhibitors in RA, psoriatic arthritis, and inflammatory bowel disease, and not uncommonly in those patient studies, they are using JAK inhibitors with other immunosuppressants, mainly methotrexate, but also rufinamide and sulfasalazine. We do have data from non-AD cohorts that you can safely use these things together.

The Dermatologist: How do you discuss the long-term management of patients on JAK inhibitors?

Dr Song: I always try to set the expectation that this is not something we are going to treat in the next couple of weeks or months, but we are probably looking at the next couple of years. We do know that in AD there are some patients who may grow out of it, but the vast majority will have some form of AD in their adult life, it is just a matter of how severe it is. Some might have mild AD on their hands and feet, but for others, it might get worse over time. We are still not great at predicting who those patients are. If someone has low levels of disease activity, where they are well controlled for a year, I am not opposed to trying to space out dosing a little bit. If the patient is on a higher dose of a JAK inhibitor, we can try dropping it to the lower dose or if the patient is taking a biologic, we can try to go every other day. If you are going to try to taper the dose or even stop therapy, you want to be under good control for a long period of time.

The Dermatologist: What advancements or ongoing research in JAK inhibitors are you most excited about?

Dr Song: What I am most excited about for JAK inhibitors, particularly in AD, is just getting more people comfortable with this class of medication. The efficacy has proven itself; it is the most effective class that we currently have right now, but I think it is the safety that keeps people from using this medication. We will get more data with time, but we do have 5 years’ worth of data with one of the JAK inhibitors, and 4 years with the other. I am really looking forward to the day where we can all feel comfortable using these medications in the right patients and not as a last resort where we scaled everything else, and this is going to be the last thing. We will feel comfortable enough to use these medications early on in our treatment sequence in the right individual and have nuanced conversations with patients so we as the experts can contextualize the efficacy and safety of these drugs and they can truly make an informed decision when it comes to benefits vs risks.