Matthew Zirwas, MD

We talked about in this discussion how there’s been so much activity in this space. There’s so much new stuff happening, education, taking care of patients, how you talk about warnings, how you talk about safety, efficacy. It can be overwhelming, especially if somebody isn’t necessarily in a place where they see almost all atopic dermatitis [AD] all the time, where you’ve been an investigator on so many different trials. Maybe we could do the same exercise, but I would love to hear any one particular pearl, recommendation, or tidbit you’ve developed in the past year. How do you recommend that somebody stays on top of what’s happening in atopic dermatitis? Maybe we’ll take this in reverse order, and I’ll start with you, Peter. What’s something you recommend, whether it’s patients or caregivers, to stay on top of the immense progress made in this space?

I have to put in a plug for the National Eczema Association [NEA]. Disclosure, I’m a board member, but I don’t get paid, I donate money. But the NEA is focused on keeping patients and families up to date on all this new information, a lot of new therapies, and even the research pipeline. They have a wonderful page, and I’m sure a lot of us here probably contribute to that and update it. But that’s a wonderful resource for patients and families to stay abreast of all the new things going on.

I was having this conversation with a resident last night, that I feel so fortunate that I got interested in adult atopic dermatitis back in 2003. And since then, I have always had a daily email, you can set PubMed to automatically do a search every day and send you any new articles. For 15 years, every day I’ve gotten an email; any article that has the word dermatitis in the title gets emailed to me. I can click on them and read the abstracts. And now I’ve got not just dermatitis, but the names of each different drug. Now my search is 15 terms long. Every day I get that email, and it might have between 2 and 60 new citations in it on a given day. I’ll probably click on the abstract for 1 in 10, and I’ll read the article for 1 in 30. But I think about the thousands of articles I’ve read over the last 15 years doing that, and how lucky it is to be able to have slowly built that knowledge base. To really understand and know what’s going on in the world of AD, and how the way we think about the disease is changing, and the drugs and everything, I think things like this are invaluable. But it is an overwhelming amount of information, and the number of publications is going through the roof, as there’s more money and therefore more interest in atopic dermatitis research.

I agree with what Matt said. But I think on a practical level, certainly I get emails every day about online training, just as this will be, and I try to share that with my colleagues, especially my residents and trainees. Because much of that education is free, you can do it at your leisure. You have libraries of information and you can have live presentations. I will say, as a former president of the Women’s Dermatologic Society, we have invited residents to become members for free, and we have a library of educational programs encompassing atopic dermatitis and many other arenas, and we have live presentations. Those residents in training and our members can certainly avail themselves, and anyone who wishes to join also would be welcome to attend. That’s my plug for the Women’s Dermatologic Society and our educational series.

I think these are all wonderful resources, and I would honestly almost even take a step back and look at everybody and say, listen, we are privileged to be dermatologists, but even beyond that, we’re physicians, we’re doctors. And it is our responsibility to put forth the effort to make sure that we are giving all of our patients the best options to make them better. There’s been a bit of a change in this post-COVID-19 world, where people are a bit complacent. But I’ll tell you, the world is evolving quickly. It was evolving quickly before COVID-19, it’s evolving quickly after, and once upon a time, if you didn’t prescribe a biologic for psoriasis, you were OK. If you didn’t want to learn about how the mechanisms work for psoriasis, you were average with the country. If you are not prescribing a biologic for psoriasis at this point, your patient will find someone else. That also applies to these newer options in atopic dermatitis. If you do not get accustomed to JAK inhibition and these newer treatment options and algorithms for our patients with atopic dermatitis, they will find someone else. Long gone are the sticky patients who used to say, “I’ve seen my doctor for 40 years.” They will leave us in a heartbeat if they feel that the person down the street is doing something more innovative or may treat them better. So, I say get to work to learn to treat our patients better.

I love the conviction. I know you believe it in the discussions we’ve had. I’m going to put my two cents in. I really enjoy stuff like this as an educational tool, because as much as I would like to tell my residents to just read the textbooks and prepare for the board exams, we know that once those things are published, they’re out of date immediately, just given how much activity is happening in this space. Even when I took my board exams, I feel like there had at least been some progress in these areas, but I was still talking about things that happened 20 years ago. So, anything that we can do, such as have these kinds of discussions, and others can watch this type of material. That’s the reason I love doing this stuff. It very much goes to the top of my list.

That being said, Drs Noor, Herbert, Zirwas, and Lio, thank you so much for joining. This has been an awesome discussion. I know I learned a lot just thinking about how I can have these discussions with my patients and step up my care. And thanks to all of you out there for watching this informative 

Remember, if you enjoyed the content here, please subscribe to the e-newsletters to receive upcoming peer exchanges and other great content right in your inbox. Thanks again, everybody.

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Experts in dermatology share advice on helping fellow physicians stay apprised of the advances in AD and treat their patients more effectively.

Keeping Physicians Up to Date With AD Advances

I love that learning machine analogy very much because it is not just sending a combination of letters and numbers to classify your patient and get you where you need to get. Now, much as we started this discussion, where Matt told us there hasn’t been anything he’s been able to incorporate in his practice that has true predictive power, I am hoping this changes in the future, and you could get a set of patient characteristics, plus some clinical outcomes and what you see, and understand what might be the optimal choice for safety and efficacy. We’re not there yet, and it probably still won’t be a vending machine, but I look forward to that day. In that vein, in the last few minutes of this discussion, I’d love to look forward, that’s the fun part now, looking at things in various phases of trials for atopic dermatitis. Maybe we can go in a circle, and everyone can mention what either MOA [mechanism of action], ongoing trial, or even potential targets are exciting to them, and let’s start with you, Omar. If there’s one thing you’re looking forward to over the next 5 to 10 years, what is it?

What I’m excited about, and I love this concept because with atopic dermatitis, which we’ve established to be a heterogeneous condition that is still complicated, we’re still learning, we’re still getting better to make sure we have more options for our patients. I’m excited about nemolizumab, which is a biologic that’s going to be targeting IL-31 [interleukin-31]. We know that the cytokine IL-31 is specifically associated with neuronal cells targeting itch, and we see these patients. My patients who are not doing well in whatever therapy they’re on, they’re just sitting there, or a new patient, and they’re scratching. We know that itch-scratch cycle promotes a lot of disease processes, and if we can target something unique, like IL-31 in neuronal cells, I’m very excited to see how that’s going to affect our patients with atopic dermatitis, as well as a lot of other disease states that are itchy for our patients.

Yes, a nice summation. And IL-31, which nemolizumab targets, right now it’s approved in Japan for pruritis associated with atopic dermatitis. It’s a unique label in terms of how that is, and to your point, we and others have published about this idea, that just because somebody has a low burden of lesions on their skin, they can still be extensively itchy, even if you’ve gotten disease control. So, taking a deeper dive into that itch, neuronal, neuroinflammation access is definitely something that excites me too. How about you, Adelaide, what’s the thing you’re looking forward to in the next few years, knowing that many of the treatments haven’t necessarily even got to those young children yet?

I am going to focus on 2 arenas, and I’ve been very privileged to be a clinical investigator in both the tapinarof and the roflumilast studies, and we are studying these down into very young age groups. Granted, these patients are sometimes in double-blinded environments, so I can’t 100% assume they’re on the medication. But we have seen amazing results. We did in one of these clinical trials have an open-label portion, so I did see children who would come in covered with Band-Aids, bleeding from their scratching, and the mother would come in in tears. We transformed not only this child but this family by using these products. Again, in this open-label study, it was very dramatic, not only for me but also for the parents. We think these are going to be wonderful medications, and we really hope they get on the market very soon, because these children are suffering terribly, and because we have more limitations in what’s available for the pediatric population. This will really expand our options and help us care for these patients in such a great way. I also have to share with my adult dermatology colleagues, I think it’s one of the things you can say when it’s approved by the FDA in a very small age group, that’s a testament to the safety of these drugs. I know you probably explain that to your older patients, that if the FDA is letting us use it in the youngest, most vulnerable patients with broken skin, certainly we should feel safe about using them in older patients who come and need care.

Those are nice points, I love it. How about you, Matt? I know there’s probably a long list, but what’s the one thing you’re most excited about?

I think the one I’m most interested in is the one that’s just on the cusp of starting. I’m doing a proof-of-concept study with this company, and it is called a reactive aldehyde species inhibitor. Essentially what it’s doing, as part of our normal inflammatory response, we generate these reactive aldehydes that then covalently bind to various things in cells, proteins in cell membranes, then cause dysfunction. There also are environmental aldehydes that can get into our skin and then cause cellular damage or irritation. And so, this is a drug that’s already been approved or at least finished phase 3 trials as an eye drop. But we’re studying it as a systemic agent for psoriasis and atopic dermatitis, because what we’ve lacked in general is a systemic anti-inflammatory that is not also an immunosuppressant. That’s what this is hoping to be.

So, it’s the equivalent of ibuprofen for your skin, where you take ibuprofen and it’s anti-inflammatory but it’s not immunosuppressant, it just unfortunately doesn’t work on your skin. But to have something like that, a totally different mechanism that we’ll be able to explain to patients as, “This is neutralizing toxins that your body is generating.” Patients will love that terminology, “Toxins, your body generates toxins, and there are environmental toxins and we’ll get rid of those toxins.” The only thing that would be better is if it was natural. “We’re going to naturally get rid of those toxins,” would be even better. “But toxins, we’re going to neutralize the toxins.” I’m excited to see if it’s going to work.

I know I was only allowed one, but the other one I’m excited about just because it’s going to be so different is the OX40 drug that’s going into phase 3 clinical trials. What’s exciting about that one, it looks like it works slower than other drugs, but in some of their phase 2 data, of the people who got to EASI-75 [75% reduction in the Eczema Area and Severity Index], 80% of them were still at EASI-75 20 weeks after their last dose. So, it really puts a high number of people into durable remissions. But there’s a cost to that, which is it takes a little longer to work. There’s the cost-benefit of, “Well, you’re going to have to suffer a bit longer before your itch starts getting better. But once you get better, we may be able to put you into a very durable remission,” which would be phenomenal.

We’ll end this segment with you, Peter. Is there anything in particular that really excites you, knowing how much activity is in the space?

I love what my colleagues said, there’s so much great stuff. The one that I feel is maybe the next big frontier that we’re just starting to enter is the microbiome. I’m fascinated by prebiotics, probiotics, symbiotics, parabiotics, postbiotics, and all these other ways to manipulate the microbiome that are not just slamming it with an antibiotic, which is all we’ve really had, or using diffuse antiseptic agents. So really being able to manipulate this. I’m not a betting guy, but I would put some money on the fact that if we can fix the microbiome, we might see all these other pieces fall into place. Because the microbiome is playing a role, even in ways I don’t think we fully appreciate yet. And Raj, before we wrap up, I want to turn it back to you. What are you excited about as our fearless leader and moderator today?

I’m glad you asked. I would have said so anyway even if you didn’t care to hear what I had to say. But I think one of the coolest things is, we’re beginning to understand that because atopic dermatitis is so heterogeneous, perhaps a single target is not going to be the answer for therapy ongoing. There’s a lot of cool science going on about how you design bivalent targets, antibodies that have multiple heads, molecules that could target 2 different things at once, and hit 2 opposite types, inflammation and disease. I think that is what excites me the most, the fact that we might be able to fine-tune our responses and get beyond some of the walls we’ve hit when it comes to maximum responses for even our best therapies right now.

Expert dermatologists consider ongoing trials and emerging treatment options for the management of AD.

Emerging Treatment Options in AD

I want to focus in on topicals, given that clinical scenario I outlined. Let’s say you were going to stick with topicals for the in-between patient we talked about. Peter, is there general guidance in terms of body surface area when you’re thinking about topicals? A lot of this ties into earlier discussion on what’s practical for a patient, something they can follow through on. Is there a sweet spot where it works, beyond which it becomes impractical even if it’s mild or mild to moderate disease?

That’s another problem with the way we categorize disease. Frequently, if we’re doing something like an easy score, that takes body surface area heavily into account. But we have patients with very small body surface area, where it’s quite severe. Other times, patients are mild, but it’s overwhelming—like 90% body surface area. Part of the calculation is responsiveness to treatment and feasibility of treatment. For littler kids, you can get away with whole-body application of topicals. When they’re little, it’s easy because they’re portable; the parents can usually do it. But as the kids get older, adolescents in particular, it’s very tough. They get easy burnout and very fatigued about putting on a lot of topicals. For those patients, even small body surface areas might be an issue.

That’s the best way to approach it: on a person-to-person basis. But I always say that everybody’s got to try some topicals. Even when we’re on systemics, almost all our patients on the systemic agent are going to use some topicals; you’re never outside that. It depends on the response. Sometimes I’m confident that this is never going to work, and that when I talk to them next week, they’re going to say they’re worse. I think that they’re going to have to go on to a systemic agent. Then I call them, and they say, “No, it’s great. Pretty much everything is healed. I did most of the body for a few days, everything responded, and I’m focusing on my hands or my ankles. We made it.” Other times it’s small. I said, “Come on. Let’s push hard. We’ll do everything. We’ll do wet wraps.” Then in 2 weeks, they call me and say, “I’ve been using it like crazy, and my hands are still miserable and cracking and bleeding.” Then we have to go to systemics.

Oftentimes, when we’re making that move on the value of step-wise therapy for atopic dermatitis, we’re adding many of those therapies together. It’s not a straightforward discussion of trading in your topical for a systemic. There’s often concurrent use. Matt, when is combination therapy viable for patients? And when do you want to see if monotherapy does its thing? Is there a difference between the 2, or are you doing everything at once and peeling off? Take me through how this works in your practice.

For me—and we all practice this way—every patient who’s on a systemic is on combination therapy. Whenever I’m talking about drugs—let’s say I’m giving a promotional talk for a systemic—I tell the audience to ignore the monotherapy data, because they’re not clinically relevant. I tell them, “Those were data the FDA required, but they’re not clinically relevant.” The data we want to look at are the combination therapy along with topical corticosteroids. That’s what’s always done in the trials. When I put somebody on systemic therapy, I’m telling them, “Use your topical, but hopefully with the systemic that we have, you won’t need to use the topical anymore.” As you get better, you don’t need to keep using it.

That’s the case when I have people on combination therapy. If they need a little topical, I’m not worried about it. It’s not, “Let’s put you on a systemic. Once you’re better, we’ll stop the systemic and see if we can keep you on the topical.” No, it’s, “Let’s start you on a systemic. Assuming the systemic works good, you don’t need to use the topical anymore.” That’s the direction that I’m going in. Part of that is because it’s so hard from an insurance perspective to start and restart the systemics because patients stopped ordering it, or their authorization immediately is revoked.

The other part of it is the experience with the drugs that we have. If you stop the systemic, at some point the disease is going to come back. Peter has published—and I agree with him—that with the biologics, the data show you can give people a long-term remission. If they have done wonderfully and are clear, a lot of times, if they stop and you pick dupilumab, it might be 3 to 6 months or even longer before the disease comes back. But it’s going to come back. I always think in terms of infection risk in these patients. If we wait until the disease starts to flare, and before we restart therapy, they’ve already been through the high-risk period for getting a skin infection that can turn into something serious.

Dr Noor, you’re no stranger to getting many things on board to get someone under control. How does the idea of monotherapy and combination therapies play a role in what you’re doing, especially for someone who’s transitioned up the severity ladder? As Matt told us, combination therapy is the most indicative of what’s happening in the real world. Tell us about your practice.

One thing that’s very consistent with essentially every patient in my practice is that I look them in the face and say, “I’m going to get you better.” I can get you better because I have all these options, and these options are extensive. We have wonderful options, all the way down to cyclosporine and methotrexate, and the ability to combine different treatments. If we can appreciate the data, if we can appreciate the safety, then we can appreciate what to expect that this individual needs.

One thing that I always stand by, and it’s going to sound silly, is that I’m not a vending machine. I don’t do the same thing for each individual. It’s not like you come in, you punch in a button and say, “I have moderate atopic dermatitis,” and out comes your drug. That’s not how it works. Every patient is an individual, and I treat everybody individually to make sure I get the best possible outcome for that individual. Every patient knows that, in every room and in every scenario. If that means that they need to go on a biologic and a topical, like ruxolitinib; a biologic; or even an oral JAK inhibitor, then I’m going to take that situation individually and determine the best option for that patient.

Experts in dermatology share general guidance for use of topicals, switching from topical to systemic treatment, and when combination therapy is an option for patients with atopic dermatitis.

Guidance for Topical Treatment Use Based on BSA in AD

Dr Noor, when you’re thinking about the extra baggage that comes into any treatment, depending on the atopic dermatitis or the systemic issues, that will require you to see your patient more or less. Some require some lab work when you’re starting or ongoing lab work; others don’t. Can you tell me a little about some of the differences across the treatment types we’ve mentioned today? What extra monitoring requirements fall on the clinician or the patient?

None of our topical options require any initial lab monitoring for the patient or monitoring over time. That’s definitely a nice option for our mild to moderate patients who don’t necessarily have to go to a systemic option. The first biologic that has come to the market for atopic dermatitis, dupilumab, does not require any blood monitoring, whether it’s initial or ongoing lab monitoring. This makes it a great option for starting patients right away. With the oral JAK inhibitors that have come to the market, and even with the topical, the onset is very quick. With dupilumab, the onset might be a little slower. We’re treating that speed of onset for more of a maintenance over time. In regard to a different type of safety profile that doesn’t require blood monitoring, we can start the patient with a loading dose right in the office, so we can get beyond needle phobia or apprehension and move toward our newer options, which are oral JAK inhibitors.

What I talk to my patients about is that I want to make sure they’re healthy prior to starting the medication. We know that there are certain parameters that we want to make sure are met. Patients have a hemoglobin greater than 8 g/dL, a neutrophil count greater than 1000 per mm3, and a lymphocyte greater than 500 per μL. These are baseline characteristics that I don’t want to overlook. There are other unique situations that I’ll keep an eye out for. I’ll look at someone’s cholesterol, especially if, at baseline, they look like they might be obese or overweight, or if they mentioned that they’re on a cholesterol-lowering agent like a statin. Let’s make sure their cholesterol isn’t too high, because with JAK inhibition, the way the molecule works is that there’s a risk for an elevation of cholesterol over time.

We also want to check with a QuantiFERON-TB Gold because there’s a theoretical risk of TB [tuberculosis] reactivation. To be honest, for access to the medications, a lot of times insurance companies will ask for that QuantiFERON-TB Gold test prior to starting the medication. For checking blood work, there’s no reason to not throw that on as well. This happens very rarely, but there’s a transient increased risk of creatine phosphokinase [CPK]. If I have a patient who’s getting ready to run a marathon or to do solid core or some other exercise regimen to get ready I may check a CPK at baseline. I might mention to that individual, “If you’re having any of the ordinary muscle pain, call me and let me know.” I’ll check these parameters in 4 or 12 weeks, depending on which oral JAK inhibitor I start them on.

Thanks for that overview. Obviously, you don’t necessarily have options to all these therapies, but you do have your adolescent group, 12 years and up. Of course, access to biologics are much longer. Historically, with methotrexate and others there was always a lot of monitoring. What does that discussion look like for you and your patients? How do you handle the aspect of a longitudinal monitoring?

Many patients are pretty desperate for additional therapy because they’ve failed everything else that I’ve tried, and we’ve been using methotrexate and cyclosporine for years. I feel strongly that the new JAK inhibitors are safer in the long run, and we have better evidence-based medicine in terms of using those medications. Ironically, insurance companies often make us use 1 or 2 non-FDA approved medicines to get the best medicine. Sometimes, that’s the harder conversation: “Your insurance company requires me to use 2 non-FDA medicines.” Patients have a hard time getting their head around that, as do parents, but we have the conversation and say, “That’s the lay of the land.”

We talk about the lab work we need. If the patient is an older teenager or immunocompromised, we talk about getting a shingles vaccine. We certainly do that with our adults who are going on some of these JAK inhibitors. First, it’s very good basic medical care. All of us have treated patients with shingles who we wish had had that vaccine and reduced their risk of having shingles, especially when it’s a very bad case. That’s another discussion that I have.

I also talk about drug interactions because we know JAK inhibitors can’t be used in concert with certain medicines. They must pay extra attention. We often have that conversation about cyclosporine, about not mixing it with grapefruit. That’s the state fruit of Texas, so that’s an imperative in my state. For methotrexate, we can’t use Bactrim and other agents in concert with that medicine. We’ve all had these conversations. It’s a little more challenging with pediatric patients because adverse effects and safety become critical.

My colleagues in general pediatrics don’t use cyclosporine, methotrexate, biologics, or JAK inhibitors. They’re totally unfamiliar with this realm. Fortunately, I trained most of the pediatricians, so they know I’m not going to give their patients something unsafe. But it’s a harder discussion because when they go back to the pediatrician, the pediatrician has never heard of this therapy, or is a little concerned. It’s a unique orientation, for the patient and the parent, to this new arena. It’s exciting, and they sense my excitement when we have an opportunity to bring their severe atopic dermatitis under control.

That’s a nice overview of the considerations in your population. No matter what age we’re seeing, there are many shared principles in this discussion. The desperation and need of our patients, particularly with uncontrolled disease, ends up guiding a lot of what we do. Frankly, it gets buy-in from patients, especially those who’ve seen many other physicians and not been able to get control of their disease.

Omar Noor, MD, and Adelaide A. Hebert, MD, discuss monitoring requirements for various classes of treatments in atopic dermatitis, including topical vs systemic.

Matthew Zirwas, MD

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