Northwestern University Feinberg School of Medicine

Peter A. Lio, MD, Northwestern University Feinberg School of Medicine 

I’ll toss it over to Peter and think about our more classic oral agents, methotrexate, cyclosporine. Maybe you can, for those who aren’t super familiar, tell us how long these have been around as an important mainstay for therapy. What are some of the challenges patients have in terms of adherence, and ease of use, and burden with these therapies?

I feel like once we have maximized and optimized our topical therapy, and my area of focus is trying all these crazy alternative and integrative approaches as well, but once we feel that we have done as best we can with that and we’ve maximized that, then I think we have to start bringing up the potential for going to a systemic agent. We know historically we’ve had, all off-label by the way, none of these we’re about to talk about are FDA approved. Well, let me say 1 is FDA approved that’s been grandfathered in, and that’s prednisone. Systemic corticosteroids technically are approved for the treatment of corticosteroid response to dermatoses, of which this would fall in place. But of course, we often try to push against using those because not only do they have a whole host of potential adverse effects, but for some patients, they can cause a pretty terrible rebound flare-up. I inherited, and I’m sure all 3 of us have inherited, lots of tough patients who have kind of become corticosteroid addicted or are really used to it, and that is a bad plan for most patients.

Now, do we meet people who sometimes use them and say I’ve never had trouble? Yes, but we’ve also met people potentially who say they’ve played Russian roulette for years and never died, but I wouldn’t recommend it. I don’t think it’s a wise game to play. I try to avoid it. Are there times when we need to use systemic corticosteroids? Yes, I would argue there are certain scenarios to use them as a rescue. If somebody’s going to Europe, somebody’s getting married, you just kind of have to do it. But in general we try to avoid it. So let’s take that off the table for a minute.

Then we have our conventional immunosuppressants. Methotrexate, cyclosporine, mycophenolate, azathioprine, those are the big 4. Most dermatologists in the United States, in particular pediatric dermatologists who use them more than adult dermatologists in this context, they’ve picked cyclosporine. I think cyclosporine really is the drug of choice. If you look, there’s this wonderful figure I was able to put together. Somebody helped me do it, but we put it together looking at the discontinuation rate of the conventional immunosuppressant agents, and it turns out that the best bang for your buck is cyclosporine. It still isn’t pretty. Many people have to discontinue due to potential adverse effects, and relatively few people get good control on that medicine long term, but compared to methotrexate it’s unbelievable.

Methotrexate is quite terrible. Approximately 6% of people get control on methotrexate, and mycophenolate was approximately 11%. These are very low numbers. I feel like it’s the wrong tool for the job for most patients. It’s kind of like using a brick to hammer in a nail, it can work, but there are all sorts of issues. Of course, with all of these agents, we have a whole host of potential adverse effects, lots of monitoring we have to do, and they’re all off-label. It’s very challenging to use them, and we’ve done it, but I think cyclosporine has been my favorite. Britt, for you too, I know you have mostly pediatric patients, do you use cyclosporine as your first line before some of the newer agents came out?

Before they came out, yes for sure. Now, I joke that the residents aren’t going to know how to use this for atopic dermatitis anymore. I think especially if you want to try to cool someone down quickly, that was always our go-to for a severe patient who failed topicals, and/or phototherapy, or where phototherapy wasn’t a reasonable option. I used a lot of it. But again, you can’t use it forever, there’s a big conversation about risk, you’re subjecting a child to blood draws. It is something that you have to worry about the patient adhering to it. You can’t give someone a prescription for 3 months and just let them go. It’s very labor-intensive on the part of both the family and the clinician because of the monitoring.

This thought about the labor associated with thinking about the treatment, then talking about the treatment, then monitoring for the treatment, and then thinking about when to stop it, that’s the big thing. It is a labor that’s on us, and it’s a labor on the patient and caregiver. If anything could highlight why we needed a bit of a revolution in treatment, I think that was it. And the fact that, bottom line, it works for some people but not everybody. You’re not getting people to the point of saying, “OK I’m almost completely clear and can get my life back.”

Videos

Peter A. Lio, MD, describes the challenges pediatric patients face with oral therapies for atopic dermatitis, focusing on ease of administration and patient adherence.

Pediatric Atopic Dermatitis: Considerations and Challenges With Oral Therapies

Before we jump into some of those newer therapies that are evolving, I want to ask you both about some of the challenges pediatric patients face in particular when it comes to some of the treatments we have right now, with both oral and topical treatments, kind of your classics. I’m thinking about topical corticosteroids, and then from an oral standpoint, thinking about methotrexate and cyclosporine as well. I’ll give the topical one to you, Britt, first. Tell me about some of the problems you feel that you face in terms of adherence, ease of application, and use and burden associated with current topical therapies.

Probably the biggest thing we face is steroid-phobia, right? Unfortunately, that gets perpetuated a lot by pediatricians. Parents have been told don’t use too much of it. I think that’s one of the things I spend the most time on. I say, “Look, this is OK. I would never give you something that wasn’t safe, and that I wouldn’t give my child. This is important because it actually may save us in the long run.” I think we do have all these fancy new therapies, but like Dr Lio said, topical steroids have been around, and they remain the mainstay of therapy. I think a lot of patients can be well-controlled with them if used appropriately.

I see a lot of patients coming in, and I will say, “OK, we’re going to do use medicine called triamcinolone,” and they say, “Oh, we already had that.” OK, how did you use it? So getting the history from the patient and asking, “How big of a tube did you have?” They maybe had a 15-g tube, and they’re covered. How did you use it? “Well, I used it for a few days.” A lot of patients, I tell them, “You had the right ingredients, but you had the wrong recipe.” I will tell them, “I am giving you a jar of this medicine. This is my way of saying this is OK. And I want you to use it. You’re going to use it for 2 weeks straight, even though Johnny’s probably going to look better in a few days, and we’re going to put that fire out.” Finding an analogy, like what you’ve been doing is like pouring water on the fire. You’ve been making it better, but as soon as you stop, it comes right back. Oftentimes, you get these kids to clear and they stay clear longer, you save them a lot in the long run. I think getting over that fear and having people understand how they’re meant to use these things, and that it’s not usually this willy-nilly thing until they are on a maintenance regimen, that’s really important.

I think older kids just don’t like the way the topical feels. Corticosteroids, like I mentioned before, if you don’t like grease, you’re not going to use an ointment. Some patients really like that, but for other patients, it sticks to their clothes, they look shiny, and it’s gross. With the parents, it’s ruining their furniture. All these little things; when I was a resident I remember thinking why can’t anyone just do what I ask them to do? It’s because they have a real life. So making sure they’re using things appropriately, again, sorting out what’s going to work for them. We have stinging and burning sometimes, that tends to less from corticosteroids and more with other things that we’ll talk about later. And also time. Sometimes we have families where there’s a single parent, and maybe they leave before the kids get up, so they don’t have time to put the stuff on, so sometimes I’ll write a note for the daycare staff to do it, or whatever. Again, is this plan reasonable for you, and if it’s not, are there ways we can tweak it so that it can happen?

Yes, I think that this whole concept of adherence, there’s a lot of power in this, right? Because we always think about it as compliance, but compliance is such a patriarchal way of thinking about it. In many ways, it’s about what we can do to try to keep people wanting to use the therapy they’re using. To your point, ointments aren’t always the end-all and be-all. In fact, systematic reviews suggests that maybe they aren’t in that sense. There’s a nice emolliating property to them, but bottom line, if someone uses the medication, odds are that they’re going to get better, if it’s something they actually want to use. I think that a lot of adherence, when this has been looked at, particularly in psoriasis literature, less so in eczema, at best in the real world, we’re talking about 40%, maybe 50% at best. So you’ve got to assume already the moment that somebody is probably leaving you, no matter how good of a job you did, they’re not executing your beautiful golden plan to fruition.

It’s one of those things that Peter harped on before. There’s a lot of education, and reeducation, and reviewing that comes with these visits, trying to get people to feel on top of what they’re doing and why they’re doing it. You’re almost like a life coach or a motivational coach in some sense. I feel like with a lot of my patients with chronic eczema, I’m not changing the plan all that much, but I’m still seeing them relatively frequently because I’m reminding them that we’re doing this, you can do it, this is what you want to do again. Largely, that’s another one of the things that makes the disease challenging. It’s not like I throw an antibiotic on it and it’s gone, the infection is gone, done deal. But rather, it’s the chronicity, it’s like a big idea.

Raj Chovatiya, MD, PhD; Brittany G. Craiglow, MD; and Peter A. Lio, MD, highlight challenges physicians face with the available atopic dermatitis treatments for pediatric patients.

Challenges With Available Atopic Dermatitis Treatments for Pediatric Patients

 Let’s shift to the other stuff coming in the future. There are other mechanisms being investigated in therapeutics in atopic dermatitis. I’ll start with topicals.

There’s a new topical JAK inhibitor that has been studied in ages 12 and older. It’s probably as strong or a little stronger than triamcinolone 0.1% as a steroid, but it’s a nonsteroid. There’s no atrophy. It may have more potency than our other nonsteroidals without a lot of irritancy, burning, or stinging at all. We’re really excited about that.

Tapinarof is a drug in a totally different class of medicines. It’s an aryl hydrocarbon receptor modulator. This is being developed both for psoriasis and atopic dermatitis. 

Another PDE4 inhibitor is under study as well. Another topical JAK inhibitor, delgocitinib, is being studied in both chronic hand eczema and atopic dermatitis. They’re not ready to be written yet, but these are other medicines that will give us different topical options.

Peter, do you want to talk about biologics?

Absolutely. We have some new biologic agents that are in development. In particular, we have 2 new IL-13 inhibitors that are in late-stage development, so that’s going to be exciting. It seems they’ll be similar to dupilumab but a different molecule. It may be for patients who have had an adverse event with dupilumab or if it didn’t work fully. This may be another option. This is going to be nice. It seems like they’re going to have a similar safety profile and lack of lab monitoring. That’s exciting.

We have an IL-31 inhibitor that’s also in development. That’s interesting because some people call IL-31 the master itch cytokine. That would be neat because that could answer our question we asked at the beginning. Is this the itch that rashes? If so, how much? Of course, nothing is quite that pure. IL-31 is doing other things too, but the early data seem very promising, so that’s exciting to me as well.

 There are some oral JAK inhibitors coming down the pike as well. They are well along the way. Baricitinib and upadacitinib have been approved for other indications and are being studied in phase 3 trials for atopic dermatitis. There’s also a new molecule, abrocitinib. These will be different. They’ll be oral. There are some more issues with monitoring blood work, but that will give another potential approach to some of our patients. Two of the 3 JAKs have been studied in ages 12 and older, and the other is being studied in adults but going younger. There’s lots of new stuff happening. 

This has been an incredible discussion and very practical, reflecting on all the changes that are happening in the field. Let’s get final thoughts from each of our participants. Jeffrey? 

I’ll go back to education. Educate the pediatrician and make sure the pediatrician educates the family and takes the time. This is not an easy process. This is not an easy disease state. If we do a good job outlining to the families what they need to do, we can see much better outcomes. That goes without saying for everything that primary care doctors do. This forum is going to be great for people to take a look and hear what’s coming on and where we should be.

We all have to work together in a therapeutic alliance. We need to get the patients on board. We need all of the specialists and primary care practitioners to work together because we’re all together for the same concept. We want the patient and their family to be better. When we bring all our forces together, it’s so much more powerful. There’s great synergy.

These are exciting times in the world of atopic dermatitis. The world is going to be a better place with all these new therapies on the way and with the advent of Dupixent 4 years ago. It’s a good time to have atopic dermatitis. We can do many more things to help.

Thank you. Great contributions from everyone today. Thank you for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box. Thank you.

Lawrence F. Eichenfield, MD; Jeffrey M. Bienstock, MD, FAAP; Peter A. Lio, MD; and Elizabeth A. Swanson, MD, review additional mechanisms being investigated in the pipeline for the treatment of atopic dermatitis. 

Emerging Agents for the Treatment of Atopic Dermatitis 

 What’s the deal with getting this drug approved? Does it require preauthorization? Is it more difficult with younger children than with adults or adolescents? Lisa, do you want to take that?

 Yes. The process for approval is designed to have a dermatologist, pediatric dermatologist, or allergist be the prescriber. It does definitely require prior authorization. Most of our offices and staff are used to that. It’s a well-oiled machine.

I find that coverage is getting much easier over time, especially as the label has been expanded younger and younger and it’s been available for longer and longer. Dupixent will turn 4 in March. It is getting easier. Even when I have to fight for it, it’s worth it. I’m happy to fight that fight.

Sometimes we get comments back from payers who deny it and say they need to go through a systemic immunosuppressant. The 1 that’s approved for kids? There isn’t 1 because there aren’t any even approved for adults. That’s when I get the name of the medical director so we can write this down and talk to them about it.

I had a recent 1 where they sent me a denial saying that they wanted the patient on adalimumab first, which is a drug used for psoriasis and has no utility for atopic dermatitis. I was like, “No, they picked the wrong disease state letter to deny this.”

Jeff, you’re knowledgeable in atopic dermatitis. I know you’ve been involved in the community. Do you think pediatricians are sufficiently aware about dupilumab? Do they need to get more educated so they’re supportive of patients considering systemic therapy? What’s your sense of where they’re at?

 I hate to keep coming back to education, but obviously this is 1 for us. Many of my colleagues can’t even spell the drug. I’ve made the analogy that we had a revolutionary drug for acne with Accutane many years ago, and all those kids do well. We’re seeing how well dupilumab works in asthma, as you mentioned. We’ve seen it with polyposis. We know about the adverse effects. I have not had to write for it, nor have I had to fight for it, but I know that the system in place is pretty easy. I know there’s a whole cheat sheet of what needs to be followed because I had seen that early on.

The big thing is that people in the trenches, primary care doctors, need to be educated. That’s like any new therapy for anything. This is 1 form to say, “This works.” We need to get on board. It took awhile to get a black box around 2 other drugs. We had crisaborole come out after that. You don’t have to spend hours—1 to 2 hours a day with topicals—when a child could potentially get 1 shot every 2 to 4 weeks. 

The topical exhaustion thing is something you can work around. 

I like your analogy to the Accutane situation. One obstacle I sometimes encounter in daily practice is a patient who really needs Accutane, but maybe the primary care doctor said something that wasn’t supportive of Accutane. It can be hard for me to turn that ship around and gain their trust while feeling like I’m not going against the wishes of the pediatrician.

It would be helpful to spread the word among primary care doctors, pediatricians, internists, and family medicine doctors to know enough about Dupixent to be supportive of their patients and encouraging of their patients to consider a treatment modality when they have this horrible atopic dermatitis. In much the same way, I would appreciate that support when it comes to a patient who needs Accutane. That’s a very good analogy.

 It’s real. Fortunately, in the coming months, there will be forums for all of us to join together to explain to pediatricians with webinars—because we’re not meeting face to face—and say, “Open your eyes, listen to what we’re saying, and fight for your patient. Because this works.”

A discussion on ease of access for dupilumab for the treatment of atopic dermatitis including the process for approval and coverage. 

Peter A. Lio, MD, Northwestern University Feinberg School of Medicine

Articles