Leon Kircik, MD

 Leon, how do you anticipate the treatment landscape evolving with JAK inhibitors and in addition to JAK inhibitors?

 Let me first go over the topical JAK inhibitors. They will really change the landscape. I can’t remember who it was, but somebody said they will probably be really useful for maintenance treatment. I agree with that, because we want to prevent the disease from coming. We have more or less good tools to get rid of the flares. Now we have dupilumab. We have topical steroids; they work really well for a week or two. The problem is we want to make the next flare as far away as possible and decrease the number of the flares. How do we get that? How do we maintain that clearance? Topical JAK inhibitors can be a great tool to do that. That’s one.

Two was brought up by Lisa. With the oral JAK inhibitors, the main use will be just for flares, right? If dupilumab doesn’t work or if something else doesn’t work, why not have another agent, that very short targeted treatment, for a couple of weeks—4 weeks, 8 weeks, whatever the period is—just to get that flare over and avoid the long-term safety issues without worrying about it. Also, they’re orals. Nobody wants a shot, but people use it because they have no other choice. Now we’ll have another choice.

 Peter, did you want to weigh in on the treatment landscape? Do you think we’re going to get more patients, or do you think we’ve seen them all? Do you see this as continued evolution and better care?

 I do hope and think we’ll see this expanding out to a lot of the people who have given up on the medical system. I meet some patients who are coming out of the woodwork because they’ve gotten the same diagnosis and treatment regimen, something like a big 1-lb jar of triamcinolone with 11 refills and were told, “Good luck.” But now they’re understanding we have new insight into the disease and new treatments. I’m seeing more patients. And we know if the numbers are correct, we’ve only seen a drop in the bucket of all these patients who are moderate, severe, and uncontrolled. Our treat-to-target keeps getting better and better. Just like what we saw with psoriasis where we used to accept, “That’s pretty good on methotrexate, you’re hanging in there,” now we’re aiming for clear or almost clear for these patients. The same is happening to atopic dermatitis. I’m excited.

 That’s great. Peter, I’m going to stay with you because you’re such an important figure in educating practitioners about atopic dermatitis. You’ve been very influential. With this changing and dynamic aspect of therapeutics, what are your recommendations for primary care practitioners [PCP] on best practices for collaborating on care and patient selection for referral?

 If I could get everybody to write out an eczema action plan, that would do 90% of the work. It’s a pain in the neck. It’s a lot of work. It takes some coordination. It takes a few extra moments, but even if it’s just some scribbles, just to give the patient a sense of where they’re going, it’s is an incredibly powerful tool that can be integrated into anybody’s practice. If you do it in a digital template, you can also copy and paste it into your notes. Now you know exactly what you told the patient. You print it for the patient so they have exactly what you’ve recommended in the order of operation, when they’re flaring up, when they’re better. It’s such an elegant thing.

As Lisa pointed out, we have those great hurdles. “Can I get you clear? Can I keep you clear safely, and can you keep it up?” Any time a patient can’t jump over one of those hurdles, that’s absolutely a reason to refer. And frankly, that applies to me, too. I have really tough patients where I’m not sure and I say, “I want another opinion. We can’t get you better, so let’s get someone else involved.” There’s no shame in that. I always try to remind our PCP colleagues that dermatologists do a fair amount of primary care medicine, so there’s no stupid consult. There’s nothing that we think is dumb. People come in for skin screening all the time, so we’re very much used to people who just want to get a check over. And in that capacity, any patient who is referred by another provider who says, “Listen, I’m not sure what’s going on,” or “I’m not able to help them,” we want to help to try to get them better. We’re all part of the same team. Our goal is not to be right, it’s not to be famous, it’s to get the patients better.

 That’s great. I’ll add to that. It sounds silly to say, but there’s consciousness raising about the disease. Even as experts who deal with a lot of atopic dermatitis on a daily basis in our practices, I’m more cognizant of what the disease impact can be. That’s across the whole spectrum.

One of the things as part of messaging to primary care is, if you’re watching this, great. The point is to get educated about the disease and recognize it. Change the messaging. For pediatricians, I talk about the asthma model because they understand an asthma model. It’s about long-term disease control and figuring out what medicines you need. And if you need someone beyond you to establish long-term disease control with minimal rash, minimal itch, and minimal sleep disturbance, then send them out. Certainly, I’m in the situation where, as Peter said, there are times it’s like, “I need an immunologist. Help me, please.”

Part of best practices is recognizing when the patients outstrip what you are able to bring to it. But also be alert to the changes that are going to happen in therapies because a lot of those are going to be incorporated into primary care practice, too, even though it may be specialists who are leading us toward that.

Let’s go to the last area of discussion on how we educate patients and their caregivers to keep them up to date on the management of atopic dermatitis. Does anyone else want to come into that, or should Peter go back to it? Peter, why don’t you lead us off on that? What’s your sense or your approach on keeping people up to date?

 It’s hard, because even we are feeling a little of that drowning sensation with so many papers. I did this plot, I used one of the scholar sites and was able to show that the number of publications in atopic dermatitis in the past decade looks exponential, and I feel like it’s going to keep going up.

What are some things I think are helpful? Certainly things like this. These are great because you get to hear a lot. Even I learn a lot from these meetings, because you get to hear the digested form of a lot of primary data, a lot of exposure to papers, and the chance to talk to our colleagues. There are many online things like this.

Another great thing to do is use email digests for topics. I use one that’s actually from the Google search engine, and I have targeted certain things so it gives me little digests every day—or you could set it every week—and I think that’s a nice way to see the papers just to read the headlines or read an abstract. And then if you’re really interested, you can click in and learn a little more.

Of course, there are some innovative things. I’m excited to be working with a group that’s creating medical video games for education. They’ve packaged, somewhat like the Duolingo language learning website and app, it’s the same concept with CME [continuing medical education]-type activities for different specialties. I love this kind of innovative thing. And then finally, I really do think that reading journals is still important. Even though we somewhat let go of them, they’re still important and I still like to flip through my journals even physically when I can, even though that dates me.

 This was an incredible discussion, really capturing some of the breadth of the issues that we deal with in atopic dermatitis. I thank you all for your contributions to the discussion. It was so reflective of where we are. I hope you get a chance to do this together with such experts. I thank all of you for contributing both your knowledge and experience with patients, and the energy that you bring to this arena of atopic dermatitis as we work together to bring better care and hopefully less influence of the disease on the life of individuals.

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Closing out its discussion on atopic dermatitis, the panel considers best practices and unmet needs in the treatment landscape.

Atopic Dermatitis: An Evolving Treatment Landscape

 That’s a great segue into the last segment of our discussion, which is a mixture of core questions for us to summarize where we’re at and what we’ve discussed through this session.

Let me start off. Lisa, discuss how and when you decide to make a change in therapy.

 For me, it’s pretty straightforward. If I can’t get a patient clear or keep them clear, then I’m going to be discussing and encouraging a change because I want to make these patients’ lives better. I want to make them look better, feel better, and do better. If I can’t get them clear or keep them clear, we should try something different. Fortunately, our option list is growing longer by the day.

 What else? Are there other times you’d like to make a change in therapy? I’m not big on changing it because someone else already used it. About half the time, people come in and they just haven’t used enough of a medicine. I don’t necessarily write a new script, I just write a more detailed care plan and do volumetric prescribing, where I tell them a certain volume. In all of medicine but especially in dermatology conditions, what’s needed in each room isn’t just walking in, making the diagnosis, and prescribing something. Partially our decision about when to change therapy and how we change therapy is individualized according to what that particular patient might need.

A brief discussion on when it is best to switch therapy while treating patients for atopic dermatitis.

When to Change Therapy for Atopic Dermatitis

 I want to take the next step of moving us over to systemic therapies. This is an area where we’re in this revolution of therapy. Our traditional systemic agents, methotrexate, cyclosporine, azathioprine, and mycophenolate, were variably used around the world and at different ages, with the United States using probably less traditional systemic therapy than, for instance, in Europe, because none were approved. In general, looking at datasets, people would use cyclosporine for rescue, and some patients would continue on it for a year. You’re not supposed to use it longer than a year, though I know people who were on it for multiple years. It clearly has an adverse effect profile, with an impact on kidneys and it being immunosuppressive. There’s some malignancy. It’s not like people ran to use it. It was used very little as you got to teens and younger.

Methotrexate remains a drug that some people like. We don’t have great data on the clear or almost clear EASI [Eczema Area and Severity Index]-75 rates. These drugs weren’t studied at the time when we had standard outcome measures, but it’s not as effective as our 1 approved biologic agent. Methotrexate is still used variably successfully.

We historically used azathioprine and mycophenolate in San Diego, but they’re pretty much historic agents for atopic dermatitis. The action it has in systemics, other than oral JAKs which we discussed in more detail, was changed with the introduction of dupilumab as the first biologic agent. Leon, do you want to make some comments about dupilumab?

 Sure. Going back to the systemic agents, you named it really well by calling them historic. They really are historic. I don’t remember the last time I used cyclosporine or methotrexate for a patient with atopic dermatitis. I still use mycophenolate a little. If they’re doing well, I keep it on. But dupilumab has revolutionized the treatment of atopic dermatitis. It gives us such an armamentarium that we never had before. It’s easy to use. We think about the biologics used in psoriasis. In this case, we don’t even have to do TB [tuberculosis] testing. It’s the first biologic that doesn’t require any monitoring. We don’t have to do TB testing. The safety profile is quite reassuring, and the efficacy is there.

However, there’s a big group going on about conjunctivitis. I’m concerned, but I can send them to the ophthalmologist upstairs or downstairs in my building, and that’s the end of it. That’s how I deal with it. It’s not something I’ve got to worry about whether it’s a lymphoma or leukemia. If worse comes to worst, they’re going to end up with a couple of eye drops and they’ll be OK. What concerns me, and is maybe more of an intellectual curiosity, is that I don’t know what’s causing it. That bothers me. And nobody has an answer for why we get this conjunctivitis with these drops. We don’t know.

The other thing that can happen that Peter brought up earlier is head and neck dermatitis. It’s a real issue. It’s happening. I see it. But there are ways to deal with it. It’s not the end of the world. The good that they get with this drug is so much better than the bad or negative noise that we get. In my mind, it changed the whole treatment paradigm of atopic dermatitis. I’m so happy that we’re getting more and more other biologics similar to this profile, efficacy and safety, and we can have more options.

 I’ll mention specifically, we had our experience where dupilumab was first approved in adults, then it was approved down to age 12, and then subsequently down to age 6, and then it’s being studied down to under a year of life. But I have to say that especially the expansion of age down to 6 has been very eye-opening and helped to change the field. Primary care pediatricians started to get a sense of the power of the medicine in changing the lives of individuals. I always consider myself aggressive in treating, but it’s different in terms of how much change can be mediated when we have more severe younger patients. The safety profile hasn’t expanded, meaning that the label hasn’t changed, which is great, and there’s still no need for blood monitoring. Nothing has come up in terms of other specific concerns so we’ll have to say it’s not immunosuppressive.

But also one of the takeaways of dupilumab, especially in pediatrics, is that it’s helped to change the messaging. It’s not about flare control and increasing the time between flares. It’s about long-term disease control, and that punch line is what I’m going for, whether it’s for patients who go into the topical bucket or the systemic bucket.

 But also, Larry, I have to say one thing. Having a first biologic for atopic dermatitis, it gives credibility to the disease that it should be treated. As Lisa brought up in the beginning, people would say, “Here’s a jar of Vaseline. Smear it, and you’re going to grow out of it.” Now we actually have a drug, a biologic, that gives the credibility to the disease of atopic dermatitis that it should be taken seriously and treated seriously.

 The other thing I’ll chime in on is, it’ll be years before we know if it could potentially have this impact, but as the label for dupilumab expands younger, I hear the next stop is 6 months, and we’re potentially treating these patients with bad atopic dermatitis at a younger age. Will we be able to impact change on the atopic march knowing now that food allergy likely stems from the atopic dermatitis? If we’re able to treat these patients at a young age, can we prevent things like food allergy? Can we even prevent things like asthma over time if we stop it in its tracks?

 That goes back to the old pimecrolimus study, right?

 The question of, “Can you change the course?” Why don’t we end with that question? Although you specifically asked for the younger kids, all across the ages, Raj, do you think that evolving therapies are going to change our patient outcomes?

 On the surface, we all agree with that. That’s a pretty obvious answer, but I there are definitely going to be challenges along the way, even though we’re going to have a lot of new great choices. There are going to be changes that have to happen on multiple levels, right? Let’s talk about the insurance companies, payers, the thoughts of this idea of step therapy, getting these actual medications approved for our patients who really need them instead of having to jump through hoops for those people who have a heavy burden of disease. That’s one area that’s still going to have to get addressed, even when we have a lot of great options. From the physician’s standpoint, for the first time in a long time, the toolbox has expanded. Everyone is going to need to know how to talk intelligently about these treatments and really understand the differences in efficacy and safety so you can have an educated discussion with your patients and answer the questions.

Education on the standpoint of the patient itself is going to have to be really important. Just like we were talking about with disease state awareness itself, people are understanding that this isn’t just a rash that comes in childhood and flexures that go away and then you’re done in adulthood. It’s much more complicated than that. Getting uptake of a lot of great therapy and implementing it into practice is definitely going to change the natural course of the disease, but it’s going to take efforts in multiple areas.

Shared insight on the armamentarium of systemic agents available to treat atopic dermatitis.

Atopic Dermatitis: Systemic Therapy Armamentarium

 Let’s take a next step in discussion of our available standard medicines. We haven’t discussed topical calcineurin inhibitors or topical PDE-4s. Raj, do you want to give us a top line?

 Sure. We can take a little trip back in time here. Tacrolimus and pimecrolimus are 2 topical calcineurin inhibitors. They’re not new by any stretch. The FDA approved them about 20 years ago in 2000 or 2001. They’re approved for greater than 2 years of age. On the whole, tacrolimus, the higher concentration, is probably more potent than the lower concentration, pimecrolimus. There are mixed data in terms of head-to-head studies. It seems like the topical calcineurin inhibitors line up with lower potency steroids that can perform somewhat similarly. There’s limited potency when you compare it with more medium or higher potency. But on the whole, there are good data showing that topical calcineurin inhibitor use reduces flares, the time between flares, and overall topical corticosteroid use. Particularly with proactive use, it’s a really good option for sensitive skin sites, where we’re not looking to use that much in the way of topical corticosteroids.

There are a couple of aspects about safety that are worth noting. There’s a boxed warning about theoretical malignancy risk, which comes up a lot with patient discussions. But it’s really important to talk about what long-term data over the past 20 years have shown, which is probably evidence to the contrary that this isn’t something we’re worried about with this class of medications topically. And then the application site symptoms can range quite a bit among patients, but there’s a lot of stinging and burning with application, which can limit the use of this medication class.

Similarly, when you look at PDE-4 inhibitors, crisaborole is the one on the market. There are several others in various phases of development. This was approved not too long ago, in 2016, and it’s approvedfor 3-plus months of age, so you can use it in young children. It’s another nonsteroidal agent. The clinical trial data showed superiority to the vehicle [placebo], but it was only mildly better than the vehicle itself. But it’s a good nonsteroidal option for those sensitive sites.

Local reactions weren’t seen so much in the trials, but real-world data suggest that there’s probably a fair bit of application site pain in patients, along with stinging and burning. That’s something that limits its use. There have been a few network meta-analyses done in the literature trying to look at all these nonsteroidal agents, of which this group is going to grow. It seems like on the whole, crisaborole is probably comparable with tacrolimus when you’re looking at rates of clearance, superior to pimecrolimus, and superior to vehicle as well.

 That was a great rocket tour through those. It’s important to include them because we use them as alternatives to steroids, either on their own or in regimens of care.

A review of topical therapies that have been long utilized for patients with atopic dermatitis.

Leon Kircik, MD

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