Safety of Topical Medications in Pediatric Atopic Dermatitis

In this exclusive interview with The Dermatologist, Dr Peter Lio discusses how new topical agents have been developed for the treatment of pediatric atopic dermatitis (AD) following his study, “Safety of Topical Medications in the Management of Paediatric Atopic Dermatitis.”

Peter Lio, MD, FAAD, is a clinical assistant professor of dermatology and pediatrics at the Feinberg School of Medicine at Northwestern University in Chicago, IL. He is also a member of the Clinical Advisory Committee of the National Eczema Association.

What new topical agents have been developed in the treatment of AD and how do these impact pediatric patients?
This is an incredibly exciting time for AD, and I think we really lean on our topical therapies. They're so important because, especially for kids, we're trying to minimize the exposure to systemic agents whenever we can. We can't always do that, of course, and so we need good systemics too, but I think there's a real impetus or pressure to try to avoid them when possible or minimize them.

Of course, our topical corticosteroids were released and developed in the '50s, which became popular in the '60s, '70s, and beyond. They've been very helpful, but they have a whole bunch of potential issues, and we really are trying to constantly minimize their use or avoid them when we can.

The next big breakthrough was around the year 2000 when we had tacrolimus, and then about a year later, pimecrolimus, our topical calcineurin inhibitors. They were great and saw a huge heyday in those first few years and then there was quite a chilling effect in March of 2005 when the US Food and Drug Administration put that black box warning on them. So, that kind of changed things. Then there was this long dearth of any innovation until 2016 when we got crisaborole, which is a neat molecule because it is sort of an anti-inflammatory molecule that works by inhibiting phosphodiesterase-4 (PDE4). It's a small molecule, it's well absorbed through the skin, and what's really neat is now it's actually approved down to 3 months of age, which is pretty exciting. It's one of the lowest levels that we have in dermatology.

Then very recently we got our newest edition, which is topical ruxolitinib, which is one of the Janus kinase inhibitors. That's exciting because topical ruxolitinib is well-penetrating into the skin at a great speed. That rapidity of effect is very, very robust, in my opinion, and I feel that it is on par with a mid-potency topical steroid. It's sort of the first non-steroidal agent that can kind of play with the big guys, so to speak.  Now, unfortunately, it's only approved right now down to age 12 years. So, for the younger patients, it's not much of an option and it has a number of warnings, including some kind of scary black box warnings that can be a real issue for patients and families. They start looking at it and it says things about major adverse cardiovascular events and more mortality, but overall, it has been really good.

Then we have 2 new topicals that have recently been released for psoriasis and have now completed their studies where we've actually seen the top line data for AD. These are tapinarof, which is kind of neat as an aryl hydrocarbon receptor modulator, and roflumilast, which is another PDE4 inhibitor, kind of like crisaborole, but different. To me, these are extremely exciting, and I'm really hopeful that these are going to make their way to pediatric AD soon.

What specific systemic adverse events for medications were largely common childhood ailments?
When we're thinking about some of the issues that come up with systemics, typically the things we're using are either off-label, like the conventional immunosuppressants: cyclosporine, methotrexate, azathioprine, and oral corticosteroids or systemic corticosteroids. They have a ton of potential side effects such as increased risk of infection. Of course, we know with cyclosporine, it can have an effect on the kidneys, blood pressure, and hyperhidrosis. I had a patient a few years ago who developed fine, kind of lanugo-like hair all over their body after a couple of months on cyclosporine. It was really uncomfortable.

With systemic corticosteroids, there are many issues, including things like avascular necrosis and sepsis. For dupilumab, our first biologic that got approved down to the pediatric age where it has recently been approved down to 6 months of age for a systemic. That one actually has a fairly favorable safety profile and fairly limited one. What's nice is the safety profile is very similar in the littlest kids all the way through adults. The big issues are conjunctivitis, eye irritation, and eye redness where keratitis is kind of closely associated with that. Then we have a few other things that are less common. There has been this face and neck dermatitis or persistence of face and neck eczema. There have been some cases of arthritis or arthralgia, joint soreness or pain, and there may be some signal for arthritis out there. So, we have to keep an eye on them.

Generally speaking, I'm pretty comfortable using these on kids and I think that's why the biologics are sort of a go-to whenever we can. We also have phototherapy, which we certainly can use in kids, but it has a little bit less evidence and we have to be cognizant of the potential for longer term issues and especially skin cancer. Although, I'm excited to say, there was recently a paper that talked about not seeing any increased risk of skin cancer in patients with AD who had been using narrowband ultraviolet B phototherapy. That's a nice piece to see after many decades of use.

How do topical calcineurin inhibitors compare with topical corticosteroids when it comes to managing pediatric AD?
We know that our topical corticosteroids, in some ways, are hard to beat because they are incredibly reliable. They help almost every single patient who we put them on. Essentially, a 100% of people are going to get better. Additionally, they're incredibly accessible and inexpensive. They’re also pretty safe when they're used correctly. We've, again, had decades and decades, we're talking almost 70 years of experience with them, which is pretty good. Even though there are risks, it’s pretty nice to have something that we've seen literally generations of people use.

The calcineurin inhibitors, which would be tacrolimus and pimecrolimus, came out in 2000 and 2001 respectively in the United States. Those are fantastic because they are nonsteroidal and they're different in that they don't have a lot of the same side effect issues. They don't thin the skin, as topical steroids do. They can't cause stretch marks or stria. They also do not seem to have the same kind of a rebound effect. Part of it is that topical steroids are vasoconstrictive, so when you stop using them, you can get this flush, blush rebounding effect. Sometimes I find that the dermatitis that we're treating actually can become worse.

Steroids can do that for some patients, although it's somewhat rare, but I do see that. I think the calcineurin inhibitors are less likely to do that, and, of course, they don't affect the blood vessels in the same way. What's the trade-off? Well, the trade-off is twofold. In general, they're less reliable. I have some patients for whom they just don't do enough, and they're less powerful overall. Then the third piece is they have different adverse effects, like stinging and burning. There are some patients who can't tolerate them, although it's fairly rare. I like to use a topical corticosteroid to cool things down, then use a nonsteroidal agent because it’s treating less severe effects, so it makes more sense, and it's much less likely to cause stinging and burning. However, there are some limitations.

Lastly, it comes down to accessibility. Both tacrolimus and pimecrolimus are very expensive, costing hundreds of dollars, even though they've been generic for years now. Sometimes patients just can't get them through insurance and they're too expensive to pay for out of pocket.

Are there any tips or insights you'd like to share with your colleagues regarding topical medications in managing pediatric AD?
I think the secret is, if you can, use them together in a harmonious way. I like to think about kind of painting a picture or putting together an orchestra using different instruments. I really like the idea that we could use some topical corticosteroids, even though there's a lot of concerns about them. I'm very cautious about them, but I still think they can play an important role when using them carefully in a targeted way for a short period of time, and then switching to some of our nonsteroidals.

Most importantly, writing out an action plan is kind of empowering the patient, and doing frequent follow-ups by having them come back and say, "How did we do? How much time did you use it? Did you have trouble? Did it sting? Did it burn?" I think those pieces to refine the therapy are critical.

Most patients can get better with topical therapy alone, but the truth is, if we don't try our best, then it's really hard to know if we skipped over something or moved on in a way that we didn't need to. I do think that we have to be willing to go to the systemics when it's warranted because I don't want people to suffer.

Reference
Zhao S, Hwang A, Miller C, Lio P. Safety of topical medications in the management of paediatric atopic dermatitis: an updated systematic review. Br J Clin Pharmacol. 2023;89(7):2039-2065. doi:10.1111/bcp.15751