Clinical and Economic Perspectives on Innovative Therapies for Pediatric Atopic Dermatitis

EINGUN JAMES SONG, M.D., FAAD
Director of Clinical Research
Co-Chief Medical Officer
Frontier Dermatology
Mill Creek, WA

Managed Healthcare Executive (MHE): What are the key clinical differences between pediatric and adult atopic dermatitis (AD), and how do these differences guide treatment decisions?

Song: AD is fundamentally a Th2-driven disease across all age groups. However, the immune response can be heterogeneous — some patients may have varying contributions from other immune axes such as Th1, Th17 and Th22, depending on age, race, ethnicity and comorbidities. This heterogeneity directly affects how patients respond to specific medications.

Disease presentation varies significantly by age. Infantile eczema typically presents as acute, exudative lesions — fiery red, oozing and crusting — primarily affecting the cheeks and extensor surfaces. In adolescents, we see more chronic, lichenified lesions in flexural areas such as the antecubital and popliteal fossae. Adult patients often present with localized chronic lesions limited to the hands, feet, ankles or wrists.

One of the most critical factors for topical treatment selection in pediatric patients is the increased absorption of topical therapies due to their higher body surface area-to-weight ratio. This means children are more likely to absorb topical corticosteroids systemically than adults, increasing the risk of steroid-related side effects. This physiological difference requires more cautious use of potent topical steroids in younger patients and influences the selection of alternative therapies in pediatric populations.

MHE: Can you describe the key mechanisms of action for recently approved nonsteroidal pediatric AD therapies, including JAK inhibitors, PDE4 inhibitors, AhR agonists and biologics?

Song: The pediatric AD treatment landscape now includes several novel nonsteroidal mechanisms that target different pathways in the inflammatory cascade.

JAK inhibitors work intracellularly to block cytokine signaling through the JAK-STAT pathway. Unlike biologics that target extracellular cytokines or receptors, JAK inhibitors intercept inflammatory signals inside the cell by inhibiting specific JAK family members. Topical ruxolitinib [Opzelura], a JAK1/2 inhibitor, is currently the only FDA-approved topical JAK inhibitor for AD.

PDE4 inhibitors are also intracellular small molecules that have been validated targets in inflammatory dermatologic conditions for years. PDE4 is highly overexpressed in immune cells relevant to AD and psoriasis. Inhibiting PDE4 increases cyclic AMP levels, shifting the immune system toward an anti-inflammatory state and reducing pro-inflammatory cytokines, including Th2,Th1, Th17 and Th22 mediators. Newer agents such as roflumilast [Zoryve] demonstrate enhanced binding affinity, which often correlates with improved efficacy.

AhR agonists target the aryl hydrocarbon receptor, a transcription factor found at environmental interfaces such as the skin, the gut and the lungs. While environmental pollutants binding to AhR can promote inflammation, therapeutic AhR agonists such as tapinarof [Vtama] promote homeostasis by enhancing skin barrier proteins, increasing antioxidant activity and reducing Th2 and Th17 cytokines.

Biologics include IL-4/13 pathway inhibitors and the newer IL-31 blocker. Dupilumab [Dupixent; IL-4 receptor blocker] is approved for patients as young as 6 months, while the IL-13 inhibitors tralokinumab [Adbry] and lebrikizumab [Ebglyss] and the IL-31 blocker nemolizumab [Nemluvio] are approved for ages 12 and older. This age restriction significantly affects pediatric treatment options and formulary considerations.

MHE: What key efficacy and safety findings from recent pediatric AD trials should inform treatment selection decisions?

Song: For topical AD therapies, two key considerations drive clinical evaluation: efficacy versus vehicle and tolerability. Vehicle responses can be substantial in dermatology, particularly in eczema, so demonstrating the benefit of an active ingredient is crucial, although the therapeutic benefits of a well-developed vehicle should also be taken into consideration. In addition, tolerability in sensitive areas such as the face and skin folds is essential for pediatric acceptance.

Recent pediatric trials demonstrate that novel topical therapies achieve meaningful efficacy with favorable safety profiles, though study designs and populations vary significantly.

The TRuE-AD3 trial [NCT04921969]¹ examined the safety and efficacy of ruxolitinib, 1.5%, in patients aged 2 to 11 years who had mild to moderate AD. The study showed exceptionally rapid response rates with large treatment differences versus vehicle at eight weeks. Safety and tolerability were reassuring and nearly identical to adult study results, indicating consistent performance across age groups.

The ADORING 1 and 2 trials [NCT05014568 and NCT05032859]² examining the safety and efficacy of tapinarof, 1%, studies were unique in enrolling patients as young as 2 years and including moderate to severe AD cases — the only topical studies to do so. This population had higher baseline body surface area involvement and disease severity scores, with some patients meeting criteria typically seen in systemic trials. Nearly 50% of patients achieved clear or almost clear skin at eight weeks with good treatment separation from vehicle. Safety was comparable to psoriasis studies, with notably lower folliculitis rates than previously observed.

The INTEGUMENT-I/II trials [NCT04773587 and NCT04773600]³ studied the efficacy and safety of roflumilast, 0.15%, in patients aged 6 and older with four-week primary end points — shorter than other trials, which limits direct comparisons. Over one-third of patients achieved clear or almost clear skin with excellent tolerability. Notably, this agent avoided the burning and stinging historically associated with PDE4 inhibitors, showing tolerability comparable to vehicle. The 52-week, long-term extension trial [NCT04804605]⁴ also mandated proactive twice-weekly maintenance therapy once clearance was achieved, better reflecting real-world practice patterns.

Overall, these studies establish that topical therapies can achieve meaningful efficacy in pediatric populations with favorable safety profiles. However, the variation in study populations and end point timelines makes direct efficacy comparisons challenging for formulary decisions.

MHE: How might recently approved nonsteroidal therapies reduce emergency department visits, hospitalizations and overall healthcare burden compared with conventional approaches?

Song: The financial burden of AD on the healthcare system is tremendous, and it’s largely driven by our current treatment approach. Here’s what typically happens: Patients wait until their disease gets really severe or they have a major flare, and then they can’t get in to see their primary care doctor or dermatologist because wait times are so long. So, where do they end up? In urgent care or the emergency department (ED), where providers aren’t dermatology specialists.

These patients get bounced around the system and keep getting the same treatments over and over — usually topical corticosteroids or even oral corticosteroids, which the most recent American Academy of Dermatology guidelines actually recommend strongly against using in most cases.⁵ And here’s what we can guarantee with corticosteroids: As soon as you stop them, not only does the disease come back, but it’s also often worse than before. We see this very clear rebound phenomenon, so patients get stuck in this vicious cycle.

Think about the burden this creates — not just the cost to the system, but also imagine what it’s like for patients and caregivers. Nobody wants to be in the hospital or ED if they don’t have to. Many of these patients have such disrupted lives that they can’t participate in normal activities because they’re worried about flares. We see a lot of absenteeism, where they’re missing school or work, and presenteeism, where they’re physically there but so focused on itching or worried about how their skin looks that they can’t concentrate. There’s a huge impact on these patients from a quality-of-life standpoint.

Now, with these newer nonsteroidal therapies designed for long-term, safe maintenance use, we can hopefully break that cycle. Hopefully, with proper education, caregivers and patients can maintain control and actually prevent flares instead of just treating them after they happen. That’s really the key advantage — these therapies are safe for long-term use. For example, in the roflumilast studies, patients were using it proactively twice weekly with very good long-term control.

It simplifies everything because you can use one topical for flares and for maintenance. If we can keep patients from having to go to the ED or urgent care by giving them a safe, well-tolerated, effective treatment that they can use long term, that’s going to reduce overall system costs. And from a quality-of-life standpoint, patients feel confident that they know how to manage a flare and be proactive with treatment because they’re not afraid of the medication. That goes a long way.

MHE: What age-specific administration, adherence and monitoring considerations should guide therapeutic selection for pediatric patients?

Song: Let me start with the age indications because they’re all different. Right now, ruxolitinib is approved for ages 12 and up for mild to moderate AD, but the pediatric study TRuE-AD3 for ages 2 to 11 has been filed, and we should hopefully get that approval soon. Tapinarof got approval for ages 2 and up right out of the gate, which is great. Roflumilast is currently approved for ages 6 and up, although the company has submitted for ages 2 to 5 using a lower concentration — 0.05% versus the 0.15% used for older patients.

From an adherence standpoint, all three can be used as monotherapy, and I think that’s huge for adherence. You don’t need different topicals for flares versus maintenance or different products for face versus body. It really simplifies the regimen.

The one caveat is with ruxolitinib. Per the FDA label, you can’t use it with systemic therapies such as biologics or immunosuppressants. So, if a patient is on dupilumab and has breakthrough disease, you could add roflumilast or tapinarof but not ruxolitinib, according to the label. Now, this isn’t based on safety data — there’s never been a study showing it’s dangerous. The FDA just applied the same labeling from oral JAK inhibitors that are approved for inflammatory conditions to the topical formulation.We just presented an abstract at the 2025 Revolutionizing Atopic Dermatitis meeting showing you can use topical ruxolitinib safely with systemic therapies,⁶ so hopefully that gives clinicians more confidence to use this combination if needed.

As far as monitoring requirements, no blood work is required for any of these products. The clinical trials showed no consistent lab abnormalities. People worry about ruxolitinib because it’s a JAK inhibitor, but the absorption is minimal when you follow the label: twice daily for up to eight weeks on less than 20% body surface area. At those parameters, we don’t expect meaningful lab changes compared to vehicle.

MHE: How might AD management strategies differ for pediatric patients with concurrent atopic comorbidities such as asthma, allergic rhinitis or food allergies?

Song: AD is really a systemic disorder, and these patients are at risk of developing other comorbidities — some directly tied to AD’s pathomechanism, others as a consequence of uncontrolled disease. The big three we think about are asthma, allergic rhinitis and food allergies, which we call the “atopic march.”

There are data suggesting that early, effective AD treatment during this window of opportunity may actually lower the incidence of developing these other comorbidities. That’s such an important piece for pediatric patients.

Right now, we have one systemic therapy approved for multiple atopic conditions — dupilumab. It’s approved for both AD and asthma, plus other type 2 inflammatory comorbidities such as asthma, chronic rhinosinusitis with nasal polyposis and eosinophilic esophagitis. For a pediatric patient with multiples of these comorbidities, that might be the medication to consider.

But here’s what’s really interesting: There was a recent study showing that patients with AD treated with topical corticosteroids had a lower risk of developing food allergies — specifically, hen egg allergies — compared to patients who didn’t treat their AD with medicated creams.⁷ That’s almost proof of principle that treating the AD itself may lower the risk of these other conditions.

The thinking is that the compromised skin barrier acts as a portal of entry for allergens. Then, the immune system starts recognizing them, and that triggers this downstream cascade of developing other atopic comorbidities. So, effective AD management isn’t just about the skin — it’s potentially helping to prevent the whole atopic march.

MHE: What other clinical factors should guide treatment selection between topical nonsteroidal options and systemic therapies?

Song: One of the big challenges with traditional nonsteroidal topicals has been that they’re often inappropriate for sensitive areas like the face or genital skin. Topical calcineurin inhibitors and older PDE4 inhibitors can cause significant burning or stinging, so we’ve had to limit their use in those areas.

With these newer nonsteroidal topicals — roflumilast, tapinarof and ruxolitinib — there’s really no limitation or concern about using them anywhere on the body. I’d feel 100% confident using all three in any area, sensitive or not. That really adds to the simplicity of these molecules and makes treatment much more straightforward for both clinicians and patients.

Disease presentation patterns also matter when choosing between topical and systemic options. For typical flexural eczema with type 2 comorbidities, biologics generally work very well. But when you have AD predominantly affecting just the hands, feet, neck or head area, that’s where oral JAK inhibitors seem to have an advantage. The thinking is that AD in these locations often has secondary or superimposed causes like an irritant or allergic contact dermatitis, and JAK inhibitors are better at treating this broader range of conditions.

Itch versus skin involvement is another key consideration. Patients with limited skin disease but very high itch scores tend to respond well to JAK inhibitors. Nemolizumab, an IL-31 receptor inhibitor, is also excellent for patients with severe itch, irrespective of body surface area involvement.

MHE: How should payers develop coverage criteria and prior authorization requirements to promote appropriate use and timely access to novel topical therapies?

Song: Clinicians understand the intent behind prior authorizations and step therapy — these are expensive medications, and cost management matters. But often, many of these requirements aren’t based on clinical data and don’t seem to have been developed with input from practicing dermatologists. They often don’t align with what dermatologists would do in clinical practice.

We end up feeling like we’re jumping through hoops unnecessarily to get patientsmedications we know they need. Because we do this so often, we’re familiar with the step therapy, but it’s really a waste of time and resources. We’re exposing patients to medications when we know there is little chance they will work, just to check that box.

My wish would be that payers work directly with dermatologists to develop criteria that make more clinical sense. Let’s agree on what’s reasonable and what’s not, so we’re not overusing costly medications for patients who don’t need them, but we can get the right patients on the right therapy quickly to limit the burden their disease is causing.

MHE: From your perspective, what types of real-world data would be most valuable to clinicians and managed care organizations when evaluating the efficacy and safety of recently approved agents for pediatric patients with AD?

Song: Real-world data will be critical for understanding how much these newer therapies are actually moving the needle. Clinical trials occur in very controlled environments that don’t always translate to real-world practice.

First, I want to know whether patients are actually adhering to and benefiting from these medications. We can measure this through prescription refill rates: Are patients continuing therapy, or is it just a one-and-done situation? Also, registry studies can capture efficacy, safety and patient-reported outcomes, including patient perceptions of how well the drug is working.

Equally important is understanding how these agents reduce usage of therapies we’re trying to minimize (such as topical corticosteroids and systemic corticosteroids)and how these agents might potentially delay or limit the need for other systemic therapies. Although systemic therapies are life-changing drugs, not every patient needs them, and they can be very costly.

If we could establish metrics showing that starting a patient on a newer topical agent and ensuring consistent use saves X dollars to the system by preventing escalation to more expensive treatments, that would provide tremendous value to managed care decision-makers.

MHE: How might biomarker-driven approaches evolve to enable more personalized therapy decisions in pediatric AD?

Song: AD is incredibly heterogeneous in both presentation and underlying immune mechanisms, often leading to inconsistent treatment responses.

Like in oncology, where tumor characteristics predict optimal treatments, we’re working toward identifying which AD therapies will be most effective for individual patients from the start. This personalized approach could eliminate stepping through multiple unsuccessful treatments.

Current research involves using tape stripping, dermal patch tests and serum biomarkers, though we’re not to the point of using these uniformly in clinical practice. I’m hopeful we’ll soon be able to select the right drug for the right patient from the start.

For pediatric patients, this has added importance, because younger patients face the highest risk for developing type 2 comorbidities. If biomarkers can identify high-risk pediatric patients, we could treat them more aggressively up front, potentially preventing complications and reducing long-term healthcare costs.

MHE: What else would you like our MHE audience to know?

Song: We often focus on treatment costs and side effects, but there’s also a substantial cost to undertreatment. Pediatric patients with poorly controlled or severe AD can experience sleep disruption, growth failure, abnormal bone development and higher risks of neuropsychiatric comorbidities.

AD isn’t just a skin disease — there are serious downstream consequences to inadequate treatment. Many patients receive suboptimal treatment where providers think they’re doing enough but aren’t achieving optimal disease control. I always ask patients: “Does your AD disrupt your life or prevent you from doing things you want to do?” If they say yes, that’s our indication to modify management, whether adding therapies or changing approaches altogether. From a managed care perspective, investing in effective treatment up front prevents these costly long-term complications.