From Mechanisms to Management in Pediatric Atopic Dermatitis

Introduction

Atopic dermatitis (AD) conveys a substantial burden on affected individuals. The hallmark signs and symptoms of AD include pruritus and lesions that follow age-specific patterns and appearance in a chronic or relapsing history.¹

Current treatment strategies center around a treatment algorithm that classifies patients according to severity of disease.² Nonlesional basic management includes trigger avoidance and skin care with moisturizers alone or after warm baths or showers. Mild disease management involves basic treatment that is supplemented with antiseptic measures to prevent recurrent skin infections. Moderate disease management includesbasic management plus maintenance topical corticosteroids (TCS), maintenance topical calcineurin inhibitors (TCIs) or JAK inhibitors (JAKi). Patients with severe disease should follow basic management, be referred to a specialist in AD, undergo phototherapy and consider dupilumab, systemic immunosuppressants and acute treatment with wet-wrap therapy or short-term hospitalizations.² Emerging treatment strategies focus less on steroidal pathways and more on alternative pathways such as type-2 immunity cytokines for inflammation.³

When considering treatment selection, healthcare providers should adopt a stepwise, multidisciplinary approach and ensure adherence with current treatments before advancing.² Pediatric patients with moderate, severe or refractory disease should be seen by a dermatologist or allergist specializing in AD; however, care is often provided by a primary care provider or within an urgent care facility or emergency department (ED).⁴ As such, the expertise and ability to manage severe disease vary, and adoption of a standardized approach is essential.

Disease Background

Also known as eczema, AD is an inflammatory skin disorder with increasing global prevalence.⁵ It is characterized by recurrent lesions that are poorly defined and with erythematous, exudative, blistering and crusting in early stages; fissuring and lichenification can occur at later stages.⁶ Patients may experience intense itching and discomfort.⁶ In general, up to 20% of pediatric and 10% of adult individuals in high-income, developed countries are affected by AD and the global prevalence of this condition appears to be increasing.⁵ In a study assessing the prevalence of AD in a US adult population including 1,278 adults, the overall prevalence of AD among patients 2 years or younger was 7.3% (95% CI, 5.9%-8.8%).⁷ When the age of onset was 18 years or older, the prevalence approached 16.1% (95% CI, 14.1%-18.1%).⁷ In a cross-sectional US study assessing the 12-month prevalence of AD in pediatric patients, the prevalence was 16.8% (95% CI, 15.4%-18.2%) in those aged 6 months to 6 years.⁸ Therewas a similar 12-month prevalence of AD (16.5%; 95% CI, 15.7%-17.3%) when patients of all ages were included.⁸ The incidence of AD peaks in infancy, and among patients with AD, signs and symptoms will appear before the age of 6 in 80% of cases.⁶

Several sets of criteria have been developed to support a diagnosis of AD. Essential presenting symptoms include intense itching; acute, subacute, or chronic eczematous lesions and a chronic or relapsing disease course. Lesions from AD can occur on any body area but often follow specific distribution patterns by age. Infants most often present with a wide distribution and more acute lesions, such as those seen in severe AD. They may present with edema, excoriations, oozing and crusting.⁶ Lesions are typically located on the face, cheeks and trunk, often sparing the diaper area. In children, AD presents as more localized and chronic lesions that are often less erythematous; patients may present with xerosis and ill-defined lesions, often in the flexor regions. More chronic areas may present with a thickened skin appearance due to long-term, repeated scratching. Adolescents and adult patients with AD can present with a diffuse or localized pattern of lesions. Although lesionsoften involve the hands, eyelids and flexures, adults may also experience AD involving only the hands or the head and neck (involving the upper trunk, shoulders and scalp).⁶

Severity scoring systems can assist clinicians in measuring the signs of AD based on factors including intensities and extent of affected regions.⁶ In the US, the prevalence of moderate and severe disease in adults with AD based on the Patient-Oriented-Eczeema Measure (POEM) score is 28.9% (95% CI, 25.3%-32.7%) and 11% (95% CI, 8.6%-13.7%), respctively.⁷ For pediatric patients with AD, the prevalence of moderate and severe disease was 29% and 5.7%, respectively.⁸ Using the POEM score, the prevalence for children ages 6 months to 6 years is 37.4% and 10.8% for moderate and severe AD, respectively.⁸

Atopy involves production of immunoglobulin E (IgE) antibodies in response to otherwise harmless antigens and development of the symptoms of atopic diseases (e.g., AD, asthma, allergic rhinitis with or without conjunctivitis and food allergy). The most substantial risk factor for AD is a family history of atopic disease with an emphasis on family history of AD; the presence of an atopic disease or AD in a parent increases a child’s risk of developing AD by one and a half times and three times, respectively. If both parents have AD, this risk is even higher. In addition to genetic risk, several environmental factors have a slight correlation with AD. These include living in urban settings and in regions with low UV light exposure or dry climates, consuming diets high in sugars and polyunsaturated fatty acids, having repeated exposure to antibiotics before the age of 5 years, being part of a small family and having a high household education level. These risk factors are associated with the hygiene hypothesis, which suggests that reduced or altered microbial exposures during early life may impact the maturation of the immune system and increase the risk of developing allergic and inflammatory diseases.⁶

IgE-mediated sensitization to allergens is a common comorbidity in patients with AD.⁶ Further, AD is associated with nonatopic comorbidities, including mental health disorders and immune-mediated diseases.⁶ It is also important to identify AD disparities. Compared to non-Hispanic White children, Black children have the highest prevalence of AD; higher odds of comorbidities; increased healthcare usage in the form of hospitalizations, ambulatory care and urgent care visits; and increased odds of poor disease control and disparate treatment selection.⁹ Compared to children with private insurance or higher income, those with no insurance or lower income have higher odds of delayed and unfulfilled prescriptions and longer time to initial appointment. Children with higher income and higher education levels or more insurance coverage have an increased risk of an AD diagnosis and lower risk of comorbidities.⁹

The pathophysiology of AD is complex, but it may be triggered by environmental factors in genetically susceptible individuals.⁶ AD involves a complex interplay of mechanisms, including epidermal barrier dysfunction mediated through genetic mechanisms (e.g., mutations in the FLG gene) that contribute to alteration in the skin barrier protein filaggrin.^5,6 Further, secondary mechanisms such as the itch-scratch cycle and reduced expression of epidermal structural proteins or lipids in response to type-2 immunity cytokines (interleukin [IL]-4, IL-13 and IL-33) in the JAK/STAT pathway that promote inflammation and release of alarmins (IL-1, IL-25 and IL-33) and production of antigen-specific IgE molecules (Figure¹⁰).^5,6 In addition to epidermal barrier dysfunction, skin microbiome abnormalities and type-2 immune dysregulation factors contribute to the pathophysiology of the disease.⁵ Acute and chronic phases of AD are dominated by different immune responses.¹⁰

Clinical Impact and Quality of Life

Key patient-reported symptoms of AD include eczematous lesions, intense pruritus, and a chronic or relapsing disease course with lesions following the aforementioned distribution based on patient age.⁵ AD can severely affect quality of life (QOL); studies in pediatric and young adult patients with AD found that itch impacts sleep, treatment preferences, participation in sports and extracurricular activities (including outdoor events and swimming), clothing choices and social interaction.^6,11 Some parents have noted that other adults and children avoid interacting with children with AD.¹¹ In terms of QOL impact, it is ranked second only after cerebral palsy among childhood disorders.⁶

Anxiety can also be severe in patients with AD, and studies have shown that effective treatment can reduce anxiety.¹² Adults also report that their disease impacts their clothing, shaving and makeup choices, and lesions in particular locations (such as the face and genitals) also appear to play a role in QOL.⁶ Among 352 adults surveyed in the 2013 US National Health and Wellness Survey, a significant reduction in health-related QOL was found compared to matched non-AD controls on the Mental Component Summary (p-value < 0.001).¹³ Work productivity in patients with AD was also impacted when compared with findings in a control group without AD; among patients with AD, there were significantly higher rates of absenteeism (9.9% vs. 3.6%; p-value < 0.001), presenteeism (21.1% vs. 16.1%; p-value = 0.027) and overall work impairment (25.6% vs. 18.1%; p-value = 0.004).¹³

The results of a retrospective point-in-time study including 394 adults and 144 adolescent patients showed that 24.5% of patients (adults, 22.8%; adolescents, 29.2%) had uncontrolled AD. More adults had uncontrolled AD when on topical therapy plus systemic AD treatment than when on topical therapy alone.¹⁴ This percentage of uncontrolled disease represents an unmet need with standard therapies.

Economic Burden of Pediatric AD

Estimating the direct and indirect economic burden associated with AD is challenging, largely due to the broad spectrum of severity and associated management costs, including direct costs (e.g., prescriptions, provider visits, emergency department and hospital visits and over-the-counter pharmacy costs) and indirect costs (e.g., presenteeism, absenteeism and the impact on QOL).¹¹

A retrospective analysis of the Medical Expenditure Panel Survey (2007-2015) included 220 pediatric patients with AD compared to 77,397 non-AD controls. Some $5 billion was spent annually on population-level expenditures with mean (SD) annual healthcare expenditures of $1,267.56 ($200.01) for outpatient visits, $445.77 ($267.29) for inpatient expenditures, $272.66 ($110.74) for emergency department expenses, $215.02 ($46.17) for prescription medications and $226.82 ($53.59) for home healthcare.¹⁵

More recent data on healthcare resource utilization for managing AD in the US are limited and often are only available for adult patients. In a retrospective, noninterventional, single-center chart review of 31 patients with AD aged 6 to 17 years in Ireland, patients had a mean (SD) of 15.3 (6.3) consultations per patient during the observational period.¹⁶ The most frequent reason for consultation was an initial appointment and follow-up. Flares accounted for up to 10% of consultation visits. The mean (SD) number hospitalization for AD was 0.4 (0.7), the majority of which were among pediatric patients (75%).¹⁶ In a retrospective database review of 4,784 US adults, 6.4% had at least one hospitalization with a mean (SD) of 6.6 (13.5) hospital days; 98.3% of patients had at least one outpatient visit, 65% had at least one dermatologist visit and 6.5% had at least one visit to an allergist/immunologist.¹⁷ Pharmacy HCRU was high in this study, with 91.5% of patients having at least one prescription; 72.9% had at least one claim for AD treatment. Differences were also observed in HCRU based on disease severity, as patients with severe AD had significantly more dermatology office visits compared to those with mild AD (73% vs. 58.5%, respectively; p-value = 0.034). Patients with severe disease also had more medication use than did those with mild AD (90% vs. 64.3%; p-value = 0.0005).¹⁷

Treatment of Pediatric AD

Diagnosis of AD focuses on key clinical features, patient history and the morphology and distribution of lesions and associated clinical signs. TheAmerican Academy of Dermatology (AAD) guidelines for managing AD separate the diagnosis into essential, important and associated features for diagnosis. Exclusionary conditions that should be noted during diagnosis include scabies, seborrheic dermatitis, contact dermatitis (either irritant or allergic), ichthyosis, cutaneous T-cell lymphoma, psoriasis, photosensitivity dermatosis, immune deficiency diseases, erythroderma or other relevant causes.¹ Essential features for the diagnosis of AD include pruritus and eczema — either acute, subacute, or chronic — presenting in age-specific ways with typical morphology and a chronic or relapsing pattern. The important features that can be evaluated to aid in the diagnosis include an early age of atopy onset (either personal or family history), IgE reactivity and xerosis.¹

The goals of AD treatment are to reduce pruritus and establish long-term disease control that allows for improved QOL. This often requires a multistep approach, including avoiding triggers, improving the skin barrier, balancing the skin microbiome and reducing inflammation.⁶

Treatment should be patient-centered; it often follows a stepwise approach to management based on disease severity and a focus on reducing inflammation.^2,5 Mild AD can often be controlled using topical treatments, whereas more severe disease may require phototherapy or systemic immunomodulatory therapy given alone or in combination.⁵ Regardless of AD severity, the American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force’s 2023 recommendations include a good practice statement. Clinicians managing AD should confirm the correct diagnosis, identify any complicating diagnoses, provide patient education, address avoidance of triggers, ensure appropriate medication use and treatment adherence and encourage patients to apply a bland moisturizer at least once daily.³ In patients who experience uncontrolled AD with the use of moisturizers alone, the task force strongly recommends adding a TCS or a TCI in patients 3 months or older.³ In patients with mild or moderate disease, the task force givesconditional recommendations in favor of adding a topical PDE4 inhibitor (e.g., crisaborole) (Eucrisa, Pfizer), and against adding a topical JAKi (e.g., topical ruxolitinib OPZELURA, Incyte), [currently approved for patients 12 years and older]).^3,18,19 There were no long-term studies of ruxolitinib at the time of guideline publication and the task force mentions the short-term (4-8 weeks) nature of available studies, however, longer-term data has since been presented.^3,20

In addition, the guidelines conditionally recommend once-daily application of mid-to-high-potency topical medications over twice-daily application; in moderate to severe disease with localized lesions refractory to mid-to-high potency topical treatment, a time- and body surface area-limited use of a low-to-mid-potency occlusive (i.e., wet wraps) topical steroid is conditionally recommended. In patients with no sign of infections, the guidelines suggest against adding topical antimicrobial treatments. Further, proactive therapy with a TCI or mid-potency TCS is strongly recommended for areas that are prone to disease flares. Use of bleach baths is not recommended in patients with mild disease.³

In appropriate patients with moderate to severe disease who have refractory disease or who are intolerant or otherwise unable to use high potency topical treatments, narrow-band UVB phototherapy and/or systemic treatments including biologics and certain small molecular immunosuppressants may be appropriate. However, the guidelines suggest against using systemic corticosteroids in any patients with AD.³

Pediatric patients with AD are a vulnerable population, and AD represents a significant burden for both pediatric patients and their caregivers.⁴ In most instances, pediatric patients may be treated with TCS for AD management.² Formulations and potencies approved for pediatric use vary in recommendations on age of use, and caregivers should ensure consistent use for the most benefit.²

Recent Topical Nonsteroid Treatment Options for Pediatric AD

The landscape of topical treatment options for AD has expanded significantly in recent years.

Tapinarof cream, 1%, (Vtama; Dermavant Sciences) is an aryl hydrocarbon receptor agonist indicated for once-daily application in patients 2 years and older with AD.²¹ Tapinarof cream was evaluated in two double-blind, randomized, controlled, phase 3 trials (ADORING 1 [NCT05014568] and ADORING 2 [NCT05032859]) lasting eight weeks in 813 adult and pediatric patients 2 years and older with moderate to severe AD (aged 2-17 years, 80%).^21,22 The primary efficacy end point was achievement of a score of zero points (clear) or one (almost clear) or at least a two-point improvement from baseline on the Validated Investigational New Drug Assessment for Atopic Dermatitis Score (vIGA-AD).²³ Tapinarof was associated with no-to-minimal burning, stinging or itching on patient- or parent/caregiver-reported tolerability assessments.²² Significantly more patients in the tapinarof group achieved the primary end point (i.e., vIGA-AD score) compared to the vehicle group (ADORING 1: 45.4% vs. 13.9%, p-value < 0.0001; ADORING 2:46.4% vs. 18%, p-value < 0.0001).²³ The most common adverse events (≥ 1%) in these trials were upper respiratory tract infection, folliculitis, lower respiratory tract infection, headache, asthma, vomiting, ear infection, pain in extremity and abdominal pain.²¹

Roflumilast cream, 0.15%, (ZORYVE, Arcutis Biotherapeutics) is a topical phosphodiesterase-4 (PDE4) inhibitor approved for once-daily application for adults and pediatric patients 6 years and older with mild to moderate AD. Approval was based on the results of the INTEGUMENT-1 (NCT04773587) and INTEGUMENT-2 (NCT04773600) parallel-group, double-blind, vehicle-controlled, randomized trials of topical roflumilast in 1,337 patients 6 years and older with mild to moderate AD (aged 6 to 17 years, 46%). Significantly more patients in the roflumilast group achieved the primary end points of vIGA-AD success (defined as a vIGA-AD score of zero to one [clear or almost clear], plus a two-grade vIGA-AD score improvement from baseline) at four weeks compared to the vehicle-controlled group (INTEGUMENT-1: 32% vs. 15.2%, p-value < 0.001; INTEGUMENT-2: 28.9% vs. 12%, p-value < 0.001).^24,25 The most common adverse events (≥1%) reported in these trials were headache, nausea, application-site pain, diarrhea and vomiting.²⁴

In addition, results of the INTEGUMENT-PED trial (NCT04845620), a phase 3 parallel-group double-blind trial that evaluated the efficacy and safety of roflumilast cream, 0.05%, in 652 patients with AD aged 2 to 5 years, were recently published. Substantial improvements were seen as early as 1 week, and significantly more patients treated with roflumilast achieved Week-4 vIGA-AD success (25.4% vs. 10.7%; p-value < 0.0001). Treatment-emergent adverse event (TEAE) rates were low in both groups, and 98.9% were mild or moderate.²⁶

Topical ruxolitinib cream, 1.5%, (Opzelura; Incyte) is a JAKi approved in nonimmunocompromised adult and pediatric patients 12 years and older for the short-term and noncontinuous chronic treatment of mild to moderate AD that is not controlled or unable to be treated with topical prescription therapy.¹⁹ Approval was based on the results of two double-blind, randomized, vehicle-controlled identically designed clinical trials (TRuE-AD1 [NCT03745638] and TRuE-AD2 [NCT03745651]), which enrolled 1,249 adult and pediatric patients (aged 12-17 years, 20%). More patients treated with ruxolitinib achieved IGA treatment success (i.e., an IGA score of zero or one point with at least two-grade improvement from baseline) and at least a four-point reduction in Itch Numerical Rating Scale in TRuE-AD1 (58.3% vs. 15.1% and 52.2% vs. 15.4%, respectively) and in TRuE-AD2(51.3% vs. 7.6% and 50.7% vs. 16.3%, respectively) compared with vehicle control. The most common adverse events (≥ 1%) in these trials were nasopharyngitis, diarrhea, bronchitis, ear infection, eosinophil count increased, urticaria, folliculitis, tonsillitis and rhinorrhea.¹⁹ In addition, 52-week safety and efficacy data outcomes using ruxolitinib in 282 patients aged 2 to 11 years (TRuE-AD3; NCT04921969) were presented at the Fall Clinical Dermatology Conference in October 2024.²⁰ Patients were treated with ruxolitinib or vehicle for eight weeks; all patients then used ruxolitinib as-needed for the remaining 44 weeks. Ruxolitinib was well tolerated in any body region with as-needed use, with no new safety signals identified; no cases of major adverse cardiovascular events, malignancy, thrombosis, folliculitis or herpes zoster were observed. Pediatric patients experienced long-term disease control, with more than 60% of patients achieving clear or almost clear skin (IGA, zero to one) and a low mean affected BSA (≤ 3%) for the majority of the as-needed treatment period.²⁰

Managed Care Considerations

A shared decision-making approach with patients and caregivers should be used when selecting therapy.²⁷ Ongoing, multidisciplinary and age-appropriate education and support are essential to ensuring the competent and confident use of therapies.⁴ Possible reasons for inadequate treatment adherence — and resulting inadequate response — include concerns about adverse events and toxicities associated with steroid use, trouble with application in more complex regimens, inadequate patient or caregiver training on treatment use, resistance to treatment among pediatric patients and poor treatment access.⁴

Patient therapy should be tailored, and healthcare providers should discuss individual triggers and lifestyle issues with patients and families. In pediatric patients receiving systemic therapy, the impact on immune response to immunization should be considered.⁴

The burden of disease on patients and their caregivers is substantial, and it significantly impacts QOL.²⁸ Access to necessary subspecialty care may be limited for some patients; this may depend on whether the insurance is federally funded or commercial.²⁸ However, multidisciplinary management by dermatologists with expertise in AD, allergists and other specialists may be appropriate, especially in patients with moderate to severe AD that is refractory or poorly controlled or those with severe or recurrent skin infections, uncontrolled atopic comorbidities or neuropsychological problems.⁴

Conclusions

Guideline-directed, stepwise therapy may be effective in many patients, yet those with moderate to severe AD may be particularly susceptible to untreated symptoms that substantially impact QOL. Along with basic management strategies such as moisturization, TCS have been the backbone of treatment with stepwise increases in dose and potency as patients progress in severity. New nonsteroidal therapeutic options approved over the past few years represent a shift in the treatment landscape for AD. Newer pediatric guidelines incorporate some of these novel nonsteroidal treatment strategies.

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