Optimizing Atopic Dermatitis Management: Navigating the Clinical and Economic Challenges Introduction
Introduction
Atopic dermatitis (AD), often referred to as eczema, is categorized as a chronic inflammatory skin disorder involving disruption of the skin epidermal barrier and T-cell–induced skin inflammation, which causes affected patients to develop rashes and patches of itchy skin.1-3 Studies have indicated a link between environmental factors and AD development, as this condition is prevalent in high-income countries, where it affects up to 20% of children and 10% of adults.1 The total economic impact of AD in the U.S. was estimated to be nearly $4.23 billion in 2004, which corresponds to $7.18 billion in 2024.4,5 This article provides an overview of AD and its effects on patients, economic considerations and the current treatment landscape and treatment strategies for improving outcomes of patients with AD.
Disease Overview
Among adult patients with AD in the U.S., 60% (9.9 million) have mild disease, and 40% (6.6 million) have moderate or severe disease.3 AD typically emerges in infants before the age of 6 months; however, it can develop at any age, and its effects may persist beyond early childhood.1 The disease course of AD varies among individuals; some children experience symptom resolution in their adolescent years, while others continue to experience the condition through adulthood.1,6
CAUSES AND RISK FACTORS
AD development is influenced by a complex interplay of genetic, immunologic and environmental factors. Food allergies early in life—such as those to cow milk, hen eggs and peanuts—are associated with an increased risk of developing AD. Other common allergens include house dust mites, pollen and pets.7
Genetic factors also play a significant role in AD susceptibility, particularly, loss-of-function mutations in the FLG gene, which produces a protein crucial for skin barrier integrity. Abnormal skin barrier function can predispose individuals to colonization or infection by pathogenic microbes, further damaging the skin barrier.7
Environmental factors can trigger AD flares or exacerbate symptoms. These factors include air pollutants (e.g., traffic exhaust, wildfires and dust storms); indoor pollutants (e.g., tobacco smoke or volatile organic compounds); food allergens, particularly in infants and children; and environmental allergens (e.g., house dust mites, pollen and animal fur), particularly in older children and adults.2,8,9 Additionally, antibiotic use has been linked to an increased risk of developing AD, possibly due to alterations in the microbiota.7
Impact of AD on Quality of Life
Results of a study reported in 2018 revealed a relationship between disease severity, comorbidities and quality of life (QOL) in patients with AD.10 Among the 602 survey respondents with AD, the mean (SD) age was 52.0 (16.3) years, and 53.6% of participants were female. The percentage of people who reported having fair or poor overall health was higher among patients with AD than among those without AD (25.8% vs. 15.8%, respectively); these groups also differed in being somewhat or very dissatisfied with life (16.7% vs. 11.4%, respectively).10
AD was associated with lower mental health scores in patients with comorbid conditions, particularly asthma and other chronic disorders. Large percentages of adults with AD reported that the condition limits their lifestyle (53.1%), leads them to avoid social interactions because of their appearance (39.1%) and affects their daily activities (43.3%). Adults with AD identified itching as the most burdensome symptom (54.4%), followed by excessive dryness or scaling (19.6%) and red or inflamed skin (7.2%).10 Another study supported that AD greatly affects patient lifestyles, with Zuberbier and colleagues revealing that more than half of patients with AD experience depression and sleep disruptions averaging 7.3 nights per flare-up or 67 nights annually.11
Economic Impact
The public health burden of AD is substantial. Patients with AD endure higher healthcare costs, increased work absenteeism and poorer overall health compared with individuals without AD. Most patients with AD have mild to moderate disease and comprise 90% of eczema-related doctor visits in the U.S.12 A 2012 study highlighted the substantial economic burden of AD. Adult patients with AD incurred approximately $29.3 billion in out-of-pocket healthcare costs in 2012 (equivalent to $40.6 billion in 2024), representing an additional $489 ($678 in 2024) per person-year compared with those without AD.4,13 Furthermore, around 68.6 million work days were missed in 2012 because of AD, with nearly 5.9 million work days missed directly due to patients’ AD symptoms, underscoring the condition’s substantial effect on productivity.13
HEALTHCARE RESOURCE UTILIZATION
Costs and healthcare resource utilization (HCRU) are much higher for patients with severe AD than in those with mild to moderate AD. A retrospective, real-world analysis was performed to evaluate HCRU and associated costs for U.S. adults (≥ 18 years of age) with AD and by disease severity using data extracted from an electronic medical record (EMR) database linked to an administrative claims database from 2016 to 2018. The study population consisted of 4,784 adults with a mean age (SD) of 42.3 (15.2) years; 64.7% were female.14
The results showed that all-cause direct healthcare costs each year totaled $10,474 per patient; outpatient visits ($4,546 per person per year [PPPY]) and pharmacy costs ($3,886 PPPY) were the primary driver of this cost (Figure 1).14 Medication costs were $1,168 PPPY, with $254 and $914 in topical and systemic therapies, respectively. Patients with clear to mild disease had fewer dermatology and allergy/immunology office visits and AD-related medications. By disease severity, annual all-cause total costs were $23,242 in patients with severe disease versus $8,936 in patients with clear to mild disease (p-value < .0001).14
Topical Treatment for AD
Topical corticosteroids (TCS) are the most widely used FDA-approved treatments for AD and are used as first-line treatment for managing mild to severe dermatitis across all areas of the skin (Figure 2).15 These agents exert both anti-inflammatory and immunosuppressive effects.2 When choosing a steroid potency, it is important to consider the anatomical site. Use of high-potency agents on the face, neck, groin and body folds should be avoided, as there is a higher risk of atrophy, telangiectasia and striae in these areas.16 Lower-potency TCS can cause similar effects if they are used continuously or for prolonged periods. Traditionally, TCS were discontinued once the signs and symptoms of AD were managed. However, another approach involves maintaining TCS use once or twice weekly between AD flares, as available data indicate fewer and increased times between relapses with this strategy.15,17-19
Topical calcineurin inhibitors (TCIs) can also be used for mild to moderate AD.20 The FDA’s boxed warning on the package insert highlights an elevated risk of cancer associated with TCIs, causing concern among clinicians and patients. However, multiple long-term safety studies indicate an increased relative risk of lymphoma but not of other cancers with TCI use.15,21-24 These topical agents reduce inflammation without causing skin atrophy and are suitable for use on sensitive areas (e.g., face, neck and skin folds) and for long-term management.1 TCIs can be used continuously or intermittently for maintenance, and side effects include burning or local irritation.16 Long-term use of TCIs should be avoided, and application should be limited to areas of involvement with AD.25,26
Pimecrolimus, 1%, is a TCI immunosuppressant for short-term, second-line treatment of mild to moderate AD in nonimmunocompromised patients aged 2 years and older.25 Tacrolimus, 0.1% (adults only) and 0.03% (adults and children aged 2-15 years), are for moderate to severe AD when other treatments fail or are inadvisable.26
Phosphodiesterase-4 (PDE4) inhibitors regulate the levels of molecules involved in causing inflammation to exert anti-inflammatory effects.27 Crisaborole, 2%, approved by the FDA in 2016, is used to treat mild to moderate AD in patients 3 months and older.28 It is an alternative to TCS and TCIs, but cost and prescription coverage may limit access.20 Roflumilast cream, 0.15%, a PDE4 inhibitor approved in 2024, treats AD in patients aged 6 years and older.29,30 This steroid-free cream reduces itch, is suitable for long-term use and is applied once daily anywhere on the body.29
JAK inhibitors block cytokine, growth factor and hormone receptor signaling pathways.1 Ruxolitinib cream, 1.5%, inhibits JAK1 and JAK2; it was FDA-approved in 2021 for short-term, noncontinuous chronic treatment of mild to moderate AD in patients 12 years and older.15,31,32 Usage should not exceed 20% of the body surface, with a maximum of 60 g per week, to reduce systemic absorption and avoid serious side effects like infections, malignancies, cardiovascular events and thrombosis.15,31
Two randomized trials showed efficacy in adults with AD: 52.2% (277/531) of ruxolitinib-treated patients achieved an investigator global assessment (IGA) score of zero or one or at least two-point improvement, compared to 11.1% (33/296) of vehicle-treated patients (RR, 4.60; 95% CI, 3.05-6.95).15,33,34 For itch reduction, 52.0% (270/519) of the experimental group versus 15.4% (43/279) of the placebo group saw at least a four-point reduction in itch numerical rating scale scores over 8 weeks (RR, 3.38; 95% CI, 2.54-4.51).15,34,35
Health-related QOL, measured by Skindex-16 scores, improved by 63.5% at week 2 and 73.2% at week eight for ruxolitinib-treated patients compared to 10.5% at week 2 (p-value = 0.001) and 19.7% at week eight for the vehicle group (p-value < 0.001). Side effects were rare and occurred at rates similar to those in patients treated with vehicle, with application site burning, pain and pruritus occurring at comparable or lower rates.15,34,35
Topical JAK inhibitors are recommended for AD in current guidelines based on the short-term safety and efficacy data that are available. These recommendations may change as long-term safety data emerge.15
Systemic Therapy for AD Refractory to Treatment With Topical Agents
Systemic therapies may be effective options to control AD symptoms and improve the QOL in patients who have severe or widespread AD, a low QOL or AD refractory to optimized topical treatments (Figure 2).36
Recent American Academy of Dermatology (AAD) guidelines strongly recommended use of dupilumab (targets IL-4Rα) and tralokinumab (targets IL-13) for patients with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. These monoclonal antibodies are FDA-approved for treating adults with AD. They are highly favored for their excellent safety track records in clinical trials. However, studies have shown inconsistencies in side effect analysis; therefore, the working group downgraded the certainty of evidence to moderate. The most common AE is conjunctivitis, occurring at an incidence of at least 1%, but it can be treated with artificial tears.36
Updated AAD guidelines also strongly recommend use of systemic JAK inhibitors to treat moderate to severe AD in adults.36 These systemic agents are used in patients in whom other systemic therapies such as biologics have not been successful in managing the patient’s AD or if other therapies cannot be used and can target JAK1 and/or JAK2. Some systemic JAK inhibitors should be started at lower doses because of the risk of side effects such as pneumonia, acute pancreatitis and appendicitis, especially in older patients.36-40
Treatment Strategies and Considerations
TCS and TCIs can be used to maintain a response and manage flares or as an adjunct treatment alongside phototherapy or systemic therapy in patients with moderate to severe disease, according to 2024 AAD guidelines.36
Methods for prolonging the use of topical and nonsystemic treatments include using a nonsteroidal topical agent to avoid use of TCS, decreasing the potency of TCS, proactively managing with stronger TCS once daily or 2 to 3 times weekly and using a combination of these approaches.41 Patient education, including providing written instructions to patients, also helps ensure adherence to treatment.41
Use of a JAK inhibitor may be effective as a monotherapy, eliminating the need for use of additional agents and complex treatment regimens. A retrospective, observational study of data in a healthcare database for prescriptions of the JAK1 and JAK2 inhibitor ruxolitinib cream showed that during the 6-month follow-up period, 43.8% of patients received only ruxolitinib cream monotherapy.42 Furthermore, use of other topical therapies (TCS, TCIs, PDE4 inhibitors) was reduced by 41.9% to 52.5% in patients who initiated treatment with ruxolitinib cream. The researchers suggested that use of ruxolitinib cream may reduce the need for other therapies for AD such as topical and oral corticosteroids and biologics.42
Pooled data from two phase 3 studies of adolescent and adult patients with AD were evaluated in a post hoc analysis to determine the effects of treatment with ruxolitinib cream (JAK1 and JAK2 inhibitor) on work productivity and activity impairment; the indirect costs associated with lost productivity per patient were also examined. Ruxolitinib was used at two different strengths (0.75% or 1.5%) and compared with vehicle; treatments were applied twice daily for eight weeks in the double-blind trial. A total of 1,249 patients were examined. Patients had a mean age of 32 years, and 61.7% were female. There were 500 patients in the 0.75% ruxolitinib group, 449 patients in the 1.5% ruxolitinib group and 250 patients in the vehicle group.43
Patients in both treatment groups reported changes in work impairment [note: higher scores indicate greater impairment] (-17.9% in the 0.75% group, -15.0% in the 1.5% group and -5.7% in the vehicle group; p-value < 0.0001 for both comparisons). These reductions were associated with indirect costs (2021 USD) of $1,313 (0.75% group), $1,242 (1.5% group) and $2,008 (vehicle group) during the eight-week trial. Cost savings were predicted to be $5,302 and $4,228 in the 0.75% and 1.5% groups, respectively, compared with that in the vehicle group. Daily activity scores also differed among groups, with values of -20.6%, -21.5% and -10.6% in the 0.75%, 1.5% and vehicle groups, respectively (p-value < 0.0001).43
Conclusions
Effectively managing AD is crucial given its high prevalence, chronic nature and considerable impact on patient QOL. AD, which affects both children and adults, is a chronic inflammatory condition marked by a variable disease course and numerous challenges in treatment. Managing AD requires a multifaceted approach because of the condition’s complexity and the various triggers, including environmental factors and allergens, that cause flare-ups. Current treatment options, while effective in symptom management, often are limited in terms of efficacy, tolerability and safety, highlighting the need for optimized strategies. Long-term safety is a critical consideration in AD management, as some therapies include boxed warnings about increased risks of certain cancers. Furthermore, although biologics can be effective treatment options, they may also require careful long-term monitoring because of their potential to cause side effects. Tailored treatment is important because of the variable nature of AD, necessitating a flexible approach that considers individual patient needs and preferences. Economic considerations are also important factors in treatment decisions, with the cost-effectiveness of therapies being a critical factor. Treatment choices should be balanced between efficacy and affordability to mitigate economic impacts on patients and healthcare systems. By continuously optimizing treatment strategies and addressing the individual needs of patients, healthcare providers can greatly improve the outcomes and QOL of people affected by AD.
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