Atopic dermatitis (AD) is a prevalent, chronic, relapsing, and inflammatory skin disorder of a multifactorial etiology characterized by intense itching and skin lesions.1 AD is a global disease that affects individuals across all age groups.2 The prevalence of AD among the pediatric population is notably high, with estimates indicating that 15% up to 30% of children seem to be affected by this disease3–5 vs a slightly lower prevalence among the adult population ranging from 7% up to 14%.2 The prevalence of AD among Spanish children remains unclear due to the lack of comprehensive, age-specific studies and scarce available data.1

AD in pediatric patients is often associated with a range of comorbidities, including other diseases such as asthma or allergic rhinitis.1 Additionally, psychiatric and psychological disorders are likely to be more prevalent in this population. In fact, there is evidence of an increased incidence of mental issues, such as attention deficit hyperactivity disorder (ADHD) and depression, which can also manifest as suicide ideation among these patients.1,6,7

The presence of these comorbidities, along with symptoms of AD such as intense pruritus, significantly impairs health-related quality of life (HRQoL), especially in severe cases.6,8

Due to disease heterogeneity, comorbidities, complexity in treatment care and differences between national or regional health care systems, managing AD in the pediatric population remains challenging.9 Short regimens of topical corticosteroids are the most widely prescribed treatment.10 However, adherence to these conventional therapies is often low,11 and their efficacy in severe cases is also limited.12,13 Fortunately, in recent years, innovative, and highly effective treatments have emerged such as biologic drugs and Janus kinase (JAK) inhibitors. However, their use in children is still restricted in some cases.10 As a matter of fact, the substantial humanistic burden of disease in patients with moderate-to-severe AD suggests potential undertreatment in this group, with few evidence available on new therapies, patient-reported outcomes (PROs), AD severity and impairment.14 On the other hand, AD represents a substantial economic burden on the health system, as well as on the patients and caregivers.14 The total direct cost was estimated to be nearly €2700 per patient per year.14 As expected, the severity of the condition had a direct impact on cost, with severe cases resulting in higher costs.14 Specifically, compared with patients with mild and moderate AD, severe AD presented significantly higher total direct costs (€1512 [SD, 854] and €1984 [SD, 2093] vs €5377 [SD, 3.518]; p<0.001, respectively).

There is no available comprehensive, updated information on the humanistic, and economic burden associated with children with AD in Spain. This systematic review aims to provide an overview based on the most recent Spanish real-world evidence.

We conducted a systematic review of observational studies on the humanistic and economic burden associated with pediatric patients with AD over the past 10 years (from March 2013 through March 2023) following the recommendations established by the “Preferred Reporting Items of Systematic Reviews and Meta-analysis” (PRISMA).15

A total of 133 reports were initially identified (Fig. 1). After duplicate removal and applying the established inclusion criteria, 11 publications (10 full-text articles and 1 conference abstract) were included in the synthesis.

Figure 1.

PRISMA flow diagram with the selection process of the included publications. IBECS, Índice Bibliográfico Español en Ciencias de la Salud; MEDES, Medicina en Español.

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The main characteristics of selected articles are summarised in Table 1. Regarding the study design, 54.5% (n=6) of the studies were cross-sectional, 27.3% (n=3) retrospective, and 18.2% (n=2) prospective. Inclusion criteria were heterogeneous regarding age range, time from diagnosis, diagnostic criteria, severity, and treatment patterns. The information source included the review of health records or databases in 54.5% (n=6) reports, whereas in 36.4% (n=4) of the publications, information was retrieved through interviews conducted with the patients or their parents/caregivers. A total of 27.3% (n=3) of studies were eventually conducted in primary care health care settings, 45.5% (n=5) in hospital health care settings, and 18.2% (n=2) in both.

Population characteristicsAge and gender

Details on the population's age and gender are detailed in Table 2. Four studies21,25–27 included a broad age spectrum from 6-month infants to younger than 18-year-old patients. In contrast, two studies20,23 focused on a narrower age range, 12–15-month-olds, and 6–7/14–15-year-olds, respectively. Overall, the most represented age group was from 2- to 15-year-olds. Regarding gender, the male/female proportion was similar, with the female representation varying from 42% up to 54.5% according to different studies and age ranges.

Table 2.

Summary of data regarding the population's age and gender.

Author (year)	Sample size (N)	Population age, yr*					Mean age, years (SD)	Gender, female (%)
		Range	0.5–1	2–5	5–15	15–18
Sánchez-Pérez (2013)17	151	2–17		X	X	X	9.4 (4.5)	48.3
Torrelo (2013)18	141	2–15		X	X		8.7 (3.6)	41.8
Ortiz de Frutos (2014)19	161	2–15		X	X		7.7 (3.9)	50.0
Draaisma (2015)20	6937	12–15 months	X				NA	46.9–50.1a
Barroso (2019)21	8	<18	X	X	X	X	12.5	NA
Sicras-Mainar (2019)22	24,374 with AD844 with severe AD	6–18			X	X	6–12 yr: 9.1 (2.0)13–18 yr: 14.8 (1.6)	6–12 yr: 4213–18 yr: 51.4
Arnedo-Pena (2020)23	3607(year 1994)	6–7			X		6.3 (0.5)	49.5
	1805(year 2002)	14–15			X		14.4 (0.5)	50.1
Darbà (2021)24	1266	0–5	X	X			1.5	40.5
Silverberg (2021)25	3465	0.5–<18	X	X	X	X	6 mo–<6 yr: 3.26–<12 yr: 9.212–<18 yr: 14.9	6 mo–<6yr: 54.56–<12 yr: 45.112–<18 yr: 46.7
Almenara-Blasco (2022)26	31,757	0–17	X	X	X	X	NA	50.0
Lázaro (2022)27	564	0.5–<18	X	X	X	X	NA	NA

NA, not available; X marks the reported age range.

a

According to regions.

*

Age expressed in years except months.

Severity of AD

Six studies17,21,25,27 assessed the severity of AD using different tools, including the Investigator's Global Assessment (IGA) (n=3),17,19,21 the SCORing Atopic Dermatitis (SCORAD) (n=1),19 the Clinical Global Impressions scale – Severity of Illness (CGI-SI) (n=1),19 the Patient Global Assessment (PtGA) (n=2),25,27 the Patient-Oriented Eczema Measure (POEM) (n=1),25 and the physician's perspective18 (Fig. 2).

16 severe AD; dSCORAD takes into account the extent and intensity of the lesions, as well as the symptoms (pruritus and loss of sleep) it causes; extent (A): the body surface is divided into four segments (head and neck, trunk, upper and lower extremities) to which a percentage is assigned based on the extent represented; intensity (B); eThe Clinical Global Impression – Severity scale (CGI-S) is a valuable tool used by clinicians to assess the severity of a patient's illness vs their past experience with similar diagnoses. It involves rating the patient's current condition on a 7-point scale, reflecting different levels of illness severity: (1) normal, not at all ill, (2) borderline mentally ill, (3) mildly ill, (4) moderately ill, (5) markedly ill, (6) severely ill, and (7) extremely ill.'> 16 severe AD; dSCORAD takes into account the extent and intensity of the lesions, as well as the symptoms (pruritus and loss of sleep) it causes; extent (A): the body surface is divided into four segments (head and neck, trunk, upper and lower extremities) to which a percentage is assigned based on the extent represented; intensity (B); eThe Clinical Global Impression – Severity scale (CGI-S) is a valuable tool used by clinicians to assess the severity of a patient's illness vs their past experience with similar diagnoses. It involves rating the patient's current condition on a 7-point scale, reflecting different levels of illness severity: (1) normal, not at all ill, (2) borderline mentally ill, (3) mildly ill, (4) moderately ill, (5) markedly ill, (6) severely ill, and (7) extremely ill.' title='AD severity. (A) Studies including mild, moderate and severe patients measured with IGA, PtGA and POEM. (B) Studies restricted to moderate-to-severe patients measured with SCORAD, IGA, CGI-SI, IGA and medical history. NA, not available; aIGA has six categories of response and its score ranges from 0 (no illness, with no inflammatory signs of AD) up to 5 (very serious illness, with intense erythema and intense papule/infiltration with crusts/exudation). Barroso et al. ranged severity from 0 up to 4, considering scores of 3 as moderate and scores of 4 as severe AD; bPatient Global Assessment (PtGA), which asks, “Please check one answer that best describes the severity of your or your child's eczema over the past week,” with responses of clear, mild, moderate, or severe; cPatient-Oriented Eczema Measure (POEM), with a total score ranging from 0 (lower severity) up to 28 (higher severity); severity groupings have been defined as bands of 0–7 indicating mild AD, 8–16 moderate AD, and >16 severe AD; dSCORAD takes into account the extent and intensity of the lesions, as well as the symptoms (pruritus and loss of sleep) it causes; extent (A): the body surface is divided into four segments (head and neck, trunk, upper and lower extremities) to which a percentage is assigned based on the extent represented; intensity (B); eThe Clinical Global Impression – Severity scale (CGI-S) is a valuable tool used by clinicians to assess the severity of a patient's illness vs their past experience with similar diagnoses. It involves rating the patient's current condition on a 7-point scale, reflecting different levels of illness severity: (1) normal, not at all ill, (2) borderline mentally ill, (3) mildly ill, (4) moderately ill, (5) markedly ill, (6) severely ill, and (7) extremely ill.'/>

Figure 2.

AD severity. (A) Studies including mild, moderate and severe patients measured with IGA, PtGA and POEM. (B) Studies restricted to moderate-to-severe patients measured with SCORAD, IGA, CGI-SI, IGA and medical history. NA, not available; aIGA has six categories of response and its score ranges from 0 (no illness, with no inflammatory signs of AD) up to 5 (very serious illness, with intense erythema and intense papule/infiltration with crusts/exudation). Barroso et al. ranged severity from 0 up to 4, considering scores of 3 as moderate and scores of 4 as severe AD; bPatient Global Assessment (PtGA), which asks, “Please check one answer that best describes the severity of your or your child's eczema over the past week,” with responses of clear, mild, moderate, or severe; cPatient-Oriented Eczema Measure (POEM), with a total score ranging from 0 (lower severity) up to 28 (higher severity); severity groupings have been defined as bands of 0–7 indicating mild AD, 8–16 moderate AD, and >16 severe AD; dSCORAD takes into account the extent and intensity of the lesions, as well as the symptoms (pruritus and loss of sleep) it causes; extent (A): the body surface is divided into four segments (head and neck, trunk, upper and lower extremities) to which a percentage is assigned based on the extent represented; intensity (B); eThe Clinical Global Impression – Severity scale (CGI-S) is a valuable tool used by clinicians to assess the severity of a patient's illness vs their past experience with similar diagnoses. It involves rating the patient's current condition on a 7-point scale, reflecting different levels of illness severity: (1) normal, not at all ill, (2) borderline mentally ill, (3) mildly ill, (4) moderately ill, (5) markedly ill, (6) severely ill, and (7) extremely ill.

(0.2MB).

Three studies focused on moderate-to-severe AD patients,18,19,21 while the other three studies included patients from all AD severities.17,25,27 In the latter studies, moderate AD was reported in 28.8% up to 50.3% of patients, and severe AD in 4.1% up to 12.6% of patients.17,25,27 Mild AD was the most prevalent disease in two of those studies according to PtGA/POEM25,27; while moderate AD was the most prevalent in study #3 according to IGA.17

Ortiz de Frutos et al. used several tools to assess disease severity. A total of 70.7% of pediatric patients had been initially diagnosed with moderate AD, based on the specialist's best clinical judgment, and, therefore, had been included in the study. However, at the time of medical consultation, only 53.4% and 50.9% exhibited moderate-to-severe AD according to IGA and CGI-SI respectively.19 Six percent of the patients had been initially included in the study as having moderate-to-severe AD, but obtained a SCORAD score <15, which ended up categorizing their AD as mild. In contrast, Silverberg et al. evaluated disease severity using PtGA and POEM, observing similar rates.25

Comorbidities

Five studies17,21,22,24,27 provided specific data on comorbidities associated with AD in Spanish pediatric patients (Fig. 3). An additional study26 listed comorbidities without providing prevalence percentages.

Figure 3.

Comorbidities associated with pediatric AD.

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One study presented aggregate data, confirming that 84.4% of pediatric patients with AD had, at least, one comorbidity, for a mean of 2.5 comorbidities per patient.27 In general, respiratory conditions such as asthma and allergies such as allergic rhinitis were the most widely reported conditions in the observational studies reviewed ranging from 2.6% up to 47% and from 7.9% up to 50%, respectively.

Interestingly, in the study conducted by Almenara-Blasco et al.,26 different gender-related comorbidity patterns were identified. Mental health disorders, dyslipidemia, and respiratory conditions were more common among men, whereas respiratory-allergic, sensitive-digestive, menstrual-dysphoric-metabolic, and cardiometabolic conditions were more common among women (percentages not provided).26

Disease burdenEpidemiology

Six articles20–25 provided epidemiological data, including prevalence (n=5) and incidence (n=2) of AD in the pediatric population of Spain. The reported prevalence rates varied significantly across the studies ranging from 0.01% up to 30% (Fig. 4).

Figure 4.

Prevalence of pediatric AD in Spanish population by different age groups. Blue dots correspond to overall prevalence while orange dots correspond to severe AD; yr, years.

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Sicras-Mainar et al.22 assessed the prevalence of AD by different age groups, with both overall and severe AD prevalence being higher in 6–12-year-olds (11.5% vs 6.4%; p<0.001) vs 13–18-year-olds (0.39% vs 0.23; p<0.001), respectively.22 Similarly, Arnedo-Pena et al.23 reported a higher prevalence in adolescents older than 12 years vs younger children, as well as in women compared to men in both 2002 and 2012 (29.80% vs 21.50% and 41.40% vs 28.30%, respectively). This study also reported an increase in the prevalence ratio from 1994 (1.02 [95% CI, 0.86–1.21]) through 2012 (1.41 [95% CI, 1.21–1.73]).23

For the incidence of AD, data were drawn from two studies.23,24 Arnedo-Pena et al.23 identified a total of 182 new cases of AD from 1994 through 2002, with an incidence rate of 15.9 per 1000 persons years. Darbà and Marsà24 confirmed an incidence rate of AD from 2000 through 2017 of 5.8 per 100,000 persons, with a higher incidence being reported in children aged 0–5 years (30.0 per 100,000 persons), and the overall incidence being stable throughout the study period.24

Treatment patterns

Three studies19,21,22 assessed treatment patterns in pediatric patients with moderate-to-severe AD in Spain (Fig. 5).

Figure 5.

Treatment patterns.

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The first-line therapy in children with moderate-to-severe AD was the use of emollients (82.8%),19 followed by topical pharmacological treatment (77.6%) including corticosteroids.21 Systemic corticosteroids were also used in children starting at the age of 6 years (37.5% up to 95.4%) being cyclosporine (40.5% up to 50%) and azathioprine (23.8%) the most widely used drugs.21,22 Only a small percentage of patients received biologic drugs (1.5%), in children older than 6 years.22

Despite pediatric patients suffering from moderate-to-severe AD, it was notable that 24.1% of patients reported not using any topical pharmacological treatment or delaying its use.19

Our systematic review synthesized findings from 11 observational studies providing an overview of the population characteristics, burden of disease, epidemiology, treatment patterns, PROs, use of resources and costs associated with the management of AD in pediatric Spanish patients.

Based on the studies assessing the severity of AD, we could conclude that differences in classification may derive from the use of different instrument measures. The observed results suggested that the use of PRO measures such as PtGA and POEM would correlate well between them. However, the results obtained using clinical measures such IGA or CGI-SI might underestimate the severity vs the results obtained using SCORAD, as it combines the clinical and the patient perspective.

Among the studies included in our review that reported data on comorbidities, respiratory diseases and allergies were found to be the most common. Notably, one of the studies of pediatric patients with severe AD reported a high prevalence (>70%) of mental illnesses.17,21,22,24,27 In this context, there is evidence of a significant association between AD in children and mental health symptoms.28 A longitudinal, population-based birth control cohort study found that children with severe AD were >2-fold more likely to have symptoms of depression vs those without AD.28 Additionally, children with AD were more likely to internalize behaviors, such as anxiety or somatic complaints.28 Moreover, a higher prevalence of ADHD in pediatric AD patients has been reported too.29

As seen in the three studies included in our review, AD affects not only the emotional domain but also other domains of HRQoL, as physical and social impairment, particularly in severe AD.17–19 Pruritus is the symptom with the greatest impact on HRQoL, as it negatively interferes with sleep quality, mood swings and restlessness.8 Consistent with this, AD has been pointed out to be the most common skin disease that causes the greatest impairment in HRQoL on account of symptoms such as pruritus and insomnia.30 One study revealed that 79% of children with AD reported sleep disturbances,31 even among patients with mild and inactive disease.32

The prevalence data from the analyzed studies revealed wide heterogeneity. For instance, significant variability in AD prevalence and incidence was observed across regions and age groups. This variability could be attributed to variations in study methodologies and design, research settings and AD definitions.

AD prevalence is heterogeneous, generally ranging from 10% up to 30% even for younger children younger than 2 years, suggesting an early onset during childhood. This early onset is usually associated with genetic predisposition and environmental factors.33 Although gender difference patterns seemed nonsignificant, the long study conducted by Arnedo-Pena et al. in a small region of Spain from 1994 though 2012 resulted in women showing a higher prevalence of AD,23 a trend not yet seen in the real-world global study conducted by Silverberg et al.25 including 18 countries. An increasing trend in AD prevalence in Spain was observed from 1994 through 2012.23 In contrast, a decrease in AD prevalence from 22.8% (1996) down to 21.3% (2006), and down to 16.3% (2017) was seen, for example, in Sweden,34 highlighting geographical variations.

Regarding AD incidence, in our review a stable trend in children aged 0–5 years from 2000 through 2017 was observed.24 Similarly, a study from Denmark and Sweden supports this stability, with consistent incidence rates throughout time.35 This stability suggests unchanged risk factors for AD development in this age group.34

In Spain, the current AD treatment guidelines for pediatric population suggest an adequate skin hydration and use of topical corticosteroids,36 which is consistent with the treatment patterns reported in the reviewed studies,19,20 yet we should mention that 24.1% of moderate-to-severe patients delayed initiation, or did not apply topical pharmacological maintenance treatment.19 The treatment adherence was low despite the patient's expressed satisfaction with treatment18 and regardless of disease severity.37 We should, also, mention the different perceptions between patients and specialists in the field, with specialists often overestimating the patient's compliance with the recommendations and prescribed treatment application.18

The use of biologic drugs as the treatment of choice among pediatric patients seemed to be limited, with only 1.5% of patients older than 6 years benefiting from this option.22 This limited usage of biologics in the Spanish pediatric population may be due to their very recent authorization for use and access barriers that might have prevented their prescription.38 However, biologic drugs may provide adequate control in moderate-to-severe cases, covering an unmet need in this pediatric population.39

Of note the significant gap in the literature on the economic burden of pediatric AD in Spain. While several studies have focused on the economic implications on adult patients,40,41 pediatric population research is lacking, despite existing research in other European countries highlighting important secondary care use of resources such as outpatient visits and pharmacy dispensations.42 The mean direct medical cost in Sweden (SD) was estimated at €1111 (3416) and €1906 (7067) for mild-to-moderate and severe AD, respectively, which is consistent with the Spanish data retrieved in our review. Nonetheless, there is a need for more targeted studies in this area.

This review presents some limitations. Variations in the definition and severity of AD across different scales had implications for the comparability and generalizability of our findings. Additionally, the heterogeneity in the available data, including differences in study design, data collection methods, and outcome measures, complicated result interpretation. Moreover, the methodologies and target populations also differed across studies, leading to variable results. There was a lack of comprehensive data on the use of resources and costs associated with AD in the pediatric population, which limits our understanding of the economic burden associated with AD.

This systematic review provides a comprehensive picture of the clinical, humanistic and economic burden of AD in pediatric patients in Spain, which may be beneficial for physicians and health care decision makers who manage this condition, as well as researchers seeking to determine the gaps in knowledge that remain that need to be addressed in future research studies. The high prevalence and early onset highlight the need for comprehensive, patient-focused care tailored to this subpopulation. Despite the existence of established treatment guidelines, low adherence to treatment indicates a need for developing better and more effective strategies. On the other hand, biological therapy, including newly available treatments and small molecule JAK inhibitors, present a promising opportunity for innovation and expansion in therapeutic interventions. As modern and effective management strategies are developed, these key factors should be considered to improve patient outcomes.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Eli Lilly sponsored this study and the publication of this article.

Rosa Moro, Silvia Díaz-Cerezo, Luis Lizán and Mercedes Núñez contributed to the conception of the work, the design, the acquisition, and analysis of the data. All authors participated in the interpretation of data for the work, the critical revision of the manuscript and approved the final submitted version.

Antonio Torrelo Fernández is member of the advisory board of Eli Lilly and Viatris, has received speaker fees from Eli Lilly, Viatris, Pfizer, Sanofi, and Novartis, and fees for attending meetings from Sanofi and Pierre Fabre.

Asunción Vicente is member of the advisory board of Eli Lilly and Amryt, has received consulting fees from Abbvie, Amgen, Amryt, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novartis, Pierre Fabre and Sanofi Genzyme, speaker fees from Abbvie, Amgen, Amryt, Boehringer Ingelheim, Bristol-Myers Squibb, Ferrer, Galderma, Janssen, Eli Lilly, Novartis, Pierre Fabre, Pfizer, and Sanofi Genzyme and fees for attending meetings from Abbvie, Almirall, Amgen, Amryt, Boehringer Ingelheim, Bristol-Myers Squibb, Ferrer, Galderma, Eli Lilly, Novartis, Pierre Fabre, Pfizer, and Sanofi Genzyme.

Ana Martin-Santiago has received speaker fees from Abbvie, Amgen, Leo-Pharma, Leti, Novartis, Pfizer, and Sanofi, payments for her expert testimony from Abbvie, Amryt, Leo-Pharma, Pfizer, and Sanofi, and fees for attending meetings from Abbvie, Almirall, Janssen, Leo-Pharma, Leti, Eli Lilly, Novartis, Pfizer, Pierre Fabre, Sanofi, UCB and Viatrix.

Raúl de Lucas Laguna is member of the advisory board of Novartis, Abbvie, Lilly, Pfizer, Sanofi, Leo-Pharma, Johnson & Johnson, UCB, Almirall, Galderma, LetiPharma, has received consulting fees from Novartis, Abbvie, Lilly, Pfizer, Sanofi, Leo-Pharma, Johnson & Johnson, UCB, Almirall, Galderma, and LetiPharma, speaker fees from Novartis, Abbvie, Lilly, Pfizer, Sanofi, LetiPharma, Johnson & Johnson, UCB, Almirall, Galderma, and LetiPharma, payments for his expert testimony from Novartis, Abbvie, Lilly, Pfizer, Sanofi, LetiPharma, Johnson & Johnson, UCB, Almirall, Galderma, and LetiPharma, and support for attending meetings from Novartis, Abbvie, Lilly, Pfizer, Sanofi, Leo-Pharma, Johnson & Johnson, UCB, Almirall, Galderma, and LetiPharma.

José Carlos Armario Hita is member of the advisory board of Abbvie, Novartis, Lilly, Sanofi, Galderma, Leo-Pharma, Janssen, Pfizer, UCB farma, and Almirall, has received consulting fees from Abbvie, Novartis, Lilly, Sanofi, Galderma, Leo-Pharma, Janssen, Pfizer, UCB farma, Almirall, speaker fees from Abbvie, Novartis, Lilly, Sanofi, Galderma, Leo-Pharma, Janssen, Pfizer, UCB farma, Almirall, and fees for attending meetings from Abbvie, Novartis, Lilly, Sanofi, Galderma, Leo-Pharma, Janssen, Pfizer, UCB farma, and Almirall.

Rosa Moro, Silvia Díaz-Cerezo and Mercedes Núñez are employees of Eli Lilly. Luis Lizán works as an independent scientific consultant (Outcomes’10) and declared to have received honoraria for conducting the systematic literature review and manuscript drafting tasks.