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Moderate-to-Severe Atopic Dermatitis
Moderate-to-Severe Atopic Dermatitis
A real-world retrospective observational study exploring resource use for secondary care management of moderate-to-severe atopic dermatitis in children and adolescents at a single site in Ireland
It is estimated that in the Ireland 14.3% of children 13–14 years of age ever experience the inflammatory skin disorder atopic dermatitis (AD).1 AD has a profound impact on the quality of life (QoL) of patients and their relatives, affecting multiple aspects of psychological, social and physical functioning.2-7 Therapeutic guidelines recommend that firstline treatment aims to control flare with local anti-inflammatory agents, including topical corticosteroids (TCS).8 For more severe AD cases, ultraviolet light and systemic immunosuppressants are suggested.8
Recognition of immunological disease mechanisms in AD has led more recently to the identification of different therapeutic targets and development of novel therapies. Regulatory approval has been gained for several of these for moderate-to-severe AD, including biologic therapies targeting specific immune pathways.9 Some biologics are now licensed for use in adolescents and/or children. However, the treatment of childhood AD remains challenging since there can be inadequate response to available therapies, and the more advanced immunological therapies are limited to late line use and are costly. This means determining when to prescribe an advanced therapy and which therapy to use is not necessarily straightforward.10
AD presents a considerable socioeconomic burden. Healthcare resource utilisation (HCRU) increases with disease severity,11 and is significantly higher after systemic therapy initiation.12 While the Irish dermatology programme ensures patients are appropriately seen, assessed, and treated,13 limited data are available describing the HCRU associated with current standard of care for paediatric AD in Europe. Furthermore, to our knowledge, there is no real-world evidence (RWE) study focusing on an Irish population of children and adolescents with moderate-to-severe AD. The RWE study reported here is the first of its kind to systematically capture data on clinical characteristics, secondary care HCRU, and patient-reported outcomes (PROs) associated with treatment of moderate-to-severe AD, in children and adolescents in a single centre in Ireland.
Patients and Methods
Study design
This was a retrospective, noninterventional, single-centre chart review of 31 patients with AD aged 6–17, conducted in the public healthcare service at Ireland's largest paediatric hospital, Children's Health Ireland, at Crumlin where around 90% of all Irish children treated with systemic therapies for AD are managed. Referrals are made from primary care in Dublin, Ireland and secondary care nationally. Data collection was from October 2020 to June 2021.
Patients meeting the eligibility criteria were selected consecutively, starting with the most recently consulting patient, and working backwards until the patient target was reached (Supporting Information: Figure 1). Data were abstracted from medical records, starting from the first secondary care appointment post 1 January 2014 when patients were 6–17 years of age, up until the most recent date/ event available when patients were also under 18 years of age. A minimum of 12 months of data was abstracted for each patient from their first secondary care appointment after January 2014. Anonymised data were collected onto a standardised, purpose designed electronic Case Report Form (eCRF) by hospital research staff.
Patient inclusion/exclusion criteria
Patients were children aged 6–11 years and adolescents aged 12–17 years with a diagnosis of moderate-to-severe AD (Box 1 above).
Results
Patient demographics
Thirty-one patients were included, made up of 22 children and 9 adolescents.
For the total 31 patient sample, mean (SD) duration, that is, time between first and most recent consultations during the observation period was 4.4 (1.9) years. Males predominated (total sample 61.3%; children, 59.1%) and, based on body mass index, 84.6% of all patients had a healthy body weight.
Patients had a mean (SD) of 2.7 (1.5) comorbid conditions, the majority of which were atopic in nature. Children most frequently had food allergies (68.2% of patients), allergic rhinitis (59.1%), and asthma (59.1%); adolescents mostly had asthma (55.6%) and food allergies (44.4%). Infectious episodes were reported for over one-third of the total population (n = 11, 35.5%).
Patient clinical characteristics and clinical investigations
The majority of patients (n = 25, 80.6%) had a clinical phenotype of mixed AD (defined as concomitant respiratory allergies). This was higher (n = 20, 90%) in the child cohort. Three patients (9.7%; all adolescents) had ‘pure’ AD without atopic comorbidities (defined as no associated respiratory conditions). Affected body surface area (BSA) was reported at earliest consultation during the observation period for only three patients (BSA range 50%–90%).
Considering BSA and other relevant factors, AD was severe in 74.2% (n = 23) of patients at first referral. Mean (SD) patient reported flare episodes/patient/ year of observation was 2.0 (1.1).
A mean (SD) of 18.5 (12.2) tests/ scans/procedures per patient/ year of observation were reported; those most frequently performed were full blood count (n = 31, 100%) and renal function tests (n = 30, 96.8%). Half of children were tested for food allergies (n = 11, 50.0%).
Treatment history
A total of 412 prescriptions were recorded, of which 298 (70.1%) were for patients in the children's cohort. Overall, patients had each tried a mean (SD) of 13.4 (4.8) different prescribed treatments over the observation period and there was a mean of 3.7 (2.2) treatments/patient/year of observation. The most frequently prescribed treatment class was TCS (n = 200 prescriptions, 48.5%).
From start to end of treatment, patients had been using TCS for a mean (SD) of 38.6 (41.1) months, with treatment ongoing for 72 (36.0%) courses of these treatments. The most common stated reason for discontinuation of TCS treatment was course completed (n = 63, 49.2%).
Fewer than 5% of prescriptions each were for nonsteroidal topical treatments (all for tacrolimus), which were used for the longest duration, amounting to a mean of 54.4 (41.4) months, and systemic corticosteroids (SCS; all oral or injections of prednisolone) that were used for a mean (SD) of 2.0 (3.1) months. As with TCS, nonsteroidal topical treatments were discontinued for reasons of ‘condition improved’ and ‘course completed’ (each n = 4/17, 30.8%), and all SCS were discontinued as the course of treatment was completed (n = 9, 100%).
Of the total 44 systemic immunosuppressant prescriptions, the most frequently prescribed were methotrexate (n = 30, 68.2%), ciclosporin (n = 7, 15.9%), and azathioprine (n = 4, 9.1%). Collectively, these were used for a mean (SD) of 27.6 (21.1) months. Treatment was ongoing for over half of these prescriptions (n = 25, 56.8%), with discontinuations due mainly to primary (n = 3/44, 15.8%) and secondary (n = 6/44, 31.6%) failure.
Only 3 (0.7%) prescriptions were for phototherapy, with a mean (SD) duration of 1.2 (0.6) months. ‘Other’ treatments, which included wet wraps, bleach baths, antihistamines, analgesics, and anti-infectives, were also frequently prescribed (n = 139 prescriptions, 33.7%), two-thirds of which were discontinued as the course was completed (n = 55, 66.2%).
Healthcare resource utilisation Consultations
Time from first to most recent consultation/patient (the observation period) was 4.4 (1.9) years. During this time, there was a mean (SD) of 15.3 (6.3) consultations/patient (virtual consultations, mean [SD] 1.2 [0.4]), or an annualised rate of mean (SD) 3.2 (1.3) consultations/patient/year of observation, suggesting that on average patients were attending the secondary care clinic every 4 months. The most frequently selected reasons for a consultation were for a routine appointment (total sample 46.9%; child cohort 50.1%) and follow up (total sample 43.8%; child cohort 40.6%), mainly for a clinical/treatment review. Flare was the reason cited for ≤10% of consultation visits (total sample 5.9%; child cohort 6.7%).
Over 70% of all consultations were with consultant dermatologists, and over 80% were with dermatology trainees; around 40% were with nurse specialists. Time allocated for consultant dermatologist/paediatrician/ registrar consultations for a clinical/treatment review or follow-up were 15 min each.
Hospitalisations
Across all 31 patients, there was a mean (SD) of 0.4 (0.7) AD-related hospitalisations/patient during the observation period, and 0.03 (0.04) AD-related hospitalisations/ patient/year of observation. While the observed annualised rates were low, a quarter of patients (8/31, 25.8%) were hospitalised at least once during the observation period. For these patients, there was a mean (SD) of 1.5 (0.5) AD-related hospitalisations/patient, and 0.07 (0.04) AD related hospitalisations/ patient/year of observation.
The majority (75.0%) of patients hospitalised were children.
The eight patients hospitalised were admitted on a total of 12 occasions; six of those patients were children (i.e., 27.3% of the 22 children in the cohort) and they were hospitalised on 9 occasions.
The total hospital stay during the observation period was 6.6 nights/ hospitalised patient (child cohort: 6.3), and 4.4 nights/hospitalisation (child cohort: 4.2). Over 90% of hospitalisations (child cohort: 88.9%) were due to flare, and over 80% (child cohort: 77.8%) for treatment administration.
Although none of the 12 hospitalisations required an ambulance call out, 7 (58.3%; child cohort n = 5, 55.6%) were classed as an emergency visit, while 5 (41.7%; child cohort: n = 4, 44.4%) were elective.
The Dermatology Life Quality Index-Children (cDLQI) (score range 0–30) was the only PRO with available data. Data for the cDLQI were available for 29 (93.5%) patients, with a mean (SD) of 5.3 (3.4) scores captured/patient.
The earliest mean (SD) cDLQI score for the overall population was 9.7 (6.2), which reduced at the latest cDLQI score to 6.6 (5.5). The cDLQI score indicated that, the change in HRQoL from earliest to latest cDLQI score improved for 72.0% (n = 18) of patients and deteriorated in 20.0% (n = 5). The minimally clinically important difference (MCID) for cDLQI has been estimated as a 6-point change, indicating that the observed reductions may not be clinically meaningful.14
Discussion
There are no data available on the impact of AD on the health service and treatment of young people in Ireland. For this reason, we undertook this study to assess the treatment journey and effects of treatment in children and adolescents with moderate-to-severe AD at Children's Health Ireland, Crumlin, the major AD centre and largest paediatric hospital in Ireland. This RWE study, covering an observation period of mean 4.4 years/patient, is the first study to highlight the substantial HCRU burden due to tests, procedures, prescriptions, therapy lines, consultations, and hospitalisations for AD in Ireland. Our results reflect a similar previous UK study in children and adolescents.15
Significant exacerbation of AD (flares) causes considerable distress to patients and we found that the moderate-to-severe AD patient cohort studied here experienced two flare episodes/ patient/year of observation. We recognise that this is considerably lower than the nine flares/ year reported in another real world interview-based study of >900 children and adolescents with moderate-to-severe disease.16 However, reasons for the discrepancy may include differences in data source (i.e., medical records vs. interview), over-diagnosis through self reporting, treatment compliance issues, or discrepancies between physician medical coding and patient perception.
The average number of tests, scans and procedures were high for this patient group, with each person having a mean of 18.5 per year of observation. All patients had full blood counts and all but one had liver/renal function tests. Immunoglobulin E (IgE) level was evaluated in many patients, yet, while a typical feature, IgE elevation is not present in all AD cases.17, 18 These tests alone place a substantial burden on patients and healthcare providers.
Our data suggest that clinicians generally followed treatment guidelines,8, 18, 19 initially prescribing TCS to control inflammation and systemic immunosuppressants for the most severe cases. Each patient studied used over three pharmacotherapies a year. TCS prescriptions predominated, with any discontinuation primarily because the patients' condition improved or the treatment course had been completed. In contrast, systemic immunosuppressant prescriptions were relatively rare and mostly ongoing, with discontinuations mainly due to treatment failure. Similarly in the US, evaluation of current treatment among >600,000 paediatric AD patients within a claims database found that about 80% of patients were prescribed ≥1 AD medication, and 87% were prescribed a TCS; SCS were prescribed in 14.7% of all patients and immunosuppressant use was rare (0.2%).20
Our data also indicate that current treatment options are not always effective in managing moderate-to-severe AD symptoms, leaving patients with inadequately controlled disease. Generally, other real-world studies have reported poor disease control across all AD severity levels,21-23 and suggested a lack of effective long-term treatment options.24
We found that children and adolescents with moderate-to-severe AD attended a consultation every 4 months, mostly for routine and follow-up appointments. Notably, while overall rates of hospitalisation were low per patient year of observation, overall, the data suggest a one-in-four chance of hospitalisation in 6–17-year-olds with AD over a ~4-year period. Additionally, those hospitalised spent approximately six nights in hospital, with each stay lasting longer than four nights, and over half were classified as an emergency. To set this in a wider international context, other studies have found that children with AD use more health services, are prescribed more therapies, are more likely to visit emergency departments, and be hospitalised than their counterparts without AD.25-28 For example, a US study reported that, among 1207 children with AD, there were 1641 hospitalisations with ≥1 overnight stay, amounting to 239,832 annual hospitalisation days.28 Additionally, those with AD had significantly higher odds of having 1–2 and ≥3 overnight hospitalisations in the past year compared with children without AD (adjusted odds ratio, 1.17 and 1.64, respectively).28 However, hospitalisations in other scenarios are not comparable for the total number of cases studied in other papers.
The paediatric AD cDLQI scores observed in our study suggest that, despite some improvement over the observation period, AD had a significant negative impact on the QoL of more than one-third of children (not assessed statistically and small sample size). This is in line with other studies in children and adolescents reporting similar point estimates for cDLQI scores, indicating the high negative impact of AD, particularly for those with severe disease.3, 4, 22, 29
This study is not without limitations. This data set represents the first study describing the treatment pathway and HCRU for children and adolescents with AD in the Irish healthcare setting and was carried out in a major influential centre that is the largest children's hospital in Ireland. While unlikely, it may differ from other sites which could have slightly different AD management practices. The findings were limited by reliance on data available from patient medical records only and patient enrolment depended on the physicians' judgement of disease severity. Although reflective of routine care, this did result in some missing data, and in particular, PRO scores were not complete. Sourcing data from hospital records alone also means their further characterisation is warranted. Additionally, the study design imparted a recruitment/selection bias, since patients at the lowest severity level of AD are evaluated less frequently, and more patients with severe AD than moderate AD were selected. We also acknowledge that the total sample size is relatively small compared to other international studies.
Children's Health Ireland receives referrals from all primary care in Dublin and from secondary care nationally with around 90% of all Irish children treated with systemic therapies for AD managed within the service.
Conclusions
This is the first study examining paediatric AD HCRU in Ireland. We found that moderate-to-severe paediatric AD is associated with complex treatment patterns and high healthcare burden in Irish outpatient secondary care. Annualised per person, hospitalisation rates are low but, for the 25% of patients who were hospitalised during the study, stay was protracted and, in some cases, repeated. Observed overall improvement in QoL was small and below the MCID for cDLQI. These data were collected from records from the main treating centre in Ireland. This may represent a limitation as primary care provision has been excluded from the analysis. We recognise that further work is needed to fully characterise the national paediatric AD burden to the Irish healthcare system but these findings highlight the significant burden that currently exists and were collected within a service which treats around 90% of all Irish children with systemic therapies for AD… As biologic therapies become increasingly available for the 6–17-year-old age group over the next few years, the data reported here may provide further justification for their uptake and use in paediatric patients with severe disease.
References available on request
