Patterns and trends in eczema management in UK primary care (2009–2018): A population‐based cohort study

Abstract Background Despite the high disease burden of eczema, a contemporary overview of the patterns and trends in primary care healthcare utilization and treatment is lacking. Objective To quantify primary care consultations, specialist referrals, prescribing, and treatment escalation, in children and adults with eczema in England. Methods A large primary care research database was used to examine healthcare and treatment utilization in people with active eczema (n = 411,931). Management trends and variations by age, sex, socioeconomic status, and ethnicity were described from 2009 to 2018 inclusive. Results Primary care consultation rates increased from 87.8 (95% confidence interval [95% CI] 87.3–88.3) to 112.0 (95% CI 111.5–112.6) per 100 person‐years over 2009 to 2018. Specialist referral rates also increased from 3.8 (95% CI 3.7–3.9) to 5.0 (95% CI 4.9–5.1) per 100 person‐years over the same period. Consultation rates were highest in infants. Specialist referrals were greatest in the over 50s and lowest in people of lower socioeconomic status, despite a higher rate of primary care consultations. There were small changes in prescribing over time; emollients increased (prescribed to 48.5% of people with active eczema in 2009 compared to 51.4% in 2018) and topical corticosteroids decreased (57.3%–52.0%). Prescribing disparities were observed, including less prescribing of potent and very potent topical corticosteroids in non‐white ethnicities and people of lower socioeconomic status. Treatment escalation was more common with increasing age and in children of non‐white ethnicity. Conclusion and clinical relevance The management of eczema varies by sociodemographic status in England, with lower rates of specialist referral in people from more‐deprived backgrounds. There are different patterns of healthcare utilization, treatment, and treatment escalation in people of non‐white ethnicity and of more‐deprived backgrounds.


| INTRODUC TI ON
Eczema (syn. "atopic dermatitis," "atopic eczema") is the most common inflammatory skin condition worldwide in children, 1 and persistence of chronic disease into adulthood is common. 2,3 Eczema can be extremely disabling and has a significant psychological impact in both children and adults. [4][5][6] In the UK, the burden of eczema management falls on primary care. Attendance rates are high, with 96% of children with eczema reported to have had a primary care attendance within the preceding year. 7 Whilst contemporary UK population-based estimates of eczema disease severity are lacking, a 1998 cross-sectional analysis in a UK general practice setting estimated 16% of eczema in children aged 1-5 to be moderate or severe. 7 Recent studies of children with eczema actively recruited from UK primary care suggest this figure may be even higher. 8,9 US population-based studies have reported 7% of children and 11% of adults with eczema have severe disease. 10,11 Whilst those with more severe disease are more likely to be referred for specialist care, the majority of these cases are managed without secondary care referral. 7 As a result, the principal costs for eczema are those of primary care attendances and prescribing. 12 Standard topical eczema care includes regular emollient application. Escalation to topical corticosteroids (TCS), or, as an alternative, topical calcineurin inhibitors (TCI), is common for maintenance and flare management, 13,14 and topical antimicrobials can be used to address secondary skin infections, or pruritis. 14 Antihistamines are also commonly used to treat pruritus associated with eczema, although evidence for their effectiveness is limited. 15 In more severe disease, systemic immuno-modulatory treatment may be required. 16,17 Recently, the first biologic therapy for eczema, dupilumab, was approved, and this can now be prescribed for adults and adolescents with moderate or severe eczema who have not responded or have contraindications to conventional systemic therapies. 18 Despite the high disease burden and multiple treatments available, a contemporary overview of UK primary care healthcare and treatment utilization patterns and trends in children and adults with eczema is lacking. We set out to describe healthcare utilization in people with eczema across the lifespan, including primary care attendances, specialist referrals, prescribing and, as a surrogate marker of moderate and severe eczema, treatment escalation patterns. 19

| Data source and setting
We used the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network database. The RCGP RSC comprises the pseudonymized primary care records of all individuals registered with a large network of general practices, providing a broadly representative sample of the English primary care population. 20 Over the entire study period, the RCGP RSC database contained data from 3.85 million people registered with 293 general practitioner (GP) practices across England.
RCGP RSC primary care records include information on demographics, clinical diagnoses, laboratory tests, prescriptions, and care processes (eg patient referrals). Data are captured using the Read coding system (a thesaurus of clinical terms). 21 Key strengths of the English primary care system include: it is a registration-based system (each patient registers with a single GP), has been computerized since the 1990s, laboratory results are electronically uploaded, and, since 2004, a pay-for-performance scheme has resulted in high-quality chronic disease clinical data entry. 22,23 Additionally, RCGP RSC practices have practice visits and receive feedback via a dashboard to improve data quality. 24 All children and adults registered with an RCGP RSC contributing practice between 1 January 2009 and 1 January 2019 were eligible for inclusion in this study. Individuals required at least 1 year of follow-up in RCGP RSC, unless under 1-year old. The full protocol for the study was pre-specified and has been previously published. 25

| Eczema definitions
People with eczema were identified using Read diagnostic codes and prescription records, applying a validated algorithm recently developed in a random sample of children and adults in UK primary care, and previously applied in several UK primary care studies. 19,26,27 The positive predictive value of this algorithm for a physician-confirmed diagnosis of eczema is 90% (95% confidence interval (CI) 80%-91%) in children and 82% (95% CI 73%-89%) in adults. 27 Active eczema was defined, as in a recent UK primary care study, 19 as two eczema records (either diagnoses or treatment) appearing within any 1-year period. Active eczema was then assumed to last for 1 year, unless another eczema record appeared, in which case its duration was prolonged for a further 1 year. 19 We utilized this approach but used the first of two codes (rather than the latter) within 1 year to signify the onset of active eczema, as this has been shown to have good agreement to physician-confirmed onset, 27 and has been used elsewhere. 26 Eczema treatments are also prescribed for other conditions, and the indication for treatment is not readily available in primary care data. We therefore excluded people with potential confounding comorbidities from our eczema cohort. We excluded people who had other skin conditions (psoriasis, contact dermatitis, photodermatitis, and ichthyosis) as these are managed with similar topical treatments to eczema. 27 In addition, we excluded people with inflammatory bowel disease (IBD), rheumatoid arthritis, and a history of organ transplantation, as these are commonly managed with treatments also used in eczema (eg methotrexate and azathioprine); topical treatments for dermatological conditions and oral immuno-modulating drugs for the other conditions listed. IBD and rheumatoid arthritis were identified using validated approaches. [28][29][30] Organ transplantation was identified using a Read code list generated in accordance with publicly available guidance. 21,31

| Definition of sociodemographic factors
Ethnicity was categorized in accordance with the major UK census categories: white, Asian, black African/Caribbean, mixed, other, and not recorded. Deprivation was defined using the official national measure of socioeconomic status, the Index of Multiple Deprivation (IMD). 32 Scores, based on postcode, were stratified by deprivation quintile according to the national distribution.

| Primary care visits and specialist referrals
The reason for primary care attendances is not always coded in the primary care record. To define primary care attendances specifically for eczema, we matched primary care appointment dates to the dates of prescriptions issued for eczema treatment (as defined below). A primary care attendance for eczema was defined as either a visit where an eczema diagnosis code was recorded or a prescription for eczema treatment was issued. Specialist referrals were identified by the presence of a Read code for referral to either a dermatologist, a GP with a specialty interest in dermatology, or a dermatology specialist nurse.

| Treatment and treatment escalation
We extracted prescription records for therapy classes commonly used to manage eczema in the UK: emollients and soap substitutes (combined into a single therapy class for the purposes of analysis), TCS, TCI, systemic immuno-modulatory therapy (ciclosporin, azathioprine, methotrexate, mycophenolate, and oral corticosteroids), oral antihistamines, and topical antimicrobial treatments.
In line with published work, we used treatment escalation as a surrogate marker to define moderate and severe eczema. 19 We  2.6.2 | Primary care visits and specialist referrals Within the prevalent cohort, we described annual rates of primary care attendances and specialist referrals for eczema. In the prevalent cohort in 2018, we calculated stratified rates of attendances and referrals by age category, sex, ethnicity, and deprivation quintile.

| Treatment patterns
We described the patterns of eczema treatment in the prevalent cohort. Results were stratified by the same sociodemographic factors and calendar year. The proportion of the prevalent cohort receiving each medication class was calculated as the number of the prevalent cohort receiving at least one prescription for a particular medication class during a year divided by the total number in the prevalent cohort for that year. As a sensitivity analysis, we repeated the analysis for antihistamine prescriptions in the subset of people with active eczema without a clinical diagnosis of allergic rhinitis, as antihistamines are commonly prescribed for this condition.

| Definition of the incident cohort
To evaluate treatment escalation, a subset of people with incident eczema were identified as those diagnosed with new-onset eczema over the study period. Patients with an eczema diagnosis recorded in their primary care record prior to the study period were excluded from this incident cohort.

| Treatment escalation
In the incident cohort, we examined each of the three treatment escalation outcomes using time to event analysis, separately analysing children and adults. First, we compared the cumulative incidence of each outcome by age at diagnosis category (age groups: 0-1, 2-11, 12-17, 18-49, and 50+) using the Kaplan-Meier estimator. Second, we examined the non-linear effect of continuous age (modelled as a restricted cubic spline with 3 knots) using multivariable Cox proportional hazards models, with adjustment for sex,

| Rates of eczema consultations and specialist referrals differ by age and sociodemographic factors
In people with active eczema in 2018 (n = 148,166), rates of eczema consultations were markedly higher in children under 2 than in other age groups, but rates of specialist referrals were highest in adults aged 50 or over ( Table 1). Rates of eczema consultations were similar by sex, but were higher in all non-white ethnicity categories. There was little difference in the rates of specialist referrals by sex or ethnicity. Primary care eczema consultation rates were highest for those in the most deprived quintile. However, rates of specialist referrals were highest in the least deprived quintile. Whilst there was no difference in rates of specialist referral between rural and urban areas, GP consultation rates were higher in urban settings.  Antihistamines and oral corticosteroids were the most common systemic therapies prescribed, with oral corticosteroids more frequently prescribed in adults than children.

| Prescribing for eczema has changed little but varies markedly by age and sociodemographic characteristics
Fewer people of non-white ethnicities and people from the two most deprived IMD quintiles were prescribed potent and very potent TCS ( Table 2). People of non-white ethnicities were also more likely to be prescribed emollients, TCI or antihistamines, and less were consistent with the whole active eczema population ( Figure S1, Table S1).

| Treatment escalation
167,311 people with incident eczema were included in the analysis of treatment escalation. Incidence of moderate and severe eczema was higher in adolescents than younger children ( Figure 4A,B, Table 3A), with both peaking at age 18 when age was analysed as a continuous measure ( Figure S2). In adults, incidence of moderate and severe eczema increased with a higher age at diagnosis, although the difference in incidence by age was more marked in moderate than severe eczema ( Figure 4A,B, Table 3B, Figure S2). Initiation of systemic immuno-modulatory therapy was low overall, was higher in adults than children ( Figure 4C), and in adults was highest in those aged 50 to 68, before declining at older ages ( Figure S2). 10-year absolute risks of progressing to each end point are reported, by age category, in Table S2.
In children, there was a greater risk of treatment escalation in people of non-white ethnicity. In adults, only in people of Asian ethnicity was there evidence of a greater risk of progression to moderate but not severe eczema (Table 3). Males were more likely to progress to moderate eczema than females (

| D ISCUSS I ON
Our study provides important insight into the primary care management and disease course of eczema across the lifespan. Both primary care consultation and specialist referral rates for eczema increased over the last decade, and we observed substantial differences in consultation rates by age, ethnicity and deprivation category. Notable findings include that, although primary care consultation rates for eczema were highest in the people of lower socioeconomic status, people of higher socioeconomic status were more likely to have a specialist referral for eczema. We also observed higher primary care consultation rates in non-white ethnicities, with the highest rates seen in people from an Asian background. Whilst over the study period there was little change in overall treatment patterns, treatment escalation varied by socioeconomic status and ethnicity, and in particular was more common in children of non-white ethnicity.

| Strengths and limitations
Strengths of this study include the use of contemporary data from a large population-representative primary care cohort with highquality ethnicity and deprivation data. Accurate prescribing data are ensured through automatic entry when prescriptions are generated.
A limitation of our study is the likelihood that some patients included in the incident eczema cohort did not have true new-onset eczema, as they had a historical onset of eczema prior to our study period that was not captured in the primary care record. Although diagnosis dates can be retrospectively coded in UK primary care, this may not always be done correctly. This limitation will be most applicable to  ing of systemic immuno-modulatory therapies. We are also likely to have underestimated specialist dermatology referral rates in this study, as it is likely that some dermatology referrals will have been coded as unspecified referrals without mention of clinical speciality and were therefore not included in our estimates. In addition, we found that phototherapy data captured in RCGP RCS were not complete enough to be used for analysis, and these data were therefore not included in our study.

| Context of previous work
The increase in primary and secondary care consultations concur with a large retrospective analysis of overall GP clinical workload in the UK, which found that annual consultation rates increased by 10.5% between 2007 and 2014. 35  Oral Corticosteroids Systemic Immuno-Modulatory Therapy TCI We found specialist referrals for eczema were highest in the over 50s age group. A qualitative study of GP's experiences of eczema stated that whilst most GPs feel confident in diagnosing uncomplicated eczema, many report uncertainty in diagnosing and managing more complex cases, particularly where potent steroids are required. 38 This may explain the increase in referral rates for eczema among the elderly, who are often resistant to standard treatments. 39 Our observation of disparities in referral to secondary care by socioeconomic status fits with the inverse care law (that those who most need medical care are least likely to receive it 40   via dashboards and observatories may be able to raise awareness of such disparities. 50 Although prescribing trends were consistent over the study period, it will be important to monitor prescribing behaviour in primary and secondary care over the coming years due to likely changes in prescribing guidelines and the availability of new systemic treatments. and is a principal investigator in the European Union Horizon 2020funded BIOMAP Consortium (http://www.bioma p-imi.eu/). His department has also received funding from Sanofi-Genzyme. All other authors have no competing interests to declare.

AUTH O R CO NTR I B UTI O N
The study concept and design were developed by C. McGovern conducted and are responsible for the data analysis. All authors critically reviewed the manuscript. S. de Lusignan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

DATA AVA I L A B I L I T Y S TAT E M E N T
The RCGP RSC data set is held securely at University of Oxford and the University of Surrey and can be accessed by bone fide researchers. Approval is on a project-by-project basis (www.rcgp.org. uk/rsc). Ethical approval by an NHS Research Ethics Committee may be needed before any data release/other appropriate approval. Researchers wishing to directly analyse the patient-level pseudonymized data will be required to complete information governance training and work on the data from university secure servers. Patient-level data cannot be taken out of the secure network.