Introduction

Some text in the Scientific summary is reproduced with permission from Chalmers et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attrition (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build on this work, for commercial use, provided the original work is properly cited. See https://creativecommons.org/licenses/by/4.0/.

Background

Terminology and disease definition: In this monograph, we use the term ‘eczema’ throughout as a term commonly used in the UK to denote atopic eczema (AE) [also known as atopic dermatitis (AD) in the USA and other countries]. It could be argued that using the term ‘eczema’ is more precise, as around 50% of cases of ‘atopic’ eczema are not atopic2 [defined as immunoglobulin E (IgE) sensitivity to common environmental allergens determined by skin prick or blood tests]. The term ‘eczema’ is also the preferred term designated by the World Allergy Organization nomenclature committee.3 A long list of major and minor clinical diagnostic criteria for eczema were suggested by Hanifin and Rajka in 1980 which were later refined in 1994 into a minimum list of reliable discriminators by a UK diagnostic criteria working party led by one of the authors (HW)4 (Table 1).

The UK diagnostic criteria have been used for this study and are supplemented by a detailed training manual for users.5

Defining a new/incident case of eczema for use in prospective studies has been challenging as most definitions rightly include an element of chronicity,6 which is important to separate true eczema from many unclassified transient irritant forms of dermatitis in early life.7 A 1-year period prevalence is used in the UK diagnostic criteria to capture chronicity and overcome seasonal variation.

What is eczema? Eczema is a chronic inflammatory skin condition characterised by symptoms of itching, stinging and burning of the skin. Itching can lead to sleep loss, poor concentration and a reduction in quality of life. Eczema can affect any part of the body. Secondary infection of the skin with bacteria (most commonly Staphylococcus aureus) is common. Involvement of the cheeks and outer limbs and trunk is common in infancy, whereas in the older child, involvement of the skin creases such as behind the knees and elbow folds is common. The skin is inflamed, appearing red in lighter skin tones and a dark purple or brown colour in dark skin. Chronic scratching leads to leathery thickening of the skin (termed lichenification).

Eczema is caused by a combination of genetic and environmental factors. Genes controlling skin barrier formation and inflammatory responses are important. Epidemiological studies indicate that environmental factors are also critical for determining disease expression: eczema has increased in prevalence over the last 30 years; people migrating from low- to high-prevalence countries develop similarly high rates in the adopted country; and eczema prevalence increases with small family size and higher socioeconomic group.8–10 Increased sensitivity to food and environmental allergens such as house dust mite is common in eczema. The role of gut and skin microbiota in driving eczema remains controversial.11 Most cases of childhood eczema improve in childhood but around 5% persist into adulthood.12 Although eczema is still considered as one disease for the purpose of scientific studies and clinical trials, recent studies suggest that it is composed of several distinct sub-phenotypes or endotypes with different disease trajectories.13 The relationship between skin barrier dysfunction and underlying upregulation of type-2-mediated immune responses is summarised elsewhere.14

Asthma, hay fever and food allergy (collectively called ‘atopic’ disorders) are also commoner in children with eczema and perhaps best considered as comorbidities rather than conditions that inevitably progress in the same individuals as part of the so-called allergic march (Figure 1).16 Some children with eczema are also allergic to foods such as egg and nuts. Current thinking is that eczema in early life leads to food allergy rather than the other way around.

FIGURE 1 Illustration of the typical onset of symptoms of allergic diseases during childhood. Reprinted from Davidsonet al. (2019),15 Copyright (2023), with permission from Elsevier. (Figure not reproduced here; see the original article.)

Eczema affects around 20% of children worldwide17 and around 5–10% of adults.18 Black children in the UK seem to have an increased prevalence of eczema, the reasons for which are unclear.19 Although around two-thirds of cases of childhood eczema are mild,20 moderate to severe eczema (Figure 2) can result in a significant quality-of-life impairment.21 Having eczema or a child with eczema also confers high direct and indirect financial costs.22

FIGURE 2 Severe eczema is associated with poor quality of life in children. (Figure not reproduced here; see the original article.)

Treatment of eczema. These are best summarised in the National Institute for Health and Care Excellence (NICE) eczema clinical knowledge summary.23 Treatment depends to a large extent on eczema severity. In clinical practice, severity is commonly assessed using the Patient-Oriented Eczema Measure (POEM) which records eczema symptoms over the last week.24 Mild eczema corresponds to a POEM score of 0–7, moderate 8–16 and severe/very severe ranging from 17 to 28.25 In addition to avoiding irritants such as soap and rough clothing, mild eczema is generally treated in the community with topical application of creams and ointments such as short bursts of mild potency topical corticosteroids for inflammatory flares and emollients for restoring the skin barrier, flare prevention and treatment of dry skin symptoms. Moderate disease requires more potent topical corticosteroids and/or the addition of topical calcineurin inhibitors such as tacrolimus and pimecrolimus, often used proactively on weekends to prevent flares. More severe eczema requires specialist input and may require third-line treatments such as ultraviolet light or systemic immunomodulatory therapy such as ciclosporin, methotrexate or biologics such as dupilumab and baricitinib.26 Three more biologics (abrocitinib and upadacitinib – both JAK1 inhibitors, and tralokinumab – a human monoclonal antibody that inhibits interleukin-13) have recently been approved by NICE for severe eczema27 and a large range of biologics are currently in development. There is a considerable unmet need for eczema care in the UK, with most treatment carried out at home with little contact with healthcare professionals.14 Self-care informed by theory-based, evidence-informed online educational programmes have been shown to result in sustained benefit for managing eczema severity.28

While good progress has been made with new topical and systemic treatments for established eczema,29 relatively little attention has been paid to the prevention of eczema – arguably a more desirable approach than the daily lifetime toil of applying greasy ointments or requiring expensive medicine that modify the body’s immune system in individuals in whom a long chain of pathological events have already occurred (Figure 3).31

FIGURE 3 Upstream prevention of eczema is a more desirable aim than treating sick individuals with costly drugs who present after a long chain of multistage events. (Figure not reproduced here; see the original article.)

Rationale for the barrier enhancement for eczema prevention trial

A summary of the approaches that have been used to try and prevent eczema and the methodological considerations for such preventive studies have been summarised elsewhere.32 In brief, systematic reviews of prevention strategies covering exclusive and prolonged breastfeeding, or those targeting reduction in food and/or airborne allergens in pregnancy and/or shortly after birth have not shown clear benefit. Maternal/infant supplements of vitamin D has also not shown any benefit. Some evidence supports the role of probiotics to prevent eczema, but the studies are quite variable and might benefit from individual patient data meta-analysis.

Interest in the use of emollients for preventing or reducing the severity of childhood eczema has been around for many years and was suggested by one of the authors (HW) at the 2001 International Symposium of Atopic Dermatitis in Portland. Although the idea gained some traction as it was already known that dry skin preceded the development of visible eczema, it was the discovery that mutations in the gene encoding filaggrin (FLG), a key skin barrier protein, that accelerated interest in emollients as a potential intervention for preventing eczema.33 FLG mutations have since been shown to represent the strongest and most consistent genetic risk factor for eczema. Later studies showed that FLG-null mutations were also associated with related atopic conditions including asthma, hay fever and peanut allergy.34 Intense interest grew in the concept of skin barrier dysfunction as the initial step in eczema development. In addition to FLG mutations, skin barrier defects are thought to arise as a result of immune dysregulation, low levels of antimicrobial peptides, a general disruption in skin flora (dysbiosis).35 The genetic predisposition to skin barrier impairment led to the idea that babies at high risk of developing eczema are born with a skin barrier that allows irritants and allergens to initiate skin inflammation and hence set up a cascade of inflammatory events that could lead to chronic eczema driven by autoimmune mechanisms as a result of chronic scratching.36

Emollients are used to improve the barrier function of skin by providing lipids to the outermost stratum corneum and by trapping water which in turn improves skin hydration. Emollients may prevent inflammation caused by external irritants as they are used to prevent irritant occupational hand eczema.37 Emollients had also been shown to reduce skin inflammation in premature babies38 as well as preventing eczema flares in those with established eczema.39 An earlier open-label pilot study of emollient therapy from birth showed that only 15% of high-risk infants developed eczema against an expected rate of 30–50%.40 A case-control study conducted in Kenya published in 1991 also suggested that petroleum had protective effect against the development of eczema.41

A workstream within a NIHR-funded programme grant conducted by several authors focused on exploring the feasibility of conducting a national trial of emollients to prevent eczema. At the time, there was considerable uncertainty of whether families with a strong history of atopic disease (eczema, asthma, hay fever) would agree to be randomised to normal care or daily application of an emollient to their newborn child. A series of pilot studies including qualitative work with families was carried out to explore emollient preferences. Full details of the pilot studies are described in the Programme Grant for Applied Research report.42 Since some emollients such as aqueous cream had been shown to paradoxically damage the skin barrier,43 a mechanistic study by experts in skin barrier science was done to show that the two preferred emollients did not cause any such skin barrier disruption.44 A feasibility randomised controlled trial (RCT) of 124 families was conducted and showed that the intervention was acceptable and that it was possible to conduct a national clinical trial. Although not powered to detect a difference in eczema prevention, infants in the emollient group in the feasibility study showed a reduced risk of developing eczema at 6 months of age compared to controls [22% vs. 43%, respectively, relative risk (RR) 0.50, 95% confidence interval (CI) 0.28 to 0.90; p-value = 0.017].42 Another small trial of 118 infants in Japan showed similar results, with 32% fewer neonates who received moisturiser developing eczema by week 32 when compared with control infants.45

On the basis of the need to prevent eczema, empirical evidence on the role of a defective skin barrier as the initial event in eczema development, growing signals from observational and randomised pilot studies, a strong case was therefore made to the NIHR Health Technology Assessment Programme to fund a national trial of emollients to prevent eczema in babies at high risk of developing the condition. Timing was important as interest in the potential for emollients to prevent eczema was now becoming an entrenched belief following the two small pilot studies, and parents with a strong family history of atopic disease across the world were beginning to use emollients to prevent eczema in their newborns. Commercial companies were responding to demand by developing ‘designer’ emollients to enhance the skin barrier. The window of public/patient and healthcare professional equipoise was limited.

We therefore sought to test the hypothesis whether daily emollient application for 12 months after birth can reduce the development of eczema.