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Atopic dermatitis/Eczema (AD) is the most common chronic inflammatory
skin disease affecting up to 30% of children. Eczema typically develops
during infancy, characterized by pruritus, dry skin, and eczematous
dermatitis/skin irritation and often represents the initial
manifestation of the so-called atopic march.
Thus, skin barrier dysfunction due to environmental factors and genetic
predisposition paired with skin inflammation is linked to AD and
consequently food sensitization, food allergy (FA) and progression of
the allergic disease complex (Figure 1).1 The
importance of barrier integrity for AD is supported by filaggrin (FLG).
It is integral in maintaining stratum corneum
integrity.1 Loss of function mutations of FLG gene
confer a greater risk of AD.2 The association between
mutations in the FLG gene and FA independently of AD is under debate due
to conflicting epidemiological data.2 However, skin
barrier dysfunction may also be relevant at subclinical levels
facilitating type-2 skin inflammation which in turn reduces FLG
expression.2 By connecting the dots between skin
barrier dysfunction and food avoidance in the context of environmental
food exposure compared to concurrent consumption, the dual-allergen
exposure hypothesis has been developed. It is strongly supported by the
results of the LEAP study.3 The hypothesis suggests
that cutaneous allergen exposure and concurrent compromised barrier with
skin inflammation while delaying food introduction results in a greater
susceptibility for FA. Allergen exposure in such an inflammatory skin
context is considered to promote type-2 inflammation.2
Increased transepidermal water loss (TEWL), a surrogate marker of
reduced barrier function, precedes AD development.2TEWL is lowest at birth and increases within the first two months before
plateauing at 6 months, identifying this period as a window of
opportunity for preventive interventions.2 Pilot
studies with paraffin-based emollients suggested a 50% risk reduction
of developing AD (43% controls vs 22% emollient treated
patients).4,5 While applying ointment is a central
therapeutic concept for AD treatment, the preventive effect of ointments
for AD and potentially allergic disease development remains to be
established via large prospective interventional trials.
Therefore, two prospective, open-label, interventional, randomized
preventive trials have attempted to assess the potential of emollients
for the primary prevention of AD. These two investigator-initiated
studies, the BEEP (Barrier Enhancement for Eczema
Prevention)6 and the PreventADALL (Preventing Atopic
Dermatitis and Allergies)7 trial have shown otherwise
(Figure 2). Both attempted to create a real-life setting giving parents
a lot of control over treatment administration: The BEEP study enrolled
1394 high-risk infants (a first-degree relative with physician diagnosed
allergic disease) to receive either a daily paraffin-based emollient or
a standardized skin-care regimen within the first 3 weeks of
life.6 The PreventADALL study studied 2397
population-based infants assessing two interventions: daily
petroleum-based emollient usage in the facial area and bathing additives
(8-month intervention, minimum four days/week) compared to a food
introduction protocol, a combination of both or best skin care practice
(controls).7 Food introduction consisted of sequential
introduction of peanut butter at 3 months of age, with cow’s milk, wheat
porridge, and scrambled egg sequentially following each week. The
primary outcome of BEEP was the development of eczema at two years of
life after the one-year intervention that consisted of a daily
whole-body application with a good adherence (minimum of application: at
least 3-4 days per week in at least two areas: face and neck, arms and
legs, or trunk) of 88% at 3 months, 82% at 6 months and 74% at 12
months.6 The PreventADALL’s primary outcomes were AD
at the age of 12 months and food allergy at age 3 (not reported yet).
In the BEEP study, AD occurred at comparable rates at the age of 2 years
(23% vs 25%, n.s.).6 The PreventADALL study also
reports null findings for AD prevention via ointment application in a
population-based setting (8% control, 11% emollient group, 9% early
allergen complementary feeding group, 5% combined intervention, at year
1).7 This study adds an additional component, the
value of concurrent early food introduction for the prevention of AD. Of
note, the combined intervention of emollient and early food introduction
had a tendency to reduce eczema prevalence (8% vs
5%).7 This finding was not considered clinically
meaningful, defined as 1 case of AD prevented in 14 cases treated
(Δ7%).7 Results raise more questions regarding
preventive approaches in the field of atopic diseases than they answer
and exemplify the complex nature of AD. There are also a number of
limitations: the PreventADALL study suffered from limited adherence
(27% skin intervention7, 30% food
intervention7), used an unusual approach when choosing
a facial application of the emollient (face only7),
and the very early introduction strategies may have impacted compliance
(3 months7). Neither of the two studies addressed a
key factor which is inflammation. Absence or suppression of inflammation
when addressing barrier dysfunction may be key. Another important
consideration is that not all emollients are the same. Petroleum-based
approaches have been demonstrated to be less effective in reducing TEWL
compared to ceramide-based approaches.8 Ointment
application may have to occur several times per day and at least 5 days
per week to affect barrier function. Moreover, poor compliance was not
due to adverse/safety effects of the interventions. These limitations
await to be addressed in future and ongoing studies (PEBBLES
(NCT03409367), CASCADE (NCT03409367), and PACI (UMIN-CTR:
UMIN000028043)).
Previous studies identified ointments, especially those of peanut oil
origin which comprise largely of lipids and not protein, as a potential
facilitator of allergy.9 The presence of emollients
may facilitate uptake of certain substances, including allergens, in the
superficial epithelial cell layers instead of protecting the skin
barrier.2 It is unclear to what extent this could have
played a role in these two studies as different preparations may elicit
different effects on the immune system.
Understanding barrier function and inflammation of the skin and the
mucosal surfaces early in life is key to design novel preventive
interventions and these two studies have added important negative data
to design alternative approaches. Thus, usage of petroleum-based
emollients specifically and emollient in general as a primary prevention
for AD is not supported until further evidence in favor is
generated.