Editorial comments on “Early initiation of short‐term emollient use for the prevention of atopic dermatitis in high‐risk infants—The STOP‐AD randomized controlled trial”—Is emollient therapy enough?

Early onset, severe atopic dermatitis (AD) is the strongest risk factor for the development of food allergy in children. The Dual Allergy Exposure Hypothesis proposes that there is a narrow window of opportunity where allergen exposure first through the skin versus the gut leads to food allergy. There is a growing body of literature on primary prevention of AD as a strategy to prevent transcutaneous sensitization and food allergy. Zhong et al.1 found that preventive emollient therapy was effective in high-risk infants (with parental history of atopy) and in participants where there was no cessation of the emollient before assessment of AD. If emollients could prevent the duration of eczema, this could give more time for parents to introduce allergenic foods.2, 3 (Figure 1). In the recent publication of “Early initiation of short-term emollient use for the prevention of atopic dermatitis in high-risk infants – The STOP-AD randomized controlled trial,” Ní Chaoimh et al. published the findings from a single-center clinical trial. The STOP-AD recruited 321 term high-risk infants (parental history of AD, asthma, or allergic rhinitis) that were randomized to either twice-daily Aveeno® Dermexa fast & long-lasting balm for 8 weeks or routine skin care.4 The primary outcome was cumulative AD incidence, defined by meeting the UK Working Party Diagnostic Criteria (UKWPDC), at 12 months of age. Point prevalence of AD was 38.2% in the control arm versus 20.5% in the intervention arm (p = .003), and cumulative incidence at 12 months was 46.4% in the control arm versus 32.8% in the intervention arm (p = .036). There was no difference in skin infections between groups: 5% (6/120) in the intervention group versus 5.7% (8/140) control group. No significant differences in transepidermal water loss (TEWL) were noted between the intervention and control group at birth, 2, 4, and 8 weeks, or at 6 and 12 months. Although this study was not powered to determine food allergic outcomes, food allergy testing was based on history on history of consumption and sensitization assessed via skin prick testing (SPT) at 12 months of age for milk, egg, and peanut. There was no significant difference between groups with a positive SPT to at least one allergen reported in 3.3% (4/120) in the intervention group and 3.6% (5120) in the control group (p = 1.0), although this study was not powered to determine food allergic outcomes. There was no measure of environmental food exposure, which is a known risk for the development of food allergy.2 Analysis of microbiome diversity and inflammatory biomarkers is being performed in a subset of patients. Limitations in the study design include that AD assessment was often done remotely and monitoring of adherence was performed only via parental reporting. The STOP-AD study differed from other prevention studies (Table 1) primarily in its short duration of treatment (2 months) at a very early age (median 3.5 days), high parental reported adherence rate to the emollients (82.4% >5 days/week at least once daily) and low “contamination” of the control arm (80% used emollient ≤3 days a week). The high adherence is likely due to the short duration of treatment. In recent large RCTs, BEEP, and PreventADALL, where emollients were used for the first year, no protective effect was found. However, the emollients were initiated later with a median age of 11 days in BEEP and initiation at 2 weeks of age in PreventADALL.5 STOP-AD trial was primarily conducted in Caucasians so it would be important to ascertain whether this treatment is effective in prevention of AD in non-Caucasians, especially given that food allergy can develop early in non-Caucasians.6 Type of emollients can also play a role in the response. In BEEP, a petroleum-based formulation and in PreventADALL a paraffin-based formulation were used. A prior publication (PEBBLES Pilot study)7 has shown a promising results toward the improved response of AD in response to ceramide containing emollients and the PEBBLES study is underway (https://clinicaltrials.gov/ct2/show/NCT03667651). Frequency and surface area application of the emollient could also matter. In Table 1, we present a description and comparison of other randomized controlled trials for the primary prevention of AD using emollients.1, 5, 8 The investigators cited increased transepidermal water loss (TEWL) from birth to 2 months and followed by stabilization as the rationale for the study based on their prior publications; however, no changes in TEWL were noted between the intervention group or control group at any of the time points. Our group has shown that even short-term use of a creams (both trilipid cream and paraffin-based emollient) can decrease TEWL after just 5 weeks of use.9 Based on the outside-in hypothesis, barrier enhancement may be sufficient to prevent AD; however, in the inside-out hypothesis whether anti-inflammatory agents are required to address the skewed immune response remains to be seen (Figure 1). Future directions in this field include combination of emollient with anti-inflammatory topical treatments. Treatment of dry skin or eczema with emollients and topical steroids is currently under evaluation in the PACI (Prevention of Allergy via Cutaneous Intervention: UMIN-CTR: UMIN000028043) and SEAL (Stopping Eczema and Allergy Study: https://clinicaltrials.gov/ct2/show/NCT03742414 study). Future implications of the STOP-AD study findings are profound. This is a simple, cheap, short intervention that could potentially affect the progression of the allergic march. It will be important to assess the impact of the prevention of AD on food sensitization and allergy. All authors contributed equally to the writing of the manuscript. We thank Dr. Vanitha Sampath for preparing the manuscript for submission. None. Dr. Sindher reports grants from NIH, Regeneron, DBV Technologies, Aimmune, Novartis, CoFAR, and FARE. She is an Advisory member at Genentech and DBV Technologies. Dr. Nadeau reports grants from National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS), and Food Allergy Research & Education (FARE); stock options from IgGenix, Seed Health, ClostraBio, and ImmuneID; is Director of the World Allergy Organization Center of Excellence for Stanford, Advisor at Cour Pharma, Consultant for Excellergy, Red tree ventures, Eli Lilly, and Phylaxis, Co-founder of Before Brands, Alladapt, Latitude, and IgGenix; and National Scientific Committee member at Immune Tolerance Network (ITN), and National Institutes of Health (NIH) clinical research centers, outside the submitted work; patents include, “Mixed allergen composition and methods for using the same,” “Granulocyte-based methods for detecting and monitoring immune system disorders,” and “Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders.” Dr. Brough reports research grants from National Institute of Allergy and Infectious Diseases (NIAID), Aimmune and DBV Technologies, speaker honoraria from DBV, Sanofi and GSK outside of the submitted work.