A randomized trial of a barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitization: the PEBBLES pilot study

Dear Editor, It is hypothesized that the impaired skin barrier in atopic dermatitis (AD) allows the immune system to be exposed to environmental allergens, resulting in sensitization and allergic disease.1 Two small trials recently found that routine use of emollients reduced the incidence of AD during the active treatment period by approximately half.2,3 It remains unknown whether prophylactic use of emollients can prevent the development of AD beyond the treatment period (as opposed simply to delaying its onset) or whether this reduction in AD leads to a reduced risk of allergic sensitization. The previous trials in this area have used standard emollients.2,3 In this trial, we chose a ceramide‐dominant emollient (EpiCeram™; PuraCap Pharmaceutical LLC, South Plainfield, NJ, U.S.A.), as it may provide greater preventive effects.4 Skin affected by AD is deficient in ceramides.5 EpiCeram has been formulated to contain physiological ratios of ceramides, cholesterol and free fatty acids, and has a slightly acidic pH (5·0), which aids the production and secretion of ceramides by the skin.6 Acidic emollients have been shown to help prevent AD and airway inflammation in a murine model.7 We have previously demonstrated parent compliance, and initial evidence of safety, for use of EpiCeram for AD prevention in neonates.8 We conducted a pilot randomized, parallel, single‐blind (outcome assessor), controlled trial of the effect of twice‐daily application of EpiCeram for the first 6 months of life on the incidence of AD and skin barrier function in high‐risk infants up to 12 months of age. Term infants with a family history of allergic disease were recruited from maternity wards (Appendix S1; see Supporting Information). At enrolment, parents of infants in the intervention group were shown how to apply approximately 6 g of EpiCeram to the full skin surface of their child twice per day. Treatment was to commence within the first 3 weeks. No other skincare instructions were provided to either group. Clinical follow‐up of infants by a blinded assessor (C.A.) occurred at 6 weeks, 6 months and 12 months of age. Transepidermal water loss (TEWL), skin pH, hydration and ‘oiliness' (sebum) were assessed using standardized protocols (Courage & Khazaka, Cologne, Germany). At 6 and 12 months, skin prick tests were performed to six common allergens along with saline and histamine controls (Stallergenes lancets: Stallergenes, Antony, France; HollisterStier aero‐allergen extracts: HollisterStier, Spokane, WA, U.S.A.; ALK food allergen extracts: ALK, Inc., Round Rock, TX, U.S.A.). A total of 1306 infants were screened and 80 were recruited. The groups were well balanced on a range of baseline factors. There was minimal loss to follow‐up at each time point (Appendix S1). There were no adverse reactions to the study cream. Adherence to the intervention was high (76% applied the cream for ≥ 5 days per week). Use of other emollients (not study treatment) for on average ≥ 3 days per week during the intervention period occurred in 39% of the control group and 18% of the intervention group. Intention‐to‐treat analysis showed no significant effect of routine barrier lipid replacement in early life on AD or sensitization outcomes. However, there was a trend towards reduced risks of AD and food sensitization in the intervention group at 6 and 12 months of age (Table 1 and Appendix S1). Adjustment for slight baseline imbalances between groups (presence of siblings, forehead TEWL) did not materially alter the results (data not shown). Per protocol analyses (only including infants who received ≥ 5 days per week of study treatment) revealed a significant reduction in food sensitization at 12 months in the treatment group (0%, 0 of 21 vs. 19%, seven of 36, P = 0·04). There were no differences between groups for biophysical properties of the skin. Among the intervention group, children who developed food sensitization had a later initiation of treatment (Appendix S1). Effect of intervention on atopic dermatitis (AD) at 6 weeks, 6 months and 12 months CI, confidence interval. aEstimated using Fisher's exact test. bCombines responses from prior clinical assessments. cFood allergens: egg white, cow's milk and peanut. dInhalant allergens: dust mite, cat dander and rye grass. Effect of intervention on atopic dermatitis (AD) at 6 weeks, 6 months and 12 months CI, confidence interval. aEstimated using Fisher's exact test. bCombines responses from prior clinical assessments. cFood allergens: egg white, cow's milk and peanut. dInhalant allergens: dust mite, cat dander and rye grass. We found that twice‐daily prophylactic use of a ceramide‐dominant emollient, from the neonatal period to 6 months of age, was associated with a trend towards reduced incidence of AD and food sensitization at age 12 months, suggesting that the beneficial effects persisted for ≥ 6 months after stopping treatment. While these results require confirmation, they support a role for skin barrier emollients in prevention of sensitization and eczema beyond the treatment period. If barrier improvement interventions can prevent sensitization and/or the development of chronic inflammatory processes in the skin that are found in adult AD, there may be long‐term preventive effects. Interestingly, we were unable to detect any effect of the intervention on skin barrier function (as measured by TEWL). While the effect size seen in this study for AD outcomes is similar to that in studies using standard emollients,2,3 this is the first study to report outcomes beyond the treatment period or trends for reduced food sensitization. Larger studies are required to examine the impact of such interventions on the development of other important outcomes, including food allergy and asthma. As EpiCeram is much more expensive than standard emollients, head‐to‐head studies and economic analysis would be required to demonstrate cost‐effectiveness. If such strategies are effective, they are likely to be incorporated into public health practice, as they are simple to implement and may help reduce the burden of these common conditions. We thank Dr Lyle Gurrin, University of Melbourne, for assistance with developing the randomization sequence, and Kaye Hynes, Royal Children's Hospital, for management of study cream dispensing and storage. Most importantly, we thank all of the PEBBLES children and parents for their participation and ongoing support for this study. M.L.K.T. and S.C.D. are equal senior authors. Funding sources: this trial was supported by the Financial Markets Foundation for Children, and the Asthma Foundation of Victoria. Additional support was obtained via an NHMRC equipment grant to purchase instruments used to measure biophysical aspects of skin. PuraCap provided EpiCeram™, the study intervention, at no cost to the study. PuraCap had no role in the study design or decision to publish the results presented in this paper. A.J.L., S.C.D., K.J.A. and M.C.M. are supported by NHMRC fellowships. Conflicts of interest: none declared. Appendix S1 Supplementary methods and results.