The State of Prevention in Atopic Dermatitis

The etiology of atopic dermatitis (AD), characterized by chronic, relapsing flares of erythema, xerosis, and pruritus,¹ likely represents a complex interplay between genetics and environment, which influences the severity of symptoms and presentation. Known risk factors for the development of AD include a first-degree relative with atopy and mutations in the gene coding for filaggrin.^2,3 The hygiene hypothesis provides an intriguing environmental explanation for the increased incidence of AD seen in recent years, especially in developed countries: as populations continue to become more urban and living conditions more sanitary, children experience reduced exposure to external antigens and microorganisms, possibly predisposing them to inappropriate autoimmune Th2 responses.^4,5

The pathogenesis of AD continues to be elucidated, but it is thought that early disruption of the skin barrier plays a significant role in its development.⁶ While therapeutic regimens for existing AD are well described in the literature, methods of prevention continue to be an area of debate. It was estimated that in 2015, the total economic burden of AD in the US was upwards of $5 billion, and the impact on the quality of life of patients and families only adds to this significant financial cost.⁷ However, a 2017 study showed that daily moisturization may represent a cost-effective, preventative strategy in high-risk infants to reduce the burden of AD. When measured in incremental cost-effectiveness values ($/QALY) for a six-month window, the benefit was significant enough (0.021) to qualify prophylactic moisturization to meet the National Institute for Health and Care Excellence of the UK’s threshold for cost-effectiveness.⁸ Currently, up to 20 percent of children and three percent of adults are affected by AD, and these numbers are on the rise, making it clear that further research into evidence-based, easy-to-implement prevention strategies is needed.⁹ This discussion explores the ways in which novel prevention strategies may target points of disruption in the pathogenesis of AD and potentially prevent or delay development of AD.

The Skin Barrier

A better understanding of the structure and function of the skin barrier has led to more sophisticated prevention strategies for AD, particularly in the fields of moisturizers and probiotics. To understand why these treatments have been effective, it is necessary to review how the skin barrier is disrupted in AD and how these modalities address these disruptions. Strugar, et al. suggest a functional model to understanding the skin barrier. An outer microbiome layer is followed by a chemical layer, a physical layer, and an inner immunologic layer. The outer microbiome of the skin is composed of a variety of commensal organisms in healthy individuals but is characterized by an increase in Staphylococcus aureus in AD.^6,10 The exact mechanism of how alterations in the skin microbiome lead to barrier disruption is unclear, but S. aureus is known to produce exotoxins that cause breakdown of the skin and may lead to increased penetration of allergens and antigens from the environment into deeper layers of the skin. These foreign antigens may subsequently sensitize resident immune cells and result in an inflammatory response.⁶ In patients with AD, both areas of normal skin and affected skin show colonization with S. aureus, at 39 percent and 70 percent, respectively.¹⁰ Probiotic-, prebiotic-, and synbiotic-based prevention strategies seek to encourage growth of commensals seen in healthy individuals and to prevent over-colonization with S. aureus.^2,10

The discovery that patients with AD often have loss of function (LOF) mutations in the FLG gene coding for filaggrin has furthered our understanding of the physical and chemical disruptions of the skin barrier present in AD. Filaggrin aggregates keratin filaments to create keratin bundles that form a rigid structure and stabilize the corneocytes of the stratum corneum (SC). The breakdown products of filaggrin make up a part of the chemical layer of the skin and form “natural moisturizing factor” (NMF) found in the SC which helps to hydrate the skin by retaining moisture with hygroscopic elements.^6,10 A combination of ceramides, cholesterol, and fatty acids forms a lipid-based binding layer between the corneocytes, which prevents additional loss of water and also helps seal the SC from epicutaneous antigens.¹² In AD, each of these physical and chemical components may be disrupted. LOF mutations in FLG result in reduced production of filaggrin and subsequent loss of stability and hydration in the SC. Reduced levels of filaggrin are also thought to play a role in the loss of lipid secretion from keratinocytes, leading to incomplete sealing of the SC and further water loss with barrier dysfunction. The combined effect of these changes results in disruption of the skin barrier and increased penetration of pro-inflammatory allergens and microorganisms into the immunologic layer.^6,13

Prevention efforts focus on the use of moisturizers to both hydrate the skin and form a protective layer within and over the disrupted skin barrier. It is possible that moisturizers may also alter the skin barrier by reducing bacterial colonization. A prospective, randomized trial compared the efficacy of a cream containing a 5% lysate of Vitreoscilla filiformis with a control cream and found that those who received the cream plus lysate had significantly decreased disease severity (as measured by SCORAD, pruritus, and lack of sleep) over 30 days. The authors posited that the antimicrobial peptides contained within the
V. filiformis lysate may have reduced the amount of S. aureus colonization. Even lesional skin without S. aureus colonization showed improvement, possibly suggesting an additional immunomodulatory effect of the lysate.⁴ While not a trial specifically measuring prevention of AD, it nonetheless is an exciting finding that supports alteration of the microbiome as a method of controlling AD.

Moisturizers

Regular application of moisturizers is a critical component of therapy for AD and currently carries a class IA recommendation.¹⁴ Moisturizers can broadly be classified into three different types: humectants, occlusives, and emollients (Table 1). Humectants work to hydrate the SC by drawing water from deeper within the skin and surrounding air into the SC.^12,13 Products containing glycerin, alpha hydroxy acids, hyaluronic acid, sorbitol, and urea all have humectant properties. Occlusives form a water-resistant layer over the surface of the skin to prevent water loss from the SC; some examples include lanolin, mineral oils, petrolatum, and silicone.¹³ AD often flares during the dry winter months, and combining a humectant with an occlusive has been shown to be effective for treatment.¹²

Emollients have a higher lipid content than both humectants and occlusives and are able to incorporate deeper into the SC, filling the gaps surrounding corneocytes and helping to retain moisture. Ingredients such as glyceryl stearate, isopropyl palmitate, shea butter, and stearic acid have emollient properties, and it may be of use to pair them with a humectant in a similar fashion as is suggested with occlusives.^6,13 Many ingredients can have multiple functions in a formulation, however, and finished products frequently have all of these properties to some degree.

Moisturizers have been a mainstay in treatment of AD, but it remains unclear which type of moisturizer and what duration of use from birth helps achieve prevention. It is known that the infant skin barrier does not function as well as adult skin during the first year of life; thus, this may be a critical time for intervention with full-body moisturizers in high risk infants.¹⁵ Although an established regimen depicting primary endpoints does not yet exist, it is thought that supporting the barrier is an appropriate goal, and as such, liberal and frequent use of the desired moisturizer may be a method for prevention of AD.^14,16

A promising pilot study sought to determine whether daily application of moisturizer therapy from birth reduces the incidence of AD in high-risk infants. Types of moisturizers used ranged from sunflower seed oil, liquid paraffin 50% in soft white paraffin, Doublebase Gel, Cetaphil Cream, or Aquaphor Healing Ointment. Results showed a 50 percent relative risk reduction between the treatment and control groups (P = .017) with no adverse effects reported.⁹ Additionally, a randomized controlled trial involving infants at high risk for AD found that combining petroleum jelly with an emollient resulted in 32 percent fewer infants developing signs of AD at 32 weeks than when using petroleum jelly alone.¹⁵ In both studies, the term “high-risk” was used to refer to an infant with a sibling or parent with diagnosed AD.^15,17

On the other hand, two newer randomized control trials, the 2017 BEEP trial and the 2018 PreventADALL trial, present somewhat discouraging data regarding the use of moisturization for preventing AD. The BEEP trial sought to determine the effectiveness and cost-effectiveness of daily all-over-body application of moisturizer during the first year of life for preventing AD in high-risk children. The study projected a protective effect of 30 percent at year one, but rates of AD were similar (23 percent vs 25 percent; adjusted relative risk, 0.95; P=.91) at year two.¹⁸ Furthermore, the PreventADALL study randomized infants to a skin intervention, food intervention, skin and food intervention, or no intervention. The infants in the skin intervention were bathed in water with liquid paraffin and trilaureth-4-phosphate oil, and their faces were covered with Ceridal cream at least 3.5 days per week for at least 16 weeks. At 12-month follow-up, it was found that AD was actually more common in those infants who had received the skin intervention compared to those who had not (11.1 vs. 8.1 percent).¹⁹ Of note, this trial differed from others as whole body emollient application was not used; rather, infants were exposed to an oil bath and facial moisturizer only. The study was also done in a more general group of children rather than high-risk individuals. Another study attempted to identify if synbiotics (a combination of probiotics and prebiotics) and emollients, either used individually or together, reduced rates of AD in infants up to one year of age. While no benefit was found either individually or in combination, this study also included infants considered to be of average risk for developing AD and parents were not explicitly instructed to apply the emollient over the full body.²⁰ These disparities emphasize the need to better understand who is at risk and which—if any—specific moisturizing regimens may be protective.

The Microbiome, Probiotics, and Prebiotics

The microbiome refers to all of the commensal organisms living on and within the human body. Alterations in the microbiome are associated with many chronic diseases, including AD. It is thought that an individual’s microbiome may affect his/her response to allergic sensitization and dysbiosis may increase the risk for developing atopic conditions. Recommendations for supporting optimal skin and gut microbiome health include vaginal delivery, feeding with breast milk, vitamin D supplementation in pregnant women and infants, and judicious use of antibiotics early in life.¹⁰

There is established evidence that the skin microbiome is altered during flares of AD. At baseline, inflamed skin in AD has increased amounts of Staphylococcus sp., especially S. aureus, and decreased amounts of Cutibacterium, Streptococcus, Acinetobacter, Corynebacterium, and Prevotella. Between 30 to 100 percent of patients with AD may carry S. aureus on their skin, while this number is closer to 20 percent in healthy individuals.¹⁰ The gut microbiome is also thought to play a role in the pathogenesis and severity of AD. Dysbiosis of the gut, along with inflammation and other stressors, may impair the gut barrier and is implicated in several disorders including AD.²¹ Disruptions in the gut barrier secondary to dysbiosis may allow antigens to pass into the systemic circulation where they could stimulate Th2 responses in the skin. Conversely, an appropriately diverse gut microbiome favors the proliferation of regulatory T-cells and inhibits the proliferation of Th2 cells and subsequent inflammation.¹⁰

Similar to changes seen in the skin microbiome during AD exacerbations, changes in the gut microbiome can also be seen. Infants with AD have a less diverse gut microbiome with lower levels of Bifidobacterium and Bacteroides and higher levels of Staphylococcus.¹⁰ Fecal analysis of 957 infants at one month of age showed an increase in E. coli and C. difficile with AD and all atopic disorders, respectively.²² Nylund et al performed microarray profiles on fecal samples of 34 infants at high risk for AD and found that the gut microbiota differed significantly by 18 months of age. Children without AD had three times as many Bacteroidetes while those with AD had more Clostridium, akin to what is seen in adults.²³ For these reasons, interventions that involve optimizing the health of the microbiome present another strategy for the prevention of AD. Although the efficacy of probiotics, prebiotics, and synbiotics is less established when compared to moisturizer use, there is some encouraging research regarding their effects in the prevention of AD.

Probiotics are non-pathogenic strains of bacteria found in abundance in individuals with a healthy gut microbiome. Commonly used strains in probiotics include Lactobacillus rhamnosus, Lactobacillus fermentum, Lactobacillus paracasei, and Bifidobacterium longum.²⁴ Prebiotics are non-living, fermentable carbohydrates that support the growth of the gut microbiome and may be found in foods such as breast milk and foods containing fermentable fiber. Like those studies which analyzed the efficacy of moisturizer therapy in the prevention of AD, research suggests that probiotic, prebiotic, and synbiotic therapy is most effective in infants considered to be high-risk for developing AD. A prospective, double-blind, randomized controlled trial conducted by Kalliomäki et al found that the infants of pregnant mothers who received 1x1010 colony-forming units of Lactobacillus GG prenatally for two to four weeks and six months postnatally were around 50 percent less likely to develop AD at two years of age.²⁵ The same group of researches followed the cohort at seven years of age and found that those in the treatment arm still reported lower rates of AD (RR = 0.64, CI 0.45-0.92).²⁶

Prebiotics showed benefit even when given to infants only during the postnatal period and in low-risk populations.² Grüber et al performed a study in which infants younger than eight weeks of age considered to be low-risk for AD received formula supplemented with prebiotic oligosaccharides. They found that for every 25 infants who received the supplemented formula, one case of AD was prevented.²⁷ These results, in combination with recommendations from the World Allergy Organization (WAO), support manipulation of the microbiome with pre- and probiotics.

Miscellaneous Approaches

Some research has been conducted regarding additional possible preventative therapies for AD (Table 2). Breastfeeding remains a popular method among high-risk families for prevention of AD. A study involving more than 2,000 children in South Korea found that parents with allergic disease were more likely to breastfeed their children and to continue breastfeeding for longer amounts of time.²⁸ It is known that breastfeeding reduces the likelihood that infants will develop infections involving the gut, and perhaps breastmilk may serve to prevent AD by improving the composition of the gut microbiome.^29,30 Schoetzau et al found that infants at high risk for atopy benefitted from at least four months of breastfeeding in order to prevent AD during the first year of life.³¹ Likewise, Kull et al reported that even in parents without atopic disease, exclusive breastfeeding for at least the first four months of life reduced the risk of AD at four years of age.³² Conversely, a study involving more than 10,000 children conducted by Hong et al found that breastfeeding for more than 12 months was actually a risk factor for developing AD.³³ A prudent counterargument posits that “reverse causation” could be a factor, as families with history of AD are more likely to breastfeed their children for longer periods of time.³⁴ Munblit et al suggest that maternal breast milk may not be entirely suited to new allergens found in the modern environment, and as such, could be a contributing factor to the mixed evidence surrounding its use in preventing AD.³⁰ Supplementation of maternal breastmilk could be an option to increase its effectiveness in preventing atopic disease, and perhaps incorporating the aforementioned strategies will provide a synergistic effect towards the prevention of AD.

More recently, vitamin D supplementation has been suggested as a preventative intervention due to its involvement in regulatory mechanisms of both the innate and adaptive immune system. Its protective effect on AD remains controversial, with some studies suggesting that vitamin D decreases the susceptibility to infection in patients with AD and controls the local inflammatory immune response.³⁵ One meta-analysis examining vitamin D supplementation and AD symptoms found a higher mean difference in AD symptoms after supplementation (mean-5.81, 95% CI: −9.03, −2.59) in established AD, suggesting that vitamin D supplementation may help ameliorate the severity of AD.³⁶ However, the protective effect of vitamin D on AD development has been both supported and refuted, making it difficult to make a firm recommendation just yet.³⁷

Long-chain n-3 fatty acids have also been studied in the prevention of AD. The mechanism is suggested to be a reduction in allergic sensitization, with two of five studies reporting reduced prevalence of IgE-mediated AD in the offspring of pregnant women treated with n-3 fatty acids.³⁸ Similar to vitamin D, the level of evidence currently remains weak for long chain n-3 fatty acids as a primary prevention strategy in AD.

Conclusion

Focusing on the disrupted skin barrier found in AD as a target for prevention in infants is an area of exciting new research. Understanding that the functions of the skin barrier are multifaceted—microbial, chemical, physical, and immunologic—provides many different areas to target. Perhaps the best method of prevention is not to target one of these barrier components in particular, but to incorporate a combined prevention strategy which tackles barrier dysfunction from different angles. Studies with larger sample sizes are likely needed to further assess the utility of moisturizers and probiotics in AD and to better understand who is at risk and which, if any, specific moisturizing regiments may be protective. Regardless, targeting skin barrier dysfunction with non-pharmacologic, low-risk therapeutics remains a promising area for future research.

Peter A. Lio, MD is a Clinical Assistant Professor of Dermatology and Pediatrics at Northwestern University Feinberg School of Medicine and a partner at Medical Dermatology Associates of Chicago.

Neha Chandan, MPH is a fourth-year medical student at the University of Illinois.

Jeffrey Rajkumar is a third-year medical student at the University of Illinois.

1. Bhanot, A., Huntley, A. & Ridd, M. J. Adverse Events from Emollient Use in Eczema: A Restricted Review of Published Data. Dermatol. Ther. 9, 193–208 (2019).

2. Szari, S. & Quinn, J. A. Supporting a Healthy Microbiome for the Primary Prevention of Eczema. Clin. Rev. Allergy Immunol. (2019). doi:10.1007/s12016-019-08758-5

3. Irvine, A. D., McLean, W. H. I. & Leung, D. Y. M. Filaggrin mutations associated with skin and allergic diseases. N. Engl. J. Med. 365, 1315–1327 (2011).

4. Gueniche, A. et al. Effects of nonpathogenic gram-negative bacterium Vitreoscilla filiformis lysate on atopic dermatitis: a prospective, randomized, double-blind, placebo-controlled clinical study. Br. J. Dermatol. 159, 1357–1363 (2008).

5. Okada, H., Kuhn, C., Feillet, H. & Bach, J.-F. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin. Exp. Immunol. 160, 1–9 (2010).

6. Strugar, T. L., Kuo, A., Seité, S., Lin, M. & Lio, P. Connecting the Dots: From Skin Barrier Dysfunction to Allergic Sensitization, and the Role of Moisturizers in Repairing the Skin Barrier. J. Drugs Dermatol. JDD 18, 581 (2019).

7. Drucker, A. M. et al. The Burden of Atopic Dermatitis: Summary of a Report for the National Eczema Association. J. Invest. Dermatol. 137, 26–30 (2017).

8. Xu, S. et al. Cost-effectiveness of Prophylactic Moisturization for Atopic Dermatitis. JAMA Pediatr. 171, e163909 (2017).

9. Nutten, S. Atopic dermatitis: global epidemiology and risk factors. Ann. Nutr. Metab. 66 Suppl 1, 8–16 (2015).

10. Kim, J. E. & Kim, H. S. Microbiome of the Skin and Gut in Atopic Dermatitis (AD): Understanding the Pathophysiology and Finding Novel Management Strategies. J. Clin. Med. 8, (2019).

11. Robinson, M., Visscher, M., Laruffa, A. & Wickett, R. Natural moisturizing factors (NMF) in the stratum corneum (SC). I. Effects of lipid extraction and soaking. J. Cosmet. Sci. 61, 13–22 (2010).

12. Elias, P. M., Wakefield, J. S. & Man, M.-Q. Moisturizers versus Current and Next-Generation Barrier Repair Therapy for the Management of Atopic Dermatitis. Skin Pharmacol. Physiol. 32, 1–7 (2019).

13. Giam, Y. C. et al. A review on the role of moisturizers for atopic dermatitis. Asia Pac. Allergy 6, 120–128 (2016).

14. Eichenfield, L. F. et al. GUIDELINES OF CARE FOR THE MANAGEMENT OF ATOPIC DERMATITIS. J. Am. Acad. Dermatol. 71, 116–132 (2014).

15. Horimukai, K. et al. Application of moisturizer to neonates prevents development of atopic dermatitis. J. Allergy Clin. Immunol. 134, 824-830.e6 (2014).

16. Huang, A., Cho, C., Leung, D. Y. M. & Brar, K. Atopic Dermatitis: Early Treatment in Children. Curr. Treat. Options Allergy 4, 355–369 (2017).

17. Simpson, E. L. et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J. Allergy Clin. Immunol. 134, 818–823 (2014).

18. Chalmers, J. R. et al. Effectiveness and cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children (The BEEP trial): protocol for a randomised controlled trial. Trials 18, (2017).

19. Carlsen, K. C. L. et al. Preventing Atopic Dermatitis and ALLergies in Children—the PreventADALL study. Allergy 73, 2063–2070 (2018).

20. Dissanayake, E. et al. Skin Care and Synbiotics for Prevention of Atopic Dermatitis or Food Allergy in Newborn Infants: A 2 × 2 Factorial, Randomized, Non-Treatment Controlled Trial. Int. Arch. Allergy Immunol. 1–10 (2019). doi:10.1159/000501636

21. Peter Lio, M. D. Leaky gut, leaky skin, or both? Dermatology Times (2019). Available at: https://www.dermatologytimes.com/article/leaky-gut-leaky-skin-or-both. (Accessed: 10th August 2019)

22. Penders, J. et al. Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study. Gut 56, 661–667 (2007).

23. Nylund, L. et al. Microarray analysis reveals marked intestinal microbiota aberrancy in infants having eczema compared to healthy children in at-risk for atopic disease. BMC Microbiol. 13, 12 (2013).

24. Lio, P. A. Non-pharmacologic therapies for atopic dermatitis. Curr. Allergy Asthma Rep. 13, 528–538 (2013).

25. Kalliomäki, M. et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet Lond. Engl. 357, 1076–1079 (2001).

26. Kalliomäki, M., Salminen, S., Poussa, T. & Isolauri, E. Probiotics during the first 7 years of life: A cumulative risk reduction of eczema in a randomized, placebo-controlled trial. J. Allergy Clin. Immunol. 119, 1019–1021 (2007).

27. Grüber, C. et al. Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. J. Allergy Clin. Immunol. 126, 791–797 (2010).

28. Lee, K. S. et al. Does Breast-feeding Relate to Development of Atopic Dermatitis in Young Korean Children?: Based on the Fourth and Fifth Korea National Health and Nutrition Examination Survey 2007-2012. Allergy Asthma Immunol. Res. 9, 307–313 (2017).

29. Kramer, M. S. & Kakuma, R. Optimal duration of exclusive breastfeeding. Cochrane Database Syst. Rev. CD003517 (2012). doi:10.1002/14651858.CD003517.pub2

30. Munblit, D. & Verhasselt, V. Allergy prevention by breastfeeding: possible mechanisms and evidence from human cohorts. Curr. Opin. Allergy Clin. Immunol. 16, 427 (2016).

31. Schoetzau, A. et al. Effect of exclusive breast-feeding and early solid food avoidance on the incidence of atopic dermatitis in high-risk infants at 1 year of age. Pediatr. Allergy Immunol. Off. Publ. Eur. Soc. Pediatr. Allergy Immunol. 13, 234–242 (2002).

32. Kull, I. et al. Breast-feeding reduces the risk for childhood eczema. J. Allergy Clin. Immunol. 116, 657–661 (2005).

33. Hong, S. et al. Effect of prolonged breast-feeding on risk of atopic dermatitis in early childhood. Allergy Asthma Proc. 35, 66–70 (2014).

34. Kim, J. H. Role of Breast-feeding in the Development of Atopic Dermatitis in Early Childhood. Allergy Asthma Immunol. Res. 9, 285–287 (2017).

35. Mesquita, K. de C., Igreja, A. C. de S. M. & Costa, I. M. C. Atopic dermatitis and vitamin D: facts and controversies. An. Bras. Dermatol. 88, 945–953 (2013).

36. Kim, G. & Bae, J.-H. Vitamin D and atopic dermatitis: A systematic review and meta-analysis. Nutr. Burbank Los Angel. Cty. Calif 32, 913–920 (2016).

37. Su, J. C. & Lowe, A. J. Prevention of atopic dermatitis: Etiological considerations and identification of potential strategies. Indian J. Paediatr. Dermatol. 20, 93 (2019).

38. Gunaratne, A. W., Makrides, M. & Collins, C. T. Maternal prenatal and/or postnatal n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood. Cochrane Database Syst. Rev. CD010085 (2015). doi:10.1002/14651858.CD010085.pub2