Ceramide-based Moisturizers as Treatment for Pediatric Atopic Dermatitis

Dušan Sajić, MD, PhD¹ and Sandy Skotnicki, MD, FRCPC²

¹Divisions of Dermatology and Occupational Health, University of Toronto Dermatology, Toronto, ON
²Bay Dermatology Centre, Toronto, ON
Adapted from Skin Therapy Letter. 2012;17(7) with content updates.

Introduction

Atopic dermatitis (AD) is a chronic inflammatory, xerotic and pruritic skin disease of increasing prevalence affecting 15-30% of children and 2-10% of adults.¹ AD and its associated health consequences present significant challenges to patients, particularly children and their families.² This includes unrelenting pruritus and an increased association with asthma, food allergies, allergic rhinitis and a predisposition to cutaneous infections.¹ While the precise sequence of biochemical events leading to the development of AD is not fully understood, increasing evidence shows a complex interplay of environmental and genetic factors that affect the epidermal barrier and immune system. Barrier repair emulsions with good efficacy and safety profiles can mitigate the negative sequelae and help reduce the need for topical glucocorticosteroids.

Epidermal Barrier Dysfunction in the Pathogenesis of AD

The “Inside-Out” Effect

• The primary initiating mechanism in the pathogenesis of AD was thought to arise from an immune dysfunction leading to a T-helper cell 2 (Th2) polarized response, which results in disruption of the epidermal barrier.^1,3,4 This is known as the “inside-outside concept” of AD.
• The “inside-out” concept of AD pathogenesis has served as the cornerstone behind many of the current therapeutic strategies which target the dysfunctional immune system in AD.
• However, a growing body of evidence shows that a primary defect in the epidermal barrier, specifically the constituents of the cornified envelope, plays a major role in initiating and driving AD, in addition to the Th2 immune response.3

The “Outside-In” Effect

• The stratum corneum (SC) provides a water-tight barrier that prevents both internal fluid loss and penetration by hostile external organisms.
• Evidence suggests that rather than just forming a static physical wall the SC is able to sense and modulate its responses depending on different external physical, biological or chemical challenges.^5,6,7 The penetration of the SC through any of these mechanisms results in the release of cytokines that can initiate, polarize and perpetuate the immune-inflammatory response of many inflammatory dermatoses. This is known as the “outside-in” concept.
• The “outside-in” concept suggests that a primary defect present in the SC is a key driver of the inflammatory cascade of AD. This predisposes to increased trans-epidermal water loss (TEWL), inflammation, penetration of irritants, allergens, and secondary infection.⁸
• Data now demonstrate the capacity of the cutaneous barrier to initiate and perpetuate AD including observations that:
  1. Defects in the barrier result in elevated pH that activates proteases capable of directly inducing a Th2 inflammatory response.⁹
  2. Severity of the barrier defect parallels AD severity.^10,11
  3. Barrier defect persists longer than both the clinical lesions and the underlying inflammation.¹¹

Morphological Changes in Epidermal Lipids in AD

• The SC is made up of a multicellular, vertically stacked layer of cells embedded within a hydrophobic extracellular matrix.
• This matrix is derived from the secretion of lipid precursors and lipid hydrolases, both of which are secreted from lamellar bodies in the stratum granulosum.
• In physiological balance, the approximate proportions of the lipid component are predominantly composed of 50% ceramides, 25% cholesterol, and 10-20% free fatty acids.⁸
• In AD, there is a decrease in all three of these lipids, especially ceramides, which are found in both lesional and non-lesional skin.¹
• A lipid imbalance and inadequate amounts of ceramides contribute to defective formation of the corneocyte lipid envelope and lipid mortar. This correlates with increased TEWL and enhanced barrier permeability.
• Moreover, ceramides may directly inhibit the immune response as evidenced by a very recent report showing that a ceramide-leukocyte mono-immunoglobulin-like receptor 3 (LMIR3) complex inhibited the activation of mast cells – a key mediator in pruritis.¹²
• In addition to ceramide defects, numerous exogenous factors can exacerbate barrier dysfunction, specifically soaps and surfactants in detergents that accelerate corneocyte and lipid degradation.
• Several antigens, including those from cockroaches, Staphylococcus aureus, dust mites, and scabies are also known irritants and can contribute further to the cycle of inflammation and pruritus.¹

Lipid Replacement Therapy in AD

• Traditionally viewed as an immunological disorder, therapies for AD have included topical steroids and immunomodulators and sometimes more aggressive immunosuppressive agents that do not target the underlying structural barrier abnormalities.^{3, 13}
• Currently, emollients, ointments and oils thought to prevent epidermal water loss and inhibit sensitizing exogenous peptides from traversing the compromised barrier have become the first-line/adjunctive therapy in patients with AD.
• A new nonpharmacologic approach has emerged resulting from an improved understanding of AD etiopathogenesis. Aimed at barrier repair, ceramide-dominant, physiological lipid-based topical emulsions involve the delivery of balanced proportions of SC-specific lipids to assist in correcting epidermal barrier dysfunction.
• In addition to assisting in restoration of the lipid defect in AD, ceramide-based emulsions also help to normalize the pH of the skin, which is separately associated with a decrease in epidermal barrier integrity, increased inflammation, and reduced antimicrobial defenses.^14,15

Ceramide-based Emulsions in the Pediatric Population

• Ceramide-based emulsions, such as EpiCeram® and TriCeram®, contain the physiological 3:1:1 molar ratio of ceramides, cholesterols, and free fatty acids, which emulates the endogenous composition of the SC and have been shown to repair SC integrity and function.¹⁶
• An analysis of the efficacy and safety of Epiceram® used in 65 patients aged three months to 16 years with mild-tomoderate AD, showed that by week three of treatment 58% of participants had an Investigator Global Assessment rating of clear or almost clear. Further, pruritis severity decreased markedly by study week three, regardless of disease severity. Patient satisfaction was reported by 71% of the study population.¹⁷
• Data from a study done in 24 children with stubborn-torecalcitrant AD who were receiving standard AD therapy demonstrated that the use of TriCeram® significantly improved Severity Scoring of Atopic Dermatitis (SCORAD) values in 22 of 24 patients by week three. Continued progressive improvement was seen in all patients between six and 21 weeks.¹⁸
• Although most early studies compared the efficacy of the three component mixtures (ceramides, cholesterols, free fatty acids) to vehicle alone, several recent reports have shown that some ceramide-dominant formulations can, on their own, induce improvements comparable to topical steroids in the treatment of mild to moderate disease.^13,19
• CeraVe®, an over-the-counter (OTC) ceramide-dominant barrier repair cream, features multilamellar vesicular emulsions (MVEs), which are similar to liposomes but facilitate a 24-hour time-released delivery.
• Time-released MVEs offer once-daily application, thereby encouraging adherence to a simplified regimen of moisturizer use.
• While no standalone trials have been conducted with MVEs, the combination of MVEs with topical fluocinonide 0.05% has recently been shown to reduce disease duration and time to clearance when compared with the same corticosteroid alone, resulting in accelerated skin barrier recovery.²⁰
• This finding has recently been confirmed in a study which showed that twice daily use of CeraVe® cleanser and moisturizer over a 42-day period significantly improved skin condition and clinical outcomes on the SCORAD severity and quality of life aspects when comparing day 0 versus day 42 results.
• Moreover, the products were shown to be comfortable and were well tolerated when used in babies, children and adults with AD, with no significant adverse events reported.²¹
• Because ceramide-dominant formulations are not associated with dosing restrictions or adverse effects such as those seenwith corticosteroid treatment, they are suitable for patients of all ages and may be used on sensitive skin sites (e.g., face and intertriginous areas) which are prone to steroid-induced atrophy.

Other Non-steroidal Barrier Repair Products

• While ceramide-based moisturizers appear to be superior to most non-ceramide OTC moisturizers, a recent trial showed the use of a glycyrrhetinic acid-containing barrier repair cream (Atopiclair®) resulted in improvement of mild to moderate AD in children that was equivalent to EpiCeram®.²²
• A recent study of topical pimecrolimus demonstrated nonsuperiority when compared with a number of different OTC creams (collectively regarded as one group), further suggesting that correction of numerous epidermal barrier derangements may be an effective way of controlling AD.14

Conclusion

Because AD follows a chronic, relapsing course it is essential that, in addition to pharmacologic intervention, hydration and proper barrier function of the SC is maintained with daily regimented moisturizer use as part of ongoing therapy. Adequate moisturization reduces the need for drug treatments and limits the severity and frequency of eczematous flares. Clinical data demonstrate that correction of the skin barrier defects through emollient therapy inhibits downstream drivers of the inflammatory response, thereby providing the rationale for prophylactic and continuous use. Ceramide-based moisturizers have demonstrated efficacy in reducing TEWL, improving barrier function, and maintaining hydration of the SC. Further, they have an excellent safety profile, and can be safely used in patients of all ages.

References

1. Danby S, et al. J Clin Dermatol. 2010;1:33-46
2. Beattie PE, et al. Br J Dermatol. 2006 Jul;155(1):145-51.
3. Elias PM, et al. Arch Dermatol. 2001 Aug;137(8):1079-81.
4. Matsushima H, et al. J Dermatol Sci. 2003 Sep;32(3):223-30.
5. Denda M, et al. J Invest Dermatol. 1998 Nov;111(5):873-8.
6. Denda M, et al. Arch Dermatol Res. 1996 May;288(5-6):230-8.
7. Elias PM, et al. Arch Dermatol. 1996 Dec;132(12):1505-6.
8. Sugarman JL. Semin Cutan Med Surg. 2008 Jun;27(2):108-14.
9. Briot A, et al. J Exp Med. 2009 May 11;206(5):1135-47.
10. Sugarman JL, et al. Arch Dermatol. 2003 Nov;139(11):1417-22.
11. Seidenari S, et al. Acta Derm Venereol. 1995 Nov;75(6):429-33.
12. Izawa K, et al. Immunity. 2012 Nov;35(5):827-39.
13. Kircik LH, et al. J Clin Aesthet Dermatol. 2011 Mar;4(3):34-40.
14. Emer JJ, et al. J Drugs Dermatol. 2011 Jul;10(7):735-43.
15. Elias PM, et al. Exp Dermatol. 2005 Oct;14(10):719-26.
16. Man MQ, et al. Arch Dermatol. 1993 Jun; 129(6):728-38.
17. Kircik SH, et al. J Clin Aesthet Dermatol. 2011 Dec;4(12):25–31
18. Chamlin SL, et al. J Am Acad Dermatol 2002;47:198-208
19. Sugarman JL, et al. J Drugs Dermatol. 2009 Dec;8(12):1106-11.
20. Draelos ZD. Cutis. 2008 Jan;81(1):87-91.
21. Lynde CW. Clinical Evaluation of a Ceramide Containing Cleanser and Moisturizer for Treatment of Atopic Dermatitis. Poster presented at: Dermatology Update, Vancouver, BC. Oct 17-21, 2012.
22. Miller DW, et al. J Drugs Dermatol. 2011 May;10(5):531-7.