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Atopic Dermatitis: The Skin Barrier and the Role of Ceramides

Rachel Asiniwasis, MD; Dusan Sajic, MD, PhD; Sandy Skotnicki, MD, FRCPC

Division of Dermatology, University of Toronto, Toronto, ON, Canada
Bay Dermatology Centre, Toronto, ON, Canada

Introduction

  • Atopic dermatitis (AD) or eczema is a chronic, inflammatory, pruritic skin condition of increasing prevalence that often precedes other atopic conditions such as asthma or allergic rhinitis.1
  • The lifetime prevalence of AD is estimated at up to 17% of Canadians having been affected.2
  • Atopic dermatitis may account for up to 30% of dermatologic consultations in general practice.3
  • Most cases of AD start in children under 5 years of age. Although 60% of patients with childhood AD are estimated to be free of symptoms in adolescence, up to half may experience adulthood recurrence.4
  • Multiple severity scales and diagnostic criteria for AD have been adopted, but Hanifin and Rajka’s clinical criteria5 has been widely accepted. AD diagnosis requires the presence of at least 3 of these major criteria :
    • Characteristic lesion distribution
    • Pruritus
    • Chronic progression with recurrences
    • Personal or family history of atopy (asthma, allergic rhinitis, AD)
  • Three clinical stages usually characterize AD, depending on age group:1
    1. in infancy AD usually presents on cheeks and scalp,
    2. in childhood on the flexural areas, neck, and dorsal limbs, and
    3. in adolescence/adulthood lichenified plaques of the head, neck, and flexural areas.

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Pathogenesis

Filaggrin Gene

  • Loss of function mutations in the filaggrin gene (also found in icthyosis vulgaris), has been identified in with patients AD.1 Filaggrin gene defects can also be associated with increased risk of allergic rhinitis and asthma in patients with eczema.6
  • Filaggrin normally assists in cytoskeletal aggregation and formation of the cornified cell envelope functioning to prevent water loss, creating a barrier to external insults.
  • There have been several potential genes identified in AD, for example those encoding cytokines involved in IgE synthesis regulation (IL-4, IL-5, IL-12, IL-13, and GM-CSF), and gene polymorphisms involved in innate immunity contributing to imbalance between Th1 and Th2 immune responses.1

Epidermal Barrier Dysfunction

  • There is strong evidence to support that barrier abnormalities play a major role in disease pathogenesis, with recent focus on emollient and lipid replacement therapy to address barrier dysfunction and decrease inflammation.7
  • The structure of the epidermal skin barrier, the stratum corneum, is commonly analogized to a “brick and mortar”8 model. The “bricks” consist of a network of compact corneocyte multilayers and the intercellular lipid matrix (composed of ceramides, cholesterol, and free fatty acids) form the “mortar”. These hydrophobic lipids function as water-retaining molecules, with their precursors secreted by the epidermal lamellar body that also deliver antimicrobial peptides and enzymes that assist in lipid generation and corneocyte shedding.7
  • An intact stratum corneum functions to maintain skin hydration and protect against water loss.
  • In AD, the pathogenic skin barrier is characterized by increased transepidermal water loss (TEWL), decreased water-binding properties, and reduced surface lipids, primarily ceramides.9

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General Treatment Principles

  • Avoidance of trigger factors and optimization of the skin barrier function with emollients/moisturizers are key elements at all stages of treatment in AD.
  • Increasing severity of disease calls for the addition of multiple therapeutic agents in stepwise fashion.
  • Current treatment options for AD target either restoration of skin barrier function, inflammation, and/or infection/ microbial colonization.
  • Production of antimicrobial peptides and molecular recognition of invading pathogens has been shown to be defective in AD.10 Colonization of the skin with Staphylococcus aureus is frequently found in AD, which in combination with a disfunctional skin barrier can result in secondary infection requiring antimicrobials, such as impetiginization, folliculitis, and cellulitis or abscesses.1

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Moisturizers

  • Moisturization has been shown to improve skin barrier function in AD with faster resolution of symptoms,11,12 and continual treatment appears to reduce re-exacerbation.13
  • Controlled clinical studies have demonstrated that moisturizers enhance topical corticosteroid efficacy. Moisturizers are also shown to have a steroid-sparing effect.9
  • Liberal use of emollients (cream or ointment) is suggested (e.g., 500 g every 1 to 2 weeks).3
  • Some emollients (e.g., containing urea, lactic acid, or propylene glycol) can cause irritation and burning, and contact dermatitis may occur in susceptible patients to certain fragrances and preservatives.14
  • A reduction in lipids, particularly ceramides, correlate positively with barrier impairment in AD. Use of lipidcontaining moisturizers may be beneficial in promoting barrier recovery.9,14

Ceramides as Moisturizers

  • Patients with AD produce fewer and different lipids, and have higher ceramide degradation,10 leading to a selective reduction in the ceramide fraction.12
  • Most current water-in-oil emollients/moisturizers do not address nor correct this underlying lipid abnormality.
  • Topical mixtures containing ceramide, cholesterol, and free fatty acids have been shown to accelerate barrier repair.11
  • Lipid-based barrier repair cream available in Canada include CeraVe® (available over-the-counter) and EpiCeram® (prescription only).
  • Ceramide-containing creams, lotions and cleansers (e.g., CeraVe®) can be delivered through time-released multilamellar vesicular emulsions (MVE).
  • Such MVEs deliver ceramides, cholesterol, free fatty acids, and other moisturizing ingredients (hyaluronic acid, glycerine and dimethicone) into the skin in a 24-hour controlled, time-released manner. This delivery advance offers once-daily application, thereby encouraging adherence to a simplified regimen of moisturizer use.
  • The combination of MVEs with other topical treatments has recently been shown to accelerate skin barrier recovery.15
  • More education for AD patients on the benefits of ceramide creams is needed, as the use of such preparations is associated with poor patient knowledge and compliance.16
  • In addition to AD, ceramide-based moisturizers may have a role in managing other cutaneous disorders that cause or exacerbate skin barrier impairment, such as acne, psoriasis, and rosacea.
  • The cost comparison of various barrier repair creams may bear an impact on therapeutic decision-making.

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Topical Therapies

Corticosteroids and Calcineurin inhibitors

  • Uninvolved skin of AD patients harbours subclinical inflammation.
  • Proactive therapy, a recent therapeutic concept, aims at targeting subclinical inflammation before it flares into clinically relevant AD.
  • There are two main topical modalities in anti-inflammatory treatment: corticosteroids and calcineurin inhibitors.
  • With mild AD, small amounts of TCS in combination with emollients/moisturizers are sufficient to maintain an acceptable skin status without significant adverse effects.10
  • Tapering of corticosteroids, in terms of progressive reduction in potency and reduction in application frequency, once the erythema has subsided is crucial.
  • Topical calcineurin inhibitors (TCIs), such as topical tacrolimus or pimecrolimus, reduce proinflammatory cytokines by inhibiting the calcineurin-dependent pathway.
  • Tacrolimus 0.1% ointment is similar to an intermediate potency corticosteroid and pimecrolimus 1.0% cream is slightly less potent.10
  • TCIs do not cause skin atrophy, and thus, may be used on sensitive areas (e.g., face, eyelids, perioral region, genital area, axillary region, or inguinal folds).
  • Health Canada has recently approved topical tacrolimus ointment twice-weekly for the prevention of eczema flares in those who experience a high frequency of flares (> 5 times per year) based on two Phase 3 multi-centre randomized clinical trials in pediatric and adult patients.17,18
    • Preventative therapy with tacrolimus has been shown to significantly reduce treatment days and prolong intervals between flares.17,18 Similar findings have also been reported in the use of pimecrolimus cream for flare prevention in children.19

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Systemic Therapy

  • Numerous systemic treatments can be used in severe acute flare-ups of AD when topical therapy with immunomodulators fails to control the disease. These include phototherapy, methotrexate, azathioprine, and cyclosporine A.
  • Antihistamines do not directly relieve pruritis; however, when taken before bed central sedative effects can discourage scratching and improve sleep quality.

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Other Tips

Patient Education

  • A survey16 of 422 patients with chronic skin conditions and compromised skin barrier function revealed general underuse of moisturizers. The survey also emphasized that patient education is important in promoting compliance and clinicians should provide more information on the essential role of moisturizers and cleansers in skin barrier repair.
    • Cleansers containing ceramides and emollients can minimize any barrier disturbance by simultaneously replacing lipids that are lost during washing.
  • Explaining the nature and course of atopic dermatitis, trigger avoidance and lifestyle changes, and therapeutic options, as well as demonstrating proper use of treatment are key to management. Supplemental educational brochures and a written plan of care that is reinforced at follow-up visits may also be helpful.3

Lifestyle Modifications

  • Identify and avoid triggers
    • Common triggers or exacerbating factors include sweating, hot baths, stress, wool clothing, dry environments, harsh soaps, and detergents
  • Avoid scratching
  • Keep nails trimmed, wear gloves at night to avoid scratching and enhance penetration of topical therapies
  • Cool wet compresses can provide temporary relief
  • Wear cotton clothing
  • Choose fragrance-free skin care products and laundry detergent
  • Double rinse clothing
  • Short (>15 minutes) lukewarm baths followed by moisturization
  • Moisturize regularly

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Conclusion

AD follows a chronic relapsing course. As such, in addition to pharmacologic intervention, it is essential to maintain hydration and barrier function of the skin with daily regimented moisturizer use. Ceramide-based moisturizers have been shown to be beneficial in reducing TEWL, improving barrier function, and maintaining hydration of the stratum corneum, and thus, can be a useful component in AD management. Adequate moisturization reduces the need for drug treatments, as well as limits the severity and frequency of eczematous flares.

References

  1. Bieber T. Atopic dermatitis. N Engl J Med 358(14):1483-94 (2008 Apr 3).
  2. Eczema prevalence in Canada. Ipsos-Insight Health (2003).
  3. Nicol NH. Use of moisturizers in dermatologic disease: the role of healthcare providers in optimizing treatment outcomes. Cutis 76(6 Suppl):26-31 (2005 Dec).
  4. Williams HC. Clinical practice. Atopic dermatitis. N Engl J Med 352(22): 2314-24 (2005 Jun 2).
  5. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 92(suppl):44-47 (1980).
  6. van den Oord RA, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and metaanalysis. BMJ 339:b2433 (2009).
  7. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol 9(5):437-46 (2009 Oct).
  8. Draelos ZD. Concepts in skin care maintenance. Cutis 76(6 Suppl):19-25 (2005 Dec).
  9. Lebwohl M, Herrmann LG. Impaired skin barrier function in dermatologic disease and repair with moisturization. Cutis 76(6 Suppl):7-12 (2005 Dec).
  10. Wollenberg A, Schnopp C. Evolution of conventional therapy in atopic dermatitis. Immunol Allergy Clin North Am 30(3):351-68 (2010 Aug).
  11. Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 47(2):198-208 (2002 Aug).
  12. Loden M, Andersson AC, Lindberg M. Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Canoderm). Br J Dermatol 140(2):264-7 (1999 Feb).
  13. Billmann-Eberwein C, Rippke F, Ruzicka T, et al. Modulation of atopy patch test reactions by topical treatment of human skin with a fatty acid-rich emollient. Skin Pharmacol Appl Skin Physiol 15(2):100-4 (2002 Mar-Apr).
  14. Ghali FE. Improved clinical outcomes with moisturization in dermatologic disease. Cutis 76(6 Suppl):13-8 (2005 Dec).
  15. Draelos ZD. The effect of ceramide-containing skin care products on eczema resolution duration. Cutis 81(1):87-91 (2008 Jan).
  16. Berson D. Recommendation of moisturizers and cleansers: a study of unmet needs among dermatology patients. Cutis 76(6 Suppl):3-6 (2005 Dec).
  17. Wollenberg A, Reitamo S, Atzori F, et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy 63(6):742-50 (2008 Jun).
  18. Thaci D, Reitamo S, Gonzalez Ensenat MA, et al. Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study. Br J Dermatol 159(6):1348-56 (2008 Dec).
  19. Sigurgeirsson B, Ho V, Ferrandiz C, et al. Effectiveness and safety of a prevention-of-flare-progression strategy with pimecrolimus cream 1% in the management of paediatric atopic dermatitis. J Eur Acad Dermatol Venereol 22(11):1290-301 (2008 Nov).

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