Sajić Dušan – Skin Therapy Letter https://www.skintherapyletter.com Written by Dermatologists for Dermatologists Tue, 09 Feb 2021 20:27:12 +0000 en-US hourly 1 https://wordpress.org/?v=6.8.1 Advances in Topical Acne Therapy: New Molecules, Vehicles and Delivery Mechanisms https://www.skintherapyletter.com/family-practice/new-molecules-vehicles-delivery/ Sun, 01 Dec 2013 18:00:48 +0000 https://www.skintherapyletter.com/?p=2508
Dušan Sajić, MD, PhD and Sandy Skotnicki, MD, FRCPC

Divisions of Dermatology and Occupational Health,
University of Toronto Dermatology, Toronto, ON
Bay Dermatology Centre, Toronto, ON

 

Introduction

Acne vulgaris is a multifactorial disease characterized by different types of lesions at various stages of development. The most frequently used therapeutic agents for acne are topical. While first generation topicals are primarily composed of single agent preparations, the increased knowledge of acne pathogenesis and the numerous steps involved in comedone formation have led to increasing development and clinical use of combination products (Table 1). Numerous studies have shown that combination therapy is more efficacious and better tolerated compared to monotherapy. Consequently, current consensus guidelines recommend the use of combination treatment as first-line therapy for most patients with acne. Nevertheless, several obstacles encountered in the treatment of acne, including irritation resulting from topical medications and the emergence of bacterial resistance to both topical and oral antibiotics, remain significant barriers to patient adherence to therapy. It is estimated that 30-40% of patients using topical formulations do not comply with their prescribed regimen.1 However, recent advances in vehicle technology have improved efficacy, local tolerance and adherence.2 Additionally, delivery mechanisms, such as pumps are convenient and preferred by patients, and may improve adherence.3

Retinoids
  • Adapalene
  • Tretinoin
  • Tazarotene
Antimicrobials
  • Benzoyl peroxide (BPO)
  • Clindamycin
  • Erythromycin
  • Dapsone
  • Sodium sulfacetamide
Combination products
  • Topical antibiotic + BPO
    • Clindamycin +BPO
    • Erythromycin + BPO
  • Topical retinoid + antibiotic
    • Tretinoin + clindamycin
    • Tretinoin + erythromycin
  • Topical retinoid + BPO
    • Adapalene + BPO
Table 1. Topical acne medications

Combination Therapy

Because the typical clinical presentation of acne vulgaris exhibits lesions at different stages, employing combination therapy that utilizes multiple agents to produce additive or synergistic benefits is logical.

  • Studies have shown that the topical combination of retinoids and antimicrobial agents expedites a clinical response.4 This may be due to enhanced penetration of agents by the retinoids.
  • Retinoids may be prescribed as initial therapy. If inflammatory lesions are present, the addition of a BPO alone, or in combination with a topical or oral antibiotic, should be the next step.
  • Data show that the combined use of a clindamycin 1%/BPO 5% formulation with a 0.04% tretinoin microsphere gel can result in good resolution of post-inflammatory hyperpigmentation in ethnic skin, i.e., individuals of colour.5
  • A once-daily, fixed-dose gel formulation containing solubilized and crystalline clindamycin phosphate 1.2% and tretinoin 0.025% (CT gel) was recently introduced in Canada.
    • Clindamycin has anti-inflammatory and antibacterial properties and tretinoin exerts comedolytic and anticomedogenic activities to target several mechanisms in acne pathogenesis.6
    • A 4-week randomized study investigated the safety and
      tolerability of combination CT gel with morning use of a
      BPO wash for mild to moderate acne. This regimen widens
      the number of targeted pathogenic factors and suppresses
      the emergence of clindamycin-induced Propionibacterium
      acnes (P. acnes) resistant bacterial strains.7
  • Combination products offer much higher levels of patient compliance with 67% adherence observed in the combination therapy group versus 8% in patients using both agents separately.8

Topical Dapsone for Inflammatory Lesions

  • Dapsone 5% gel is a new, twice daily topical treatment that is effective against both inflammatory and noninflammatory acne, however greater improvement occurs with inflammatory lesions.9
  • In two identically designed 12-week, phase 3, double-blind, randomized, vehicle-controlled trials in acne (total N=3010), significant reduction in non-inflammatory, inflammatory, and total lesion counts were noted with dapsone gel versus vehicle groups (32% versus 24%, 39% versus 32%, 48% versus 42%, all P>0.001, respectively).10
  • An investigator-blinded, randomized, split-face study assessed female subjects aged 18-40 years, with Fitzpatrick skin types I, II, or III. The results suggest that dapsone applied prior to tretinoin 0.1% may mitigate the irritation potential of tretinoin.11

Retinoids for Initial/Maintenance Therapy

Retinoids are pivotal for treatment in the early stages of acne as well as for maintenance therapy, and have both anti-comedonal and anti-inflammatory activities.

  • Topical retinoids can be used for all types and grades of acne, either initially or early in the therapy.
  • Topical retinoids are effective as monotherapy in pure comedonal acne.
  • Topical retinoids down-regulate TLR2 and CD14 messenger RNA, which, in turn, reduces their cell surface expression, resulting in anti-inflammatory activity.12
  • Evidence shows that retinoids can enhance the effects of topical antibiotic-BPO combination creams.4 In addition to their synergistic effect, this may be because retinoids can improve the penetration of other topical agents.
  • Maintenance therapy or long-term use of retinoids may help to prevent the re-emergence of micro-comedones.
  • The tretinoin gel microsphere (TGM) 0.04% pump formulation protects tretinoin from degradation by BPO and from photoinactivation in daylight: this enables its use in the morning, and with a BPO wash, without diminishing efficacy.13
  • A phase 4 study showed that TGM resulted in a 95% compliance rate.14
  • Maintenance therapy with retinoids may diminish the need for chronic antibiotic use, especially oral antibiotics. This may lead to decreased bacterial resistance associated with long-term oral and topical antibiotic use.
  • Due to a complex pathogenesis, maintenance therapy may need to be continued for months to years after resolution.15
  • Therapy with topical antibiotics but without BPO should be avoided so as to prevent development of resistance to P. acnes.15
  • Adapalene is photostable and may be applied immediately before or after a BPO containing product.16

Tretinoin Microsphere Technology and Pump Delivery Systems

Tretinoin has been formulated with a patented microsphere delivery system and a novel metered pump bottle design, which, according to the manufacturer, allows for proper dosage and clean dispensing of the active agent. Clinical trials have shown:

  • Lower levels of irritation due to the slow release of tretinoin from the microspheres into the epidermis.12,17
    • Reduced irritation may increase tolerability and patient adherence.
    • This is a less irritating water-based gel formulation that contains no alcohol and may be applied to the face immediately after washing with no waiting period.
  • TGM delivery entraps the active ingredient, releasing it in a time-controlled manner, reducing irritation.14,18
    • The controlled dispensing with this delivery system can mitigate the overuse of tretinoin, thus reducing irritation and increasing treatment adherence.12
    • A multicenter trial of 544 acne patients who were dissatisfied with their current treatment used TGM for 12 weeks. Most patients (82.3%) rated the pump as an excellent or very good method of dispensing acne medication. The tretinoin pump system significantly increased adherence, quality of life, and treatment satisfaction for study patients.14
  • The dual chambered pump dispenser releases the correct pea-sized amount for full face application and may help to maintain the optimal dosing level.
  • Microsphere technology allows for 3-fold greater deposition of tretinoin in the deep dermis and the pilosebaceous unit and may account for its stability.19
  • The microsphere technology leads to greater photostability of the tretinoin and allows for morning use, if necessary, and is minimally degraded when combined with BPO.20,21
    • Retinoids formulated in a conventional gel or cream vehicle are unstable in the presence of ultraviolet light or BPO.12

Vehicle Technology Advancements

Patient preferences go beyond side-effects and studies have shown that several variables decrease adherence including vehicle composition, difficulty of use, lack of early improvement, messiness, odours, and staining.22

  • In a Patient Preferences in Acne: A Point-of-Care Educational Initiative, a survey of 1709 patients across Canada found that pump delivery systems are the preferred format (42% of patients).3
  • Many new topical acne formulations have aqueous-based gel vehicle delivery systems that do not contain alcohol and are suitable for use in all skin types.
  • It is known that topical acne agents cause cutaneous irritation related in part to impaired epidermal barrier function.23
    • The use of gentle cleansers and moisturizers has been shown to reduce this cutaneous irritation.24
    • Moisturizers containing ceramides can be considered to improve skin barrier function in acne.
    • Dimethicone’s occlusive properties result in less greasiness for enhanced cosmetic acceptability.
  • Vehicle advances, such as microsphere technology and solubilized crystalline formulations reduce the potential of irritation from tretinoin.
  • Microsphere tretinoin and adapalene do not increase photosensitivity, allowing for morning application.
  • Clindamycin/BPO formulations with humectants and emollients may reduce the dry skin associated with BPO use.
  • Clindamycin/BPO formulations without preservatives may reduce the irritation associated with these agents.25
  • The risk of bacterial resistance is decreased due to the addition of BPO to topical antibiotic agents, and the use of BPO with long-term oral antibiotics.

Conclusion

The multifactorial nature of acne vulgaris often requires a combination of topical and/or oral agents for successful management. Common challenges of this multipronged approach include the potential development of skin irritation, which results in nonadherence, as well as concern over bacterial resistance. Recent advances in topical acne agents offer simpler dosing regimes that can promote patient adherence. Furthermore, the cumulative benefits of these advances may lead to improved therapeutic outcomes and overall increase in quality of life.

References

  1. Finlay AY. J Eur Acad Dermatol Venereol. 1999 Sep;12(Suppl 2):S77.
  2. Koo J. Skinmed. 2003 Jul-Aug;2(4):229-33.
  3. Vender R, et al. Patient preferences in acne: a point-of-care educational initiative. Poster presentation.
  4. Kircik L. Cutis. 2007 Jul;80(1 Suppl):10-4.
  5. Taylor SC. Cutis. 2007 Jul;80(1 Suppl):15-20.
  6. Abdel-Naser MB, et al. Expert Opin Pharmacother. 2008 Nov;9(16):2931-7.
  7. Draelos ZD, et al. Cutis. 2010 Dec;86(6):310-8.
  8. Yentzer BA, et al. Cutis. 2010 Aug;86(2):103-8.
  9. Ofori AO. Treatment of acne vulgaris. In: UpToDate, Basow DS (Ed). UpToDate: Waltham, MA, 2011. Available at www.uptodate.com.
  10. Draelos ZD, et al. J Am Acad Dermatol. 2007 Mar;56(3):439 e1-10.
  11. Moreira V, et al. Quality of life in patients with acne vulgaris. Poster 5399 presented at: 70th Annual Meeting of the American Academy of Dermatology. San Diego, CA. March 16-20, 2012.
  12. Berger R, et al. Cutis. 2007 Aug;80(2):152-7.
  13. Pariser D, et al. J Drugs Dermatol. 2010 Jul;9(7):805-13.
  14. Eichenfield LF, et al. J Drugs Dermatol. 2008 Dec;7(12):1129-36.
  15. Wilford J, et al. Skin Therapy Lett (FP Edition). 2011 Sep;7(4):1-3.
  16. Jain S. J Dermatolog Treat. 2004 Jul;15(4):200-7.
  17. Webster GF. J Am Acad Dermatol. 1998 Aug;39(2 Pt 3):S38-44.
  18. Embil K, et al. J Microencapsul. 1996 Sep-Oct;13(5):575-88.
  19. Del Rosso JQ. J Clin Aesthet Dermatol. 2012 Jan;5(1):27-9.
  20. Nighland M, et al. Cutis. 2006 May;77(5):313-6.
  21. Nyirady J, et al. Cutis. 2002 Nov;70(5):295-8.
  22. Kircik, LH, et al. Practical Dermatol. 2010 Jun;7(6 Suppl):1-16.
  23. Del Rosso JQ, et al. J Drugs Dermatol. 2006 Feb;5(2):160-4.
  24. Gollnick H, et al. J Am Acad Dermatol. 2003 Jul;49(1 Suppl):S1-37.
  25. Zeichner JA. J Drugs Dermatol. 2012 Mar;11(3):313-7.
]]> Ceramide-based Moisturizers as Treatment for Pediatric Atopic Dermatitis https://www.skintherapyletter.com/atopic-dermatitis/ceramide-moisturizers/ Wed, 01 May 2013 18:00:30 +0000 https://www.skintherapyletter.com/?p=2490
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.
]]> A Look at Epidermal Barrier Function in Atopic Dermatitis: Physiologic Lipid Replacement and the Role of Ceramides https://www.skintherapyletter.com/atopic-dermatitis/epidermal-barrier-function/ Sun, 01 Jul 2012 21:12:08 +0000 https://www.skintherapyletter.com/?p=564
Dušan Sajić, MD, PhD; Rachel Asiniwasis, MD; Sandy Skotnicki-Grant, MD, FRCPC


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

Conflict of interest: The authors have no conflicts of interest to declare.

ABSTRACT
This review summarizes and discusses the role and efficacy of moisturizers, particularly the more recently introduced ceramide-based formulations, in the skin care regimen of patients with both active and quiescent atopic dermatitis (AD). It is now well established that a complex interplay of environmental and genetic factors are responsible for disease onset and chronicity. Indeed, several novel genetic mechanisms have been recently discovered to be associated with AD pathogenesis. Moreover, it is increasingly recognized that the epidermal barrier plays a critical role in the initiation, perpetuation, and exacerbation of AD. The skin of patients with AD harbors several defects in epidermal barrier function, including filaggrin and ceramides. An improved understanding of these etiopathogenic factors has led to the development of topical ceramide-dominant moisturizers to replace the deficient molecules and re-establish the integrity of barrier defenses. Some of these products have demonstrated efficacy in the treatment of adult and childhood AD that are similar to mid-potency topical steroids. More importantly, they have been shown to be safe with very few associated side-effects. We recommend the addition of such new agents as both the first step of treatment and in the maintenance of clinically quiescent skin of patients with AD.

Key Words:
atopic dermatitis, ceramides, eczema, emollients, epidermal barrier, lipids, transepidermal water loss

Introduction

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic skin disease of increasing prevalence (affecting 15-30% of children and 2-10% of adults).1 AD is considered by many to be the first step in the “atopic march” that can progress to include asthma and allergic rhinitis, as well as be a precursor to, rather than a consequence of, food allergies.1 The precise sequence of biochemical events leading to the development of AD has still not been fully elucidated, but most experts agree that it involves a complex interplay of environmental and genetic factors that induce derangements in the structure and function of the epidermal barrier and immune system. Diagnosis can be challenging, as the variability of clinical presentation can be confounding. Morphology alone cannot reliably confirm the diagnosis and the spectrum of features associated with AD must be considered. While several sets of diagnostic criteria for AD have been proposed and validated, the traditionally used being that of Hanifin and Rajka, full agreement amongst clinicians and uniformity of criteria are still lacking.2

Epidermal Barrier Dysfunction

Traditionally, it was thought that the primary pathogenic mechanism of atopic dermatitis was initiated by immune dysfunction leading to a Th2 cytokine imbalance, increased inflammation, and secondary disruption of the epidermal barrier.1,3 However, accumulating evidence suggests that rather than merely having a bystander effect, a primary defect in the stratum corneum plays a major role in driving the pathogenesis of atopic dermatitis that leads to sustained cytokine release, recruitment of pro-inflammatory molecules, and stimulation of a Th2 response.3,4 Moreover, further barrier disruption in the chronic stages of AD, through mechanical scratching, not only perpetuates but alters the response to a mostly Th1 type.5 In addition, while several other cytokines and T cell subsets like IL-31 and Th2,6 respectively, have recently been identified within the skin of patients with AD, the role of the skin barrier influencing their expression remains unclear.7

AD has been separated into two different subtypes, i.e., intrinsic and extrinsic, which were derived on the basis of the extrinsic subtype stemming from allergic sensitization to an external antigen with subsequent allergen specific IgE production, and the intrinsic variant describes patients with all clinical features of AD, but no detectable allergen specific IgE. However, these subtypes may actually represent different stages of evolution based on the relative degree of sensitization. Under this view, AD in infancy is thought to begin as “intrinsic” or non-atopic dermatitis, and over time it progresses to “true” atopy in the majority of cases via allergen exposure through what is now being more widely recognized as a primarily defective epidermal barrier function.1,2

It is well established that the first line of defense within the epidermal barrier is the stratum corneum, which serves several fundamental roles in maintaining protection from the environment as well as preventing water loss. This “outside-in” theory views a primary defect in the stratum corneum as a key condition that drives the inflammatory cascade of AD, predisposing to increased transepidermal water loss (TEWL), penetration of irritants, allergens, secondary infection, and increased inflammation.8 Several lines of evidence demonstrate the capacity of the cutaneous barrier to initiate and perpetuate AD including observations that:

  1. the defects in the barrier result in elevated pH that activates
    proteases capable of directly inducing a Th2 inflammatory
    response,9
  2. the severity of the barrier defect parallels AD severity,10,11
  3. the barrier defect persists longer than both the clinical lesions
    and the underlying inflammation,11
  4. several genetic disorders with skin lesions similar to AD
    implicate abnormal gene coding that affect the epidermal
    barrier, and lastly,12
  5. therapeutic strategies aimed at repairing the epidermal
    barrier, as further discussed below, also ameliorates both the
    inflammation and the clinically involved skin.13

Morphological Changes in Epidermal Lipids in AD

The stratum corneum represents 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. These hydrolases cleave the precursors to form essential and non-essential fatty acids, cholesterol, and at least 10 different ceramides, which self-organize into multilayered lamellar bilayers between the corneocytes (“bricks”), resulting in the formation of watertight “mortar”, thus, maintaining skin hydration.12 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 atopic dermatitis, there is a decrease in all three key 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, which correlates with increased TEWL and enhanced barrier permeability.

Filaggrin Mutations and Exogenous Factors in AD Contribute to Epidermal Barrier Dysfunction

There has been a large focus on the role of genetic abnormalities leading to defects in key structural components of the epidermal barrier. Perhaps the best example of this is a loss of function mutation in the filaggrin gene, which encodes for the filament aggregating protein (FLG), found in up to 60% of AD patients.12 While there are various other candidate genes that lead to increased susceptibility, including KLK7, SPINK5, and CSTA, FLG remains by far the most prominent.14 Although filaggrin is certainly one of the most important single genes involved in AD susceptibility, inherent redundancy in the epidermal differentiation complex with several other similar genes may mitigate the negative effect of filaggrin mutations and explain the incomplete penetrance in AD. As such, patients carrying a mutation in the FLG gene display a wide spectrum of disease, ranging from mildly dry skin to more severe manifestations of ichthyosis vulgaris.15 Moreover, since only 44% of AD patients carry the heterozygous mutation and 76% of homozygous or compound heterozygous FLG mutation carrying patients suffer from AD,16 this further implicates the role of other genes and the environment in disease pathogenesis. Nevertheless, complete absence of FLG, either as a homozygous mutation or a compound heterozygote mutation, clearly disrupts the epidermal barrier, as all of these patients to date have been shown to present with a clinical picture of ichthyosis vulgaris.17,18

Filaggrin normally assists in cytoskeletal aggregation and formation of the cornified cell envelope (CCE), providing additional strength and structure. It is required for normal lamellar body formation and content secretion. Furthermore, as corneocytes mature and start losing water, FLG dissociates from the CCE and is processed into acidic metabolites acting as osmolytes that help to retain hydration and keep the pH below the threshold required for the activation of Th2-inducing endogenous serine proteases.9 Therefore, a FLG mutation contributes to a disrupted epidermal barrier, increased water loss, and inflammation. There are also many exogenous factors that 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 induce endogenous proteolytic activity, cleaving corneodesmosomal proteins and filaggrin, thus contributing 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 immunosuppressives that do not target the underlying structural barrier abnormalities.4,19 As well, most conventional moisturizers do not address this underlying lipid deficiency. With an improved understanding of AD etiopathogenesis, a new nonpharmacologic approach has emerged aimed at barrier repair involving the delivery of balanced proportions of stratum corneum specific lipids to assist in correcting this epidermal barrier dysfunction.

With accumulating evidence supporting barrier defect-initiated disease pathogenesis and its effects on both triggering and perpetuating AD, it is not surprising that 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. While the use of sophisticated moisturizers has been shown to confer protective effects on the skin barrier by delaying onset and decreasing AD severity and flares,1 it is not appropriate to generalize this benefit to all moisturizers, as they not only differ widely in their compositions, but are classified into subcategories based on the therapeutic properties of their key ingredients, e.g., occlusives, humectants, emollients (e.g., intercellular lipids), or some combination of the three. Within the intercellular lipids category, moisturizers contain a variable mix of ceramides, cholesterol, and free fatty acids.

One of the most promising barrier repair methods have been ceramide-dominant physiological lipid-based barrier repair topical emulsions. In contrast to traditional moisturizers, these formulations focus on physiologic lipid replacement therapy, particularly ceramides, to restore normal balance of the epidermal barrier. In comparison with other emollients (e.g., petrolatum) that form a more superficial occlusive barrier, ceramide-dominant moisturizers are thought to permeate the stratum corneum and are synthesized in the keratinocytes, processed in lamellar bodies, and secreted back into the stratum corneum to become a part of the dermal matrix.8,20

Interestingly, while cholesterol, ceramides, and fatty acids are all required for repair, individually they encumber rather than facilitate barrier recovery.21 Moreover, incomplete mixtures can also result in suboptimal recovery,22 underlining the importance of proper physiological ratios of individual components to achieve maximal efficacy. 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 stratum corneum and has been shown to repair its integrity and function.21 While several reports have shown that the 3:1:1 ratio seems to be important in barrier repair,21-24 it appears that the “3” does not necessarily need to be a ceramide, as both three-fold higher ratios of a fatty acid or cholesterol rather than a ceramide can significantly improve barrier function when compared to vehicle alone.23 Moreover, while both TriCeram® and EpiCeram® contain 2.1% of ceramides, one study showed that a dilution of 1:9 also has significant effects on barrier repair.21 In addition to assisting in restoration of the lipid defect in AD, these products also help to normalize the pH of the skin, which itself is separately associated with a decrease in epidermal barrier integrity, increased inflammation, and reduced antimicrobial defenses.25,26

Although most of the early studies compared the efficacy of the three component mixtures 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.19,27 Therefore, avoiding associated adverse effects from corticosteroid treatment and certain dosing restrictions, as therapy is 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

Another ceramide-based barrier repair cream is CeraVe™, the first over-the-counter (OTC) product featuring multilamellar vesicular emulsions (MVEs), which are similar to liposomes, but facilitate a slow 24-hour controlled, time-released delivery of the contents. This delivery advance offers 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.28

Natural vs. Synthetic Ceramides

As previously discussed, ceramides are the main components of the multilayered lamellar bilayers between the corneocytes and, thus, a key factor in water retention and overall integrity of the barrier. Chemically, they are amide-linked free fatty acids with long-chain amino alcohol sphingoid bases, which are amidelinked to hydroxylated, x-hydroxylated or nonhydroxylated fatty acids, and shown to also have functions in apoptosis, cell growth, senescence, and cell cycle control.29 Clinically, while many other moisturizers are important in providing short-term relief from dryness in AD, long-term benefits can only be derived through restoring adequate ceramide levels. While replacement with natural ceramides seems to represent the most logical step in the correction of the barrier, there are three important considerations connected with the use of “natural” ceramides. Firstly, there is a high cost associated with nature-identical, synthetic ceramides (e.g., $2,000-$10,000/kg).30 Secondly, inexpensive naturally occurring ceramides are typically extracted from bovine central nervous system, which raises concerns about bovine spongiform encephalopathy (‘mad cow disease’). Thirdly, excess intracellular ceramides can be linked with significant toxicity and lead to cell growth retardation and apoptosis.20,30 Synthetic ceramides are capable of overcoming most of these obstacles and are currently being explored as potential alternatives to natural ceramides.

Kang et al. showed that application of 1% K6PC-9p (a synthetic ceramide derivative of PC-9S) resulted in similar improvement of tetradecanoylphorbol acetate (TPA)-induced skin inflammation, when compared to 0.1% hydrocortisone.31 Moreover, application of a ceramide complex (pseudoceramides and eucalyptus leaf extract) resulted in not only improved TEWL and erythema gradings of treated AD patients when compared to vehicle control, but also increased levels of endogenous stratum corneum ceramides.32 Another study investigated a synthetic pseudoceramide and eucalyptus leaf extract formulation in patients with mild to severe AD.33 This double-blind, within subject vehicle-controlled study of patients with AD lesions on the arms and legs assessed TEWL, global assessment, and erythema. A significant differential benefit for the ceramide complex over vehicle was shown. Additionally, the findings demonstrated that this ceramide complex of pseudoceramides appears to work similar to the endogenous ceramindes found in the skin.

Other Non-steroidal Barrier Repair Products

While ceramide-based moisturizers clearly appear to be superior to most non-ceramide OTC moisturizers, it should be noted that 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®.34 Similar findings were seen in another recent study that demonstrated non-superiority of topical pimecrolimus when compared to a number of different OTC creams (collectively regarded as one group),25 suggesting that correction of numerous epidermal barrier derangements may be an effective way of controlling AD. As well, a multicenter, observational, uncontrolled study of 2456 AD patients aged 2-70 years showed that regular use of a barrier cream containing lipids and N-palmitoylethanolamine (MimyX®) significantly reduced AD skin symptoms (e.g., erythema, pruritus, excoriation, scaling, lichenification, and dryness), sleep disturbance, and topical steroid use.35 Eletone® is another FDA-cleared 510(k) prescription medical device moisturizer that helps to improve stratum corneum impairment and restore barrier integrity. The product contains 70% oil dispersed in 30% water, but it uses a proprietary reverse emulsion technology that produces a formulary consistency of a cream with occlusive properties of an ointment, resulting in enhanced cosmetic acceptability. In a study assessing the use of twice-daily Eletone® in 133 pediatric patients with mild to moderate AD, at 4 weeks 54% of patients experienced improvement in pruritus and average body surface area involvement decreased by 43.6%. 36 Whether such treatments lead to an indirect restoration of ceramide levels remains unknown and warrants further investigation.

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. Indeed, more studies are showing 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. Furthermore, the ceramidebased barrier repair emulsions have an excellent safety profile, without significant adverse events other than occasional transient tingling upon application, and thus, can be safely used in patients of all ages and on sensitive skin regions, including the face and intertriginous areas. Additional research is warranted and will lead to a better understanding of the optimal formulary compositions as well as development of a better treatment ladder for varying severities of AD. Also, long-term studies would be helpful in establishing whether lipid barrier replacement therapy reduces bacterial colonization or prevents progression of the atopic march.

References

  1. Danby S, Cork MJ. A new understanding of atopic dermatitis: the role of epidermal barrier dysfunction and subclinical inflammation. J Clin Dermatol. 2010;1:33-46.
  2. Bos JD, Brenninkmeijer EE, Schram ME, et al. Atopic eczema or atopiform dermatitis. Exp Dermatol. 2010 Apr;19(4):325-31.
  3. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Allergy Asthma Rep. 2009 Jul;9(4):265-72.
  4. Elias PM. An Appropriate response to the black-box warning: corrective, barrier repair therapy in atopic dermatitis. Clin Med Dermatol. 2009 Feb 9;2:1-3.
  5. Matsushima H, Hayashi S, Shimada S. Skin scratching switches immune responses from Th2 to Th1 type in epicutaneously immunized mice. J Dermatol Sci. 2003 Sep;32(3):223-30.
  6. Jin H, He R, Oyoshi M, et al. Animal models of atopic dermatitis. J Invest Dermatol. 2009 Jan;129(1):31-40.
  7. Szegedi K, Kremer AE, Kezic S, et al. Increased frequencies of IL-31 producing T cells are found in chronic atopic dermatitis skin. Exper Dermatol. 2012 Jun; 21(6):431-6.
  8. Sugarman JL. The epidermal barrier in atopic dermatitis. Semin Cutan Med Surg. 2008 Jun;27(2):108-14.
  9. Briot A, Deraison C, Lacroix M, et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med. 2009 May 11;206(5):1135-47.
  10. Sugarman JL, Fluhr JW, Fowler AJ, et al. The objective severity assessment of atopic dermatitis score: an objective measure using permeability barrier function and stratum corneum hydration with computer-assisted estimates for extent of disease. Arch Dermatol. 2003 Nov;139(11):1417-22.
  11. Seidenari S, Giusti G. Objective assessment of the skin of children affected by atopic dermatitis: a study of pH, capacitance and TEWL in eczematous and clinically uninvolved skin. Acta Derm Venereol. 1995 Nov;75(6):429-33.
  12. Elias PM, Wakefield JS. Therapeutic implications of a barrier-based pathogenesis of atopic dermatitis. Clin Rev Allergy Immunol. 2011 Dec; 41(3):282-95.
  13. Elias PM, Wood LC, Feingold KR. Epidermal pathogenesis of inflammatory dermatoses. Am J Contact Dermat. 1999 Sep;10(3):119-26.
  14. Cork MJ, Danby SG, Vasilopoulos Y, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol. 2009 Aug;129(8):1892-908.
  15. Heimall J, Spergel JM. Filaggrin mutations and atopy: consequences for future therapeutics. Expert Rev Clin Immunol. 2012 Feb;8(2):189-97.
  16. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006 Apr;38(4):441-6.
  17. Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006 Mar;38(3):337-42.
  18. Hu Z, Xiong Z, Xu X, et al. Loss-of-function mutations in filaggrin gene associate with psoriasis vulgaris in Chinese population. Hum Genet. 2012 Jul; 131(7):1269-74.
  19. Kircik LH, Del Rosso JQ, Aversa D. Evaluating clinical use of a ceramidedominant, physiologic lipid-based topical emulsion for atopic dermatitis. J Clin Aesthet Dermatol. 2011 Mar;4(3):34-40.
  20. Anderson PC, Dinulos JG. Are the new moisturizers more effective? Curr Opin Pediatr. 2009 Aug;21(4):486-90.
  21. Man MQ, Feingold KR, Elias PM. Exogenous lipids influence permeability barrier recovery in acetone-treated murine skin. Arch Dermatol. 1993 Jun; 129(6):728-38.
  22. Man MQ, Brown BE, Wu-Pong S, et al. Exogenous nonphysiologic vs physiologic lipids. Divergent mechanisms for correction of permeability barrier dysfunction. Arch Dermatol. 1995 Jul;131(7):809-16.
  23. Man MM, Feingold KR, Thornfeldt CR, et al. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol. 1996 May;106(5):1096-101.
  24. Yang L, Mao-Qiang M, Taljebini M, et al. Topical stratum corneum lipids accelerate barrier repair after tape stripping, solvent treatment and some but not all types of detergent treatment. Br J Dermatol. 1995 Nov;133(5):679-85.
  25. Emer JJ, Frankel A, Sohn A, et al. A bilateral comparison study of pimecrolimus cream 1% and a topical medical device cream in the treatment of patients with atopic dermatitis. J Drugs Dermatol. 2011 Jul;10(7):735-43.
  26. Elias PM, Choi EH. Interactions among stratum corneum defensive functions. Exp Dermatol. 2005 Oct;14(10):719-26.
  27. Sugarman JL, Parish LC. Efficacy of a lipid-based barrier repair formulation in moderate-to-severe pediatric atopic dermatitis. J Drugs Dermatol. 2009 Dec;8(12):1106-11.
  28. Draelos ZD. The effect of ceramide-containing skin care products on eczema resolution duration. Cutis. 2008 Jan;81(1):87-91.
  29. Sawai H, Domae N, Okazaki T. Current status and perspectives in ceramidetargeting molecular medicine. Curr Pharm Des. 2005;11(19):2479-87.
  30. Uchida Y, Holleran WM, Elias PM. On the effects of topical synthetic pseudoceramides: comparison of possible keratinocyte toxicities provoked by the pseudoceramides, PC104 and BIO391, and natural ceramides. J Dermatol Sci. 2008 Jul;51(1):37-43.
  31. Kang JS, Yoon WK, Youm JK, et al. Inhibition of atopic dermatitis-like skin lesions by topical application of a novel ceramide derivative, K6PC-9p, in NC/ Nga mice. Exp Dermatol. 2008 Nov;17(11):958-64.
  32. Ishikawa J, Shimotoyodome Y, Chen S, et al. Eucalyptus increases ceramide levels in keratinocytes and improves stratum corneum function. Int J Cosmet Sci. 2012 Feb;34(1):17-22.
  33. Ishida K, Takahashi A, Koutatsu B, et al. The ability of ceramide complex to reduce erythema and enhance barrier function of atopic skin. Poster #5433 presented at: American Academy of Dermatology 70th Annual Meeting. San Diego, CA. March 16-20, 2012.
  34. Miller DW, Koch SB, Yentzer BA, et al. An over-the-counter moisturizer is as clinically effective as, and more cost-effective than, prescription barrier creams in the treatment of children with mild-to-moderate atopic dermatitis: a randomized, controlled trial. J Drugs Dermatol. 2011 May;10(5):531-7.
  35. Eberlein B, Eicke C, Reinhardt HW, et al. Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). J Eur Acad Dermatol Venereol. 2008 Jan;22(1):73-82.
  36. Abramovits W, Alvarez-Connelly E, Breneman D, et al. A double-blind, randomized, vehicle-controlled trial to determine the efficacy and safety of hydrocortisone butyrate 0.1% lipocream in the treatment of mild to moderate atopic dermatitis in pediatric subjects. Poster presented at: 25th Anniversary Fall Clinical Dermatology Conference. Las Vegas, NV. October 6-9, 2006.
]]> Atopic Dermatitis: The Skin Barrier and the Role of Ceramides (Pediatric Edition) https://www.skintherapyletter.com/atopic-dermatitis/atopic-dermatitis-skin-barrier-ceramides/ Wed, 01 Feb 2012 17:27:21 +0000 https://www.skintherapyletter.com/?p=3113 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).
]]> Atopic Dermatitis: The Skin Barrier and the Role of Ceramides https://www.skintherapyletter.com/atopic-dermatitis/ceramides-role-fp/ Sat, 01 Oct 2011 18:12:55 +0000 https://www.skintherapyletter.com/?p=2548
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.

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

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

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.

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

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.

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

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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