Topical Ceramides for Cosmetic Dermatological Concerns

 

When one integrates aesthetics into their clinical practice, there are a few noted therapies which offer a benefit across most patient populations and concerns. In the realm of cosmeceutical ingredients, ceramides are a prime example of such therapeutic products, given their applicability for many common cosmetic/dermatological conditions. Further to the information provided in my Introduction to Naturopathic Aesthetics course, we will review the structure, role, and production of ceramides in the skin, as well as the supporting research regarding its topical use for concerns such as acne, atopic dermatitis, and rosacea.

Role in Stratum Corneum Barrier Support

As a brief review, the epidermis is comprised of four cellular layers: the stratum basale, overlaid by the stratum spinosum, the stratum granulosum, and finally, the stratum corneum. Our focus will reside here, in the outermost stratum corneum, whose structure is often likened to that of a ‘brick and mortar’ design. The bricks represent the terminally differentiated keratinocytes, embedded within a lipid matrix, representing the mortar, which are arranged into lamellar layers (multiple bilayers) comprised of ceramides (40-50%), free fatty acids (10-15%) and cholesterol (25%) ^[1]. Among various functions, the stratum corneum barrier plays an essential role in water retention and in the protection against a wide array of external insults. However, any disruption or depletion of stratum corneum lipids can weaken the integrity of the barrier function, and give rise to the progression of various skin concerns, such as dry skin, psoriasis, acne, and atopic dermatitis. All of these conditions have been associated with an alteration and/or depletion of these stratum corneum lipids, and ceramides in particular. Clinically, ceramides are being added to cosmetic products as a means of replenishing skin ceramide content, and to improve skin barrier functioning. Of the stratum corneum lipids, ceramides are the most effective at restoring barrier function and increasing hydration of skin. ^[2,3]

Basic Structure and Production of Ceramides

The base structure of a ceramide is comprised of a fatty acid conjugated to a sphingoid base via an amide bond. There is much heterogenicity, however, of ceramide structure within human skin. Thus far, there are 4 different sphingoid bases and 3 types of fatty acids identified, leading to a current total of 12 different classes of ceramides. The wonders of nature do not stop there as, for example, chain lengths for the fatty acid moiety can vary as well, further differentiating and determining a specific ceramide’s structure.^[3] Ceramide synthesis begins in the stratum basale, where ceramides are synthesised de novo in the endoplasmic reticulum via the fatty acid-to-sphingoid base conjugation. They are then either glucosylated or converted to sphingomyelin within the Golgi apparatus, and incorporated into secretory vessels. Once at the level of the stratum granulosum, these vessels exocytose into the extracellular space within the stratum corneum. The enzymes beta-glucocerebrosidase and sphingomyelinase convert them back to the original ceramide structures, which then arrange into the lamellar layers along with fatty acids and cholesterol in the intercellular spaces between corneocytes. ^[3] For those of you biochemical enthusiasts, feel free to explore the Meckfessel & Brandt and/or Sahle et al citations below for further details regarding ceramide biosynthesis and nomenclature.

Factors Influencing the Skin Barrier

Numerous factors can affect the organization and composition of stratum corneum lipids. Among those which our patients may, unconsciously, be exposing themselves to include: topical ethanol (thus the need for barrier supportive moisturizer following ethanol-based hand sanitizer use); contact irritation or allergy to, for example, fragrances, preservatives, botanical extracts, metals, etc.; excess heat exposure (thus the benefit of washing face/body with more tepid water temperature over hot); deficiency of dietary Linoleic Acid (needed for the formation of longer chain ceramides); aging; and psychosocial and/or sleep-deprivation related stress (which has been shown to disrupt the skin barrier, possibly via stress-induced alterations to cytokine secretion). ^[2]

Research Highlights for Various Skin Concerns

Acne

Despite the bulk of pathogenic focus on the likes of hyperkeratinization, Propionibacterium acnes, sebum production, and follicular plugging, our understanding of epidermal changes associated with acne vulgaris development is continually growing. As such, research support for epidermal barrier dysfunction is now adding a unique element to our understanding of the processes underlying acne development. In this context, the barrier functions for both the epidermis of exposed skin, as well as that of the follicular epithelial lining, are potentially involved in acne vulgaris pathophysiology and/or impairment in water flow and epidermal hydration. It has been theorized that the presence and intensity of inflammation may further impact the follicular epidermal barrier integrity [4]. What follows are key findings in the elucidation of the role of the skin barrier as it relates to acne vulgaris:

• In addition to increased sebum production and sebaceous gland size, those with acne exhibit a marked increase in Trans Epidermal Water Loss (TEWL – a measure of barrier integrity) and reduced stratum corneum hydration. This finding exhibits a positive correlation with acne severity. ^[4]
• Acne patients are found to have significantly reduced free sphingosine and total amounts of ceramides in their stratum corneum, further evidence pointing to barrier impairment. ^[4]
• The reduction in sphingosine, in particular, phytosphingosine, is also believed to contribute toward skin inflammation and infection associated with acne vulgaris. ^[5]
• Various lines of emerging research are pointing toward the beneficial effects of barrier-supportive topical moisturizers, formulated to contain those physiologic lipids as found in the barrier lipid matrix, in the management of acne. ^[5]
• Incorporating the combination of both a ceramide-based cleanser and moisturizer in conjunction with conventional topical therapies, such as clindamycin phosphate (1.2%), benzoyl peroxide (2.5%), or micronized tretinoin (0.05%), has been shown to improve tolerability (thus compliance) of the traditional treatments, as well as overall treatment efficacy. ^[1]

Atopic Dermatitis/Eczema

In addition to the altered immunologic involvement characterizing atopic dermatitis, an impairment in skin barrier function can also be seen as an essential contributing factor. An impaired barrier can further facilitate the triggering of the immune response, given the ease by which environmental antigens may breach the barrier. Genetically, there is a strong association with a mutation in the filaggrin gene.^[3] Filaggrin is a high molecular weight protein residing inside corneocytes from which is derived Natural Moisturizing Factor amino acids, which serve as the skin’s own humectant-based moisturizer.^[6] In addition to this, skin barrier integrity can again be explored for its involvement in the pathophysiological underpinnings of eczema:

• Both the overall amount and composition of ceramides have been found to be altered in eczematous skin. Of note, a reduction in ceramide 1 (CER 1) levels (a long-chain ceramide containing an ester-linked fatty acid), has been found. In relation to composition, elevated levels of smaller carbon chain-length ceramides (<40 carbons), along with a decrease in longer carbon chain-length ceramides (>50 carbons), have also been found. As a generality, longer chain length ceramides predominate in the stratum corneum of healthy skin samples.^[3]
• Some research has also found reductions in ceramide 3 (CER 3), in addition to CER 1, along with a relative increase in cholesterol within the barrier lipid matrix. Further to this, and as would be expected in the context of barrier perturbations, increased Trans Epidermal Water Loss has also been found in skin of patients with atopic dermatitis.^[7]
•  Increased expression and activity of enzymes such as sphingomyelin deacylase, glucosylceramide deacylase, and ceramidase, have been noted in atopic dermatitis. Sphingomyelin deacylase and glucosylceramide deacylase will together compete with the sphingomyelinase and beta-glucocerebrosidase enzymes for the sphingomyelin and glucosylceramide substrates. Conversely, ceramidase will convert ceramides into sphingosine. ^[3,8] Together, this will lead to a reduction in ceramide levels.
• Impairment in ceramide amounts and composition have been found not only in the affected skin of patients with atopic dermatitis but also in the unaffected skin as well. ^[1,2]
• The use of both a ceramide-based cleanser and moisturizer, in combination with a fluocinonide cream (0.05%), has been shown to improve clearance rates of eczematous lesions, with a noted improvement in erythema, scaling, pruritis, lichenification, and excoriation. Of note in this 4-week study, the speed of skin clearance, along with the degree of improvement, were highest when both the cleanser and moisturizer were used together, as compared to use of the fluocinonide cream with either a non-ceramide mild cleansing bar or ceramide-based cleanser alone. Another unique aspect of this study was the delivery technology of the ceramide products, such that they were configured into a time-released multilamellar vesicular emulsion (MVE). This allows the ingredients to more gradually be released onto the skin for a period of time after application. ^[9]

Rosacea

Rosacea represents another common dermatological and cosmetic concern for which patients will often seek support. In addition to the presence of visible symptoms such as erythema, telangiectasias, papules and pustules, patients often experience the challenge of managing sensitivity symptoms like burning, stinging, and itching.  The skin barrier can, yet again, figure prominently in its pathogenesis and management.

•  Water content of the stratum corneum, along with lipid levels on the skin surface, were significantly lower in patients with papulopustular rosacea as compared to those with acne vulgaris and healthy skin. Interestingly, although this study noted a higher stratum corneum water content and lower TEWL in the acne patient comparison group, this was speculated as owing to sebaceous hypersecretion onto the skin surface. ^[10] The sebum would effectively act as an occlusive moisturizer to trap water in the epidermis, and thus the lower TEWL. However, in this context, it may not necessarily represent a healthy functioning skin barrier per se.
•  Positive results to skin irritation testing have also been used to suggest impairment in skin barrier function in both papulopustular and erythematotelangiectatic forms of rosacea. ^[11]
•  Much like atopic dermatitis above, permeability defects seem to characterize both affected and non-affected skin areas on the face. The gives rise to the necessity of barrier support measures both during, and in between, flares. Barrier repair-focused moisturizers, and use of gentle cleansers, have been reported to reduce flare frequency, along with overall dryness and sensitivity. ^{[1, 11]}
•  Multilamellar vesicular emulsion (MVE)-based ceramide moisturizers have been shown to reduce stinging from, and improve compliance with, the use of traditional topical rosacea medications such as azelaic acid gel (15%). ^[1]
• An impaired barrier can create a vicious cycle such that it may first predispose the skin to allow for the easy entry of irritants, precipitating rosacea symptoms. Triggering of inflammation may itself then further disrupt the barrier, propagating the cycle. ^[11]

As our knowledge base builds regarding the pathophysiological basis behind common cosmetic-dermatological concerns, we are beginning to truly appreciate the role played by the epidermal skin barrier. As such, the role we can play as aesthetics-focused Naturopathic doctors can be found in educating and helping our patients integrate dietary adjustments, lifestyle approaches, and topical skin care regimens, toward the ultimate goal of a healthy skin barrier, and thus healthier skin.

References

1. Zeichner JA & Del Rosso JQ. Multivesicular Emulsion Ceramide-containing Moisturizers: An Evaluation of Their Role in the Management of Common Skin Disorders. J Clin Aesthet Dermatol. 2016; 9(12):26–32
2. Sahle FF et al. Skin Diseases Associated with the Depletion of Stratum Corneum Lipids and Stratum Corneum Lipid Substitution Therapy. Skin Pharmacol Physiol 2015;28:42–55
3. Meckfessel MH & Brandt SB. The structure, function, and importance of ceramides in skin and their use as therapeutic agents in skin-care products. J Am Acad Dermatol 2014; 71:177-84
4. Thiboutot D & Del Rosso JQ. Acne Vulgaris and the Epidermal Barrier: Is Acne Vulgaris Associated with Inherent Epidermal Abnormalities that Cause Impairment of Barrier Functions? Do Any Topical Acne Therapies Alter the Structural and/or Functional Integrity of the Epidermal Barrier? J Clin Aesthet Dermatol. 2013 Feb; 6(2): 18–24
5. Lynde et al. Moisturizers and Ceramide-containing Moisturizers May Offer Concomitant Therapy with Benefits. J Clin Aesthet Dermatol. 2014;7(3): 18-26
6. Dasgupta BR et al (2016). Cosmeceuticals: Function and the skin barrier. In Cosmeceuticals, 3rd ed., edited by Z.D. Draelos, 3-9. Elsevier, 2016
7. Di Nardo et al. Ceramide and Cholesterol Composition of the Skin of Patients with Atopic Dermatitis. Acta Derm Venereol 1998; 78: 27–30
8. Tessema EN et al. Potential Applications of Phyto-Derived Ceramides in Improving Epidermal Barrier Function. Skin Pharmacol Physiol 2017; 30:115–138
9. Draelos ZD. The Effect of Ceramide-Containing Skin Care Products on Eczema Resolution Duration. Cutis. 2008;81:87-91
10. Zhou M et al. Clinical characteristics and epidermal barrier function of papulopustular rosacea: A comparison study with acne vulgaris. Pak J Med Sci. 2016; 32(6):1344-1348
11. Del Rosso JQ. The Role of Skin Care and Maintaining Proper Barrier Function in the Management of Rosacea. Cosmetic Dermatology 2007; 20(8): 485-490