Chronic, itchy skin conditions and inflammation can result from compromised stratum corneum function. Dr Carl Thornfeldt discusses the importance of barrier repair and optimisation, and his research behind the Epionce skincare range
My goal as a dermatologist has always been to achieve what I desired for my own chronic skin condition—to become clear and itch-free, and stay clear. When I began private practice, I believed people did not get better because the physician wasn’t intelligent enough or diligent enough to leave no stone unturned in searching for the cause of the disease. Within the first two years of practice, I realised how foolish this thought was.
Two diseases in particular were conundrums—polymorphous light eruption (PMLE) and asteatotic dermatitis (ASD). Both magically appeared and then resolved at specific times each year. This was unexplained by our understanding of skin function and structure.
PMLE is commonly known as “sun allergy”. The condition presents with itchy red bumps or hives, or dermatitis patches occurring at any sun-exposed site on the body, usually starting in the spring. It is more common in patients who have allergies and sensitive skin. Despite our treatments, most PMLE patients completely cleared by early August.
ASD or “winter itch” would start during the winter holidays with itchy dermatitis, usually on the lower legs before spreading to the feet, hands and trunk. After months of battling this disease, ASD would spontaneously clear by mid-April. Moreover, our treatment success for completely clearing the common chronic scaly inflamed skin diseases like psoriasis and dermatitis was modest, but keeping them clear had a poor success rate.
As I pondered these therapeutic dilemmas, I considered the facts. PMLE resolved when the stratum corneum was thickened in response to solar radiation as summer progressed. ASD resolved when the ambient humidity and warmth increased, causing the fractured, dehydrated stratum corneum to become supple and thickened.
In a scientific epiphany, I realised that in both cases, chronic inflammation resolved after the stratum corneum barrier was strengthened and thickened and that the inflammation and itchy dermatitis must also follow a compromise of the stratum corneum barrier. This made sense—the poorest barrier occurs at the sites of lowest sebum production, such as lower legs, and is also deficient in those with atopy.
This was also a partial answer for the treatment of chronic inflammatory scaly skin diseases and maintaining their remission. The standard treatment of corticosteroids was effective in reducing inflammation, but induced further barrier thinning and disruption, allowing pollutants, radiation, microbes and chemicals to penetrate through to a greater degree.
Corticosteroids also stimulated the growth of these pro-inflammatory microbes—when the corticosteroid treatment was stopped, chronic inflammation roared back. It also provided an explanation for Koebner response, where injury to the skin activates diseases like psoriasis.
The skin barrier compromise was therefore usually intertwined with the chronic inflammation that is critical in a significant number of skin disorders and conditions.
Dr Albert Kligman and Dr Robert Lavker reported that inflammation played a role in extrinsic skin ageing in 1988. But the question remained—how did the stratum corneum barrier and the chronic inflammation respond differently to their seasonal insults?
Twenty-five years ago, the epidermis was considered to be like a cellophane wrap of dead and inactive cells. I believed more scientific investigation in all physiologic aspects of skin barrier and cutaneous inflammation, including their regulation, was warranted.
That led to the scientific hypothesis: if we could optimise the structure and function of the skin, can we treat disease and conditions better and prevent them from flaring or rebounding? Moreover, could these morphologic adjustments impact visible skin ageing and even skin cancer incidence?
Epidermal skin biology research carried out with Dr Peter Elias two decades ago resulted in the understanding of the brick and mortar skin barrier structure and destructive chronic vs. healing acute cutaneous inflammation.
We found that a variety of environmental exposures damage the skin by disrupting the skin barrier, inhibiting its repair which then activates multiple inflammatory cascades that damage existing cutaneous structures.
Damage can be caused by not only pollution, sunlight, smoking and poor diet, but also X radiation, heat, premature or elderly age, humidity extremes, high testosterone, low oestrogen, severe emotional and physical stress, ingestion of lipid-lowering medications, insufficient consumption of “good” fats, excess consumption of “bad” fats and sugars and exposure to heavy metals in diet and contacting in workplace.
A number of compounds used in therapeutic products for skin diseases and conditions—including propylene glycol, lactic acid, retinoic acid, as well as preservatives formaldehyde, quaternium 15 and sodium lauryl sulfate—not only induced barrier disruption, but activated inflammation by releasing tumour necrosis factor alpha.
Further research showed that skin conditions and diseases characterised by chronic inflammation coupled with a compromised permeability barrier, include visible skin ageing and also sensitive skin; all dermatoses (eczema), including atopic, seborrheic, chronic contact and asteatotic; most types of ichthyoses, keratosis pilaris, rosacea, PMLE, certain types of psoriasis and premalignant actinic keratoses.
The foundation for the most effective treatment and longest lasting remission of these diseases therefore rests upon optimising barrier function and safely reversing and preventing destructive chronic inflammation.
Chronic inflammation is activated in the epidermis and dermis by persistent or recurrent barrier disruption of any cause in two ways. First, protective endogenous inflammatory pathways are activated by the release of biologic response modifiers sequestered in granules within the deepest stratum corneum corneocytes—released when these cells extrude the granules that are disrupted with stratum corneum injury.
Secondly, pro-inflammatory insults penetrate at a much greater amount and depth that magnifies its inflammatory effect.
We have discovered that five pathways of inflammation are activated with stratum corneum barrier damage from any cause. The first four include the release of cytokines, such as interleukins and tumour necrosis factor alpha, growth factors such as transforming growth factor beta, histamine and nuclear receptors such as PPAR and LXR.
All these paths ultimately upregulate matrix metalloproteinase enzymes (MMPs) that destroy cutaneous structures inducing micro scars that progress to wrinkles, dysplasia that progresses in to skin cancer and sensitive skin.
Bacterial and yeast invasion that is increased with barrier damage also upregulates inflammation via toll-like receptor activation. Two other cutaneous inflammatory pathways not related to barrier disruption include glycation reaction and the upregulation of arachidonic acid synthesis, a group of pro-inflammatory molecules
Acute inflammation is characterised by polymorphonuclear leukocytes infiltration, proliferation and chemotaxis which is necessary for protection and initiating repair. It converts into chronic inflammation 12–20 days after the skin is damaged.
Chronic inflammation, on the other hand, is characterised by lymphocytic cell infiltrate and upregulation of MMPs. With frequent, recurrent or prolonged insult, accumulation of excessive amounts of MMPs results in excessive damage of collagen and elastin fibres and glycosaminoglycan ground substance.
Reversing and preventing this destruction is needed with therapeutic ingredients focusing on chronic inflammation, while at the same time attempting to slam the incompetent skin barrier shut.
Barrier repair utilises five pathways that lead to increased keratinocyte proliferation then to enhanced differentiation into the corneocytes—protein bricks of the barrier—with rejuvenation of lipid lamellae mortar located between these cells.
The normal stratum corneum barrier requires the key physiologic lipids, cholesterol, ceramide and free fatty acids, in a specific molar ratio to maximise repair and optimise barrier function.
Many different ratios were tested but the ratio ultimately found to be most effective to accelerate barrier repair nearly 2.5 fold over any other ratio was cholesterol 3; ceramide 1; and linoleic acid 1.
Our research also found that it was not possible to produce chemically and visually stable results using known synthetic ingredients at that time. Our search therefore turned to herbal extracts that each had multiple biological functionalities within the skin.
In nature, these herbs contain stable but biologically active molecules that perform many different functions for the plant. After years of research, I settled on a barrier repair formula based on extracts of safflower, mountain rose, avocado and flax to achieve the optimum ratio of barrier lipids and their precursors.
This product accelerated barrier repair more than twice as effectively as 100% petrolatum and four times better than any commercially available moisturiser product used by the dermatology community.
Additionally, an anti-inflammatory formulation was created based on extracts of date, meadowfoam, apple, flax and avocado, all of which were more potent than grape, olive, teas and soy, respectively. This product inhibited chronic inflammation 2.5 fold better than 1% hydrocortisone.
The barrier repair and anti-inflammatory components were formulated together and tested for safety—patients expect products to be effective and safe, just as those determined for procedures and prescriptions. This test was a repeat insult patch test, which tests for irritant and allergic contact reactions. Neither was induced by this formulation.
The key test to determine if a product is effective is a double blind prospective controlled clinical trial graded by third party investigators with enough human subjects to determine statistically significant value. It is the marketed, final formulation that should be tested for true efficacy.
This type of study is not required to market a cosmeceutical, but there is no other scientifically valid method to determine the effectiveness of a product. As a physician, I felt it was critically important that any new products claiming to be effective for any skin condition should adhere to this standard for efficacy and safety.
These barrier repairing (BR) products that also reverse and prevent chronic inflammation (AI) have been tested against six different prescription products and were superior to all six. Initially, retinoid induced contact dermatitis was effectively treated to a statistically significant degree that was superior to mometasone.
This BR product was used twice daily with a once daily comedolytic, anti-inflammatory (AI/C) product. It was compared to emollient tretinoin (ET) 0.05% once daily combined with a moisturiser containing lactic acid twice daily, to assess impact upon visible photoageing.
In a six-month trial on 25 subjects, the BR/AI/C regimen was numerically superior in reducing tactile roughness, fine lines, wrinkles, clarity and visible actinic keratoses while ET was numerically superior in reversing mottled hyperpigmentation and laxity.
But histologically, the combined BR/AI and AI/C products statistically significantly (p<0.05) increased epidermal glycosaminoglycans by 13.3%, double that of ET. On dermal ultrasound, BR/AI/C produced a highly statistically significant (p<0.001) doubling of the dermis, by 20.8%, measured by density versus ET.
No subjects experienced true contact dermatitis to BR/AI and AI/C with 20% noting only transient eyelid erythema. The ET product subjects experienced frank contact irritant dermatitis in 40%.
To prove a concept is valid, a second formulation (BR/AI/C) with different ingredients but same mechanisms of action for the concept is required. This related product contains potato and yeast peptides to further increase barrier repair and an anti-inflammatory triterpenoid that also realigns elastin fibres (ursolic acid) was formulated with a low concentration of azelaic acid.
A 12-week study against the most potent antioxidant product on the market at that time containing idebenone was conducted.
After six weeks of use, this related BR/AI/C product was statistically superior (p<0.05) in reducing shallow wrinkles, triple the efficacy of idebenone and twice as effective in reducing laxity and hyperpigmentation. It was also superior in reducing roughness and improving clarity.
One third of the idebenone patients dropped out of the study after the six-week time point because of moderate to severe contact irritant reactions. When compared to the ET trial, BR/AI/C improved dermal density by a highly statistically significant 19.4% at 12 weeks as measured by extensibility twice as fast as in the ET study.
One BR/AI/C subject dropped out from eyelid irritation. This was the only subject using BR/AI products based to drop out of any of the 15 blinded clinical trials that included 390 subjects.
Since this project began, a total of 15 blinded clinical trials have been performed with BR/AI, AI/C and BR/AI/C products. These products were designed to focus on the foundational mechanisms of skin diseases as skin ageing, which includes repairing and optimising barrier function while reversing and preventing inflammation. The data shows that this concept is not only novel, but has become a valid cosmeceutical offering superb safety and efficacy for treating photoageing.
Dr Carl Thornfeldt is a dermatologist and founder of Episciences, W: epionce.com