Protecting the Skin Barrier in Atopic Dermatitis

Atopic dermatitis (AD) is a common, chronically relapsing inflammatory skin disease with a complex pathogenesis affecting 17.8 million people in the United States, and between 15% and 20% of all children in affluent countries. This dermatitis often appears as a red, itchy condition that typically appears on the cheeks, arms, and legs (Figure 1).1,2 Considered the most common form of eczema, AD is associated with pruritus, sleep disturbance, psychosocial symptoms, and impaired quality of life.3 Furthermore, AD is a complicated skin condition for dermatologists to treat and manage because its exact cause is unknown.

 

“AD is probably not just one disease, but more likely a group of similar conditions. Specifically, we know that some patients have a mutation in the gene that codes for filaggrin, an important structural protein in the skin. Others, do not,” said Peter Lio, MD, assistant professor clinical dermatology & pediatrics at Northwestern University Feinberg School of Medicine and director of The Chicago Integrative Eczema Center in Chicago, in an interview with The Dermatologist. “More importantly, perhaps, AD involves skin barrier dysfunction, dysregulation of the immune system, changes in nerves (specifically with respect to the sensation of itch), and often involves behavioral aspects as well. It has so many moving parts that it is difficult to get folks better by just focusing on one aspect of the disease.”
    
Role of Skin Barrier in AD

Changes in the skin barrier play a critical role in the pathogenesis of AD.4 “We feel that the skin barrier is of central importance in AD. For those that have a mutation in a skin structural protein, it makes sense that they have ‘leaky skin’: that allows water to escape unnaturally, but also allows allergens, irritants, and infectious agents to enter. Perhaps more importantly, even those that appear to start with normal skin barrier function can actually develop secondary barrier damage in the presence of inflammation,” explained Dr Lio, who practices at Medical Dermatology Associates of Chicago and also serves on the Scientific Advisory Board for the National Eczema Association. “In particular, IL-4 and IL-13 seem to decrease production of filaggrin, making a functional barrier deficiency. This, of course, is beyond the direct effects of inflammation on the skin and the itch-scratch cycle which further damages the barrier.”

Up to one-third of all patients with AD have it due to a filaggrin gene mutation. Lack of filaggrin results in a skin barrier defect with dry and cracked skin.2

Recent studies indicate that defects in the epidermal barrier function contribute significantly to the initiation and perpetuation of skin inflammation in AD. Lee and colleagues5 investigated if AD was associated with reduced corneodesmosin (CDSN) expression in 10 healthy controls and 10 patients with AD using real-time reverse-transcriptase polymerase chain reaction and immunostaining. They found that CDSN, an adhesive protein that maintains cohesion and intercellular integrity in the skin, plays an important role in epidermal barrier function, and its deficiency may contribute to viral infection in AD.

Repairing the Skin Barrier

Repairing the skin barrier or preventing barrier dysfunction is the cornerstone of AD management.3 “Restoring the skin barrier does so many things at once and there is excellent data that using a good moisturizer helps directly with eczema severity,” said Dr Lio.

In a systematic review of 48 studies with 3262 individuals, Lindh and Bradley6 investigated the effects of emollients, as a group and individually, in the treatment of AD and related conditions. The researchers found that a vast majority of studies indicated that moisturizers have beneficial effects on clinical symptoms (Figure 2). SCORing Atopic Dermatitis, a widely used clinical tool to assess the extent and severity of eczema, showed reductions ranging from 0 to 2.7 points. The study also showed that emollients had benefits in transdermal water loss (TEWL, range 0 to -12.2 g/m2h) and stratum corneum hydration (range +8 to +100%). Although direct comparisons between individual moisturizers are lacking, the researchers found that the clinical effectiveness appears most well-documented for urea-based preparations. They noted, however, the need for large, well-designed comparisons between the individual emollients to help clinicians in their choice of first-line therapy.

In separate study,7 researchers sought to determine the skin barrier effects of emollients commonly prescribed in the United Kingdom. Two cohorts of individuals with quiescent AD were included. The first cohort (n=18) treated the volar side of one forearm with Doublebase gel twice daily for 4 weeks. The second cohort (n=19) used the same regimen with Diprobase cream. Danby and colleagues found that neither Diprobase cream nor Doublebase gel significantly affected the underlying skin barrier function. Both products were associated with significantly increased skin surface pH immediately following application (by 0.8±0.19 and 1.0±0.18 units, respectively), and no erythema. Diprobase cream artificially and transiently (6 hours) improved permeability function by 2.9 to 3.1 g/m2h TEWL and increased skin hydration by 6.0 to 6.2 units. Doublebase was associated with greater (between 10.1 and 13.0 units during the first 6 hours) and more sustained hydration, extending more than 12 hours following repeated use.

Strategies to Heal the Skin

In treating individuals with AD and parents of small children with this skin disease, dermatologists can recommend various strategies to help heal the skin. “Apply a good moisturizer frequently is critical. This will help to maintain and repair the barrier, keeping water in and keeping allergens and irritants out,” said Dr Lio. “Even simple moisturizers like petrolatum have been show to help encourage endogenous ceramide production, which is fantastic. Avoiding triggers and irritants is also key. Harsh cleansers, fragranced products, and for some animal dander and saliva can irritate the skin and kickoff a flare-up. Prompt treatment of a flare with an appropriate anti-inflammatory topical can really help abort a vicious cycle of worsening from developing, but for more severe cases, the most cutting-edge approach is called ‘proactive therapy.’ This means treating trouble spots twice weekly in a proactive way with a topical calcineurin inhibitor such as tacrolimus to actually prevent flare-ups before they start.”

Treatment Options

One factor of AD is the itch/scratch cycle, which is the most common symptom Dr Lio sees among his patients. “Many patients are extremely distraught by the constant, terrible itching. This can of course affect sleep, but also affects them during waking hours both directly and indirectly because of sleep deprivation.” He added that infection of the skin is also a common problem for his more severe patients and is another issue dermatologists have to address.

Topical agents, including emollients, tacrolimus, and topical corticosteroids, are pivotal in the treatment of atopic itch, reported Kamata and colleagues8 in their study on the management of atopic itch. Phototherapy has also been shown useful in the treatment of severe AD and associated pruritus. Systemic treatments such as cyclosporine A and aprepitant are used to treat severe and intractable pruritus in patients with AD. Furthermore, new antipruritic approaches are showing promise. Clinical trials of dupilumab, a fully human monoclonal antibody that blocks signaling from both IL-4 and IL-13, significantly reduced the severity and pruritus score in AD; similar results were observed with CIM331, a humanized antihuman IL-31 receptor A monoclonal antibody.8

Effective management of AD should be individualized, and include an assessment of severity and impact on quality of life, treatment of the inflamed epidermal skin barrier, recognition and treatment of infection, and assessment and management of environmental and allergic triggers.3

Dr Lio pointed out that dermatologists have various treatment regimens available to manage this complex multifactorial disease. When determining an action plan for treatment, he uses a pyramid with 4 points: moisturization, anti-inflammatory, antipruritics, and antibiotics (Figure 3). “For moisturization, we can have them use something lighter in the day (such as a cream) and then perhaps a heavier ointment at night after bathing. Sometimes we will incorporate a topical antibiotic, or perhaps to something less specific like dilute bleach baths,” he said. “We have a variety of topical anti-inflammatory agents to choose from, but by far the most common is a topical corticosteroid. Usually these are an excellent first-line agent for inflammation, but they cannot be used long-term. Ideally, we will use them for 5 to 7 days to get things better, and then either take a break from medications completely, or switch to a topical calcineurin inhibitor. For pruritus, we don’t have many great options, but camphor, menthol, and topical pramoxine can all be helpful in certain scenarios.”

“Using an ice pack, cool compress, or a wet wrap can also help with itch in some patients,” continued Dr Lio. “If things are still not improving, or we feel that patients are requiring too much topical corticosteroid, we then need to think about systemic therapies, from phototherapy to cyclosporine.”

Dr Lio shared additional thoughts on skin barrier protection and potential future treatments: “Moisturizers are such an exciting field, and we’ve had so many breakthroughs in the past decade. The ceramide movement has been very exciting, and I really think these can have a significant impact on some patients,” he said. “More sophisticated ‘barrier repair creams’ have also come to the market, some of them with very drug-like claims. These have been a bit more confusing given their (generally) high prices compared with over-the-counter moisturizers, but for some they may make a significant difference that could be worth the cost difference. I think we are seeing how things connect in ways that we were not aware of which hopefully means that newer treatments will be better still.”

References
1. Facts about atopic dermatitis. National Eczema Association website. https://nationaleczema.org/wp-content/uploads/2016/08/Media-Kit-FINAL-08.11.16.pdf?2b800d. Accessed September 21, 2016.
2. Stalder JF, Tennstedt D, Deleuran M, et al. Fragility of epidermis and its consequences in dermatology. J Eur Acad Dermatol Venereol. 2014;28(suppl 4):1-18.
3. Hon KL, Leung AK, Barankin B. Barrier repair therapy in atopic dermatitis: an overview. Am J Clin Dermatol. 2013;14(5):389-399.
4. Zaniboni MC, Samorano LP, Orfali RL, Aoki V. Skin barrier in atopic dermatitis: beyond filaggrin. An Bras Dermatol. 2016;91(4):472-478.
5. Lee UH, Kim BE, Kim DJ, Cho YG, Ye YM, Leung DY. Atopic dermatitis is associated with reduced corneodesmosin expression: role of cytokine modulation and effects on viral penetration [published online August 30, 2016]. Br J Dermatol. doi:10.1111/bjd.15010.
6. Lindh JD, Bradley M. Clinical effectiveness of moisturizers in atopic dermatitis and related disorders: a systematic review. Am J Clin Dermatol. 2015;16(5):341-359.
7. Danby SG, Chalmers J, Brown K, Williams HC, Cork MJ. A functional mechanistic study of the effect of emollients on the structure and function of the skin barrier [published online April 21, 2016]. Br J Dermatol. doi:10.1111/bjd.14684.
8. Kamata Y, Tominaga M, Takamori K. Itch in atopic dermatitis. Curr Probl Dermatol. 2016;50:86-93.