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Atopic dermatitis (AD) is a commonly occurring chronic inflammatory skin disease affecting 10-20% of children and 1-3% of adults. According to American Academy of Dermatology, atopic dermatitis is defined as "the itch that rashes. Intensely itchy patches form. These patches can be widespread or limited to a few areas. Scratching often leads to redness, swelling, cracking, weeping of clear fluid, crusting and scaling of the skin. Constant scratching can cause skin damage, infection, and sleep loss". More than 60% of AD cases manifest during the first year of life, and 80% of cases occur before the age of five (American Academy of Dermatology). Race does not play a role in the development of AD. The prevalence of AD has increased over the last 30 years in industrialized countries. As Nichols & Cook-Bolden reported, children in urban areas use more antibiotic and they are good in hygiene, hence they have less exposure to microbes, and do not have necessary immune protection against AD. In the United States alone, it is reported that average medical cost of an AD patient is about $600 per year and more than 15 million people have the symptoms of AD. It costs approximately $3 billion each year for direct treatment costs such as visits to doctor's office and medicine (National Institute of Arthritis and Musculoskeletal and Skin Diseases). In some cases, the cost of AD is incalculable; the crippling quality of life due to limited mobility and anxiety, and depression from visible skin changes. One study finds that dermatology patients are more susceptible to mental disorders compared to the general population. A negative body image and severe stress caused by skin problems can attribute to suicide attempts (Potocka et al).
The clinical manifestation of AD varies with age and it can be divided into three stages (Terui). During an infancy, the lesions of AD present as "generalized xerosis and erythematous scaly exudative plaques" usually affecting the cheeks and scalp (Nichols & Cook-Bolden). In childhood years, the lesions appear as lichenification and excoriations in the flexures and extensor regions of the limbs. In adolescent years and during adulthood, "lichenification, hyperpigmented patches resulting from previous excoriations" exhibit in the flexures regions, face and neck (Nichols & Cook-Bolden).
The pathogenesis of AD has long been believed as an immune system defect, namely Th1 and Th2 lymphocytes, immunoglobulin E production, mass cell hyperactivity and dendritic cell signaling (Elias et al). The rationale behind this is that defects in the immune system promote hyperactivity to environmental allergens or scratching, and more susceptible to infections resulting a skin injury. This in turn activates keratinocytes or basal cells to release cytokines and chemokines. These immune mediators induce inflammatory signaling cascade which clinically manifest as inflammation, pruritus and xerosis on the skin. Recent studies have shed a new light on the pathogenesis of AD. They strongly support defective skin barrier as the primary reason behind atopic dermatitis. Normal skin is composed of four epidermis layers: 1st stratum corneum at the surface of the skin, 2nd granular layer, 3rd spinous layer, and 4th basal layer. Stratum corneum is composed of filaggrin, breakdown-product of filaggrin, natural moisturizing factors (NMF), trans-Uurocanic acid, cornified envelope and intercellular lipids such as ceramide, cholesterol and free fatty acids. The granular layer is composed of keratohyalin granules, pro-filaggrin, lamellar body, precursor of lipids and anti-microbial peptides (Terui). In the case of AD skin, stratum corneum is compromised due to its loss in water binding capacity, caused by a deficiency of ceramide. Stratum corneum is also affected by filaggrin genes mutations in AD skin. As Nichols & Cook-Bolden reported, "filaggrin is essential to the formation of the cornified envelope, which is the basic of normal barrier function in the skin". During the formation of cornified envelope, series of events occur-pro-filaggrin from granular layer is dephosphorylated and cleaved into filaggrin copies; the breakdown product of filaggrin is degraded into hydrophilic amino acids called NMF; the secretion of lamellar body that not only carries antimicrobial peptides, hydrophobic lipids such as ceramides, cholesterol, and free fatty acids into the intercellular spaces of the stratum corneum but also the enzymes to make the hydrophobic lipids. NMF hydrates the skin and trans-Uurocanic acid maintains the pH of the skin surface (Terui). "These findings of filaggrin dysfunction, coupled with evidence of ceramdie deficiency in AD skin, have led many investigators to conclude that epidermal barrier disruption is the primary cause of AD; that, in fact, the breakdown of the skin barrier is what drives allergic sensitization and skin inflammation in AD, not the converse, which has been the conventional belief" (Nichols & Cook-Bolden). Elias et al. reported that exogenous stressors such as prolonged exposure to reduced environmental humidity during winter further aggravate barrier function in AD. Also, AD skin is susceptible to pathogen colonization, mainly with S aureus, due to structural defect, lipid replete, increase in surface pH, and reduction in free fatty acids in stratum corneum. Failure of permeability barrier function and antimicrobial function are reported to be interdependent in AD (Elias et al).
The treatment for AD has traditionally been either corticosteroids or immunomodulators or both. Immunomodulators such as calcineurin inhibitors namely tacrolimus 0.1% or 0.3% ointment (Protopic) and pimecrolimus 1% cream (Elidel), when given systemic, has a potential to cause malignances of skin and lymphoma. There have been reported cases to FDA that malignant disorders such as Bowen disease or squamous cell carcinoma in situ, para-psoriasis en plaque, or Paget disease of the nipple develop in the areas of prolong use of Elidel and Protopic (Elias). It is still under debate whether long term use of these topical agents is safe or poses cancer risk. Corticosteroids are used to suppress skin inflammation in AD, however, long term usage of steroids can have a harmful systemic side effects, particularly in children. Typical petroleum based moisturizers were also recommended for AD patients previously to relieve itching and dryness. They provide some temporary relief through moisturization, but in fact they delay skin barrier repair process rather than improving the condition (Elias).
The new understanding of AD pathophysiology allows researches to develop treatments that focus on repairing skin barrier dysfunction. Such therapy does not have potential toxicity profile as previously mainstay therapy with steroids or immunomodulators. Different approaches are being targeted from a pH reduction in stratum corneum, application of topical plasminogen activator inhibitor type-2 to hydration with general moisturizers or specific lipid replacement therapy (Elias et al). Many moisturizers which specifically aim to repair skin barrier defect have entered the market recently. One of the products to emerge is a skin barrier repair cream called EpiCeram emulsion, which is ceramide dominant, lipid replacement therapy and composed of 3:1:1 ratio of ceramides, free fatty acids and cholesterol. EpiCeram's efficacy has been shown in two clinical studies and approved by the FDA in April 2006 and available for prescribing in September 2008 (Elias). The first study published in 2002 showed "dramatic improvements in clinical disease activity, permeability barrier function, and stratum corneum integrity when an over-the-counter version of this technology (TriCeram) was substituted for standard moisturizers in children with severe recalcitrant AD" (Elias at al). The second study published in 2008 demonstrated EpiCeram's comparable efficacy to a mid-strength topical corticosteroid (Fluticasone Propionate 0.05%) in a multicenter, randomized and controlled clinical trial in 113 children, aged 6 months to 18 years with moderate-to-severe AD. The study reported that at 14 days, fluticasone propionate cream showed a faster improvement in SCORAD and IGA score, but at 28 days of treatment, both agents demonstrated significant improvements in pruritus, sleep habits and in both SCORAD (Scoring Atopic Dermatitis) and IGA (Investigator Global Assessment) scores. There was no statistical difference between EpiCeram and fluticasone propionate at 28 days. Also in the efficacy comparison, SCORAD scores decreased 37% and 51% from baseline at day 14th and 28th (P< 0.001). The study concluded that EpiCeram was highly effective as stand-along therapy, or coupled with anti-inflammatory therapy initially or only as needed, and comparable in both clinical efficacy and itch reduction to Fluticasone cream by 28 days (Madaan). Other products that are ceramide-based moisturizers include CeraVe, Proderm and its much stronger version, Neosalus. In order to achieve optimal disease management, AD patients are recommended to apply moisturizer to the body once a day after bathing. During flares or relapse, mid potency topical corticosteroids or immunosuppressive drugs such as tacrolimus can be applied BID on a two weeks on and two weeks off schedule. Once remission is achieved, patients are advised to apply topical emollients and immunomodulators (Nichols & Cook-Bolden).
Other nonsteroidal, barrier repair products that are cleared for marketing by FDA are MimyX and Atopiclair. "Mimyx is a palmitamide monoethanolamine (PEA)-containing nonsteroidal and topical calcineurin inhibitor-free designed to replace PEA deficient in atopic skin" (Nichols & Cook-Bolden). PEA is found in the 2nd layer of epidermis, the granular layer, and believed to reduce the inflammation by reducing histamines, cytokines and IL-4,-6, and -8. In a European study, the efficacy of Mimyx was assessed by applying twice a day for 38 days in 2456 subjects who had AD. The study concluded "physician assessment scores demonstrated that pruritus improved by 56%, erythema by 54%, dryness by 57%, lichenification by 55%, and excoriations by 63%" (Brunk). Atopiclair or MAS063 is another nonsteroidal topical cream, dye and fragrance free, that contains glycyrrhetinic acid (licorice extract), hyaluronic acid, vitis vineifera (grape leaf extract), telmesteine, and shea butter. The efficacy of Atopiclair was tested in 106 infants and children with mild to moderate AD in a randomized, double-blind, vehicle-controlled trial. They were given hydrolipidic cream MAS063DP or vehicle alone three times a day for 43 days. The study concluded "pruritus, EASI scores, subject and caregiver assessment of global response, onset and duration of itch relief, and need for rescue medication were all significantly improved in the treatment group, compared with the vehicle group" (Brunk).
Oral antibiotics also have been used in order to treat Staphylococcus aureus colonization in AD patients. Since recent studies have shown that permeability barrier function and antimicrobial defense are interdependent, antibiotics have been used as an adjunctive therapy to topical corticosteroids (Elias et al). Topical antiseptics such as triclosan and chlorhexidine have not shown to be promising in the treatment of S. aureus infections in AD. In addition to topical therapy, systemic treatment with low-dose anti-IgE therapy is being studied in AD patients. Omalizumab is a FDA approved drug in treating moderate to severe persistent asthma in patients who are at least 12 years old. Omalizumab works by "stopping free-serum IgE from attaching to mast cells and other immune cells and prevents IgE-mediated inflammatory changes" (Nichols & Cook-Bolden). Nichols & Cook-Bolden reported that Omalizumab usage has shown a significant improvement in AD symptoms and it may be "a safe and effective therapeutic option in patients who have severe AD, especially those who have high IgE levels".
In conclusion, ceramide-dominant barrier repair cream has demonstrated efficacy and tolerability in the treatment for AD. The risks associated with corticosteroids and immunomodulators are quite significant that they should not be used for long term treatment. With a better understanding of epidermal barrier dysfunction in AD, products that target barrier repair function will hopefully replace traditional steroid therapy as a safe and effective treatment.