inhibiting influences, as well. Misbalance between commensals and pathogens often appears with elevation of skin surface pH and thereto related barrier dysfunction. Bacterial proteases worsen the situation by further impacting SC cohesiveness and the TJ system.
Topical Approaches to Manage Epidermal Barrier Disruption
When the epidermal barrier is compromised, as is the case for many common skin conditions including AD, eczema, and psoriasis, the skin is susceptible to excessive water loss, xerosis, and infection.56 These same skin conditions are characterized by an inflammatory response which manifests in pain, redness, irritation, and pruritus. The increased understanding of the complex pathology associated with diseases that impact the skin barrier has shown that barrier disruption and inflammatory events most often coincide.40,57 Therefore, effective treatment approaches should address both the recovery of the epidermal barrier and suppression of the underlying inflammatory conditions that, if left untreated, can further impede barrier repair.58
Factors that influence the therapeutic intervention include chronicity and severity of the disease, age, and general health of the individual.56 When considering topical versus systemic administration of therapeutic actives, topical administration is generally preferred for less severe cases due to potential risks associated with systemic exposure.58 Penetration of actives through an intact epidermis can vary greatly based on factors including anatomical location and surface area, the nature of active ingredient, and environmental factors.59 Such complexity has necessitated models and imaging modalities to accurately predict and visualize penetration.59 However, in the case of skin barrier-associated diseases, improved penetration of topicallyapplied active ingredients through the compromised barrier is expected.60 This, in combination with the reduced risk of systemic exposure, have made topical therapies the common first-line approach to manage disease symptoms associated with impaired skin barrier.
The mechanisms of action for many topical, pharmacologic approaches for skin conditions such as AD involve antiinflammatory and immunomodulatory interventions.61 Corticosteroids have been used for more than 50 years to reduce inflammation. They act on T lymphocytes, monocytes, macrophages, and dendritic cells, suppressing pro-inflammatory cytokine release and leading to a reduction of redness, swelling, and itching.62 The incidence of negative side effects is low; however, there are concerns linked to skin discoloration and atrophy following prolonged use of corticosteroids.61,62 Calcineurin inhibitors, including tacrolimus and pimecrolimus, have been in use since 2000 as a more targeted approach that reduces T-cell activation and subsequent cytokine release.57,58,61,62 An association with malignancy resulted in a black box warning related to cancer risk from the United States Food and Drug Administration (FDA) in 2005, although it is not clear whether there is a causal relationship.58,61 Examples of other topical treatments currently in development and testing include modulators of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which is activated by proinflammatory cytokines and downregulates the expression of structural skin proteins, and phosphodiesterase-4 (PDE-4) inhibitors aimed at reducing production of pro-inflammatory cytokines and signals.37,58
In addition to anti-inflammatory and immunomodulatory approaches, there is a continued role for topical products that restore, reinforce, and maintain the barrier function of the SC. Without effective barrier recovery, the skin is susceptible to prolonged and repeated inflammatory flares. In the case of chronic conditions such as AD and psoriasis, daily application of products that support skin barrier maintenance between flares can reduce the onset of symptoms and improve general quality of life.62–64 Moisturizers, creams, and lotions, including cosmetics, are safe, readily-available, and inexpensive products that have been mainstays among the skin care community for years. Moisturizers, alone or in combination with other antiinflammatory/ immunomodulatory agents, have demonstrated clinical benefit to reduce the onset, symptoms, and progression of diseases characterized by compromised barrier.50,61–64 Clinical benefits have been observed in cohorts ranging from adults to neonates. A preventive role of such approach against declaration of AD has been evidenced in a study in which neonates benefited from daily moisturizer application for 32 weeks after birth.65
The ingredient list, complexity, and overall understanding of moisturizers has evolved in order to provide coverage to the SC, reduce water loss and hydrate the skin. Standard ingredients of many commercially-available moisturizers include emollients to soften the skin, humectants to attract and bind water (eg, glycerin), and/or occlusive agents (eg, dimethicone) that physically prevent liquid from leaving the skin.56,62 This approach to maintain the protective and hydrating function of the skin barrier has made frequent and routine use of the skin care products the recommendation of many health care professionals.64 Given the role of ceramides in epidermal barrier function, many moisturizers include ceramides to help support the restoration of the skin barrier.
Several clinical reports have demonstrated the ability of lipidbased emollients and ceramide-containing moisturizers to support accelerated repair, reduce symptom intensity, and promote soft, healthy-looking skin when applied alone or in combination with other therapies to skin conditions linked to impaired barrier. When used in combination with topical corticosteroids and/or calcineurin inhibitors, pediatric AD
Topical Approaches to Manage Epidermal Barrier Disruption
When the epidermal barrier is compromised, as is the case for many common skin conditions including AD, eczema, and psoriasis, the skin is susceptible to excessive water loss, xerosis, and infection.56 These same skin conditions are characterized by an inflammatory response which manifests in pain, redness, irritation, and pruritus. The increased understanding of the complex pathology associated with diseases that impact the skin barrier has shown that barrier disruption and inflammatory events most often coincide.40,57 Therefore, effective treatment approaches should address both the recovery of the epidermal barrier and suppression of the underlying inflammatory conditions that, if left untreated, can further impede barrier repair.58
Factors that influence the therapeutic intervention include chronicity and severity of the disease, age, and general health of the individual.56 When considering topical versus systemic administration of therapeutic actives, topical administration is generally preferred for less severe cases due to potential risks associated with systemic exposure.58 Penetration of actives through an intact epidermis can vary greatly based on factors including anatomical location and surface area, the nature of active ingredient, and environmental factors.59 Such complexity has necessitated models and imaging modalities to accurately predict and visualize penetration.59 However, in the case of skin barrier-associated diseases, improved penetration of topicallyapplied active ingredients through the compromised barrier is expected.60 This, in combination with the reduced risk of systemic exposure, have made topical therapies the common first-line approach to manage disease symptoms associated with impaired skin barrier.
The mechanisms of action for many topical, pharmacologic approaches for skin conditions such as AD involve antiinflammatory and immunomodulatory interventions.61 Corticosteroids have been used for more than 50 years to reduce inflammation. They act on T lymphocytes, monocytes, macrophages, and dendritic cells, suppressing pro-inflammatory cytokine release and leading to a reduction of redness, swelling, and itching.62 The incidence of negative side effects is low; however, there are concerns linked to skin discoloration and atrophy following prolonged use of corticosteroids.61,62 Calcineurin inhibitors, including tacrolimus and pimecrolimus, have been in use since 2000 as a more targeted approach that reduces T-cell activation and subsequent cytokine release.57,58,61,62 An association with malignancy resulted in a black box warning related to cancer risk from the United States Food and Drug Administration (FDA) in 2005, although it is not clear whether there is a causal relationship.58,61 Examples of other topical treatments currently in development and testing include modulators of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which is activated by proinflammatory cytokines and downregulates the expression of structural skin proteins, and phosphodiesterase-4 (PDE-4) inhibitors aimed at reducing production of pro-inflammatory cytokines and signals.37,58
In addition to anti-inflammatory and immunomodulatory approaches, there is a continued role for topical products that restore, reinforce, and maintain the barrier function of the SC. Without effective barrier recovery, the skin is susceptible to prolonged and repeated inflammatory flares. In the case of chronic conditions such as AD and psoriasis, daily application of products that support skin barrier maintenance between flares can reduce the onset of symptoms and improve general quality of life.62–64 Moisturizers, creams, and lotions, including cosmetics, are safe, readily-available, and inexpensive products that have been mainstays among the skin care community for years. Moisturizers, alone or in combination with other antiinflammatory/ immunomodulatory agents, have demonstrated clinical benefit to reduce the onset, symptoms, and progression of diseases characterized by compromised barrier.50,61–64 Clinical benefits have been observed in cohorts ranging from adults to neonates. A preventive role of such approach against declaration of AD has been evidenced in a study in which neonates benefited from daily moisturizer application for 32 weeks after birth.65
The ingredient list, complexity, and overall understanding of moisturizers has evolved in order to provide coverage to the SC, reduce water loss and hydrate the skin. Standard ingredients of many commercially-available moisturizers include emollients to soften the skin, humectants to attract and bind water (eg, glycerin), and/or occlusive agents (eg, dimethicone) that physically prevent liquid from leaving the skin.56,62 This approach to maintain the protective and hydrating function of the skin barrier has made frequent and routine use of the skin care products the recommendation of many health care professionals.64 Given the role of ceramides in epidermal barrier function, many moisturizers include ceramides to help support the restoration of the skin barrier.
Several clinical reports have demonstrated the ability of lipidbased emollients and ceramide-containing moisturizers to support accelerated repair, reduce symptom intensity, and promote soft, healthy-looking skin when applied alone or in combination with other therapies to skin conditions linked to impaired barrier. When used in combination with topical corticosteroids and/or calcineurin inhibitors, pediatric AD
