It has been recognized for approximately 50 years that the stratum corneum exhibits biological properties that contribute directly to maintaining and sustaining healthy skin. Continued basic science and clinical research coupled with keen clinical observation has led to more recent recognition and general acceptance that the stratum corneum completes many vital “barrier” tasks, including but not limited to regulating epidermal water content and the magnitude of water loss; mitigating exogenous oxidants that can damage components of skin via an innate antioxidant system; preventing or limiting cutaneous infection via multiple antimicrobial peptides; responding via innate immune mechanisms to “cutaneous invaders” of many origins, including microbes, true allergens, and other antigens; and protecting its neighboring cutaneous cells and structures that lie beneath from damaging effects of ultraviolet radiation. Additionally, specific abnormalities of the stratum corneum are associated with the clinical expression of certain disease states. This article provides a thorough “primer” for the clinician, reviewing the multiple normal homeostatic functions of the stratum corneum and the cutaneous challenges that arise when individual functions of this thin yet very active epidermal layer are compromised by exogenous and/or endogenous factors.
Rosacea is a chronic inflammatory disease affecting roughly 16 million Americans. Topical and oral antibiotic/anti-inflammatory agents are currently the mainstay of therapy and are often used in combination. In this article, the authors discuss the use of oral isotretinoin in the management of rosacea, exploring dosage, comparable efficacy, safety, and cost.
Excess cathelicidin and kallikrein 5 (KLK5) have been hypothesized to play a role in the pathophysiology of rosacea.
We sought to evaluate the effects of azelaic acid (AzA) on these elements of the innate immune system.
Gene expression and protease activity were measured in laboratory models and patients with rosacea during a 16-week multicenter, prospective, open-label study of 15% AzA gel.
AzA directly inhibited KLK5 in cultured keratinocytes and gene expression of KLK5, Toll-like receptor-2, and cathelicidin in mouse skin. Patients with rosacea showed reduction in cathelicidin and KLK5 messenger RNA after treatment with AzA gel. Subjects without rosacea had lower serine protease activity (SPA) than patients with rosacea. Distinct subsets of patients with rosacea who had high and low baseline SPA were identified, and patients with high baseline exhibited a statistically significant reduction of SPA with 15% AzA gel treatment.
Study size was insufficient to predict clinical efficacy based on the innate immune response to AzA.
These results show that cathelicidin and KLK5 decrease in association with AZA exposure. Our observations suggest a new mechanism of action for AzA and that SPA may be a useful biomarker for disease activity.
antimicrobial peptides; azelaic acid; cathelicidin; kallikrein 5; LL-37; rosacea; serine protease
The development of new drug classes and novel molecules that are brought to the marketplace has been a formidable challenge, especially for dermatologic drugs. The relative absence of new classes of antimicrobial agents is also readily apparent. Several barriers account for slow drug development, including regulatory changes, added study requirements, commercial pressures to bring drugs to market quickly by developing new generations of established compounds, and the greater potential for failure and higher financial risk when researching new drug classes. In addition, the return on investment is usually much lower with dermatologic drugs as compared to the potential revenue from “blockbuster” drugs for cardiovascular or gastrointestinal disease, hypercholesterolemia, and mood disorders. Nevertheless, some researchers are investigating new therapeutic platforms, one of which is boron-containing compounds. Boron-containing compounds offer a wide variety of potential applications in dermatology due to their unique physical and chemical properties, with several in formal phases of development. Tavaborole, a benzoxaborole compound, has been submitted to the United States Food and Drug Administration for approval for treatment of onychomycosis. This article provides a thorough overview of the history of boron-based compounds in medicine, their scientific rationale, physiochemical and pharmacologic properties, and modes of actions including therapeutic targets. A section dedicated to boron-based compounds in development for treatment of various skin disorders is also included.
A commonly encountered skin disorder in outpatient dermatology practice is hand dermatitis. In a considerable subset of patients, hand dermatitis can be a major source of prolonged distress when a pattern of chronicity develops due to repeated exposure to a variety of potential etiological factors. Most of the etiological factors are exogenous in nature. Hand dermatitis is an equal opportunity disease that affects both genders and occurs in individuals from all ethnic and cultural backgrounds. It is important to note that the term hand dermatitis does not refer to one specific diagnostic entity. Rather, hand dermatitis refers to multiple patterns of clinical disease that can be induced by a variety of exogenous sources. Occupational exposures with inadequate hand protection may be an important cause of epidermal barrier disruption, and in some cases contact allergy may be the primary cause or contribute to chronic hand dermatitis. In certain individuals, endogenous sources, such as atopic skin, cutaneous allergy (eczematous pattern), or skin hypersensitivity (urticarial pattern), may innately create predisposition to the development of hand dermatitis. Hand dermatitis can become a chronic problem that is often difficult to manage effectively. As consistency with hand protection and avoidance of irritant and allergenic contactants are integral to the effective treatment of chronic hand dermatitis, there is a high dependence on consistent patient adherence. Regardless of the etiological factors causing chronic hand dermatitis, lack of consistent hand protection is often a major reason why therapeutic results are suboptimal in some cases as exposure to the causes of the hand dermatitis are not adequately prevented. Regular wearing of protective gloves is not always feasible depending on the occupation, and although topically applied skin barrier protectants may be helpful in some cases, scientific data are generally limited with many products. This article provides an overview of hand dermatitis, reviews data supporting the therapeutic benefit of a specific barrier protection hand cream, and discusses ingredient modifications to the original formulation. The newer formulation does not alter the skin barrier protection components; however, the new ingredients were selected to add barrier repair properties to the original product, which was designed only as a skin barrier protectant.
Rosacea is a chronic inflammatory condition of facial skin estimated to affect more than 16 million Americans. Although the pathogenesis of rosacea is not fully understood, recent evidence in vitro as well as in vivo has supported the role of increased levels of the trypsin-like serine protease, kallikrein 5, in initiating an augmented inflammatory response in rosacea. The increase in the quantity and magnitude of biological activity of kallikrein 5 leads to production of greater quantities of cathelicidin (LL-37), an antimicrobial peptide associated with increases in innate cutaneous inflammation, vasodilation, and vascular proliferation, all of which are characteristic features of rosacea. In this article, the authors review the literature supporting the role of kallikrein 5 in the pathophysiology of rosacea, including how therapeutic interventions modulate the effects of kallikrein 5, thus providing further support for this pathophysiological model that at least partially explains many of the clinical features of cutaneous rosacea.
This article is the first in a periodic series of therapeutic topics with short reviews gleaned from major dermatology meetings, especially Scientific Poster Sessions, and is designed to provide information that may assist the readers in adapting information from the literature to their clinical practice. The topics covered in this issue are discussions of the clinical relevance of newer information about acne pathophysiology, acne in adult women, and topical corticosteroid spray formulations for chronic plaque psoriasis.
Topical corticosteroids are a very important part of the treatment of many skin disorders, especially eczematous dermatoses. When utilized properly and judiciously these agents often achieve excellent results in clearing or markedly improving many dermatological disorders. As some studies have shown, topical corticosteroids, despite their ability to decrease inflammation through several mechanisms, induce abnormalities in lipid synthesis and intercellular bilayer structure in the stratum corneum, which appear to prolong epidermal barrier recovery. These adverse effects may contribute to eariier eczematous flaring if measures to provide barrier repair are not undertaken. In addition, although topical corticosteroids are applied only to sites affected by the skin eruption, the incorporation of “barrier friendly” excipients into the vehicle that improve stratum corneum permeability barrier function and integrity is very rational.
This three-part review presents what is currently known about the involvement and interdependency of the epidermal barrier and immune response in the etiopathogenesis of atopic dermatitis. Part 1 of this review depicted the role of filaggrin in atopic dermatitis while this article, Part 2, evaluates the role of serine proteases and specific lipids in the structural and functional integrity of the stratum corneum and its multiple barrier functions in atopic dermatitis. Upregulation of serine protease activity causes adverse structural changes of the stratum corneum due to degradation of certain stratum corneum proteins that are integral to epidermal structure and functions, interference with the formation of the stratum corneum intercellular lipid membrane, which normally regulates epidermal water flux and gradient, and induction of a TH2 pattern of inflammation, which is the hallmark profile of atopic skin. Alteration in lipid ratios and changes in lipid-directed enzymes may play a role in the impairment of barrier functions that are associated with atopic dermatitis. In Part 3, immune dysregulation, including upregulation of a TH2 inflammation pattern, augmented allergic sensitization, sustained wound healing inflammation, and impaired innate immunity are discussed. The roles of the stratum corneum permeability barrier, the immune defense barrier, and antimicrobial barrier in AD pathogenesis are explained in detail. With this explanation, the interdependence of the multitude of polymorphisms and dysregulations seen in AD skin will become clear. The condensing of these impaired and/or dysregulated functions and how they interact should provide further knowledge about the pathogenic mechanisms that cause atopic dermatitis, how they are clinically relevant, and how they may assist in developing more specific therapies directed at the pathogenesis of atopic dermatitis.
This three-part review presents what is currently known about the involvement and interdependency of the barrier properties of the epidermis, especially the stratum corneum and various specific immunological responses in the etiopathogenesis of atopic dermatitis. Part 1 of this review depicts the role of filaggrin in atopic dermatitis while Part 2 (which will be published in an upcoming issue of The Journal of Clinical and Aesthetic Dermatology) evaluates the role of serine proteases and specific lipids in the structural and functional integrity of the stratum corneum and related barrier functions in atopic dermatitis. Filaggrin is a key component of the stratum corneum that is derived from a larger precursor protein and contributes to its physical strength, hydration status, skin pH, and buffering capacity among other physiochemical properties. Filaggrin gene loss of function mutations appear to play a pathophysiological role; however, they are not the sole pathogenic factor in atopic dermatitis. Adverse structural changes of the stratum corneum are caused by upregulation of serine proteases activity, which causes degradation of certain stratum corneum proteins that are integral to barrier functions; interference with the formation of the stratum corneum intercellular lipid membrane, which normally regulates epidermal water flux and gradient; and induction of a TH2 pattern of inflammation, which is characteristic of atopic skin. Alteration in lipid ratios and changes in lipid-directed enzymes may play a role in the impairment of epidermal barrier functions that are associated with atopic dermatitis. Part 3 of this review (which will be published in an upcoming issue of The Journal of Clinical and Aesthetic Dermatology) discusses how immune dysregulation, including upregulation of a TH2 inflammation pattern, augmented allergic sensitization, sustained wound healing inflammation, and impaired innate immunity all play a role in the development of atopic dermatitis. An increased understanding of the interdependence, polymorphisms, and dysregulations of epidermal barrier functions, including the stratum corneum permeability barrier, immune response barrier, and antimicrobial barrier, should provide further knowledge about the pathophysiological mechanisms that are related to the development of atopic dermatitis, are clinically relevant, and can better direct researchers to develop therapies that are targeted at important pathogenic components of the disease state.
This article reviews background on proteases and their functions, their physiological significance in skin, and the potential implications of incorporating specific proteases and protease blends into dermatological products, including skin care formulations. The history of protease blend formulations used in wound model studies and for other disorders is reviewed. In vitro data with use of a specific 3-protease blend with evaluation of the impact on various skin proteins and peptides is also discussed in this article.
Background: Onychomycosis is a chronic condition that often requires long-term management to eradicate the causative fungus, allow a healthy nail to grow, and prevent relapse. As a successful outcome depends highly on patient adherence with treatment, a low risk of periungual skin irritation with topical medication is clinically relevant. Objectives: To study the potential for efinaconazole 10% solution and its corresponding vehicle to induce delayed contact skin sensitization and evaluate its skin irritation potential. Methods: Efinaconazole 10% solution and its vehicle were studied in 239 healthy volunteers for the potential to induce contact skin sensitization. This included a series of induction, challenge, and re-challenge phases. An additional 21-day cumulative irritation study was undertaken in 35 healthy volunteers to compare three concentrations of efinaconazole (1%, 5%, and 10%), vehicle, and positive/negative controls. Results: There was no evidence of induced contact sensitization under occlusive, semi-occlusive, and open (open rub-in) applications of efinaconazole 10% solution. Efinaconazole 1%, 5%, and 10% solutions have mean cumulative irritancy indices of 1.12, 1.26, and 1.18, respectively, where a range of >0 to ≤1 is classified as “mildly irritating.” Results were comparable to vehicle (1.04). Conclusion: Efinaconazole 10% solution did not cause contact sensitization and induced only minimal skin irritation in the studies completed.
Acne vulgaris is a common dermatological disorder that predominantly affects teenagers, but can also affect preadolescents and post-teen individuals. Despite the fact that acne vulgaris is the most common skin disorder encountered in ambulatory dermatology practice in the United States, there has been limited research on the epidermal permeability barrier in untreated skin of people with acne vulgaris and also after use of acne therapies. This article reviews the research results and discusses the available literature on this subject area. The importance of proper skin care as a component of the management of acne vulgaris is supported by the information that is currently available.
The treatment of cutaneous lupus erythematosus is centered upon formulating a regimen of topical and systemic therapies designed to reduce disease activity and minimize cosmetic damage. Sun avoidance and sunscreen are important preventative measures proven to minimize cutaneous lupus erythematosus exacerbations. Limited disease is typically managed with topical corticosteroids or calcineurin inhibitors. Antimalarial therapy is the gold standard of systemic therapy. Many other treatments have been studied in patients with recalcitrant cutaneous lupus erythematosus, and their use must be evaluated based on individual risk-benefit concerns. R-salbutamol and pulsed dye laser therapy have proven to be effective topical alternatives. Additional systemic agents include retinoids, immunosuppressants, immunomodulators, biologics, and other experimental therapies with novel modes of action. According to the Oxford Centre for Evidence-based Medicine criteria for evaluating the strength of evidence supporting an individual treatment measure, no therapy for cutaneous lupus erythematosus has achieved Level 1 status. This demonstrates the need for randomized, controlled trials and systematic reviews of all cutaneous lupus erythematosus interventions in order to meet increasing standards and demand for evidence-based practice.
Oral isotretinoin, available in the United States for four decades, has been used for the treatment of recalcitrant nodular and deep inflammatory acne vulgaris. This drug revolutionized the management of patients affected by severe inflammatory disease due to its ability to markedly induce acne clearance coupled with prolonged durations of remission after completion of a course of therapy, usually over approximately five months. Over time, it has become recognized that prolonged remission correlates with achieving a threshold cumulative exposure range of approximately 120 to 150 mg/kg of oral isotretinoin. Lesser exposures have demonstrated a higher risk of earlier recurrence of acne vulgaris and a greater likelihood that the patient will require retreatment. As the oral bioavailability of oral isotretinoin is variable, and highly dependent on administration with food, it is very conceivable that earlier relapse may occur if patients have often ingested oral isotretinoin on an empty stomach, thus leading to lesser actual cumulative drug exposure despite the daily dose administered. This article provides an overview on the dosing of oral isotretinoin, reported data on factors that influence relapse after oral isotretinoin therapy, and the potential impact of coadministration with food.
For decades, transepidermal water loss and corneometry have been accepted as measures of skin barrier function. However, these tests are not capable of informing clinicians of the biochemical constituents and biophysical status of the stratum corneum. Knowledge of how the stratum corneum reacts to topical agents is important, as it reveals significant detail regarding the composition and function of this vital skin layer. Furthermore, transepidermal water loss and corneometry serve only as surrogate markers of barrier function. A more precise method of assessing stratum corneum hydration and lipid levels is emerging; in vivo confocal Raman spectroscopy is able to detect and quantify specific biochemical constituents in skin. This information then allows for assessment of the actual physiological status of this vital layer of the skin. This pilot study sought to elucidate a biophysical rationale for the clinical improvement achieved by hyaluronic acid/ceramide barrier repair foam in prior studies as measured by in vivo confocal Raman spectroscopy. Study results include increased lipid and hydration levels in the stratum corneum to depths of 25µm and 40µm, respectively, at the 2-hour, 48-hour, and 7-day time points.
While it is well known that a balanced level of hydration is fundamental for healthy skin, the physiological mechanisms underlying the control of hydration, particularly in the epidermis, are yet to be fully elucidated. Over the past 10 years, much research has been carried out to understand the nature and regulation of the water gradient that exists across the layers of the epidermis. Of central importance is the role played by membrane-bound pores called aquaporins, which facilitate the passage of water and, in some cases, small molecules such as glycerol. This paper provides an overview of the principal aquaporin present in the epidermis, aquaporin 3, and how the level of hydration of the epidermis is correlated to endogenous levels of glycerol and to the distribution of aquaporin 3 channels. The role of aquaporin 3 in skin diseases is considered along with possible clinical implications of aquaporin 3 modulation.
Clocortolone pivalate is a mid-potency topical corticosteroid available as a 0.1% emollient cream approved by the United States Food and Drug Aministration for use in the treatment of corticosteroid-responsive dermatoses. The vehicle is formulated for application to a variety of corticosteroid-responsive skin disorders, including those with inflamed and fissured skin, such as eczematous dermatoses. Hence, the potency of the formulation and its vehicle characteristics are important when treating disorders, such as atopic dermatitis and other eczematous dermatoses, which are prone to cutaneous irritation and skin sensitivity to exogenously applied agents. As both localized and diffuse eczematous dermatoses and seborrheic dermatitis are common in pediatric patients (including infants) as well as in adults, the fact that clocortolone pivalate 0.1% cream has no age restriction related to its use according to United States Food and Drug Aministration-approved product labeling is important to recognize. The chemical structure of clocortolone pivalate is a unique design that provides high lipid solubility. Highly lipophilic topical corticosteroids exhibit augmented penetration through the stratum corneum, which provides higher epidermal concentrations. It has been reported that the structural characteristics of this molecule enhance its potency without increasing the potential for topical corticosteroid-related adverse effects. Clocortolone pivalate 0.1% cream has been studied in randomized, controlled trials of patients with atopic dermatitis and other eczematous dermatoses, psoriasis vulgaris, contact dermatitis, and seborrheic dermatitis. It has been shown to be more effective as monotherapy in the treatment of these corticosteroid-responsive dermatoses than the vehicle. Its efficacy and safety in pediatric patients and patients with facial dermatoses have also been demonstrated. Patients using clocortolone pivalate 0.1% topical cream in clinical trials had a low rate of adverse events, which were primarily minor application-site reactions. Systemic reactions related to the drug were not observed in these trials. Clinical studies of patients with corticosteroid-responsive dermatological conditions have found that clocortolone pivalate 0.1% cream is an effective class 4 topical corticosteroid with a favorable safety profile.
In this article, the second part of a two-part series on rosacea, emphasis will be placed on persistent facial erythema. Despite variations in the intensity of visible redness, persistent facial erythema is a very common and consistent finding among patients with rosacea, including those with presentations classically defined as papulopustular rosacea, erythematotelangiectatic rosacea, and in many patients with phymatous rosacea. The underlying mechanisms of rosacea and their correlation with specific clinical features have been discussed in Part 1 and are referred to here where applicable. An overview of cutaneous vasculature, role of alpha-adrenoreceptors, and a discussion of available medical therapies and treatment selection are also presented, including emerging topical options for diffuse and persistent facial erythema of rosacea.
Oral spironolactone has been used for over two decades in the dermatological setting. Although it is not generally considered a primary option in the management of female patients with acne vulgaris, the increase in office visits by post-teenage women with acne vulgaris has recently placed a spotlight on the use of this agent in this subgroup of patients. This article reviews the literature focusing on the use of oral spironolactone in this subset of women with acne vulgaris, including discussions of the recommended starting dose, expected response time, adjustments in therapy, potential adverse effects, and patient monitoring.
Rosacea is a common inflammatory facial dermatoses affecting primarily adults with fair skin, although all skin types may be affected. The diagnostic term “rosacea” reflects a spectrum of clinical features with the more common presentations characterized by increased blood flow and vasodilation during disease flares, which accentuate central facial erythema. Inflammatory lesions, usually papules and/or pustules are present in some cases. Variations in magnitude of the associated features of rosacea are noted clinically. Over time, other clinical features emerge or may be further accentuated, such as diffuse facial erythema and telangiectasias, as fixed changes in cutaneous vasculature occur. These later findings account for persistent diffuse facial erythema usually accentuated centrally on the inner cheeks, chin, nose, and/or medial forehead. Some patients may also develop phymatous changes and/or have concurrent ocular rosacea. Augmented innate immune response to certain triggers (often exogenous) and neurovascular/neuroimmune dysregulation appear to be involved early in the pathophysiological sequence of cutaneous rosacea and appear to signal other downstream inflammatory or physiochemical cascades that contribute to the pathogenesis of the disorder. In this article, Part 1 of a two-part series, emphasis is placed upon the correlation of clinical features and underlying pathophysiological changes in the more common presentations of rosacea encountered by the clinician. The importance of this information is that some of these pathogenic mechanisms are modulated by available therapies, and others remain as targets for the development of new therapeutic agents or modalities.
Tinea capitis is a reasonably common infection among the pediatric population; however, it is still a relatively rare entity among infants less than one year of age. As such, a high index of suspicion is necessary for diagnosis among infants and an appropriate diagnostic work up should be employed in any case where a dermatophyte infection is suspected. Several methods are available for diagnosis. In addition, proper identification of the specific dermatophyte genera involved should be considered as treatment options may be altered based on the causative pathogen identified.
Background: Various formulations of tretinoin (gel, liquid, cream) have been reported to be unstable on the skin under bright artificial light or sunlight. This photodegradation can potentially influence treatment regimens and possibly modify efficacy. The maximum light energy absorption of tretinoin is in the ultraviolet A region. Objective: To compare the photostability of a micronized formulation of tretinoin (0.05%) aqueos gel with tretinoin (0.025%) gel following exposure to ultraviolet A light for eight hours. Methods: Micronized tretinoin (0.05%) gel and tretinoin (0.025%) gel were then exposed to ultraviolet A light with an integrated intensity from 315 to 400nm of 22watt/m2. Samples of both products were prepared and analyzed for tretinoin and its degradation products using a high-performance liquid chromatography method. Additional duplicate samples were similarly prepared and analyzed after 2,4,6, and 8 hours. Results: There was a nine-percent degradation of micronized tretinoin in the 0.05% aqueous gel compared to 72-percent degradation of tretinoin in the 0.025% gel following eight-hour ultraviolet A light exposure. The small increase in tretinoin degradation products with micronized tretinoin (0.05%) aqueous gel remained below six percent of the labeled concentration compared to a marked increase in tretinoin degradation products with tretinoin 0.025% gel at two hours that increased to over 66-percent labeled concentration at eight hours. Conclusion: Micronized tretinoin (0.05%) aqueous gel showed less than 10-percent degradation when exposed to eight hours of ultraviolet A light, while tretinoin (0.025%) gel showed significant tretinoin degradation.