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.
Clindamycin phosphate 1.2%/tretinoin 0.025% gel is a topical combination formulation used once daily for the treatment of acne vulgaris, with approval in the United States for patients >12 years of age. Three 12-week, randomized, vehicle-controlled, pivotal trials included > 1,800 actively treated subjects. In addition, an open-label, 52-week study was also completed with 442 subjects enrolled. The skin tolerability, safety, and efficacy of clindamycin phosphate 1.2%/tretinoin 0.025% gel applied once daily is well-established based on data from pivotal studies and analyses in other subsequent publications including from pooled analysis of results from 4,550 subjects. This article discusses results from the pivotal 12-week, Phase 3 studies of clindamycin phosphate 1.2%/tretinoin 0.025% gel applied once daily in 845 subjects with mild, moderate, or severe facial acne vulgaris and differentiates patterns of therapeutic response using study endpoint successes defined as clear, almost clear, or at least a 2-grade improvement in the AV severity rating.
Oral antibiotics have been used for the treatment of acne vulgaris for six decades. Among dermatologists, tetracyclines represent at least three-fourths of the oral antibiotics prescribed in clinical practice. Unlike other specialties, antibiotic use in dermatology is predominantly for the treatment of noninfectious disorders, such as acne vulgaris and rosacea, which usually involves prolonged therapy over several weeks to months as compared to short courses used to treat cutaneous infections. At the present time, doxycycline and minocycline are the most commonly prescribed tetracyclines in dermatology, used primarily for treatment of acne vulgaris with a long overall favorable track record of effectiveness and safety. Although both are commonly used, doxycycline may be chosen by clinicians more readily as there is a lower risk of rare yet potentially serious adverse reactions, although doxycycline does warrant preventative measures to reduce the risks of esophagitis and phototoxicity reactions. This article reviews data with a new double-scored small 150mg tablet of doxycycline hyclate that has proven functional scoring, exhibits bioavailability similar to enteric-coated doxycycline, and has been shown to be associated with a low potential for gastrointestinal adverse reactions very comparable to what is achieved with enteric-coated tablets.
Onychomycosis is a common infection of the nail unit that is usually caused by a dermatophyte (tinea unguium) and most frequently affects toenails in adults. In most cases, onychomycosis is associated with limited treatment options that are effective in achieving complete clearance in many cases. In addition, recurrence rates are high in the subset of treated patients who have been effectively cleared, usually with an oral antifungal agent. There has been a conspicuous absence of medical therapies approved in the United States since the introduction of topical ciclopirox (8% nail lacquer), with no new effective agents introduced for more than 10 years. Fortunately, newer agents and formulations have been under formal development. While patients might prefer a topical therapy, efficacy with ciclopirox 8% nail lacquer, the only available agent until the very recent approval of efinaconazole 10% solution, has been disappointing. The poor therapeutic outcomes achieved with ciclopirox 8% nail lacquer were not unexpected as the cure rates achieved in the clinical trials were unimpressive, despite concomitant nail debridement, which was an integral part of the pivotal trials with ciclopirox 8% nail lacquer. Efinaconazole 10% solution and tavaborole 5% solution are new topical antifungals specifically developed for the treatment of dermatophyte onychomycosis. In Phase 3 clinical trials, both newer agents were applied once daily for 48 weeks without concomitant nail debridement. Mycologic cure rates with efinaconazole 10% solution are markedly superior to what was achieved with ciclopirox 8% nail lacquer. To add, they appear to be nearly comparable to those achieved with oral itraconazole in pivotal clinical trials. However, it is important to remember that direct comparisons between different studies are not conclusive, are not generally considered to be scientifically sound, and may not be entirely accurate due to differences in study design and other factors. Well-designed and properly powered head-to-head studies are needed in order to draw definitive conclusions about efficacy comparisons between therapies, at least based on academic and regulatory standards. Although tavaborole 5% solution is in an earlier phase of development for onychomycosis, treatment success rates reported thus far for both efinaconazole 10% solution and tavaborole 5% solution are superior to ciclopirox 8% nail lacquer. As a result, a new era of onychomycosis appears to be upon us that incorporates topical therapy more effectively than in the past. Not only may these newer topical agents provide viable monotherapy alternatives to oral therapy for onychomycosis, topical therapy for onychomycosis that is effective, well tolerated, and easy to use may also find a role in combination therapy, and/or as continued therapy after initial clearance to reduce recurrence or re-infection.
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.
Acne vulgaris is a very common facial skin disorder accounting for approximately 10 percent of all visits to ambulatory dermatology practices across the United States annually. Over time, greater attention has been directed to the roles of multiple epidermal barrier functions in various dermatological disorders, especially the stratum corneum permeability barrier and antimicrobial barrier. As a result, it has become readily apparent that professional direction of skin care is very important in the overall management of acne vulgaris. This article discusses several reasons that support the importance of incorporating specified skin care recommendations and instructions into the overall management plan for acne vulgaris. In addition, the article reviews formulation characteristics and some of the scientific data on two commercially available products that are recommended for use as a skin care regimen in patients with acne-prone and acne-affected skin, a foam wash and a moisturizer with a sun protection factor 30 broad spectrum photoprotection rating. The rationale for inclusion of specific ingredients are discussed along with an overview of research results including use in patients with acne vulgaris.
Proper skin care is considered to be an important component of the total management plan for patients with acne vulgaris. A 28-day, open-label study provided both practical and scientific information on a designated skin care regimen in subjects with acne vulgaris. The cutaneous tolerability overall performance, and assessment of objective parameters evaluating the epidermal permeability barrier were documented with use of a specific foaming skin cleanser and a moisturizer with an SPF 30 broad spectrum rating in actively treated subjects with acne vulgaris. The results were favorable overall with the regimen shown to be nonirritating based on investigator and subject assessments, with high subject satisfaction and cosmetic acceptability ratings reported for both the foaming skin cleanser and the moisturizer with an SPF 30 broad spectrum rating. Objective instrumental testing of transepidermal water loss and epidermal hydration support that this skin care regimen assists in correcting epidermal permeability barrier dysfunctions that are innately present in acne vulgaris, worsened during a flare, and are known to be associated with many medications used to treat acne vulgaris. The recommendation of a specified skin care regimen incorporated into the overall management of acne vulgaris simplifies and standardizes the program for the patient, demonstrates a high level of interest by the clinician, and reduces the risk of the patient self-acquiring facial skin care products that may increase skin irritation.
Part 3 of this three-part review of atopic dermatitis and the stratum corneum barrier discerns how immune dysregulation, including upregulation of a TH2 inflammation pattern, augmented allergic sensitization, sustained wound healing inflammation, and impaired innate immunity, plays an integral role in the pathogenesis of atopic dermatitis. An increased understanding of the interdependence, polymorphisms, and dysregulations of epidermal barrier functions, including the stratum corneum permeability barrier, immune defense, and antimicrobial barriers, should provide further knowledge about the pathophysiological mechanisms that are clinically relevant and that contribute to the development of atopic dermatitis. Further understanding of these mechanisms should lead to newer therapies that target specific pathogenic components of atopic dermatitis.
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.
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.