Advances in management of atopic dermatitis: new therapies and novel uses of existing treatments

Atopic dermatitis (AD) is a chronic inflammatory skin condition marked by intensely pruritic, eczematous changes. First-line therapy includes topical corticosteroids during an exacerbation and long-term emollient use, followed by topical calcineurin inhibitors, phototherapy, and systemic therapy in more difficult cases. The need for more effective AD therapies with safer side effect profiles has pushed researchers to devise new therapies and to recycle traditional treatments for use in a novel manner. Innovative therapies include barrier therapy, novel antistaphylococcal treatments, new immunomodulatory agents, unconventional antipruritic agents, exclusionary diets, and probiotics. Advancements in these options have paved the way for a targeted approach to AD therapy. We will review the latest clinical research exploring these cutting-edge AD treatment modalities and discuss forward-thinking therapy strategies that use conventional AD medications in a novel manner.     

Atopic dermatitis: an update and review of the literature

Atopic eczema/dermatitis from the aspects of immunologic background, genetics, skin barrier dysfunction, IgE receptors, and triggers of AD (including allergens, microorganisms, and autoantigens) is described. Also reviewed are diagnostic procedures, treatment modalities with topical treatment (emollients, topical corticosteroids, topical calcineurin inhibitors, wet wrap therapy, and topical antimicrobial therapy), systemic management (antimicrobials, systemic corticosteroids, cyclosporine A, azathioprine, antihistamines), and phototherapy. Primary and secondary prevention are discussed and the role of the different cell receptors and their up-and down-regulation in this setting are emphasized.     

Atopic dermatitis: systemic immunosuppressive therapy

Atopic dermatitis (AD) is a pruritic, relapsing skin disorder that negatively impacts the quality of life of those affected and that of their families. Treatment options for AD encompass a variety of emollients, topical corticosteroids, topical immunomodulators, phototherapy, and systemic agents. Such agents as systemic corticosteroids, cyclosporine, azathioprine, interferon-gamma, methotrexate, and mycophenolate mofetil have been shown to be efficacious in the treatment of moderate-to-severe AD but are not officially approved for this purpose. In this article, we review some of the data supporting efficacy of these medications and discuss some of the adverse events associated with their use.     

Guidelines for management of atopic dermatitis

Atopic dermatitis (AD) is a chronic relapsing eczematous skin disease characterized by pruritus and inflammation and accompanied by cutaneous physiological dysfunction (dry and barrier-disrupted skin). Most of the patients have atopic diathesis. A standard guideline for the management (diagnosis, severity classification and therapy) of AD has been established. In our guideline, the necessity of dermatological training is emphasized in order to assure diagnostic skill and to enable evaluation of the severity of AD. The definitive diagnosis of AD requires the presence of all three features: (i) pruritus; (ii) typical morphology and distribution; and (iii) chronic and chronically relapsing course. For the severity classification of AD, three elements of eruption (erythema/acute papules, exudation/crusts and chronic papules/nodules/lichenification) are evaluated in the most severely affected part of each of the five body regions (head/neck, anterior trunk, posterior trunk, upper limbs and lower limbs). The areas of eruption on the five body regions are also evaluated, and both scores are totaled (maximum 60 points). The present standard therapies for AD consist of the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation, topical application of emollients to treat the cutaneous physiological dysfunction, systemic antihistamines and anti-allergic drugs as adjunctive treatments for pruritus, avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. Tacrolimus ointment (0.1%) and its low-density ointment (0.03%) are available for adult patients and 2–15-year-old patients, respectively. The importance of the correct selection of topical corticosteroids according to the severity of the eruption is also emphasized. Furthermore, deliberate use of oral cyclosporine for severe recalcitrant adult AD is referred.     

Topical therapy in pediatric atopic dermatitis

With a prevalence of 10% to 20% in the first decade of life, atopic dermatitis (AD) is one of the most common skin disorders in young children. It is a chronic illness with limited therapeutic options. Topical anti-inflammatory agents remain at the core of medical management; however, their efficacy must be balanced with safety concerns, especially as they relate to the pediatric population. This article discusses the principles of topical AD therapy with a detailed review of the differences between topical corticosteroids and topical calcineurin inhibitors. It also includes specialized topical treatment strategies for AD, such as wet wraps and diluted bleach baths, and highlights the most common challenges to patient compliance in atopic dermatitis.     

Therapy of atopic eczema

When a decision is being made on the therapy of atopic eczema, the complex pathogenetic interactions involved in this disease have to be taken into consideration. The acute inflammatory changes respond to short-term glucocorticoid steroid treatment (topical); long-term steroid therapy should be avoided. In chronic lichen-type lesions, non-steroid topical applications can be helpful. Frequent acute infections of the skin require the application of antimicrobials. Intense pruritus is treated by antihistamines (possibly also H2-antagonists). Due to the well-known psychosomatic influence in this disease, careful counseling of the patient (and if a child, of the family) is necessary. Pathogenetically relevant allergic reactions of the immediate type can be treated successfully in some cases by hyposensitization. Prophylactic measures include allergen avoidance (climate therapy, no pets, well-established food allergens etc.). Possible new perspectives may be seen in the development of agents acting at the disturbed T-cell regulation, as well as by the introduction of mast-cell-blocking substances. The basis of every therapeutic approach in atopic eczema is, however, intensive skin care, using emollients and oil baths, especially during the remission phase.     

A randomized comparison of an emollient containing skin-related lipids with a petrolatum-based emollient as adjunct in the treatment of chronic hand dermatitis

Hand dermatitis is a multifactorial skin disorder in which skin barrier impairment is involved in the pathogenesis. The development of topical agents that improve skin barrier function is therefore a promising approach for the management of hand dermatitis. Topically applied lipids may interfere with skin barrier function, and emollients containing skin-related lipids have been suggested to facilitate repair of the skin barrier. However, evidence for the superiority of emollients containing skin-related lipids over the more traditional emollients is still lacking. The aim of this study was to compare an emollient containing skin-related lipids (Locobase Repair) with a traditional petrolatum-based emollient for the management of hand dermatitis. Adult males and females (n = 30) with mild to moderate chronic hand dermatitis were treated twice daily for 2 months either with an emollient containing skin-related lipids or with a pet.-based emollient. In the case of exacerbation, the patients of both treatment groups were allowed to use a mild corticosteroid according to instructions. Both treatment regimes significantly improved clinical signs of hand dermatitis as assessed by the investigator global assessment, hand eczema area and severity score. We did not observe significant differences in the improvement of clinical signs, itching, patients' assessment of efficacy, cosmetic acceptability or usage of topical corticosteroids between both treatment groups. In conclusion, this study confirms that the frequent use of emollients may be useful in the therapy of hand dermatitis. However, we could not demonstrate the superiority of this particular emollient containing skin-related lipids in patients with chronic hand dermatitis.     

Therapeutic New Era for Atopic Dermatitis: Part 2. Small Molecules

Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disease driven by immune dysregulation and skin barrier dysfunction. Currently, we are experiencing a new era of understanding of the pathogenesis of AD and, as a consequence, a new era of innovation in therapeutics, including small molecules and biologic therapy. In contrast to biologics, small molecules are similar to conventional pharmacologic chemical agents used as drugs and are generally prepared by chemical synthesis. Unlike biologics, these drugs often are taken orally or formulated for topical use. The purpose of this review is to summarize the efficacy and safety of the current topical and systemic new therapies in AD by reviewing recently published papers on therapies currently in phase 2 or 3 clinical trials. In this review, it is important to note the characteristics of the study population, the primary endpoints, and whether or not there was concomitant topical therapy allowed. These study design elements may significantly alter the results of studies and should be taken into account. Targeted therapy help push AD treatment into a new era of personalized medicine.     

The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition

Atopic dermatitis (AD) is a highly prevalent, chronic inflammatory skin disease that affects children and adults. The pathophysiology of AD is complex and involves skin barrier and immune dysfunction. Many immune cytokine pathways are amplified in AD, including T helper (Th) 2, Th22, Th17 and Th1. Current treatment guidelines recommend topical medications as initial therapy; however, until recently, only two drug classes were available: topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). Several limitations are associated with these agents. TCSs can cause a wide range of adverse effects, including skin atrophy, telangiectasia, rosacea and acne. TCIs can cause burning and stinging, and the prescribing information lists a boxed warning for a theoretical risk of malignancy. Novel medications with new mechanisms of action are necessary to provide better long‐term control of AD. Phosphodiesterase 4 (PDE4) regulates cyclic adenosine monophosphate in cells and has been shown to be involved in the pathophysiology of AD, making it an attractive therapeutic target. Several PDE4 inhibitors are in clinical development for use in the treatment of AD, including crisaborole, which recently became the first topical PDE4 inhibitor approved for treatment of mild to moderate AD. This review will further describe the pathophysiology of AD, explain the possible role of PDE4 in AD and review PDE4 inhibitors currently approved or being investigated for use in AD.     

Optimizing the treatment of atopic dermatitis in children: a review of the benefit/risk ratio of methylprednisolone aceponate

Atopic dermatitis (AD) is a chronic, recurring, pruritic, inflammatory skin condition which has its onset in early childhood in most cases. A stepped approach to therapy, starting with emollients and adding first mild and then more potent topical medications is recommended. For more than 50 years, topical corticosteroids (TCs) have been the gold standard in AD therapy. Increasingly potent TCs have tended to come with increasing risk of adverse events, however. Calculating the benefit/risk ratio [or therapeutic index (TIX)] for TCs when treating children and infants is more challenging in this population. Not only does their increased surface area to volume ratio as a result of their small size mean that they are likely to absorb a greater proportion of any active agent applied to their skin, but drug metabolism is slower than in adults and the systemic effects of corticosteroids are more pronounced (in particular reduction of serum cortisol levels through suppression of the hypothalamic–pituitary–adrenal axis). Unlike traditional TCs, topical calcineurin inhibitors are not associated with the systemic effects and have shown good efficacy in treating AD in children. Parental/Carer concerns about their long‐term use can limit their acceptance for treatment in the paediatric population, however. Modifications to the structure of fourth generation corticosteroids mean that increased potency is not accompanied by increased risk of adverse events and hence they have an improved TIX. Methylprednisolone aceponate is a potent fourth generation corticosteroid which has demonstrated efficacy and safety in acute and maintenance programmes in infants and children. It is licenced for once‐daily use, and is available in four formulations – ointment, fatty ointment, cream and milk, which combine with its improved TIX to meet the needs of young patients and their carers.     

Electrical conductance: a controversial parameter in the evaluation of emollients in atopic dermatitis

Background/aims: Essential fatty acids are important in maintaining skin function and their deficiency is associated with scali-ness and increased transepidermal water loss (TEWL). This can be one of the pathogenic processes implicated in atopic dermatitis (AD). Several studies have assessed the value of essential fatty acid-enriched diets in AD but the benefits of topical γ-lino-lenic acid (GLA) therapy have been less well evaluated. The aims of this study were: a) to compare the effects of GLA-con-taining emollients and classical emollients, regarding clinical benefits, cutaneous hydration (by a conductance method) and TEWL; b) to assess the clinical relevance of these two biomet-rical methods (conductance and TEWL). Methods: Twenty-three AD children were randomised into four groups, to compare three emollients containing GLA in different concentrations and one classical emollient. They were evaluated in eight visits for 12 weeks, using a clinical score and measurements of TEWL with the Tewameter? and of cutaneous hydration with the Nova?. Results: Kruskal-Wallis statistical analysis showed significant differences in cutaneous hydration (P<0.05) between each of the three treatment groups and the control group. TEWL and clinical scores did not show statistically significant differences. During the study no children from the GLA groups developed eczematous lesions versus two children from the non-GLA group. Conclusions: Discrepancies between conductance and TEWL measurements may represent false positive results of the former method due to electrical phenomena related to polarity of the GLA molecule or of other elements in the formulations. However, some differences in clinical evolution between the GLA and non-GLA groups require further studies to assess the possible additional benefits of topical emollients containing GLA.     

Topical Therapy in Atopic Dermatitis in Children

Atopic dermatitis (AD) is a common, chronic childhood skin disorder caused by complex genetic, immunological, and environmental interactions. It significantly impairs quality of life for both child and family. Treatment is complex and must be tailored to the individual taking into account personal, social, and emotional factors, as well as disease severity. This review covers the management of AD in children with topical treatments, focusing on: education and empowerment of patients and caregivers, avoidance of trigger factors, repair and maintenance of the skin barrier by correct use of emollients, control of inflammation with topical corticosteroids and calcineurin inhibitors, minimizing infection, and the use of bandages and body suits.     

Optimal Management of Severe Plaque Form of Psoriasis

Psoriasis is a chronic, inflammatory, hyperproliferative skin disease that affects 1-2% of the general population in the UK and US. Plaque psoriasis is the most common form, accounting for approximately 90% of cases. The disease is usually chronic and persistent, although up to 50% of patients may enter spontaneous remission for varying periods of time. There is no cure for psoriasis; therefore, the aim of treatment is to minimize the extent and severity of the disease to the point at which it no longer substantially disrupts the patient's quality of life. First-line therapy of psoriasis usually consists of topical agents, such as emollients, tar, dithranol, and vitamin D3 analogs. In cases of severe, extensive psoriasis, where topical therapy is either impractical or not sufficiently effective, systemic treatment may be warranted at the outset. In these circumstances, the therapeutic options include: (i) intensive inpatient or day center topical therapy; (ii) phototherapy; and/or (iii) systemic agents. There are now a number of systemic agents available for the treatment of severe psoriasis, but all have potential adverse effects. We review the current treatment options, which include the use of phototherapy and systemic agents, and provide recommendations on their use in clinical practice. Importantly, treatment should be tailored to each individual patient depending on concurrent medical problems (which might preclude certain agents), patient choice and acceptance of the risk of adverse effects.     

Personalized Immunomodulatory Therapy for Atopic Dermatitis: An Allergist's View

The current standard medical therapy for atopic dermatitis (AD) mainly focuses on symptomatic relief by controlling skin inflammation with topical corticosteroids and/or topical calcineurin inhibitors. However, the clinical efficacy of pharmacological therapy is often disappointing to both patients and physicians. The terminology of AD contains a historical meaning of eczematous dermatitis caused by hypersensitivity reaction to environmental inhalant or food allergen. Complex interrelationships among genetic abnormalities, environmental triggers, skin barrier defects, and immune dysfunction resulting in a vicious domino-circle seem to be involved in the development and maintenance of AD. In the viewpoint of AD as an allergic disease, complete avoidance of clinically relevant allergen or induction of specific immune tolerance through administrations of allergen (allergen immunotherapy) can provide clinical remission by breaking the vicious domino-circle maintaining a chronic disease state. In recent clinical studies, monoclonal antibodies including the anti-interleukin-4 receptor antibody and anti-B cell antibody induced significant clinical improvements in patients with AD. The detailed characteristics of immune dysfunction are heterogeneous among patients with AD. Therefore, a personalized combination of immunomodulatory therapies to reduce hypersensitivity (allergen immunotherapy) and correct immune dysfunction (monoclonal antibody therapy) could be a reasonable therapeutic approach for patients with AD. Future immunomodulatory therapies for AD should be developed to achieve long-term treatment-free clinical remission by induction of immune tolerance.     

Tacrolimus ointment: utilization patterns in children under age 2 years

Atopic dermatitis (AD) is a common eczematous skin condition; as many as 10-17 percent of all children are affected, and 35-60 percent of affected patients manifest symptoms manifest during the first year of life. Treatment principles for AD in young children involve conservative measures such as avoidance of hot water and environmental irritants, combined with liberal use of emollients after bathing. Low potency topical corticosteroids (TCS) are the current standard of therapy for AD in young children, reserving mid- and high-potency TCS for severe disease. However, complications of long-term use of TCS include skin atrophy, stria formation, telangiectasia, hypopigmentation, secondary infections, steroid acne, allergic contact dermatitis, and miliaria. The pediatric population is also at increased risk for systemic absorption because of their high ratio of skin surface to body mass. Systemic absorption may result in hypothalamic-pituitary-adrenal axis suppression and ultimately growth retardation. Although most topical and systemic corticosteroids are not approved by the Food and Drug Administration for use in children less than 2 years of age, conservative treatment often fails in this age group and frequently patients are treated with TCS, antibiotics, and antihistamines.     

Intermittent topical corticosteroid/tacrolimus sequential therapy improves lichenification and chronic papules more efficiently than intermittent topical corticosteroid/emollient sequential therapy in patients with atopic dermatitis

Atopic dermatitis (AD) is a common, chronic, relapsing, severely pruritic, eczematous skin disease. Topical steroids are the mainstay of treatment. However, the adverse effects of steroids on hormonal function are the major obstacle for their use as long-term topical therapy. Intermittent dosing with potent topical steroids and/or combination therapy with steroid and tacrolimus have been frequently used in the daily management of AD to overcome the problems accompanying the long term use of steroids. We compared the clinical effects of topical steroid/tacrolimus and steroid/emollient combination treatments in 17 patients with AD. An intermittent topical betamethasone butyrate propionate/tacrolimus sequential therapy improved lichenification and chronic papules of patients with AD more efficiently than an intermittent topical betamethasone butyrate propionate/emollient sequential therapy after four weeks of treatment. Only one out of 17 patients complained of a mild, but temporary, burning sensation after tacrolimus application. The intermittent topical steroid/tacrolimus sequential therapy may be a useful adjunctive treatment for AD.     

Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity

BACKGROUND: It is currently fashionable to consider atopic dermatitis (AD), like other inflammatory dermatoses, as immunologic in pathogenesis ("inside-outside" hypothesis). Accordingly, topical glucocorticoids and other immunosuppressive agents are mainstays of therapy, but the risk of toxicity from these agents is not insignificant, particularly in children. Alternatively, because stratum corneum (SC) permeability barrier function is also abnormal in AD, it has been hypothesized that the barrier abnormality could drive disease activity. Yet commonly used emollients and moisturizers do not correct the SC ceramide deficiency, the putative cause of the barrier abnormality. OBJECTIVES: We assessed the efficacy of a newly developed, ceramide-dominant, physiologic lipid-based emollient, when substituted for currently used moisturizers, in 24 children who were also receiving standard therapy for stubborn-to-recalcitrant AD. METHODS: All subjects continued prior therapy (eg, topical tacrolimus or corticosteroids), only substituting the barrier repair emollient for their prior moisturizer. Follow-up evaluations, which included severity scoring of atopic dermatitis (SCORAD) values and several biophysical measures of SC function, were performed every 3 weeks for 20 to 21 weeks. RESULTS: SCORAD values improved significantly in 22 of 24 patients by 3 weeks, with further progressive improvement in all patients between 6 and 20 or 21 weeks. Transepidermal water loss levels (TEWL), which were elevated over involved and uninvolved areas at entry, decreased in parallel with SCORAD scores and continued to decline even after SCORAD scores plateaued. Both SC integrity (cohesion) and hydration also improved slowly but significantly during therapy. Finally, the ultrastructure of the SC, treated with ceramide-dominant emollient, revealed extracellular lamellar membranes, which were largely absent in baseline SC samples. CONCLUSION: These studies suggest that (1) a ceramide-dominant, barrier repair emollient represents a safe, useful adjunct to the treatment of childhood AD and (2) TEWL is at least as sensitive an indicator of fluctuations in AD disease activity as are SCORAD values. These studies support the outside-inside hypothesis as a component of pathogenesis in AD and other inflammatory dermatoses that are accompanied by a barrier abnormality.     

Clinical Practice Guidelines for the Management of Atopic Dermatitis 2016

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. Most patients have an atopic predisposition. The definitive diagnosis of AD requires the presence of all three features: (i) pruritus; (ii) typical morphology and distribution of the eczema; and (iii) chronic and chronically relapsing course. The current strategies to treat AD in Japan from the perspective of evidence‐based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity‐related patient outcomes with respect to several important points requiring decision‐making in clinical practice.     

Skin absorption through atopic dermatitis skin: a systematic review

Patients with atopic dermatitis (AD) have skin barrier impairment in both lesional and nonlesional skin. They are typically exposed daily to emollients and intermittently to topical anti‐inflammatory medicaments, thereby increasing the risk of developing contact allergy and systemic exposure to chemical ingredients found in these topical preparations. We systematically searched for studies that investigated skin absorption of various penetrants, including medicaments, in patients with AD, but also in animals with experimentally‐induced dermatitis. We identified 40 articles: 11 human studies examining model penetrants, 26 human studies examining AD drugs, and three animal studies. We conclude that patients with AD have almost twofold increased skin absorption compared with healthy controls. There is a need for well‐designed epidemiological and dermatopharmacokinetic studies that examine to what extent AD causes patients to be systemically exposed to chemicals compared with nonatopic dermatitis.