Skin barrier defects in atopic dermatitis: From old idea to new opportunity.

Atopic dermatitis (AD) is the most common chronic skin inflammatory disease, with a profound impact on patients' quality of life. AD varies considerably in clinical course, age of onset and degree to which it is accompanied by allergic and non-allergic comorbidities. Skin barrier impairment in both lesional and nonlesional skin is now recognized as a critical and often early feature of AD. This may be explained by a number of abnormalities identified within both the stratum corneum and stratum granulosum layers of the epidermis. The goal of this review is to provide an overview of key barrier defects in AD, starting with a historical perspective. We will also highlight some of the commonly used methods to characterize and quantify skin barrier function. There is ample opportunity for further investigative work which we call out throughout this review. These include: quantifying the relative impact of individual epidermal abnormalities and putting this in a more holistic view with physiological measures of barrier function, as well as determining whether these barrier-specific endotypes predict clinical phenotypes (e.g. age of onset, natural history, comorbidities, response to therapies, etc). Mechanistic studies with new (and in development) AD therapies that specifically target immune pathways, Staphylococcus aureus abundance and/or skin barrier will help us understand the dynamic crosstalk between these compartments and their relative importance in AD.

Halting the March: Primary Prevention of Atopic Dermatitis and Food Allergies.

Atopic dermatitis (AD) is one of the most common inflammatory skin conditions, affecting 15% to 30% of children and 2% to 10% of adults. Population-based studies suggest that having AD is associated with subsequent development of other atopic diseases, in what is known as the "atopic march." We will provide an overview of studies that investigate primary prevention strategies for the first 2 diseases in the march, namely, AD and food allergies (FA). These strategies include emollients, breastfeeding, microbial exposures, probiotics, vitamin D and UV light, water hardness, and immunotherapy. Some studies, including randomized controlled trials on emollients and microbial supplementation, have found encouraging results; however, the evidence remains limited and contradictory. With regard to breastfeeding, microbial and lifestyle exposures, vitamin D and UV light, water hardness, and immunotherapy, the lack of randomized controlled trials makes it difficult to draw definitive conclusions. Current American Academy of Pediatrics guidelines support the idea that breastfeeding for 3 to 4 months can decrease AD incidence in children less than 2 years old. Recommendations regarding a direct relationship between breastfeeding on FA, however, cannot be made because of insufficient data. Regarding microbial supplementation, most guidelines do not recommend probiotics or prebiotics for the purpose of preventing allergic diseases because of limited evidence. Before definitive conclusions can be made regarding these interventions, more well-designed, longitudinal, and randomized controlled trials, particularly in at-risk populations, are required.

Treatment-resistant atopic dermatitis: challenges and solutions.

Atopic dermatitis (AD) is a common, chronic, relapsing-remitting inflammatory disease that can be challenging to treat. Patients with mild disease are usually managed well with good skin care practices including moisturization and appropriate bathing along with intermittent use of topical therapies such as topical corticosteroids and/or topical calcineurin inhibitors during flares. Patients with frequent flares may benefit from proactive application of topical therapies twice a week to the most troublesome areas. Patients with severe disease often present significant treatment challenges. Systemic therapies are usually required for severe AD but have varying degrees of success and can be associated with side-effect profiles that require counseling and close monitoring. Phototherapy has been shown to have success in treating moderate-to-severe AD, but several factors can limit its utility and efficacy including cost and access. New therapies are in development targeting specific pathways relevant for AD. Dupilumab was the first biologic treatment approved in North America, Europe, and Japan for adults with moderate-to-severe AD. Although this treatment can lead to rapid improvement in the majority of patients, there are inadequate responders. In this review, we discuss the clinical challenges and treatment options for moderate-to-severe refractory AD.

Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia.

Spinal sensorimotor networks that are functionally disconnected from the brain because of spinal cord injury (SCI) can be facilitated via epidural electrical stimulation (EES) to restore robust, coordinated motor activity in humans with paralysis1-3. Previously, we reported a clinical case of complete sensorimotor paralysis of the lower extremities in which EES restored the ability to stand and the ability to control step-like activity while side-lying or suspended vertically in a body-weight support system (BWS)4. Since then, dynamic task-specific training in the presence of EES, termed multimodal rehabilitation (MMR), was performed for 43 weeks and resulted in bilateral stepping on a treadmill, independent from trainer assistance or BWS. Additionally, MMR enabled independent stepping over ground while using a front-wheeled walker with trainer assistance at the hips to maintain balance. Furthermore, MMR engaged sensorimotor networks to achieve dynamic performance of standing and stepping. To our knowledge, this is the first report of independent stepping enabled by task-specific training in the presence of EES by a human with complete loss of lower extremity sensorimotor function due to SCI.

Atopic dermatitis.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, with a lifetime prevalence of up to 20% and substantial effects on quality of life. AD is characterized by intense itch, recurrent eczematous lesions and a fluctuating course. AD has a strong heritability component and is closely related to and commonly co-occurs with other atopic diseases (such as asthma and allergic rhinitis). Several pathophysiological mechanisms contribute to AD aetiology and clinical manifestations. Impairment of epidermal barrier function, for example, owing to deficiency in the structural protein filaggrin, can promote inflammation and T cell infiltration. The immune response in AD is skewed towards T helper 2 cell-mediated pathways and can in turn favour epidermal barrier disruption. Other contributing factors to AD onset include dysbiosis of the skin microbiota (in particular overgrowth of Staphylococcus aureus), systemic immune responses (including immunoglobulin E (IgE)-mediated sensitization) and neuroinflammation, which is involved in itch. Current treatments for AD include topical moisturizers and anti-inflammatory agents (such as corticosteroids, calcineurin inhibitors and cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) inhibitors), phototherapy and systemic immunosuppressants. Translational research has fostered the development of targeted small molecules and biologic therapies, especially for moderate-to-severe disease.

Long-Term Treatment of Atopic Dermatitis.

Many patients with mild to moderate atopic dermatitis (AD) are managed by identifying and avoiding allergens and irritants, ensuring skin moisturization, and graded use of topical corticosteroids and/or calcineurin inhibitors. There is little consensus on the next step. Most systemic therapies are "off label" in the United States and include phototherapy, cyclosporine, mycophenolic acid precursors, azathioprine, and methotrexate. The decision to use these therapies should be based on efficacy and safety readouts from well designed, long-term trials. This article reviews the long-term randomized, controlled trials examining safety and/or efficacy of interventions recommended for patients with mild to severe AD.

Enabling Task-Specific Volitional Motor Functions via Spinal Cord Neuromodulation in a Human With Paraplegia.

We report a case of chronic traumatic paraplegia in which epidural electrical stimulation (EES) of the lumbosacral spinal cord enabled (1) volitional control of task-specific muscle activity, (2) volitional control of rhythmic muscle activity to produce steplike movements while side-lying, (3) independent standing, and (4) while in a vertical position with body weight partially supported, voluntary control of steplike movements and rhythmic muscle activity. This is the first time that the application of EES enabled all of these tasks in the same patient within the first 2 weeks (8 stimulation sessions total) of EES therapy.

Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair.

Atopic dermatitis (AD) is characterized by epidermal tight junction (TJ) defects and a propensity for Staphylococcus aureus skin infections. S. aureus is sensed by many pattern recognition receptors, including Toll-like receptor 2 (TLR2). We hypothesized that an effective innate immune response will include skin barrier repair, and that this response is impaired in AD subjects. S. aureus-derived peptidoglycan (PGN) and synthetic TLR2 agonists enhanced TJ barrier and increased expression of TJ proteins, claudin-1 (CLDN1), claudin-23 (CLDN23), occludin, and Zonulae occludens 1 (ZO-1) in primary human keratinocytes. A TLR2 agonist enhanced skin barrier recovery in human epidermis wounded by tape stripping. Tlr2(-/-) mice had a delayed and incomplete barrier recovery following tape stripping. AD subjects had reduced epidermal TLR2 expression as compared with nonatopic subjects, which inversely correlated (r=-0.654, P=0.0004) with transepidermal water loss (TEWL). These observations indicate that TLR2 activation enhances skin barrier in murine and human skin and is an important part of a wound repair response. Reduced epidermal TLR2 expression observed in AD patients may have a role in their incompetent skin barrier.

Fibroblast growth factor-peptide improves barrier function and proliferation in human keratinocytes after radiation.

PURPOSE: Epidermal keratinocytes, which can be severely damaged after ionizing radiation (IR), are rapid turnover cells that function as a barrier, protecting the host from pathogenic invasion and fluid loss. We tested fibroblast growth factor-peptide (FGF-P), a small peptide derived from the receptor-binding domain of FGF-2, as a potential mitigator of radiation effects via proliferation and the barrier function of keratinocytes. METHODS AND MATERIALS: Keratinocytes isolated from neonatal foreskin were grown on transwells. After being exposed to 0, 5, or 10 Gy IR, the cells were treated with a vehicle or FGF-P. The permeability of IR cells was assessed by using transepithelial electrical resistance (TEER) and a paracellular tracer flux of fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) with Ussing chambers. The cell proliferation was measured with yellow tetrazolium salt (MTT) and tritiated thymidine ([3H]-TdR) assays. The phosphorylation of extracellular signal-regulated kinases (ERK) was measured in an enzyme-linked immunosorbent (ELISA)-like assay, and the proteins related to tight junctions (TJ) and adherens junctions (AJ) were examined with Western blotting. We used a mouse model to assess the ability of FGF-P to promote the healing of skin ß burns created with a strontium applicator. RESULTS: We found (1) FGF-P reduced the permeability of irradiated keratinocytes, as evidenced by increased TEER and decreased diffusion of FITC-BSA, both associated with the regulation of different proteins and levels of TJ and AJ; and (2) FGF-P enhanced the proliferation of irradiated keratinocytes, as evidenced by increased MTT activity and [3H]-TdR incorporation, which was associated with activation of the ERK pathway; and (3) FGF-P promoted the healing of skin ß burns. CONCLUSIONS: FGF-P enhances the barrier function, including up-regulation of TJ proteins, increases proliferation of human keratinocytes, and accelerates the healing of skin ß burns. FGF-P is a promising mitigator that improves the proliferation and barrier function of keratinocytes after IR.

Emerging therapeutic options for atopic dermatitis: beyond TIMs.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that significantly impacts both patients and their families. Although current therapies provide relief of symptoms for most but not all patients, they do not prevent or eradicate the disease. In this new era of biological therapy, medications that precisely target the molecular mediators of inflammation are being developed at a rapid pace. These biologic agents have proven useful for treating many inflammatory illnesses, as well as providing insight into disease pathogenesis. In atopic dermatitis, these new therapies may prove highly useful to both treat and prevent the disease. In this review article, we briefly review the pathogenesis of AD to discuss current therapies and to introduce potential new treatments.