eczema?

Review

What is new in atopic dermatitis/eczema?

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.

Sabine G Pl€otz, Markus Wiesender, Antonia Todorova & Johannes Ring† †

Technical University Munich, Department of Dermatology and Allergy am Biederstein (Head: Univ. Prof. Dr. med. Tilo Biedermann), Mu¨nchen, Germany

1.

Background

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Medical need

3.

Existing treatment

4.

Current research goals and scientific rationale

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Competitive environment

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Potential development issues

7.

Expert opinion

Introduction: Atopic eczema (AE) is a chronic relapsing inflammatory skin condition and one of the most common, potentially debilitating diseases with increasing incidence. Areas covered: The complex etiology of AE with multiple systemic and local immunologic and inflammatory responses and interactions between susceptibility genes and environmental factors leading to defects in skin barrier function and eczematous skin lesions is presented. Knowledge of pathogenesis is important for understanding the more innovative treatment approaches discussed. Expert opinion: Basic therapy consists of hydrating topical treatment and avoidance of specific and unspecific provocation factors. For acute eczematous skin lesions, anti-inflammatory treatment consists mainly of topical glucocorticoids and topical calcineurin inhibitors. Microbial colonization and superinfection may induce skin exacerbation, which can be treated by either topical or systemic antimicrobial treatment. Systemic anti-inflammatory therapy is limited to severe cases and consists of systemic steroids, cyclosporine A or mycophenolate mofetil. Novel anti-inflammatory concepts that go beyond corticosteroids are in the early phases of development. There are targeted therapeutic approaches, such as cytokine and chemokine modulators, and it remains to be investigated how effective they will be and what side effects they may carry. Existing treatment modalities such as barrier repair therapy, topical immunosuppressive agents, antiseptic treatment as well as systemic treatment options are discussed. Keywords: anti-inflammatory treatment, atopic eczema, biologicals, calcineurin inhibitors glucocorticosteroids, systemic therapy, topical therapy Expert Opin. Emerging Drugs [Early Online]

1.

Background

Atopic eczema (AE), also called atopic dermatitis (AD), is a chronic, pruritic skin disease with a broad spectrum of clinical manifestations, which affects up to 20% of children and 1 -- 3% of adults in most countries of the world [1,2]. Approximately 40 million patients suffer from AE, and this inflammatory skin disease is often the first step in the so-called ‘atopic march’ that results in asthma and allergic rhinitis [2]. The ‘atopic march’ or ‘allergic march’ [2] is a term used for a typical sequence of clinical symptoms consisting for years. AE is occurring first, followed by the development of asthma and allergic rhinitis in later life. As a result of the increasing prevalence of atopic disorders in developed countries, the burden of healthcare cost increases, and the quality of life of affected patients is significantly lowered by chronic eczematous lesions, pruritus, sleep loss, dietary restrictions and psychosocial affections. Although the prevalence of atopic diseases rapidly increased over the last half century, AE and other atopic diseases have already been described in ancient china [3] and --according to Suetonius -- emperor Augustus was, suffering from ‘extremely 10.1517/14728214.2014.953927 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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itchy skin, seasonal rhinitis and tightness of the chest’ (Suetonius: De Vita Caesarum [3]). The peculiar, antique, instrument-based scratching behavior (frequent use of a scraper) was one of Octavian’s atopy defining, eczema-specific habits. The term ‘atopy’ was first defined in 1923 by Coca and Cooke, as a proclivity to develop rhinitis, asthma and urticaria. They found that these patients possessed a distinct antibody, which they termed ‘reagin’ or ‘skin-sensitizing antibody’, after intradermal tests to a variety of inhalant allergens-elicited urticarial lesions. In the early 1930s, Sulzberger encountered atopic patients with eczematous lesions that favored the antecubital and popliteal fossae and initially called the disease ‘neurodermatitis of atopic type’, later ‘AE’ and ‘AD’ [4]. Today, the terminology is still a subject of ongoing controversy and different synonyms are used for the disorder: ‘neurodermatitis’, ‘endogenous eczema’, ‘neurodermitis constitutionalis sive atopica’, ‘Prurigo Besnier’ and more; the heterogeneity of the terms used reflects the different concepts of pathophysiology. One major feature of AE is the occurrence of eczematous lesions. The term ‘eczema’ is derived from the Greek word ‘ekzein’, that is, to ‘boil out’, which refers to the skin lesions flaring up (‘boiling out’) in a relapsing course. Nowadays, the terms ‘dermatitis’ and ‘eczema’ are regarded as synonymous. The term ‘atopic’ refers to the frequent association with atopy, and the need to separate this skin disease from other forms of eczema, such as seborrhoeic, allergic contact, primary irritant, photo-allergic, phototoxic, nummular, asteatotic, stasis, dyshidrotic and drug-induced eczema. These other forms of eczema have other causes and distinct patterns. The clinical definition of AE includes a typically agerelated distribution and morphology [5]. Hanifin and Rajka stated the necessity of three of four main criteria (pruritus, typical morphology and distribution, chronic or chronically relapsing course and atopic personal or family history) in addition to three minor criteria among a list of 21. Various further attempts have been made to lay down a specific set of criteria for AE, among them the UK Working Group classification [6] and the millennium criteria [7]. Pruritus is the most common feature in AE. The pruritus can be severe, sometimes causing sleep disruption and generalized stress for affected patients and family members. Pruritus leads to scratching which results in secondary skin changes such as excoriation and disrupted skin barrier. The skin lesions observed in AE vary greatly, depending on the severity of inflammation, different stages of healing, chronic scratching, frequent secondary infections and the age. Eczematous lesions usually present during infancy and childhood but can persist or even start in adulthood. In the first months of life, yellowish desquamation on the scalp may be present followed by eczematous lesions, oozing and crusting preferentially on the cheeks and the chin, usually sparing the perioral region. Cheilitis is common. A significant 2

number of infants develop a generalized eruption, and involvement of the cubital/popliteal fossae is common. During the childhood phase, eczematous lesions frequently involve the flexural areas, the neck, wrist and ankles. During the adult phase, eczematous involvement of the flexures, neck and hands are typical findings. Additionally, hand eczema or eczematous lesions of the periorbital region are common. Intense pruritus and scratching on persistent eczematous lesions result in thickening of the skin, the socalled ‘lichenification’. Patients with the pruriginous type of AE present with localized or widespread pruritic papules, which are partly excoriated due to intense pruritus. Of patients with AE, 50 -- 80% have or develop asthma or allergic rhinitis. IgE-mast-cell-mediated allergies to different allergens are a common feature in patients with AE. Food allergens, such as egg, milk, wheat, soy and peanuts, may induce eczematous skin rash in 40% of the children with moderate-to-severe AE. After the age of 3, children frequently outgrow food allergies but may become sensitized to inhalant allergens such as dermatophagoides pteronyssimus, birch pollen, hazelnut pollen, grass pollen and other common aeroallergens. Epicutaneous application of aeroallergens by atopy patch test on uninvolved skin of patients with AE may elicit eczematoid reactions [8]. Serum levels of IgE and specific IgE antibodies directed against environmental antigens can be detected in most AE patients. However, a subgroup of patients exists, in which IgE-mediated mechanisms are not detectable (‘intrinsic type’ [9]). Furthermore, elevated detectable specific IgE antibodies and positive prick test results are not linked to clinically relevant sensitizations in all cases. Hygiene hypothesis Prevalence of AE and other atopic allergic disorders were continuously increasing in Western industrial countries [10]. This led to the conclusion that declining family size, improvement in household amenities and higher standard of personal cleanliness reduced childhood infections and contact to bacterial endotoxins at home [11]. Reduction of exposure to bacterial endotoxins with increase in hygiene and living standard may result in a skewed development of the immune system, and an abnormal response to various environmental allergens which are otherwise innocuous and the lack of antigenic competition led to increased incidence of the phenomena seen in atopy. These explanations had several supporting observations. Several studies had shown that atopic disorders were less frequent in positive tuberculin responders, and bacterial infections reduced the incidence of atopy in children [12,13]. Moreover, the incidence of atopic disease had been shown to be related to the age of entry into the nursery in a large study conducted by Kramer et al. [14] in Germany. Those children from small families who entered nursery at a later age (who were less exposed to infections from other children) had higher rate of getting atopic disorders than those who 1.1

Expert Opin. Emerging Drugs (2014) 19(3)



had entered nursery at a younger age. Moreover, further studies found that farmer’s children, who grow up with an increased exposure to bacterial and fungal components, had a significant lower risk to develop atopic asthma [15]. In a recent systematic review, parasitic infections decreased the risk of allergen sensitization [16]. A recent German nationwide cross-sectional study including 17,641 children found positive associations between parent-reported infections after birth and the prevalence of eczema [17]; other environmental factors (mold on the walls, pets except of keeping a dog) showed no significant associations with eczema. In this study, migrants or dog keepers had a lower risk to develop eczema [17]. The so-called hygiene hypothesis was explained by crossregulation between the two subsets of T helper cells with down-regulation of TH2 cells by release and overproduction of TH1 cytokines and vice versa. Also, increased incidence of atopy was explained by the lack of infections with consecutive reduced stimulation of TH1 cells resulting in increased TH2 cytokine release leading to the inflammation [18]. These observations led to the use of diet supplementation with Lactobacillus CG, marketed as probiotics. However, it has been stated that the ‘hygiene hypothesis’ works only for respiratory atopy, whereas AE does occur less frequently in these conditions [19]. Immune dysregulation in AE AE may be considered as a cutaneous manifestation of a systemic disorder that gives rise to asthma and allergic rhinitis. These conditions are all characterized by elevated serum levels of IgE and peripheral eosinophilia. Key effector cells of atopic diseases are T cells, which are divided into various groups (TH0, TH1, TH2, TH3) according to the type of cytokines they produce. TH2 cytokines such as IL-4, IL-5 and IL-10 and IL-13 play an important role in the skin inflammatory response in AE. In consequence of an impaired balance of the CD4-positive T helper cell populations TH1 and TH2, enhanced IL-4 and IL-13 productions by TH2 cells, induces isotype switching to IgE synthesis. The evidence for a central role of IgE was provided by several studies showing that IgE is expressed on epidermal Langerhans cells (LC) and dendritic cells (DC), which are overexpressed in lesional skin of AE and play a central role due to allergen presentation in AE. In lesional as well as in non-lesional skin of atopic patients, epidermal LC were shown to express the high-affinity IgE receptor on the cell surface and carry IgE via the high-affinity IgE-receptor in a significant higher amount compared to skin of healthy subjects [20,21]. Allergen uptake by IgE-receptor-bearing DCs and consecutive skin homing of cutaneous lymphocyte antigen (CLA)bearing T cells are assumed to mediate the inflammatory response [22]. In addition, release of chemokines and chemoattractant factors followed by recruitment of inflammatory cell subtypes is assumed to represent a causative factor for the 1.2

inflammatory response, leading to the development of eczema [23], and improvement of the eczematous lesion has been shown to correlate with reduced chemotaxis of inflammatory cell subtypes [22,23]. Furthermore, due to an impaired epidermal barrier function (as discussed below), aeroallergens known to elicit IgEmediated reactions are able to penetrate the skin barrier and provoke eczematous lesions. This finding can be used for the diagnosis in AE patients with suspected allergy to aeroallergens by using the atopy patch test [8]. Epidermal keratinocytes from AE patients produce a unique profile of chemokines and cytokines [2] following mechanical stimulation, for example, scratching. As compared to psoriasis, molecules like IL-16, a LC-derived chemoattractant cytokine for CD4+ cells, RANTES, monocyte chemotactic protein (MCP)-4 and eotaxin are overexpressed in atopic skin and may contribute to the chemotaxis of eosinophils, macrophages and TH2-lymphocytes. Impaired skin barrier Inflammatory skin responses with eczematous flares have been assumed to reflect the consequences of the above-described immunologic abnormality (the inside--outside view of AE pathogenesis). However, it has as well been proposed that the skin lesions and barrier abnormality is not merely an epiphenomenon, but rather the cause of disease activity (the reverse outside--inside view of disease pathogenesis [24]. The epidermis and the outermost skin layer (stratum corneum) provide the permeability barrier and is an antimicrobial, antioxidant, ultraviolet (UV)-filtering, mechanical and sensory interface [24]. Moreover, the epidermal barrier has an important role in trapping moisture and preventing dry skin. Based on the association of inherited abnormalities in the intracellular protein filaggrin expression, AE is as well considered as a disorder of epidermal structure and function [25] and a disease of primary barrier failure, characterized by a defective permeability [26] and an antimicrobial function. Loss of filaggrin, a protein needed for terminal differentiation, provokes a loss of permeability-barrier abnormality, but the exact mechanism is not known. The gene coding for filaggrin was found to be mutated in many patients with AE [25]. However, it is not clear what drives impaired barrier dysfunction in the skin of patients without a filaggrin mutation. It has been hypothesized that loss of filaggrin not only could induce corneocyte deformation but also could be combined with a lack of filaggrin as a substrate for processing polycarboxylic acids, such as pyrrolidone carboxylic acid and trans-urocanic acid. These polycarboxylic acids act as osmolytes, drawing water into corneocytes, partially accounting for corneocyte hydration. Hence, filaggrin deficiency could result in decreased stratum corneum hydration. Interestingly, a recent multiple regression analyzes revealed that levels of natural moisturizing factors such as pyrrolidone carboxylic acid and urocanic acid were associated with filaggrin genotype and AE severity [27]. 1.3


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A large pool of preformed pro-inflammatory cytokines is stored in the stratum corneum layer, and the cytokine cascade helps to restore the barrier function in normal skin. The mediators are released into the lower epidermis if the barrier function is perturbed, and as the barrier function is abnormal in AE, cytokine release is sustained and the ongoing cytokine cascade leads to the recruitment of additional, pro-inflammatory mediators (hence, the ‘outside-to-inside’ concept of AE pathogenesis). Additionally, failure of barrier function triggers AE through the increased penetration of haptens, which stimulate immunologic responses [24]. Tight junction defects of epidermal cell may also contribute to the impaired skin barrier in AE patients [28]. Interestingly, histamine-induced suppression in the differentiation of cultured keratinocytes as well as suppression of the expression of tight-junctions proteins was reported, and these findings led to the conclusion that mast cell activation with subsequent histamine release may enhance to skin barrier defects in AE [29]. Susceptibility to pathogens Patients with AE are highly susceptible of cutaneous bacterial, fungal and viral infections [1,2]. Staphylococcal and streptococcal infections are common complications of atopic lesions. Cutaneous and nasal colonization with Staphylococcus aureus contribute to the exacerbation of AE, and the density of S. aureus colonization correlates with clinical severity [30]. Due to a number of defects in the innate cutaneous immunology, colonization with S. aureus is increased. It was found that staphylococcal exotoxins exacerbate AE via T-cell activation not only as superantigens but, to a great extent, also as conventional allergens [31]. Moreover, keratinocytes from patients with AE are deficient in their ability to synthesize AMPs needed for the innate immune responses against microbes [2] and reduced levels of AMPs [32] have been detected in acute and chronic skin lesions of AE compared with lesions of other inflammatory diseases. A variety of defects in the innate immune system, such as the reduction of AMPs in the skin of atopic patients, diminished recruitment of innate immune cells to the skin, epithelial barrier disturbance and defects in pattern recognition molecules of the innate immune system (Toll-like receptors or TLRs) may account for the susceptibility of patients with AE to pathogens such as S. aureus [27,30,33,34]. The superinfection of AE lesions with staphylococci has been showed to be associated with temporal shifts in the skin microbiome [35]. S. aureus produces small vesicles, which contain proteins and which can be isolated by ultracentrifugation of cultured media [36]. These vesicles induce the release of pro-inflammatoric mediators and chemokines by dermal fibroblasts and were shown to elicitate AE-like skin infiltration after appliance to tape-stripped skin [36]. Cell wall compounds of S. aureus are recognized by TLR-2-receptors, thus activating the first-line antimicrobial defense. Polymorphisms in the TLR-2 receptor were found 1.4

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in a subgroup of AE patients with a severe phenotype [34] possibly contributing to impaired microbial defense. Monocytes of patients with severe AE and a heterozygous TLR-2 polymorphism express more IL-6 and IL-12 on TLR-2 activation compared to nonmutated monocytes of AE patients [37]. Most recently, it was reported that in a mouse model TLR-2 ligands promote skin inflammation in AD through IL-4-mediated suppression of IL-10 [38]. In summary, increasing knowledge about the complex background of interactions of the skin immune system and microbes and their influence on skin inflammation may help to develop new treatment modalities.

2.

Medical need

AE with its increasing incidence worldwide and its relapsingintermitting course reflects a burden for the affected patients, their families and the society. Therapy in AE largely consists of topical immunomodulators or steroids. Modification of the hydrocortisone, which was introduced by Sulzberger et al. 1953 into clinical practice, led to the development of more potent topical steroids with the benefit of increased efficacy but the disadvantage of increased side effects mostly due to skin atrophy. In the past decade, two new agents, topical calcineurin inhibitors (TCI), tacrolimus ointment and pimecrolimus cream, were licensed for topical eczema treatment and were found not to cause skin atrophy. This favors their use in body areas with thin skin such as the eyelid region, the perioral skin, the genital area or the inguinal fold. Concerns about the adverse side effects of topical steroids and warnings about the potential toxicity associated with prolonged use of these immunosuppressive calcineurin inhibitors could stimulate search for alternative forms of therapy. Despite recognition that AE is one of the most frequent chronic skin diseases, there is a high unmet need for immunomodulating, anti-inflammatory compounds that can be topically administered. There is also a high level of unmet need for safer systemic therapies and effective drugs against itch. Recent advances in immunology and increased understanding of the basic pathophysiology as well as the advent of the genetic engineering techniques led to the development of a new group of drugs referred to as biologicals, which are proteins against cell surface markers, cytokines and adhesion molecules. Currently, biologicals are available for psoriasis, another inflammatory skin disease and these available agents target either T cells or antigen-presenting cells or block the inflammatory action of cytokines. The efficacy of biologicals in AE needs to be investigated. Furthermore, cytokines or chemokines play a critical role in perpetuating inflammation in atopic skin. Several specific cytokine and chemokine inhibitors are in development for the treatment of asthma, another atopic disease with similar pathogenesis, and these medications may be effective in the treatment of AE as well.



Systemic therapy or UV therapy en

sit y

Recalcitrant severe AD

Step 3

Mid/high potency TCS and/or TCI

Di se a

se

in t

Moderate/severe AD

Mild/moderate AD


Dry skin

Low/mid potency TCS and/or TCI

Step 2

Step 1

Basic treatment: Skin hydrate, emollients, avoid irritant, identify and address the trigger

Figure 1. Stepwise management of patients with AD suggested by Akdis et al. [41]. AD: Atopic dermatitis; CyA: Ccyclosporine A; TCI: Topical calcineurin inhibitors; TCS: Topical corticosteroids.

Despite recognition that AE is a major public health concern, many treatment modalities are not based on evidence. The chronic course of AE and the lack of cure by specific medications led to the treatment modalities with dubious efficacy. Thus, guidelines were developed for the diagnosis and treatment of AE based on literature review and repeated consenting group discussions [39,40]. Although there have been therapeutic advances in the past decades, representative, randomized, placebo-controlled studies evaluating the efficacy and safety of different treatment modalities are not available for many therapeutic strategies, especially the basic application, and this needs to be addressed in future studies.

3.

Existing treatment

The treatment of AE requires a complex approach. Primarily, irritants and specific immunologic stimuli such as environmental allergen, such as food or inhalants, have to be identified and need to be avoided as they are known to induce or trigger eczematous lesion. Irritant factors such as chemicals or physical agents may also complicate the disease and have to be avoided. Psychosomatic counseling may help to cope with stress. Typical step-wise treatments for AE are shown in Figure 1 [41].

3.1

Topical treatment of AE Emollient therapy

3.1.1

Hydration of the skin is a key part of the management and helps to improve the dryness, the pruritus and restore the disturbed skin barrier. Evidence-based proofs for the use of emollients, however, are limited, but clinical experience as well as a few randomized controlled trials showed that adjunctive emollient therapy may reduce the need for treatment and related side effects and may lead to reduction of steroid therapy [39,40].

3.1.2

Anti-inflammatory therapy Topical corticosteroids

3.1.2.1

Topical steroids are the mainstay in treating acute flares of AE. In 1953, Sulzberger et al. reported about successful treatment of eczematous lesions with topical hydrocortisone, leading to widespread use and modification of the basic molecular structure of hydrocortisone with development of more potent topical compounds. Widespread use of these more potent steroids with excellent short-term efficacy, however, led to the knowledge of the disadvantage of adverse effects including skin atrophy, striae, telangiectasia, acneiform eruptions and the risk of absorption, with potential systemic effects in long-term use or in widespread application. However, topical steroids are first-line anti-inflammatory treatment, provide rapid relief and are used for short periods (5 -- 7 days) to settle eczema flare ups. Unfounded steroid phobia is a major problem and leads to suboptimal treatment of eczematous lesions in some cases. However, used for prolonged periods, topical glucocorticoids can cause side effects such as skin atrophy including increased tendency to develop tachyphylaxis and rebound flares following discontinuation of therapy [42]. Therefore, topical steroids should be used with care especially in areas with thin skin, such as the periorbital or the genital region, and in children. Nonfluorinated steroids are normally less potent and show less adverse effects. Nonfluorinated steroids, such as hydrocortisone valerate, hydrocortisone probutate, mometasone fuorate are less prone to provoke local or systemic side effects in long-term application. Therefore, nonfluorinated corticosteroids are used more often in patients with chronic disease and for children. However, there are reports that nonfluorinated corticosteroids are more likely to induce contact allergy than fluorinated ones. Fluorinated steroids, such as dexamethasone, triamcinolone, fluocortolone, flumethasone, betamethasone valerate or dipropionate are those steroids, which are substituted with one or more fluorine atoms in any position to enhance the efficacy. The term ‘topical fluorinated steroid’ is frequently used as a synonym for a potent steroid. In recalcitrant


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eczematous lesions, absorption and efficacy of topical steroids can be increased by occlusive therapy or wet wraps [43]. Although acting immunosuppressive, it should be noted that even in long-term, topical use of steroids, no increased risk of either lymphoma or sun-induced skin cancer has been reported. Topical steroids bind to an intracellular glucocorticoid receptor (GCR) that forms a complex (corticosteroid/GCR complex) upon ligand binding and affecting a wide variety of cells. Upon ligand binding, the corticosteroid/GCR complex translocates into the nucleus inducing gene transcription by binding of GCR dimers to glucocorticoid response elements in the promoter regions of target cells. This process, known as transactivation, is responsible for many side effects of glucocorticoids. The second major action of the GCR is the ligand binding to various transcription factors, a process called transrepression, which is independent of GCR-DNA binding. In this process, ligand-bound GCR binds to various transcription factor, such as NF-kB, and activator protein-1 mediated by protein--protein interactions inhibiting the transcriptional activity of various genes encoding proinflammatory proteins such as cytokines (IL-1, IL-2-IL-3, IL-4, IL-5, IL-6, IL-11, IL-13, TNF-a and GM-CSF), chemokines (IL-8, RANTES, macrophage inflammatory protein 1a, MCP-1, MCP-3, MCP-4 and eotaxin) and adhesion proteins (intercellular adhesion molecule 1, vascular cell adhesion molecule -1[VCAM-1] and E-selectin). On the cellular level, further studies demonstrated that topical corticosteroids reduce viability and function of LC and DC of skin and lymph nodes, contributing to a reduction in TH1-promoting cytokines. In in vitro studies of mononuclear cells obtained from healthy volunteers, corticosteroids have been shown to cause apoptosis of monocyte-derived DC precursors and inhibit expression of DC-specific antigens such as CD83 and CD86 and the ability of CD to activate primary CD4+ T-cell proliferation [44] and have an adverse effect on IL-12 expression on LC/DC. Wet wraps Application of damp tubular elasticized bandages and occlusive dressing to the limbs at night promotes skin hydration and the absorption of emollients and topical corticosteroids. These wet wraps are effective in severe childhood eczema with exudates. First, steroid ointment with plenty of moisturizing emollients are applied on acute flares; over that the inner layer of a tubular bandage is applied on the affected limb, the second outer layer is applied dry. 3.1.2.2

Topical calcineurin inhibitors Topical tacrolimus and pimecrolimus are approved for the treatment of AE in the EU from 2 years of age onwards [45]. Many placebo-controlled clinical trials for short-term and long-term use [45,46] have shown both topicals to be effective. In contrast to topical pimecrolimus cream and tacrolimus ointment, systemically administered tacrolimus and 3.1.2.3

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cyclosporine A have been shown to induce systemic immunosuppression, thus increasing the risk of malignancies and UV-light induced cancers in patient having undergone organ transplantation. Additionally, cases have been reported in which cancers have developed at sites of prolonged use of topical application or in draining lymph nodes. However, some of the reported cases of ‘recalcitrant’ eczema were in fact malignant disorders, such as Bowen disease, Paget disease or Parapsoriasis en plaque. Therefore, it has been recently recommended to biopsy ‘recalcitrant’ eczema prior to treatment with TCIs. All these findings prompted the US FDA to reconsider the risk/benefit profile of the topical use of calcineurin inhibitors and add a ‘black box warning’, as these agents were widely used in children with AE. However, a scientifically based, critical statement regarding that warning, authored by many leading European dermatologists, was published in 2005 [47], reporting that neither tacrolimus nor pimecrolimus have been associated with increased malignancy risk in clinical studies (FDA) and that there is no evidence of systemic immunosuppression. In years of usage in > 5 million patients using pimecrolimus cream and over 1.7 million patients using tacrolimus ointment, the safety of both of these treatments has been established. Moreover, many studies in adults and children [45-47] showed efficacy and safety in topical use. However, the increased photocarcinogenicity risk in solid organ transplant patients under medication with the oral calcineurin inhibitor cyclosporine and experimental data in immunodeficient hairless mice led to the recommendation of UV-protection, for example, with sunscreens in patients under topical anti-inflammatory therapy. In contrast to topical glucocorticoids, TCIs do not lead to skin atrophy and may therefore be used for the regions where low potency steroids are used due to fears of skin atrophy, such as the eyelid eczema, the perioral skin and the genital region. The clinical efficacy of TCIs are similar to topical steroids with more moderate activity and should be used in moderate-to-severe AE in case of no satisfactory response to conventional therapy. On the molecular level, both tacrolimus and pimecrolimus selectively inhibit the activation of T cells by inhibiting calcineurin through binding with high affinity to the 12-kDa macrophilin and inhibit the phosphatase activity of the calcium-dependent serine/threonine phosphatase, calcineurin. Calcineurin inhibits the dephosphorylation of the transcription factor and nuclear factor of activated T-cell protein. The inactive form of nuclear factor of activated T cells cannot enter the nucleus, and the activation of transcription of various TH1 and TH2 cytokine genes is inhibited. Pimecrolimus potently inhibited the proliferation of antigen-stimulated T cells and the production and release of inflammatory TH1 and TH2 cytokines. Moreover, it was shown that pimecrolimus inhibited the expression of the cell surface co-receptor CD134, which is increased in activated T cells and inhibits their apoptosis.




It was demonstrated that pimecrolimus, in contrast to steroids, does not suppress viability and function of LC in animals and humans [44]. These and other studies [48,49] led to the assumption that calcineurin inhibitors act more selectively on the skin immune system. In a recent study, which investigated the mRNA levels of various genes encoding markers of inflammation in betamethasone valerate versus pimecrolimus treated skin samples, minor reduction was found for pimecrolimus than for betamethasone valerate. However, betamethasone but not pimecrolimus reduced the expression of enzymes for lipid synthesis and proline-rich proteins, which contribute to restoration of the stratum corneum layers. This led to the conclusion that corticosteroids have a more potent anti-inflammatory effect but also impair skin barrier restoration [48,49]. 3.1.2.4 Topical anti-inflammatory therapy: reactive versus proactive treatment

Due to potential side effects following chronic use, topical corticosteroids are not used for maintenance therapy. The common traditional treatment concept for AE was based on use of anti-inflammatory agents for symptomatic skin on a ‘needed’ basis, and a long-term treatment with daily application of emollients with or without antibacterial ingredients. This so-called ‘reactive treatment’ was eventually combined with UV phototherapy and antihistamines. However, several studies demonstrated that normal appearing skin in AE patients is not normal. First of all, in eczematous lesions as well as in normal appearing, non-lesional skin epidermal dysfunctions could be detected. These findings confirmed that normal looking, nonlesional skin is characterized by a clinically meaningful, barrier-dysfunction defect, a subclinical inflammation, suggesting that maintenance anti-inflammatory treatment may be required to prevent relapses. Several studies using topical corticosteroids showed that long-term control can be maintained with twice weekly therapy. An alternative treatment approach, the so-called ‘proactive treatment’ [50,51] starts with an intensive topical anti-inflammatory therapy until clearance of lesions followed by long-term, low-dose, intermittent application of anti-inflammatory therapy, especially TCI, to the previously affected skin together with daily application of emollients to unaffected areas. Phototherapy Phototherapy is effective in treating refractory AE. This treatment may be administered as UVA, especially UVA-1, UVB or combined treatment. Psoralen administered topical by bathing followed by UVA treatment (PUVA photochemotherapy) may be a treatment option in patients with extensive refractory disease. Recent studies have underlined the efficacy of suberythemal UVB phototherapy in the treatment of AE, by defecting the permeability barrier and regulating the AMP expression [5254]. The beneficial effect of the low-dose UVB therapy seems 3.2

to depend on the activation of the cutaneous vitamin D system [52]. UVB phototherapy in appropriate physiological doses seems to protect from microbial infections by inducing the innate- and releasing cutaneous AMPs, but suppressing the adaptive immune system [54]. Tar preparations Tar has anti-inflammatory and antipruritic effects on the eczematous lesions. They were a mainstay of therapy in the past before introduction of topical steroids. The disadvantages of tars are their odor and dark staining color. Covering the treated areas can decrease these problems. Although used as a traditional therapy in the past, there are no controlled studies. However, used as an agent with the adequate vehicle such as lotio alba in acute lesions and creams in chronic lesions, their use may help reduce topical steroid treatment. Bituminosulfonates (e.g., ichthyol) do not have the carcinogenic risk of tars and are used as antipruritic and anti-inflammatory agents in chronic eczema lesions. 3.3

Antihistamines Therapy with systemic antihistamines is traditionally used in acute flares of AE. Although being used widely, there are only a few controlled studies [39]. Thereby, sedative H1 antihistamines such as hydroxyzine and diphenhydramine are considered to be more effective than recently developed less sedative antihistamines. Although a direct effect of newer non-sedating H1 receptor blockers on eczematous lesions could not be shown in the few controlled studies, the older sedative antihistamines are used to reduce pruritus and permit sleep in acute phases of the disease. An evidence-based review of the efficacy of antihistamines in relieving pruritus in AE revealed, that, although antihistamines are frequently used, little objective evidence exists to demonstrate their efficacy and the majority of trials are flawed in terms of the sample size or study design. Oral sedative antihistamines may provide benefit to patients who have poor sleep secondary to pruritus. Ongoing studies investigate the blockade of alternative histamine receptors, which may be important in AE [55-57]. 3.4

Antibacterial and antimycotic therapy Patients with AE are more prone to skin infections (bacterial, fungal and viral). Bacterial superinfections cause deterioration of the skin lesions with crusting, oozing and diffusive skin redness. However, patients with severe AE may improve but not be cured by antistaphylococcal treatment. Antibiotic eradication may therefore -- with regard to increasing prevalence of antibiotic resistance -- not always be an appropriate long-term strategy [56]. Topical antiseptics such as triclosan, chlorhexidine or crystal violet or antibiotic skin creams (e.g., fusidic acid), retapamulin and occasionally oral antibiotics are prescribed to treat acute flares with clinical signs of bacterial 3.5


7



impetiginization. The use of gentian violet as a topical agent led to improvement in S. aureus-colonized AE [58]. In summary, moderate eczematous flares with good response to topical steroids or calcineurin inhibitors should not be treated with additional antiseptic agents. Solely eczematous lesions with signs of superinfection such as oozing lesions or lesions with yellowish crusts represent an indication for topical antiseptic treatment. In our opinion, traditionally used colored solutions (eosin- or gentiana violet solution) are well tolerated even in children, do have good antiseptic and anti-inflammatory properties, do have no risk of development of antibiotic resistance and can be used for acute lesions with signs of superinfections. Due to risk of antibiotic resistance and due to potential risk of allergic sensitization, longterm use of systemic and topical antibiotics in AE is not recommended [56]. Other secondary infections such as Malassezia sympodialis superinfection have also been implicated as a further disease factor. Thus, ketoconazole and ciclopirox olamine are proposed for topical treatment of ‘head and neck’ AE. Systemic immunosuppressive therapy Most patients with AE respond to conventional therapies with topical emollient, topical corticosteroids, TCIs, systemic antihistamines and abstinence from potential trigger factors. However, in patients with severe manifestation of the disease in whom corticosteroid resistance contributes to treatment failure, therapy directed for correcting the immune function is suggested. Prednisone, cyclosporine or azathioprine may be used in these patients with widespread, incapacitating eczema, which is not responding to optimized topical therapy. 3.6

Systemic steroids Systemic steroids are controversial in the treatment of AE. In cases of severe, incapacitating eczema, systemic steroids may be used as a short-term solution to interrupt acute phases in adult patients. Due to side effects such as diabetes, skin atrophy, hypertension, osteoporosis, gastric ulcers and glaucoma, long-term use of systemic steroids is not recommended in AE. Systemic use of steroids should be restricted to cases of severe exacerbations of AE and should be avoided in preadolescents. Patients with AE often exhibit the rebound phenomenon with exacerbation of the eczematous lesions when systemic steroids are tapered or discontinued. 3.6.1

Cyclosporine A Cyclosporine A is a potent systemic calcineurin inhibitor and is the most established systemic immunosuppressant agent in patients with AE and widespread, severe, recalcitrant disease who has failed topical treatment. Analogous to the TCIs, pimecrolimus and tacrolimus, cyclosporine inhibits the activation of T cells by inhibiting calcineurin-dependent signal transduction. Patients need close monitoring (full blood count, renal function and blood pressure). A maximum course of 3.6.2

8

6 -- 9 months of cyclosporine treatment is recommended as toxicity, primarily renal, limits its chronic use. Rebound phenomenon may be seen if cyclosporine is tapered or discontinued. In restricted cases of severe AD and frequent exacerbations, long-term therapy with individually adjusted maintenance may be necessary. Due to concerns of development of skin cancer, phototherapy is not recommended during administration of systemic cyclosporine. Antimetabolites Methotrexate can be used to treat widespread but milder, recalcitrant disease; it is generally not effective for more severe cases. Mycophenolate mofetil, a purine biosynthesis inhibitor, has also been utilized for recalcitrant AE, although the potential for systemic toxicity restricts the use of antimetabolites and requires close monitoring. Mycophenolate mofetil may be used in AE in adult patients if therapy with cyclosporine is contraindicated. Mycophenolate mofetil (CellCept, Roche Pharmaceuticals) is a noncompetitive inhibitor of inosine monophosphate dehydrogenase and inhibits de novo purine synthesis. In a recent study, after inducing remission with high-dose cyclosporine, maintenance therapy with mycophenolate was effective as low-dose cyclosporine treatment of AD [59]. 3.6.3

Azathioprine Several open studies showed that azathioprine, which blocks the synthesis of RNA and DNA inhibiting the T- -and Bcell proliferation, is effective in moderate-to-severe AE [60]. A double-blinded, randomized controlled trial of 63 patients showed efficacy of azathioprine monotherapy in AE and pointed to therapeutic importance of the thiopurine methyltransferase (TPMT) polymorphism, a key determinant of azathioprine-induced myelotoxicity, by using TPMT enzyme activity [61]. Patients with homozygous or heterozygous TPMT mutations and low or absent TPMT activity often develop profound, myelotoxicity with azathioprine. Therefore, in the above-mentioned trial, patients with heterozygous range TPMT activity received azathioprine in a reduced dose. Azathioprine may be an effective treatment in AE, which is inadequately controlled by topical steroids and emollients. Gastrointestinal symptoms such as nausea, leukopenia and hypersensitivity may occur. Azathioprine may be used in AE if therapy with cyclosporine is contraindicated; however, limited possibility to examine TPMT polymorphism will restrict its use. 3.6.4

Current research goals and scientific rationale

4.

In the past decade, several key steps were described in the maintenance of a vicious circle of AE associated with deviated T lymphocyte and LC activation, effects leading to weakened TH1 immunity and IgE overproduction.




The understanding of the pathogenesis of AE has advanced during the past decades; however, the detailed mechanisms of AE still remain unknown. Attempts to understand the mechanisms through animal models have proven difficult. An important question is which factors primarily promote the disease in contrast to factors which act secondarily as a consequence of modification on the genetic, immunological and environmental levels. It is, furthermore, necessary to characterize the key immune pathways leading to AE. The role of allergens and microbes in the initiation and progression of AE also requires further classification. Genetic background AE is a clinically and genetically heterogenous disease. Atopy is a common finding in patients with AE and their families, which documents the genetic background in these diseases. AE is not a monogenic disease, but a complex disease with several genetic factors contributing to the pathophysiology. Efforts to define gene regions characteristic for AE or to predict severity and course of AE based on the genetic repertoire provided heterogeneous results and were complicated by the genetically complex constellation [62]. Genes predisposing to AE fall into two broad categories: there are skin-related genes that affect barrier function and further on, there are atopy-related genes that affect the tendency towards immune deviation in the direction of allergy. Polymorphisms in the filaggrin gene, an important protein that is essential to maintain the formation of stratum corneum barrier function, and changes in the gene for IL-4 and its receptor are all associated with AE [25,26]. Loss-of-function mutations in the filaggrin gene were found to be associated with AE and specific clinical features and subforms of AE were shown to be associated with these mutations [63]. In the context of a genetically determined disturbed skin barrier in AE, association with polymorphism in the SPINK5 gene, were described [64], although no association has been found in one study [65]. Knowledge of an individual’s risk alleles could be used to tailor therapy and to identify individuals at risk for progressive sensitization, allowing early intervention to improve barrier function. Epigenetic changes may explain why some individuals develop AE later in life, and the environment also plays a critical role. 4.1

Immune deviation TH0 cells are the naive T cells whose polarization occurs through the release of cytokines from the cells of the innate system such as macrophages, basophils, eosinophils, mast cells and natural killer cells. TH1 cells produce IL-1, IFN-g, which stimulate macrophages and cytotoxic T cells. TH2 cells produce lymphokines that stimulate B cells to proliferate and produce antibodies. These lymphokines are IL-4, IL-5, IL-6 and IL-13. The regulatory cell of a TH3 type (TREG) is now recognized to be important in regulating or switching 4.2

off the immune response by production of IL-10 or TGF-b [21]. Mediator substances and pro-inflammatory cytokines are important for the pathogenesis of AE. In particular, AE has been shown to be associated with increased TH2 (IL-4; IL-5, IL-13) cytokine production that causes activation of eosinophils and T cells and production of chemokines (e.g., eotaxin, RANTES, thymus- and activation-dependent chemokine [TARC]). Thus, selective inhibition of the inflammatory cascade has become possible with novel therapeutic approaches, which have been developed recently. Such approaches comprise treatment with recombinant anti-inflammatory cytokines, treatment with TH1-inducing cytokines, inhibitors of IgE and antagonists of pro-inflammatory cytokines (e.g., IL-4 and IL-5) and their receptors. These genes technologically prepared biological agents (‘biologicals’) present new therapeutic tools in the treatment of severe psoriasis and other inflammatory diseases such as rheumatoid arthritis and Crohn’s disease. A number of case reports and pilot studies with these available and approved medications have been published recently reporting about therapeutic trials in AE. However, to date representative, randomized, placebo-controlled studies evaluating the efficacy and safety in AE are still not available. Moreover, the clinical value of these novel therapeutic approaches in AE remains to be determined. In particular, long-term efficacy and safety of immunomodulatory therapy has to be studied in more detail. 5.

Competitive environment

Skin care There is limited evidence-based proof for the use of emollients in AE [39]. A lack of important stratum corneum intercellular lipids and an inadequate ratio between compounds (cholesterol, essential fatty acids, ceramides) as well as the newly described filaggrin defect enhance transepidermal water loss leading to epidermal microfissuring. Recent genetic studies point to the primary role of a defective barrier to water loss and microbial invasion which may provoke eczematous lesions in affected patient. These finding led to the rationale for barrier repair therapy [24]. With increasing evidence supporting the role of abnormal permeability barrier function [24-26], emphasis has been placed on restoring the physiologic barrier functions of AD by medications that claim to assist barrier repair (Table 1). In prestudies, addition of a ‘ceramide dominant’ emollient leads to clinical improvement and decreased transepidermal water loss as a result of improvement of the stratum corneum integrity. EpiCeram is a ceramide-dominant, triple-lipid barrier repair formulation based on optimization of barrier lipid composition that is so far yet available in the US. A recent randomized, controlled multi-centre trial in 121 patients with AD investigated its efficacy compared to fluticasone propionate 0.05% cream. The investigators described reduced disease severity and decreased pruritus 5.1


9


Table 1. Template competitive environment. Compound


Omalizumab Xolair Mepolizumab Nuvance Pitrakinra Infliximab Remicade Alefacept Ethanercept Enbrel Rituximab MabThera Rituxan Dupilumab

Company

Latest development

Genentech/Novartis

Approved (chronic idiopathic urticaria, asthma) Phase III Phase II (asthma) Phase II (asthma) Approved (psoriasis, morbus chron, rheumatoid arthritis) Approved (psoriasis)

GlaxoSmithKline Immunex Aerovance, Inc. Janssen Biotech, Inc. Biogen Dompe, Zug, Switzerland Wyeth Pharma

Approved (rheumatoid, arthritis, psoriasis) Approved (lymphoma, rheumatoid arthritis)

Roche (EU) Biogen/Idec/ Genentech (USA) Regeneron Pharmaceuticals, Inc./ Sanofi

Phase II (atopic dermatitis)

and concluded that this formulation could represent an effective primary or ancilllary therapy especially for pediatric patients with AD [66]. Also, adjuvant treatment with an emollient containing Npalmitoylethanolamine has proven to be beneficial (ATOPA study) [67]. MimyX, launched in the US, has also barrier repair claims. Physiogel AI cream contains the same ingredient (cannabinoid N-palmitoylethanolamine) and has been studied in an open-label trial [67], which demonstrated significant improvement in patients with AD. MAS063DP, also known as Zarzenda or Atopiclair is another hydrolipidic cream with barrier repair claims. It contains hyaluronic acid as well as Vitis vinifera (grapevine) extract with antioxidant and antiprotease activity. A randomized, vehicle-controlled study revealed efficacy of MAS6063DP in children and adults with AD [68].

Drug class/mechanism of action Anti-IgE mAb Anti-IL-5 mAb sIL-4R mAb Anti-IL-4 mAb Anti-TNF-a mAb Fusion protein lymphocyte function antigen -3 (CD58) and IgG1 sTNF-aR mAb Anti-CD20 mAb

Anti IL-4Ra mAb

house dust mites [69,70,72] and birch pollen [73]. In patients with AE allergic to birch pollen, who exhibited exacerbation during birch pollen season, specific immunotherapy with birch pollen extracts resulted in a significant improvement of skin symptoms as well as quality of life [73]. A recent systematic review and meta-analysis of randomized controlled trials on specific immunotherapy in patients with AE revealed a significant efficacy [74]. So far, recent studies showed that specific immunotherapy might lead to a significant improvement in clinical symptoms, combined with immunological changes [69,70,72-74]. In summary, further studies are warranted to evaluate the benefit of the different therapeutic modalities of specific immunotherapy and the immunological changes induced by specific immunotherapy in AE. Alitretinoin Alitretinoin, 9-cis retinoic acid, is an antagonist vitamin A derivate binding to retinoic acid receptors (RAR) and retinoid X receptor. Alitretinoin is an approved therapy not only for hyperkeratotic but also for atopic hand eczema and should be considered for cases with severe hand involvement not responding to topical corticosteroids and phototherapy. Extrapalmar AE lesions have been reported to improve due to therapy with allitretinoin in six patients with severe atopic hand eczema [75]. Due to teratogenic properties, treatment with alitretinoin is not indicated in pregnant women and treatment of woman in child-bearing age should be restricted and given under strict contraception. 5.3

5.2

Allergen-specific immunotherapy

Allergen immunotherapy is one of the oldest treatment form (the first ‘biological’) against sensitizations in allergeninduced asthma or allergic rhinoconjunctivitis. Subcutaneous immunotherapy with allergen extract adsorbates is currently the most widely used treatment modality worldwide. Either subcutaneous (SCIT) or sublingual (SLIT) immunotherapy, which is prescribed with increasing frequency, represent the only disease-modifying treatment modalities and the only causal therapy for allergic diseases apart from allergen avoidance. Mainly, allergen specific immunotherapy (ASIT) is applied for allergic rhinitis and asthma. In AE patients, aeroallergens are capable to provoke not only immediate allergic reactions but also delayed-type reactions and eczematous lesions [8]. In the past, ASIT has not been recommended due to concerns of lesion exacerbations or potential relapses of latent AE. However, reports and studies about the benefit of allergen immunotherapy in AE exist [69-73]. ASIT has been studied in patients sensitized to 10

Probiotics Rising evidence of AE in industrialized countries was explained by reduced exposure to immunostimulation by dirt in clean environment, reduced family size and reduced exposure to childhood infections and microbes, which play a crucial role in the maturation of the host immune system during the first 5.4




years of life. Clean and hygienic environment is supposed to lead to a skewed development of the immune system resulting in an abnormal response to various environmental allergens. Allergic responses may arise if there is absence of microbial exposure, while the immune system is still developing [76]. Therefore, one hypothesis is that feeding children with bacteria of healthy gut microflora could reduce incidence of atopy [77]. Some studies indicate that taking dietary supplement containing viable bacteria (probiotics) may help reduce the severity and extent of the disease [76,78]. It has been suggested that these viable microorganisms may modulate TLR receptors and the proteoglycan recognition proteins of enterocytes, leading to activation of DC and a TH1 response. Pediatric studies suggested that the probiotic use in children with AE results in the increase of IFN production and decrease of IgE- and antigen-induced TNF-a, IL-5 and IL-10 secretion. However, a recent study investigated the efficacy of Lactobacillus GG treatment during pregnancy revealed that prenatal probiotic supplementation did not reduce the risk of AE [79]. In summary, many studies showed significant clinical improvement in AE; however, studies have yielded inconsistent findings on the usefulness of the intake of probiotics in allergic diseases. There is rising evidence that modulating immune responses using nonpathogenic bacteria, which may even be topically administered, may be a promising treatment modality [33,8082] by activating pathways mediating tolerance such as TLR-2 signaling. Microbes on the skin and bacterial stimuli seem to have a key role in the balance of inflammation, and possible beneficial effects of nonpathogenic bacteria have been addressed in recent studies [80-82]. Topical application of probiotics and nonpathogenic bacterial compounds might be promising [80-82]. As the development of topical treatments other than topical steroids or topical treatments with antibiotic agents is a high unmet medical need, more studies are necessary to predict whether these bacterial compounds may be beneficial in preventing or treating AE. Intravenous immunoglobulins Intravenous immunoglobulins (IVIG) treatment has been shown to be beneficial in a few open studies, but evidence of effectiveness is still lacking [83,84]. In a study of six patients, IVIG therapy resulted in a clinical improvement. In a case series with children with AD, IVIG therapy resulted in a significant decrease in disease activity and therefore should be considered as a therapy in children refractory to systemic immunosuppressive therapy [84]. More studies will be important to refine the current knowledge base for potential use of IVIG. 5.5

have a role in the treatment of AE, but there are only single reports describing the successful use in the treatment of AE. In a study investigating the efficacy of montelukast against conventional therapy with topical steroids in 32 patients, therapy with montelukast resulted in decrease of SCORAD and serum levels of eosinophil cationic protein (ECP) [85]. In study of 2005, no effect of treatment with montelukast was observed [86]. Thus, with controversial study results, leukotriene inhibitors may be a potentially useful agent in severe AE. Larger studies need to be undertaken to more fully characterize the use of leukotriene inhibitors in the treatment of AE. Targeted immunomodulating therapies Most of the traditional therapies aim at clinical improvement without targeting the factors that primarily promote AE. Biologic agents hold the promise for a more targeted and less toxic approach to systemic therapy. A recent study reviewed publications reporting about the use of biologicals in the treatment of AE. These diverse biologicals were primarily approved for other diseases such as psoriasis. The safety of biologics in the treatment of AE was confirmed, as few side effects such as thrombocytopenia and no type-I immediate hypersensitivity reactions were reported. 5.7

Anti-IgE treatment Omalizumab, a humanized IgG1 monoclonal antibody recognizing human IgE in the same position as the high-affinity receptor Fc"RI, has been shown to be effective in treatment of severe allergic asthma and severe allergic rhinitis and thus has been approved to treat moderate-to-severe allergic asthma. Omalizumab produces significant and rapid reduction of serum IgE levels. In several studies and case reports, anti-IgE (omalizumab) therapy showed beneficial effects in patients with AE [87-89]. However, divergent results have been reported for its efficacy in patients with refractory AE, and a randomized, placebocontrolled study showed no clinical efficacy despite of decrease in serum IgE-levels, surface IgE and Fc"RI receptor cells on blood cells. In a recent study, AE patients with wild-type filaggrin status responded to omalizumab treatment [89]. Interestingly, in patient with severe AE, treatment with omalizumab combined with IVIG [90] or combined with rituximab [91] resulted in drastic clinical improvement. In summary, anti-IgE treatment may have a potential role in the treatment of AE, but studies to date have not been conclusive. However, the effect may to be determined and may depend on the target population. 5.7.1

Inhibition of T-cell responses TH2 cytokines play an important role in orchestrating and perpetuating the inflammatory response in AE, which suggests that blocking the release or the effects may be useful to diminish inflammation. 5.7.2

5.6

Leukotriene inhibitors

Leukotriene inhibitors are registered for the treatment of asthma. Because asthma and AE have a similar pathogenesis, leukotriene inhibitors such as montelukast or zafirlukast may


11



Approaches resulting in reduced T-cell activation used agents such as alefacept and efalizumab. Alefacept, a fusion protein of lymphocyte function antigen-3 (CD58) which inhibits costimulation and induces apoptosis of T cells, has been shown to be effective in patients with moderate-to-severe AE [92,93]. Ten patients with moderate-to-severe AE have been treated in an open-label pilot study with 12 weekly intramuscular injections. The study revealed clinical improvement in all 10 patients and decreased numbers of skin T cells as well as reduced T-cell activations with therapy [92]. Inhibition of pro-inflammatory cytokines Common drugs that inhibit cytokine synthesis are glucocorticoids, cyclosporine A and tacrolimus. Pro-inflammatory cytokines, particularly IL-1b and TNF-a may amplify inflammatory response in atopic diseases by amplifying inflammation through the activation of NF-kB and other transcription factors. These findings suggested that blocking pro-inflammatory cytokines could have beneficial effects, particularly in severe AE. 5.7.3

TNF-a-blocking agents TNF-a-blocking agents have been used in rheumatology primarily in the treatment of rheumatoid arthritis and in the treatment of psoriasis, and these agents have been extensively studied in the above-mentioned diseases. In a preliminary study of nine patients with moderate or severe AE, therapy with infliximab (anti-TNF-a monoclonal antibody) significantly improved all clinical parameters, but this improvement was not sustained through maintenance therapy [94]. Severe exacerbation of AE following anti-TNF-a treatment was observed [95]. Thus, treatment of AE with anti-TNF-a has not been recommended [56]. 5.7.3.1

Anti-IL-4 strategies, soluble IL-4 Anti-IL-4 plays an important role in the synthesis of IgE by Blymphocytes. IL-4 promotes differentiation of TH2 cells and therefore mediates important pro-inflammatory functions in atopic disorders such as induction of the IgE isotype switch, expression of VCAM1, promotion of eosinophil transmigration across endothelium, and differentiation of TH2 lymphocytes leading to cytokine release as a critical site in atopic disorders. A key function of IL-4 is the induction of ‘master switch’ transcription factor GATA3 leading to TH2 differentiation and inhibiting the induction of regulatory T cells [96]. Thus, IL-4 has been identified as a potential target for allergic diseases. In atopic diseases, another therapeutic approach is to inhibit IL-4R with a mutated form of IL-4, which binds and blocks to the IL-4Raa and IL-13Ra, consecutively inhibiting both IL-4Ra and IL-13Ra1, as these two closely related cytokines signal through a shared surface receptor, IL-4Ra [97]. Also, endogenous inhibitors of STATS, suppressor of cytokine signaling -1 are potent inhibitors of the IL-4 signaling pathway and offer novel therapeutic approaches [97]. 5.7.3.2

12

In a placebo-controlled trial, efficacy of soluble treatment of asthma was described [98]. Thereby, nebulized administration of rhuIL-4R once weekly (NuvanceTM, Immunex) resulted in a clinical improvement of asthma. Another humanized anti-IL-4 antibody, Pitrakinra (SB240683, Pascolizumab, BAY16-9996), a recombinant IL-4 variant that binds IL-4Ra receptor inhibiting the binding of both IL-4 and IL-13, administered subcutaneously or via nebulizer showed clinical efficacy in trials in asthmatic patients [99]. In a recent study, dupilumab (REGN668/SAR2318939), a human monoclonal antibody IL-4Ra-chain agent blocking the IL-4/IL-13 signaling pathway, was evaluated in a clinical trial in 18 patients with severe AE [100]. In this study, dupilumab was well tolerated and demonstrated clinical efficacy besides disease suppression on the molecular level inhibiting the expression of genes related to T- and DC and TH2-inducing chemokines [100]. In a further Phase Ib study with 37 patients with moderate-to-severe AD treated with dupilumab, Hamilton et al. found clinical efficacy parallel to decrease of serum TARC-levels as well as serum IgE [101]. Yosipovitch et al. reported recently reported of improvement in AD itch investigating the clinical efficacy of dupilumab in a double-blind, placebo-controlled trials including 37 patients with AD [102]. The authors concluded that the observed improvement of pruritus support IL-4/IL-13 signaling pathway as a key mechanism in atopic itch. [102]. Most recently, a 12-week European controlled study revealed marked improvement with dupilumab monotherapy in adults with moderate-to-severe AD (Bieber T, Annual Meeting of the AAAAI, 4.3.2014, Sang Diego, presentation). However, all these results have been demonstrated recently as oral- or poster presentation, so far only abstracts are published yet [100-102]. To date, these limited clinical studies with IL-4-blocking agents indicate clinical efficacy in AE; however, further investigations in larger patient populations are necessary. The fact that in asthmatic patients nebulized preparations have been used leads us to the suggestion that these agents should be also developed and investigated for their efficacy in topical administration. Anti-IL-5 TH2-cells to produce IL-5, a cytokine which accounts for eosinophilia, as eosinophil development from hematopoietic progenitors is regulated mainly by IL-5 which in turn has a selective role in eosinophil maturation, differentiation, mobilization, activation and survival. Eosinophils are important effector cells in atopic diseases and deposition of their toxic granule proteins (eosinophil degranulation) such as ECP are assumed to be an important process in mediating the tissue damage in this disease. ECP serum levels are highly elevated in patients with AE. Anti-IL-5 is a drug that is effective in patients but is not yet approved by FDA. Mepolizumab is a fully humanized, antiIL-5 monoclonal immunoglobulin antibody (IgG1-k, mAb) 5.7.3.3




and blocks binding of human IL-5 to the a chain of the IL-5 receptor complex expressed on the eosinophil cell surface. In preliminary studies of patients with hypereosinophilic dermatitis and AD, mepolizumab had few side effects and lowered blood eosinophil levels [103,104] but had moderate clinical effect in patients with AE in a short-term study with two infusions per patient [104]. Unfortunately, a long-term study has not been performed with anti-IL-5 antibodies after these promising results. Subsequent studies suggested that mepolizumab may have substantial clinical value in patients with the hypereosinophilic syndrome [105]. These initial reports led to an international multi-centre study, which showed that treatment with mepolizumab can result in corticoid-sparing for patients with the lymphocytic variant of hypereosinophilic syndrome [105]. It had been shown to be effective in lowering eosinophils and steroid doses as well as being well tolerated. Anti-CD20 The depletion of B cells by rituximab, a monoclonal antiCD20 antibody, which so far has been used for therapy of hematologic disorders, resulted in a rapid and sustained decrease of skin inflammation in AE patients, suggesting an important role of B cells in the pathogenesis of AE [106]. Although IgE levels remained mainly unchanged, antiCD20 treatment led to improvement of the skin lesions, implying that B cells play an important role in AE [106]. 5.7.3.4

6.

Potential development issues

Antiproteases There is evidence for an imbalance between proteases and antiproteases in impaired skin in AE. Polymorphonuclear and also eosinophil leukocytes are present in inflamed atopic skin and contain well-defined proteolytic enzymes in their granules. These can be released into tissues, producing a localized excess of proteases that causes a protease-antiprotease imbalance with subsequent tissue destruction. This suggests that either inhibiting proteolytic enzymes or increasing the levels of antiproteases may be beneficial and theoretically should prevent the progression of the inflammatory response in AE. At present, for the treatment for asthma, nebulized inhibitors are in clinical development, and further work in this area is indicated to clarify any potential benefit either with systemic or topical use for patients with AE. 6.3

Inhibition of histamine receptors Antihistamines have been widely applied in the treatment of atopic disease such as allergic rhinitis. Its effect in AE has been described as poor [39]. In a murine mouse model, histamine receptor-1 (H1R) combined with histamine receptor-4 (H4R) improved clinical scores and cytokine levels in the skin [55]. Therefore, blocking H1R and H4R might serve as potential therapeutic target [56] and may inhibit pruritus and skin inflammation. 6.1

Inhibition of chemokines Many chemokines are involved in the recruitment of inflammatory cells in atopic diseases. Chemokines play an important role in orchestrating recruitment of leukocytes in inflammatory diseases [23] and therefore may represent a possible important target for anti-inflammatory therapies. Chemokines are important recruiters and activators of inflammatory cells, and these infiltrating cells interact with resident cells, such as keratinocytes and fibroblasts, and may exert multiple biological actions through these pathways. Over 50 chemokines are recognized so far activating > 20 different surface receptors. Chemokine receptors belong to the seven transmembrane receptor superfamilies of G-protein-coupled receptors. Some chemokines are selective for single chemokine receptors, whereas others are promiscuous and 6.2

mediate the effects of several related chemokines. Chemokine receptors are assumed as possible therapeutic targets for inflammatory diseases such as asthma or AE. CCR4 are selectively expressed on TH2 cells and are activated by two chemokines: monocyte-derived chemokine (MDC) and TARC. These chemokines are increased in affected skin as well as in serum of patients with AE, and levels of TARC were proposed as suitable markers of disease activity of generalized AE patients. TARC/CCL17 is an important chemotactic factor for the migration of T cells into the epidermis [107]. Therefore, it has been suggested that small molecule antagonists against CCR4 may prevent the migration of pathologically relevant skin-homing CLA plus memory T cells to the inflammatory cutaneous site. The chemokine system is complex and about 50 ligands and 20 receptors are known so far, making a selection of appropriate specific antagonists difficult. Thus, another approach may be the development of broad-spectrum chemokine inhibitors (BSCIs). The BSCI was investigated in a first human trial (Phase I trial, FX 125L) in 66 healthy volunteers and was tolerated well. Thus, BSCIs might be a novel approach to treat severe AE [108] or might even be developed for topical use in future. Clinical trials are underway with therapeutics targeting chemokine pathways in other inflammatory diseases. It is hoped that the information generated from these studies will contribute towards our knowledge and be applied towards targeting severe AE.

Selective glucocorticoid receptor agonists or dissociated glucocorticoids

6.4

Because of the numerous adverse effects that can be seen by using glucocorticoids, research focused on the development of improved glucocorticoids or GCR ligands. SEGRAs (selective glucocorticoid receptor agonists or dissociated glucocorticoids) could represent a novel future treatment option as recent studies have shown that SEGRAs compared to glucocorticoids have comparable anti-inflammatory and immunosuppressive effects but less adverse effects such as skin atrophy [109,110]. ZK


13


245186 (Mapracorat) was proven to be a potent antiinflammatory compound and has been investigated in clinical trials, but no results are available yet [111]. Anti-IL31 IL-31 is a cytokine that -- if overexpressed -- induced severe dermatitis in transgenic mice [112,113]. In patients who suffer from AE significantly higher serum levels of IL-31 could be detected compared to nonpruritic skin inflammation [112]. In human skin, IL-31 was mainly produced by CLA-positive T cells [113] and upregulated in patients with pruritic inflammatory diseases, especially in those with AE [114]. Further studies are required to investigate the role of IL-31 in AE and the role of IL-31 as a potential target for the treatment of eczema. Currently, a two par Phase I single-dose study of anti IL-31mAb (BMS-981164) in healthy subjects and adults with AE is recruiting patients [115].


6.5

7.

Expert opinion

To improve therapy in AE, we do not only need novel drugs for treatment, but also better guidelines that are followed more closely by the patient and the medical community. Guidelines for AE diagnosis and treatment based on literature review and repeated consenting group discussions have been established [39,40]. Finally, we have to work on the Issue of patient adherence. So far, corticosteroids are by far the most effective topical treatment for AE and part of their efficacy is due to inhibition of inflammatory cytokine expression. Tacrolimus and cyclosporine inhibit the transcription factor NF-kB that regulates the secretion of different cytokines such as IL-2, IL-4, IL-5 and GM-CSF by T lymphocytes. The toxicity of cyclosporine limits its usefulness, when given orally. Tacrolimus and pimecrolimus have been successfully developed for topical use, and their efficacy has been shown in many clinical trials. Traditional systemic agents used for the treatment of AE are associated with significant potential side effects and often do not provide adequate therapeutic responses. Further development of new immunomodulating agents even for topical use of eczematous lesions should be encouraged. Choice of topical formulation is another important issue that will have to be addressed. In spite of the need for systemic therapy, the overall demand for topical therapies will remain high. Despite multiple therapeutic modalities, treatment of AE with its chronic relapsing nature remains a challenge. Severe AE often cannot be adequately controlled with topical agents. Although remarkable therapeutic efforts have been achieved, patients suffering from the severe form of AE often remain refractory to topical treatment. The continuous use of current systemic therapies for AE is limited by end-organ toxicities. The systemic treatment options to date (cyclosporine A, systemic glucocorticoids, azathioprine and mycophenolate

14

mofetil) are limited in their applications and usually restricted to short-term use. Their use requires careful monitoring because of potential adverse effects (risk of myelosuppression, tumors and infections). Thus, novel therapeutic strategies with low side effect profiles are needed in the long-term treatment of these patients. Safe and effective topical and systemic therapy is greatly needed. Biologic agents may offer distinct advantages over conventional pharmacotherapy in the treatment of AE. Biological agents have an immunomodulatory effect such as allergen immunotherapy. In general, in AE patients, biological agents were studied in clinical trials that included relatively small patient populations. Further studies with a larger patient population are warranted. The immunologic pathways leading to atopic inflammation system are complex, making a selection of appropriate specific antagonists difficult. First trials with monoclonal antibodies against single cytokines have shown diverging results. As the immune pathways that lead to AE are complex, it is likely that too selective anti-inflammatory or immunomodulatory agents might have limited effects. Because so many cytokines are involved in orchestrating and perpetuating inflammation in AE, development of a drug that inhibits the synthesis of multiple TH2 cytokines or chemokines may be a promising strategy to treat patients with severe AE. Thus, an approach may be the development of broadspectrum cytokine inhibitors or combination of different monoclonal antibodies as shown in limited case [90,91]. Thus, these ‘broad spectrum’ biologicals might be a novel approach to treat severe atopic diseases and further immunomodulating agents might even be developed for topical use in future. Research into new drugs for the treatment for atopic diseases may lead to the development of drugs with novel mechanism of actions and a refinement of the use of current drugs through modification of the molecular structure, new galenic systems and new combinations. Drugs with such novel mechanism of action may provide a therapeutic profile not seen with current drugs. Another approach is to manipulate the molecular structure of an existing therapeutic class (e.g., in a way that may improve the benefit-risk ratio). New delivery systems for existing drugs should be investigated, with the hope of improving tolerability, patient acceptance and adherence to therapy. Closer work between clinical academics and industry will be necessary to ensure that there is a rapid transfer of knowledge. The development of more effective and safer drugs will be an important goal for the future.

Declaration of interest J Ring has received grants and or financial sponsorship from Novartis, Astellas, Meda, Galderma and Stiefel GlaxoSmithKline. The other authors declare no conflicts of interest.




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Affiliation Sabine G Pl€otz1, Markus Wiesender2, Antonia Todorova3 & Johannes Ring†4 † Author for correspondence 1 Professor, Dermatology Munich-Harlaching, Gru¨nwalderstrae 248, 81545 Munich, Germany 2 Dermatology Munich-Harlaching, Gru¨nwalderstrae 248, 81545 Munich, Germany 3 Technical University Munich, Department of Dermatology and Allergy am Biederstein (Head: Univ. Prof. Dr. med. Tilo Biedermann), Biedersteiner Str. 29, 80802 Mu¨nchen, Germany 4 Professor, Technical University Munich, Department of Dermatology and Allergy am Biederstein (Head: Univ. Prof. Dr. med. Tilo Biedermann), Biedersteiner Str. 29, 80802 Mu¨nchen, Germany Tel: +49 (89) 4140-3335; Fax: +49 (89) 4140-3503; E-mail: [email protected]

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