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Emerging Treatment of Atopic Dermatitis

Chih-Jung Hsu&Li-Fang Wang

Published online: 13 July 2007

# Humana Press Inc. 2007

Abstract Atopic dermatitis is a chronically relapsing eczematous disease of the skin. A wide range of therapeutic regimens has been used for atopic dermatitis. A better understanding of its pathogenesis will also lead to the development of novel approaches to treating this disease. This article reviews the recent advances in allergen-specific sublingual immunotherapy and therapy with antileukotriene drugs, probiotics, mycophenolate mofetil, leflunomide, and intermittent fluticasone propionate ointment, which the authors expect will be clinically useful therapies in the near future.

Keywords Atopic dermatitis . Sublingual immunotherapy . Probiotic . Leukotriene antagonists . Mycophenolate mofetil . Leflunomide . Fluticasone propionate Abbreviations

AD Atopic dermatitis LTs Leukotrienes

MMF Mycophenolate mofetil

SLIT Allergen-specific sublingual immunotherapy FP Fluticasone propionate

Introduction

Atopic dermatitis (AD) is a chronically relapsing eczem-atous disease that occurs in persons of all ages but is more common in children. AD has been reported to affect more

than 10% of children in most countries [1]. The disease is characterized by intense pruritus and a course marked by exacerbation and remissions. The pathogenesis of AD is complex and mostly obscure, involving epidermal barrier defect, genetic predisposition, and immunological dys-function [2]. Although skin hydration, irritant avoidance, antihistamine, topical corticosteroids, phototherapy, and im-munosuppressive agents are the mainstays of therapy, AD is usually poorly responsive or refractory to them. Thus, new therapies with good efficacy, safety, and tolerability are continually being sought. This review article is not intended to be a comprehensive survey of the reported literature about new AD treatments. Nevertheless, among the clinical trials presented, some are not double-blind, randomized in design and, therefore, are of less scientific merit. Our purpose is to select those emerging strategies that we expect will help AD patients in the near future.

Leukotriene Antagonists

The leukotrienes (LTs) are products of the arachidonic acid metabolism by way of the 5-lipoxygenase pathway. LTs are divided into two groups according to their chemical structure: those that have a sulfur linkage (cysteinyl LTs: LTC4, LTD4 LTE4), and those that do not (LTB4) [3]. Eosinophils, basophils, and mast cells are the most important sources of LTs. It has long been known that cysteinyl LTs contribute to airway smooth muscle constric-tion, eosinophil migraconstric-tion, vascular permeability, and edema in the pathogenesis of asthma [4]. Thus, research programs aimed to identify substances that could inhibit the action or synthesis of LTs have been ongoing since the 1980s. In the late 1990s, three chemically distinct cysteinyl LT-receptor antagonists (montelukast, pranlukast, and zafir-C.-J. Hsu

:

L.-F. Wang (*)

Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan, Republic of China e-mail: lifangwa@ha.mc.ntu.edu.tw

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lukast) became available for the treatment of asthma [5]. Many studies have demonstrated the efficacy and tolerabil-ity of these novel drugs as therapeutic agents for asthma. There are two rationales for using these drugs to treat AD. First, their use for asthma has led to the observation of favorable outcomes in cases with concomitant AD. Second, LTs have been implicated in the pathogenesis of AD [6]. In 1998, one pilot study from the US reported that the LT antagonist zafirlukast successfully alleviated symptoms of AD [7]. Thereafter, four groups from the US, Italy, and Hong Kong reported that montelukast is an effective adjuvant treatment for AD [8–11]. Recently, Hon et al. reported that montelukast at doses recommended for asthma treatment reduces disease severity and increases soluble CD14 levels in children with AD [12]. Another inhibitor of LT synthesis, zileuton blocks both cysteinyl LTs and LTB4 (the latter directing T cell migration and recruitment to allergic sites [13]). Woodmansee and Simon published the only report to describe the effect of zileuton in AD. In their pilot study, zileuton significantly improved the symptoms and objective skin findings seen in AD [14]. Although most studies showed favorable effects of LT antagonists in AD, the study of Silverberg and Paller found that LT receptor antagonists are ineffective for severe AD [15]. Thus, more trials and studies are needed to determine the role of LTs in the pathogenesis of AD and to confirm the efficacy and tolerability of LT receptor inhibitors, as well as to determine the optimal timing and dosing for their treatment of AD.

Probiotics

The“hygiene hypothesis” proposed by Strachan suggested that the increase in prevalence of atopic disease noted in the last several decades is related to reduced exposure to microbes [16]. Immune responses in neonates are dominat-ed by Th2 cytokines and require the stimulation from various microorganisms in the environment to shift to Th1-based immune responses. One important source of stimu-lation is gastrointestinal microflora. The gastrointestinal tract of the newborn is sterile at birth, but throughout the first year of life, it is colonized by many microorganisms. These resident microflora are involved in the activation of innate and adaptive immunity. Their essential roles in the development of appropriate immunity were repeatedly demonstrated by studies in germ-free animals, which have diminished intestinal lymphocytes and poor immunoglob-ulin diversity [17]. Thus, several studies have hypothesized and confirmed that allergic disease in children may be associated with differences in their intestinal microflora. Bjorksten’s study showed that allergic children were less often colonized with lactobacilli and harbored higher counts of coliforms and Staphylococcus aureus [18]. Kirjavainen

et al. assessed the fecal microflora of healthy infants and infants with AD during breast-feeding and after weaning and showed that atopic infants had lower counts of Gram-positive species and bifidobacteria and higher counts of bacteroides [19]. Kalliomäki et al., via analysis of the bacterial cellular fatty acid profile of stool samples, demonstrated that difference in neonatal gut microflora precedes development of atopy [20].

Probiotics are microbial cell preparations or components of microbial cells that have a beneficial effect on the health and well-being of the host. Lactic acid bacteria, in particular specific lactobacilli and bifidobacterium species, are widely used because they can resist gastric acid and enzymes, adhere to colonic mucosa, and colonize the intes-tinal tract easily. Although the exact mechanism of action of probiotics is still unknown and nowadays under intensive investigation, probiotics are believed to restore intestinal permeability, microecology, and immunological barrier function, and to downregulate proinflammatory cytokines [21]. In clinical trials to date, probiotics appear to be useful for the treatment of AD and even in primary prevention of atopy. In 1997, Majamaa et al. from Finland reported that the clinical score of AD improved significantly during the 1-month study period in infants treated with extensively hydrolyzed whey formula fortified withLactobacillus GG, but not in those treated with the same formula without Lactobacillus GG [22]. In 2000, Isolauri et al. reported a similar favorable result when probiotic-supplemented formulas were given to infants for 2 months [23]. In 2003, a group from Denmark reported a double-blind, placebo-controlled, crossover study of probiotics given to 1- to 13-year-old children with AD for 6 weeks. After active treatment, more patients experienced improvement of their eczema in the probiotic group than in the placebo group, although the total SCORAD index did not change significantly [24]. Very recently, Weston’s study showed that supplementation with probiotics is beneficial in improving the extent and severity of AD in young children with moderate or severe disease [25]. By contrast, Viljanen reported no difference between the probiotics group (given probiotics concomitant with elimination diet and skin treatment) and placebo group [26] of a randomized double-blind study in infants with suspected cow’s milk allergy (CMA). Most importantly, Kalliomäki assessed the effect of probiotics on atopic disease by giving Lactobacil-lus GG parenterally to mothers (who had at least one first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma) and to their infants postnatally for 6 months. Follow-up of these children at the ages of 2 and 4 years both showed that the frequency of atopic eczema in the probiotic group was only half that of the placebo group [27,28]. Hence, probiotics are effective in preventing early atopic disease in children at high risk, and the preventive

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effect extends beyond infancy. With regard to cytokine profiles after probiotic treatment, data are limited and conflicting. Pessi et al. reported that serum IL-10 level was elevated after treatment, whereas serum IL-6, IL-12, IFN-γ, and TNF-α levels were low and remained compa-rable throughout the study period [29]. In contrast, Pohjavuori et al. reported that secretion of IFN-γ by peripheral blood mononuclear cells before the treatment was significantly lower in infants with CMA than in non-CMA infants. Among the infants who received probiotic, the level of secreted IFN-γ increased when compared with the placebo group [30]. Collectively, evidence supports that probiotics may be an important complementary approach in the treatment and prevention of AD.

Allergen-Specific Sublingual Immunotherapy

Allergen-specific immunotherapy is the practice of admin-istering increasing amounts of allergens to allergic individ-uals to hyposensitize and reduce the symptoms stemming from natural exposure to the allergen. Although subcutane-ous immunotherapy (SCIT) is common, other routes of administration (oral, nasal, sublingual, or bronchial routes) have been evaluated [31]. The nasal and bronchial routes have been gradually abandoned because of local side effects, and the oral route is less favored because the dose required is large and more likely to induce gastrointestinal side effects [32]. In contrast, allergen-specific sublingual immunotherapy (SLIT) was proven to be an effective treatment for respiratory allergy in a great number of trials [33]. Therefore, SLIT is presently the most widely used noninjection immunotherapy in Europe. Two important points are worth noting. The first is that SLIT (unlike SCIT) has an extremely satisfactory tolerability and safety [34, 35]. The second is that its effect is long-lasting, as demonstrated recently by Rienzo et al. [36]. There are only a few reports of SLIT of AD. In the 1990s, there were two studies [37]. One showed significant skin lesion improve-ment in 64.4% of SLIT-treated patients with moderate-to-severe AD, and the other showed significant reduction in total IgE levels and symptoms in children with AD treated 2 years with SLIT. In 2000, Mastrandrea et al. reported that 3 years of SLIT resulted in complete disappearance of skin lesions at 6-year follow-up in 70% of 35 consecutive patients with mild to moderate AD [38]. In 2003, Bordignon et al. reported a decrease in skin reactivity after SLIT [39]. Double-blind, well-controlled studies will be required before SLIT can be accepted as a standard treat-ment of AD. However, because it is safe and potentially able to induce mucosal immunity to interfere with the systemic aspects of allergic inflammation, SLIT is regarded as a candidate treatment for AD.

Mycophenolate Mofetil and Leflunomide

Immunosuppressive agents, including glucocorticoid, aza-thioprine, and cyclosporine, are effective to treat severe AD. However, their usage is usually limited by a wide range of severe side effects [40]. Thus, new immuno-suppressive agents with an improved risk–benefit ratio are of great interest. Among them, mycophenolate mofetil (MMF) and leflunomide have attracted the most attention. MMF inhibits the enzyme inosine monophosphatase de-hydrogenase (IMPDH), which is a key enzyme in de novo purine biosynthesis. Moreover, MMF is a fivefold more potent inhibitor of the type II isoform of IMPDH, which is expressed in activated B and T cells, than of the type I isoform, which is expressed in most mammalian cells. Therefore, MMF function is a specific inhibitor of T and B lymphocyte activation and proliferation [41]. Several studies have examined the efficacy of MMF in the treat-ment of AD. In 1999, Grundmann-Kollmann et al. first reported successful treatment of severe refractory AD with a 2-month course of MMF [42]. The next year they reported that MMF was effective in 10 consecutive patients with moderate-to-severe AD nonresponsive to standard therapy [43]. No relapse of the disease was noted 20 weeks after the cessation of treatment. Then, Neuber et al. and Benez and Fierlbeck reported similar favorable results [44, 45]. However, Hansen et al. reported a negative result and Satchell and Barnetson reported that staphylococcal septi-cemia and endocarditic complicated the MMF treatment of AD [46,47].

Leflunomide inhibits the de novo synthesis of pyrimi-dine. Unlike other cells, activated lymphocytes expand their pyrimidine pool approximately eightfold during prolifera-tion. To meet this demand, lymphocytes must use both salvage and de novo synthesis pathways, and as a result, leflunomide inhibits autoimmune T-cell proliferation and B-cell antibody production. In contrast, other B-cells can maintain their basal homeostasis and meet cell division requirements for pyrimidine nucleotides through the use of salvage pathways for pyrimidine synthesis. Thus, other cells are not subject to leflunomide inhibition [41]. In 1999, one study showed that leflunomide inhibits murine IgE and immediate cutaneous hypersensitivity responses to ovalbu-min [48]. Till now, only one clinical report has evaluated the efficacy of leflunomide as long-term treatment of AD. They treated two patients with severe AD for 20 months with leflunomide and observed a significant improvement [49]. In summary, compared with most systemic immuno-suppressive agents, MMF and leflunomide seem to have more favorable risk–benefit ratios. These agents may prove to be especially beneficial for patients with hypertension, impaired renal function, or liver diseases that rule out the use of other immunotherapies.

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Intermittent Maintenance Treatment with Fluticasone Propionate

Whereas the efficacy and safety of topical corticosteroids in the treatment of active AD is well-documented, their use as maintenance treatment, which seeks to control symptoms without incurring side-effects, is just emerging. Compared with corticosteroids of similar potency, fluticasone propio-nate (FP) ointment is as effective in treating the acute symptoms of AD but has a more favorable safety profile. In 1999, Van Der Meer et al. reported that long-term treatment with FP ointment applied once daily, two times per week for 16 weeks to known healed lesions resulted in significant improvement of moderate-to-severe AD [50]. Later, Hanifin et al. reported that the risk of relapse of AD can be significantly reduced by extended intermittent dosing with FP cream [51]. Berth-Jones et al. did a randomized, double-blind, parallel group study and got similar favorable results [52]. Kirkup et al. performed a study in 2- to 14-year-old children with moderate-to-severe AD, comparing FP with hydrocortisone 1% cream and hydrocortisone butyrate 0.1% cream, and got significantly better results in the FP group in both the acute and maintenance phases [53]. Because topical steroid has been shown to be an effective treatment for autoimmune bullous disease and its effect on regulatory T cells is important in allergy, topical steroid is expected to have a role in maintenance treatment of AD [54,55].

Conclusions

Significant gains have been made in our understanding of AD, including discovery of factors controlling recruitment of effector T cells, the role of cytokines and chemokines, and the role of infection and regulatory genes. These discoveries will continuously provide new targets for AD prevention and treatment.

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