Abstract

1. Introduction

Atopic dermatitis (AD), also known as atopic eczema, is the most common chronic inflammatory skin disorder of childhood and is characterized by pruritus, dryness of skin, and scratching [1]. The disease presents with eczematous, itchy lesions that show distinct distribution in different pediatric age groups, and episodes of clinical exacerbation called flares or flare-ups [1]. AD affects 5%–20% of children [1], and the prevalence differs among geographical regions [2]. The disease usually occurs in early childhood; about 85% of cases are observed during the first 5 years of life [3], and the disease alleviates substantially by the age of 7 [4]. In a small percentage of patients, the disease may begin in adulthood [5]. In addition, AD may be the first manifestation of “atopic march”, which is characterized by development of asthma and allergic rhinitis at a later age [6].

AD is a multifactorial heterogeneous disorder that results from the interaction of genetic and epigenetic factors, environmental agents, immunological defects, and epithelial barrier dysfunction [7]. As understanding underlying disease mechanisms is critical for the development of effective treatment strategies, studies focusing on the pathogenesis of AD have increased in recent years [8]. This review focuses on the pathogenesis of the disease and recently discovered novel therapies, in addition to classical treatment methods.

2. Epidemiology

Although AD lesions were well described in antique texts [9], the disease was first described and named by Wise and Sulzberger in 1933 [10]. There are many studies on the frequency and pathogenesis of this common disease; however, the International Study of Asthma and Allergies in Childhood (ISAAC) can be considered the most comprehensive and largest study on AD. According to ISAAC, prevalence of AD varies considerably in different regions [11], and the frequency of childhood AD was reported to range from 0.2% to 24.6% worldwide [1]. Phase 3 of the ISAAC study [12] showed that AD occurs at a higher, relatively stable ratio in developed countries and urban areas, whereas the prevalence is steadily rising in developing countries. Likewise, Civelek et al. reported that the frequency of AD is lower in developing rather than developed Mediterranean countries. In the same study, risk factors and progression of AD also showed differences in developing Mediterranean countries [13]. Compared to ISAAC phase 1, the ISAAC phase 3 study showed stable or decreased AD frequency in developed countries [2], while low-income countries were surprisingly shown to have an increase in frequency. This increase has been attributed to changes in lifestyle [14], as the short time period between phases 1 and 3 would have been insufficient for the emergence of substantial genetic changes [15]. Therefore, it is believed that a modern lifestyle may have caused changes in daily practices, eating habits, and the perception of hygiene among people living in developing countries. The use of household cleaning products containing strong chemicals and increased frequency of soap, shampoo, and shower gel usage are among the factors believed to have contributed to the increased prevalence of AD in these countries [2].

3. Diagnosis and scoring systems for clinical assessment and severity

AD is diagnosed by clinical examination mainly based on morphological features and distribution of lesions; however, no laboratory or pathological findings specific to the disease have been discovered to date. Therefore, strict application of standard diagnosis criteria is important and even necessary to prevent misdiagnoses of atopic dermatitis in cases of other kinds of dermatitis. Until 1960, there were no criteria for the diagnosis of AD. In 1961 Georg Rajka established the first criteria, followed by Jon Hanifin, who published 13 features for the diagnosis of AD in 1977 [16]. After these initial efforts, Hanifin and Rajka proposed modified diagnostic criteria for AD in 1980 [17]. This modified set of criteria has been shown to have high sensitivity, up to 93% to 96% according to several studies [18,19], and this set of criteria has been used as a basis for later versions of AD diagnostic criteria [20]. According to the original Hanifin and Rajka criteria, a patient was diagnosed with AD when at least 3 of 4 major and at least 3 of 23 minor features were met [16]. However, the minor criteria were not practical to use in clinical practice [21]. The Hanifin and Rajka criteria were used by Kang and Tian (1987, China), Schultz Larsen (1992, Sweden), Japanese Dermatological Association (JDA) (in 1994), Danish Allergy Research Center (DARC) (in 2005), Korean Dermatological Association (KDA) (in 2006), and American Academia of Dermatology in 2003 [22]. Unfortunately, the Hanifin and Rajka criteria were deemed unsatisfactory for epidemiological surveys [20]. Therefore, the United Kingdom Working Party diagnostic criteria (UK criteria, in 1994) [23] and the ISAAC criteria (in 1995) [24] were used for epidemiological studies. Although the UK criteria were appropriate for clinical practice, they were not applicable for small children, especially infants. The ISAAC criteria have been utilized as the gold standard diagnostic criteria in global surveys for all childhood age groups since the 1990s [20,25].

Assessment of disease severity is particularly important in clinical practice when determining appropriate treatment for the patient, identifying the time of treatment cessation, and for epidemiological surveys. For this purpose, a comprehensive scoring system was published in 1993 based on a consensus by the European Task Force Group on Atopic Dermatitis (ETFAD), with participation of over 20 experts [26]. This scoring system was named SCORAD, an acronym for “SCORing Atopic Dermatitis” [26]. This scoring system comprises both objective (A. Extent: area involved according to the rule of nines; B. Intensity: erythema, edema/papules, scratching, crust formation, lichenification, and dryness) and subjective symptoms (C. Pruritus and loss of sleep) [26], and total score is calculated with the formula A / 5 + 7B / 2 + C [26]. The final score is extremely variable and is highly dependent on the physician’s examination. Consequently, an objective SCORAD which omits the subjective C criteria was put forth in 1997 [27]. Other than these scoring systems, a simplified score named Three-Item Severity (TIS) which evaluates erythema, edema, and excoriation [28], SASSAD (Six Area, Six Sign Atopic Dermatitis) that encompasses 6 signs (erythema, exudation, excoriation, dryness, cracking, and lichenification), each on a scale of 0 (absent), 1 (mild), 2 (moderate), or 3 (severe), at each of 6 sites (arms, hands, legs, feet, head and neck, and trunk) [29]; finally, the EASI (Eczema Area and Severity Index) has been developed [30]. Nevertheless, TIS is less sensitive than SCORAD [31]; SASSAD does not have the parameters of pruritus and loss of sleep and has disadvantages in calculation of an objective score; EASI scoring is a time-consuming and rather complex system [32]. Nowadays, objective SCORAD has been widely used and is considered the most accurate scoring system for AD [32].

AD may be confused with many other skin diseases, and differential diagnosis should be made with these disorders. Several diseases, including diseases causing immunodeficiency, may present with eczematous skin rash and could mimic AD. Seborrheic dermatitis, especially in infancy, dermatitis herpetiformis, irritant contact dermatitis, nummular dermatitis, and psoriasis are common inflammatory skin disorders that are often mistaken for AD [33,34]. Other skin conditions which may be ascribed to AD include allergic contact dermatitis, scabies, molluscum contagiosum, tinea corporis and capitis, mycosis fungoides, Langerhans cell histiocytosis, and pityriasis lichenoides chronica [35]. Additionally, a long list of immunodeficiency disorders, such as hyperimmunoglobulin E syndrome, Wiskott–Aldrich syndrome, Netherton syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX), severe combined immunodeficiency (SCID), and Omenn syndrome may be diagnosed in children who present with symptoms suggestive of AD [33,36].

4. Novelties in pathogenesis of atopic dermatitis

AD is a multifactorial and heterogeneous skin disorder resulting from genetic predisposition, environmental factors, skin barrier defects, and immunological abnormalities [8] (Figure 1). Elucidating the underlying pathogenesis and understanding the mechanism that causes itching are essential for determining the most effective treatment.

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Figure 1

Overview of the pathogenesis of atopic dermatitis [254].

5. New insights in the mechanism of pruritus

Cytokines and other chemical molecules that cause itching (pruritogens) are released from eczematous skin areas where they activate the relevant sensory nerves and cause pruritus; thus, the patient feels the need to scratch these areas [87]. Hyperesthesia in AD is due to aberrantly elongated sensory nerves in the upper layer of the skin which are increasingly exposed to environmental factors such as dryness, irritation, and chemicals [88]. Histamine, substance P, TSLP, and IL-31 act on these elongated nerve fibers, contributing to the itching sensation [89,90]. Heat is an important aggravating factor for itching in AD [91]. Artemin (enovin, neublastin) is a substance which has been shown to increase in AD lesions and is reported to cause itching, especially in warm temperatures [92].

Pruritus has detrimental effects on sleep and may reduce the length and quality of sleep, which leads to a decrease in melatonin levels. Decreased melatonin levels have been suggested to promote further itching [93]. Additionally, decreased cortisol level and increased inflammatory status due to elevated IL-2 levels are other factors that contribute to itching at night [93]. Sweating is another factor that exacerbates itching in AD, due to the normal effects of excess sweat on the skin and also the abnormal composition of sweat in patients with AD [94]. Conversely, keratinocyte debris may obstruct sweat glands and prevent normal sweating; this also leads to raised body temperature and could increase pruritus [95].

6. Genetic and epigenetic factors

Fillagrin mutation is the most important predisposing genetic change in AD. However, it is found in only 10%–50% in patients with AD, and in 9% of the healthy population [69]. Therefore, AD cannot be explained only by Fillagrin mutation. Genome-wide association studies (GWAS) have been initiated to elucidate the pathogenesis of AD. Many novel genes have been identified in patients with AD, especially after the first GWAS published by Esparza-Gordillo et al. in 2009 [96]. Genes responsible for the pathogenesis of AD are given in Table 1. TRAF6, RAG1, RAG2, SOCS1, NGFR, 4q27 IL2/IL21, 11p13 PRR5L, 16p13.13 CLEC16A/DEXI, and 17q21.32 ZNF652 are the novel genes that have been reported in GWAS studies on AD [97]. Additionally, several genetic polymorphisms have been found to be related to AD [98]. These include polymorphism of vitamin D pathway molecules [99] and polymorphisms of cytokines IL-4, IL-5, IL-9, IL-13, and IL-31, as well as their receptors [100]. Aside from genetic mutations, epigenetic mechanisms have been implicated in AD pathogenesis [101]. Epigenetic mechanisms regulate expression of genes without altering the DNA sequence [102]. These mechanisms are mainly DNA methylation, microRNA (miRNA), and histone tail modification [102]. It has been shown that epigenetics affect gene expression through environmental factors such as pollutants, tobacco smoke, aging, and diet [103]. DNA methylation differences between normal epidermis and AD epidermis have been shown in a study focusing on epigenetic factors [104,105]. miRNAs have fundamental roles in cell proliferation, differentiation, apoptosis, signal transduction, and organ development [106]. miRNAs are upregulated in the skin of patients with AD [107]. Children who were exposed to smoking during pregnancy have high miRNA-223 and low T regulatory (Treg) lymphocytes [108]. These children were found to have a higher tendency to develop AD during the first 3 years compared to children without exposure to smoking during pregnancy [108].

7. Current treatment of atopic dermatitis

7.1. Moisturizers and bathing

Treatment of AD is aimed at suppressing inflammation, eliminating identified triggers, reducing pruritus, and combating the development of xerosis, a major feature of AD [109,110] (Figure 2). For this purpose, conventional therapy is the first-line treatment approach. However, new therapeutic strategies and agents are continuously being developed with the help of advances in the understanding of AD pathophysiology. Basically, topical moisturizers are the mainstay of AD treatment, as they prevent dehydration, soften the skin, and increase water retention. Above all, they serve to minimize the need for pharmacological drugs for AD [110,111]. Moisturizers are the first line of therapy in mild AD and constitute an important and primary step in moderate and severe forms of AD [112]. Moisturizing the skin with different types of emollients, occlusive agents, and humectants decrease inflammation, pruritus, and xerosis, and also reduce the requirement for topical steroids and antibiotics [110]. There are many types of products in the form of ointments, lotions, creams, emollients, oils, and gels. Even though there are some differences with regards to their contents, the most important aspect of these moisturizers are to ensure that they are perfume- and fragrance-free and do not contain harsh chemicals [110]. In addition to moisturizers, daily bathing with warm water is an extremely important step for hydration of skin, as well as removing allergens, irritants, crusts, and bacteria [113]. Applying moisturizing agents immediately after bathing has been a fundamental approach for treatment in patients with AD [113]. Otherwise, bathing without moisturizing has a negative impact on AD.

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Figure 2

Treatment algorithm of atopic dermatitis in children [113,255,256].

8. Topical antiinflammatory therapy

Antiinflammatory therapy with topical calcineurin inhibitors (TCI), including tacrolimus and pimecrolimus, as well as topical corticosteroids (TCS), is reported to be the most effective approach in the treatment of acute flares [118]. Excessive inflammatory response in the skin is minimized by antiinflammatory treatment agents during flares [118]. Both TCS and TCI suppress T lymphocytes and inhibit proinflammatory cytokine release from immune cells [110,129]. Therefore, these agents are useful in controlling inflammation, pruritus, and skin eruptions [118].

9. Topical corticosteroids

TCSs are widely used; they are the first-line treatment for acute flares in AD [110,130]. They are indicated for eczematous lesions unresponsive to daily skin care and proper usage of emollients, creams, and ointments [116]. TCSs exhibit their effect by inhibition of T lymphocytes [110], thus reducing inflammation on the skin; they are also known to abate pruritus. In addition, topical corticosteroids are not only used for acute attacks but also for prevention of relapses [110].

TCSs are divided into 7 categories according to their potency [110]. Corticosteroids with higher potency should be applied for acute flares, whereas low potency corticosteroids are highly recommended for chronic long term usage [110,131]. The optimal suggested period of application is twice daily for 2 weeks, and only on affected surfaces of the skin for protection from local adverse effects of corticosteroids [116]. Many local side effects have been reported, including hypertrichosis, striae, telangiectasia, and skin atrophy for long term skin application, as well as glaucoma and cataract after use on the periorbital region [116]. Therefore, TCIs are recommended for thin skin surfaces such as eyelids and periorbital areas [132]. Studies have demonstrated that skin atrophy is extremely rare in children [133]. Systemic adverse effects, including the suppression of the hypothalamic–pituitary–adrenal (HPA) axis, have been reported after use of high potency topical corticosteroids in children [134]. Use of low to moderate potency topical corticosteroids for 3 to 4 weeks has been demonstrated to rarely affect the HPA axis [134]. Additionally, the possibility of growth retardation in children has been researched in many studies; however, results have mostly revealed only insignificant delays in growth [135].

10. Topical calcineurin inhibitors

Tacrolimus and pimecrolimus were approved for AD treatment in 2000 and 2001, respectively [136]; they are safe for use in adults and children over 2 years old [136]. TCIs are a product of the Streptomyces genus that inhibits calcineurin-dependent T-cell activation and proinflammatory cytokines. They exert their effects by inhibiting mast cells, dendritic cells, and T lymphocytes [137]. In studies, TCIs have been shown to be more effective than mild TCSs and as effective as moderate TCSs [111,138,139]. Therefore, TCIs are suggested for severe, TCS-unresponsive AD lesions, and also for sensitive areas such as eyelids and the face, and when concerned about steroid-related adverse effects [132,140]. However, erythema, burning, and itching sensations have been frequently reported with TCIs [141]. Additionally, many carcinogenic effects were reported during trials on animals [136]. Systemic absorption of TCI has been shown in patients with AD through the disrupted skin barrier and other skin areas [136]; therefore, side effects may be seen more frequently in pediatric age groups [136]. Pimecrolimus 1% and tacrolimus 0.03% are approved for children who are between 2 and 15 years old; 0.1% ointment of tacrolimus is not allowed for pediatric patients [110,136]. Both pimecrolimus and tacrolimus are contraindicated in acute viral skin infections, suspicion of skin malignancy, or immunodeficiency [136]. Although the exact relationship between malignancy and calcineurin inhibitors cannot be demonstrated, skin tumors and lymphoma have been reported [142]. Therefore, long-term use of these agents in all age groups should be avoided. In clinical trials, tacrolimus and pimecrolimus have been shown to be effective on moderate to severe and mild to moderate AD, respectively [143]. TCI should be used twice a day over 2 to 3 weeks, then should be reduced to once a day for 2 weeks [144]. At the beginning of the treatment, burning and itching are significant problems for patients and may reduce treatment compliance. Concomitant steroid therapy may overcome this issue [144]. Although safe for use and very effective, there is a risk for rebound after the cessation of therapy with TCIs; in the event of a rebound or flare-up, TCIs may be restarted twice a day again [144].

11. Systemic treatment

Systemic therapy for AD is considered when the skin lesions do not ameliorate after usage of topical treatments [145]

12. Other therapies

Extracorporeal photopheresis and intravenous immunoglobulin therapies have been applied to patients with AD [165,166]. There are limited data available about these methods, and results of studies which utilized these methods showed that they had little efficacy on AD.

13. Biological agents and new treatment strategies

14. Biological agents in trials

Biological agents are new therapeutic drugs targeting the molecules responsible in the pathogenesis of disease. Omalizumab, rituximab, interferon gamma, and mepolizumab have already been tried, while new agents that function by affecting the various stages of pathogenesis are under ongoing investigation. The primary agents among these new potential treatments are nemolizumab, ustekinumab, tralokinumab, lebrikizumab, antithymic stromal lymphopoietin receptor (TSLPR), and phosphodiesterase (PDE) inhibitors.

15. Burden of atopic dermatitis

AD mostly begins in childhood and may persist throughout adulthood [206]. Therefore, it may have both economic and psychosocial impacts on patients and their families [207]. Evaluation of quality of life (QoL), social, academic, and occupational impacts, and financial costs are important in capturing the whole picture when assessing the burden of AD. Patients with AD were shown to have lower overall QoL [208], especially in the form of mental health and social function [208]. A study by Solomon et al. showed that children with AD had severe sleep difficulties and were more dependent on their caregivers than patients with other chronic disorders [209]. Chamlin et al. also showed that these children were avoided by other people, causing social isolation [210]. Many studies have shown that sleep deprivation, isolation from social activities, and feelings of embarrassment due to itching and appearance of the eczematous lesions were the major problems faced by children with AD [211,212]. In a study performed on children and adults with AD, it was reported that 87.1% of patients had difficulties falling asleep, and 73.5% reported that severe itching was the cause for waking up [213].

AD also affects parents. The parents of children with AD also reported sleep disturbance [210] and stress [214], and were found to spend a significant amount of time on daily skin care [210] and hygiene [215]. Furthermore, the time spent by parents with the siblings of children with AD was also reported to be decreased [216], suggesting that AD has detrimental effects on the entire family. Lifestyle changes including modified dietary habits and usage of cleaning products and moisturizers for the skin in patients with AD were also shown to cause a substantial burden on the family budget [217]. Additionally, regular physician visits may cause loss of worktime for parents, while spending excessive time and effort on the care of a child with AD may also cause social isolation for the parents [217].

Assessing the exact financial burden of AD on the family budget and the health system is very difficult due to the indirect costs as well as direct expenditures. Additionally, the total costs of AD are also dependent on disease severity and may differ significantly from country to country [218]. Indirect costs include loss of labor and decrease in productivity at work [207]. Direct costs consist of pharmacy expenditures, follow-up visits, applications to emergency departments, and spending on special diet programs [207]. A striking result reported by Storan et al. indicated that 86% of the children admitted to their inpatient clinic were diagnosed with AD [219]. This study demonstrates the financial strain caused by AD on the health system. According to studies on economic costs of chronic diseases, AD was in fourth place among skin diseases [220]. In 2004, the annual cost of AD was 4.228 billion dollars in the United States [220], and had increased to approximately 5.297 billion dollars in 2015 [207]. Although indirect costs are not exactly estimated, the direct costs of AD have increased significantly over the years.

16. Future perspectives

The complexity of AD pathogenesis, the lack of a definitive treatment, and the fact that available therapies only provide transient well-being are among the factors that fuel the research for a cure for AD. Mainly due to this enthusiasm, experts have explored many novel molecules, mutations, and genes responsible for the disease. New treatment modalities are reported to be promising for the treatment of AD. However, it is also important to consider that current treatments (and the majority of proposed treatments) do not aim to prevent the development of atopic march. For this reason, researchers on this field concentrate not only on antiinflammatory drugs, but also on immunological and biological agents. With our knowledge today, it is evident that AD has a significant immunological background, and if the immunological dysregulation underlying the disease can be elucidated and targeted in treatment, success in AD treatment and prevention will be achieved. Pruritus is one of the most important problems of AD and suggested treatments must address this problem. Pruritus causes exhaustion, despair, and sleep deprivation in patients. Unfortunately, current drugs are insufficient for the control of pruritus. Therefore, development of antipruritic drugs with higher effectiveness should be regarded as high priority. The current therapeutic approach to AD, the advantages of treatments, and unmet needs are summarized in Table 2.

17. Conclusion

The aims of new therapies for AD are not only to procure a definite treatment but also to enhance the adherence of patients and parents to the therapy [221]. Other factors to consider as treatment goals in AD are the prevention of secondary infections, providing support to patients with psychological problems, and increasing the awareness of the population and physicians to a disease with severe consequences on the patient, family, and country.

References