Turkish Guideline for Atopic Dermatitis 2018

Review DOI: 10.6003/jtad.18122r1

Burhan Engin,1 MD, Emel Bülbül Başkan,2 MD, Murat Borlu,3 MD, Selda Pelin Kartal,4 MD, Başak Yalçın,5 MD, Savaş Yaylı,6 MD, Server Serdaroğlu,1 MD

Address: 1İstanbul Üniversitesi-Cerrahpaşa, Cerrahpaşa Tıp Fakültesi, Deri ve Zührevi Hastalıkları Anabilim Dalı, İstanbul, 2Uludağ Üniversitesi Tıp Fakültesi, Deri ve Zührevi Hastalıkları Anabilim Dalı, Bursa, 3Erciyes Üniversitesi Tıp Fakültesi, Deri ve Zührevi Hastalıkları Anabilim Dalı, Bursa, 4Sağlık Bilimleri Üniversitesi, Ankara Dışkapı Yıldırım Beyazıt Eğitim ve Araştırma Hastanesi, Deri ve Zührevi Hastalıkları Anabilim Dalı, Ankara, 5Ankara Yıldırım Beyazıt Üniversitesi, Deri ve Zührevi Hastalıkları Anabilim Dalı, Ankara, 6Karadeniz Teknik Üniversitesi Tıp Fakültesi, Deri ve Zührevi Hastalıkları Anabilim Dalı, Trabzon, Türkiye E-mail: [email protected] Corresponding Author: Dr. Burhan Engin, İstanbul Üniversitesi-Cerrahpaşa, Cerrahpaşa Tıp Fakültesi, Deri ve Zührevi Hastalıkları Anabilim Dalı, İstanbul, Türkiye

Published: J Turk Acad Dermatol 2018; 12 (2): 18122r1. This article is available from: http://www.jtad.org/2018/2/jtad18122r1.pdf Keywords: Turkish guideline, Atopik dermatit

Abstract

Background: Atopic dermatitis (AD) is a common inflammatory skin disease worldwide and life-long prevalence thereof can exceed 20% in developed countries. The prevalence of the disease increases gradually in developing countries and in African and Asian countries with low income.

AD affects quality of life unfavorably in a significant manner. The cost of AD is quite high both due to healthcare expenses required for treatment and causing labor loss. Patients receive long-term treatments owing to the fact that it is a disease with a chronic course and there is no curative treatment which also cause medicine expenses and a number of toxicities.

This guideline covers etiology, clinic diagnosis, laboratory, complications and treatment approaches for atopic dermatitis in details.

Atopic Dermatitis and in African and Asian countries with low income [1]. I. Epidemiology Generally, atopic dermatitis affects 25% of Atopic dermatitis (AD) is a common inflammatory skin disease worldwide and life-long children and 2-3% of adults [2]. Data regar- prevalence thereof can exceed 20% in develo- ding the prevalence of atopic dermatitis in ped countries. The prevalence of the disease adults has been reported as variable with increases gradually in developing countries 0.3%-14.3% due to lack of multicenter stu-

Page 1 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf dies and well-established diagnostic criteria Overactivation of the immune system is con- [3]. ventionally predominanted by the profile of T- helper cell 2 (Th2) in atopic dermatitis. The age of onset of the disease is generally 3- Thymic stromal lymphopoietin (TSLP), inter- 6 months and clinical findings are observed leukin 25 (IL-25) and IL-33 are produced by in 45%, 60% and 85% of patients in the first keratinocytes damaged by the protease acti- 6 months, before the age of 1 and before the vation developing due to barrier impairment age of 5, respectively [4, 5]. Only in a patient in epidermis caused by genetic or environ- group as small as 2%, the symptoms appear mental factors. These cytokines initiate Th2 after the age of 20 [6]. Family history is ob- cell activation. Activated Th2 cells produce IL- served in 70% of the patients [7]. 4, IL-5, IL-13, IL-25 and IL-31. T2 cells, along with many other immune system cells and The course of the disease is mild in approxi- are responsible for increased levels of IL-4 mately 80% of children with atopic dermatitis and IL-13 in atopic dermatitis lesions. IL-4 [8]. In more than 70% of case, complaints do and IL-13 cause an increase in the inflamma- not continue in adulthood [8]. tory cell infiltration to skin and as aforeme II. Pathogenesis ntioned, cause a decrease in filaggrin expression by keratinocytes hence an impairment in In the last decade, substantial developments skin barrier function. IL-4 induces IgE pro- have been recorded with the importance of fi- duction from B cells provides IL-5 eosinophil laggrin, immunologic changes in subtypes activation [4]. (Th17, Th22) of T-helper cells other than Th1 As the lesions become chronic, differences are and Th2 and identification of the effect of observed in cell infiltration; T2 cytokines do- many cytokines mainly IL-4 and IL-13 [9]. minant in the acute phase are replaced by Basically, two important events which are Th1-associated cytokines such as interferon- responsible for the pathogenesis of atopic gamma (IFN- γ) and IL-12 in the chronic dermatitis is skin barrier dysfunction and phase. In late lesions of atopic dermatitis, it overactivation of the immune system [4]. is acknowledged that Th2 cells are accompanied by Th22 cells producing IL-22. IL-22 is Pathogenetic mechanisms set forth in the responsible for keratinocyte proliferation and skin barrier dysfunction can be listed as im- acanthosis developing correspondingly. In ad- pairment in the proteins of various epidermal dition IL-22, along with IL-4 and IL-13, dec- differentiation complexes and filaggrin, decreases the expression of barrier-related rease in skin ceramides, impairments in the genes, such as filaggrin, loricrin and involuc- pH of stratum corneum and overexpression rin, decreasing the skin barrier function. It of chymotryptic enzyme [5]. Filaggrin is an es- plays a role in the late-stage tissue remodel- sential protein responsible for the prevention ling by increasing the expression of IL-17 pro- of transepidermal water loss and microbial fibrotic cytokines released from IL-13 and invasion ensuring the natural moisturization Th17 cells [4, 5]. of the skin by the breakdown products [10]. Reduction of filaggrin metabolites in the skin Increase in the density of nerve fibers in epi- causes skin barrier dysfunction also by cau- dermis and low stimulation threshold in ner- sing a decrease in skin acidification [11]. One ves are blamed for the pathogenesis of of the most well-known causes of skin barrier pruritus in atopic dermatitis. It is considered impairment observed in atopic dermatitis is that TSLP, IL-4, IL-13 and IL-31 are the cyto- the mutation in the filaggrin gene and is ob- kines playing a role in itching in atopic der- served in 10-30% of atopic dermatitis pati- matitis [4]. ents. Except the filaggrin gene mutations, in The role of microbial pathogens in the deve- almost all moderate-severe atopic dermatitis lopment of atopic dermatitis have been de- cases, there is an acquired defect in filaggrin monstrated. S. aureus, Malassezia species expression. This is explained by the fact that and Candida albicans are the microbial pat- overexpression of IL-4 and IL-13 causes a hogens which play a role in the pathogenesis decrease in filaggrin expression by kerati- of atopic dermatitis [13]. Bacterial coloniza- nocytes [12]. tion with S. aureus is associated with skin

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barrier dysfunction associated with the in- atopic eczema. In patients carrying filaggrin crease in protease activity in skin and basop- mutation, risk of early-onset severe atopic hil activation in skin and increase in the dermatitis and incidence of asthma have in- proinflammatory cytokine levels such as IL- creased [7]. In the genome-wide association 31 [14]. S. aureus density on lesional and analyses performed, common variants on non-lesional skin correlates with eczema se- 11q13 and 1q21 chromosomes have been ob- verity [15]. served. Hornerin, a protein that plays a piv otal role in the region keratinocyte differen- III. Histopathology tiation on 1q21 chromosome, encodes loricrin Histologic features of atopic dermatitis show and involucrin. The only nucleotide poly- similarity to a large extent with allergic con- morphism on the genetic region encoding tact dermatitis. In acute lesions, intercellular claudin-1 causes decreased gene expression edema in epidermis and marked perivascular of claudin functioning in the structure of tight T-cell infiltration accompanied by monocytes junctions between keratinocytes [11, 19]. A and macrophages in dermis are observed. relationship has been demonstrated between Lymphocytic infiltrate is formed of activated atopic eczema and mutations in SPINK5 gene memory T-cells carrying CD3, CD4, HLA-DR, encoding a serine protease inhibitor. The mu- CD25 and CD45RO. In acute lesions, eosi- tation in this gene impairs the protease-an- nophils and mast cells are observed whereas tiprotease balance that is necessary to ensure basophils and neutrophils are sporadic. Epi- skin barrier function. It is suggested that, in dermal hyperplasia, elongation of the rete rid- the genetic studies, the variants detected in ges, hyperkeratosis and minimal spongiosis the genes encoding IL-4, IL-4 receptor and IL- are observed in acute lichenified lesions. In- 13, play a role in the development of eczema crease in the count of dendritic cells in epi- [20]. dermis and monocyte-rich infiltration in ii. Environmental Factors dermis occur. Elevated count of eosinophils are detected in dermis with the immunoche- The fact that the prevalence of atopic derma- mical stain of eosinophil products such as eo- titis varies within the same country, higher sinophil major basic protein, eosinophil incidence of atopic dermatitis is observed in cationic protein, and eosinophil-derived neu- people migrating from the countries with low rotoxin [5, 16]. prevalence to developed countries and the IV. Etiology prevalence increases correspondingly with urbanization demonstrates the importance of I. Genetic Factors environmental factors in etiopathogenesis [1]. Environmental factors causing an increase in Genetic factors play a role in predisposition the risk of atopic dermatitis are summarized to atopic dermatitis. Familial history is posi- in (Table 1). tive in 70% of patients. The risk is increased 2-3 fold with the presence of atopic dermatitis It is acknowledged that climate conditions af- in one of the parents and 3-5 fold in case both fect the prevalence of atopic dermatitis. Ex- parents have atopic dermatitis [2]. In twin posure to low humidity and low ultraviolet studies, concordance ratios has been found (UV) are among the risk factors for atopic der- to be 85% in monozygotic twins and 21% in matitis. When the income levels of countries dizygotic twins [17]. are equalized, symptoms of atopic dermatitis have been found to be directly proportional Genetic factors play a role in immune with latitude and inversely proportional with dysfunction and skin barrier dysfunction ambient temperature. It is suggested that this mentioned in the pathogenesis section. A data is related to UV light exposure which strong association has been demonstrated have immunosuppressive effects. However, it between atopic dermatitis and mutations should be noted that exacerbations may be causing loss of function in the gene encoding observed in summer season in some patients. the filaggrin protein [18]. In the filaggrin gene, The incidence of atopic dermatitis increases the mutation has been detected in approxi- in adults migrating to temperate climate from mately 40% of patients with moderate-severe tropical climate [1, 8, 21].

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The incidence of atopic dermatitis is higher therefore manifestation of the allergic disease in cities compared to rural areas. Traffic-as- is suppressed [8, 17, 30]. In uncrowded fa- sociated air pollution increasing with urba- milies, increased incidence of asthma and nization has been found to be related to the atopic dermatitis is observed in children who development of atopic dermatitis [22, 23]. live under hygienic conditions and use ant ibiotics in the early periods of life [31]. In ad- High education level of families are one of the dition, it has been demonstrated that pre- risk factors for atopic dermatitis. However, sence of an older sibling increases the risk of the results of the studies investigating the ef- atopic dermatitis in children with filaggrin fects of socioeconomic level are controversial deficiency [32]. [2, 8]. As mentioned under the topic Pathogenesis, Western style diet rich in polyunsaturated skin barrier dysfunction is the main factor fatty acids and sugar has been reported as responsible for the development of atopic the risk factor for the development of atopic dermatitis. Therefore, environmental factors dermatitis. It has been demonstrated that such as frequent detergent use, use of soaps consumption of fresh fruits has a protective that increase the pH of skin, water hardness effect against atopic dermatitis whereas con- are also responsible for the exacerbations of sumption of convenience food is related with the disease [33]. severe eczema [8, 24]. Albeit controversial studies, it is accepted Even though it has been suggested that lac- that smoking and exposure to cigarette tation has a protective effect against asthma smoke have no significant effect on the risk and atopic dermatitis, in the studies conduc- of atopic dermatitis [2]. ted, it has been demonstrated that the diets of babies in the first 6 months are not asso- V. Clinic ciated with the risk of atopic dermatitis [25, I. Atopic Dermatitis in Infancy 26]. Current data indicates that partially hydrolized formulae and probiotic support Atopic dermatitis in infancy is observed in prevent atopic dermatitis development in ba- children between the ages 0-2 [34]. During bies who are not only fed with breast milk [2, this period, face and extensor region involve- 27]. In addition, there is insufficient data to ment is typical whereas any region may be recommend any diet in the prevention of ato- affected [35]. The first signs of atopic derma- pic dermatitis development. There are stu- titis in infants are eczematous papulovesicu- dies setting forth the relationship between lar and patchy lesions generally localized on atopic dermatitis and obesity in children and cheeks. After a few weeks, excoriations due to pruritus and crusty erosions develop. Ini- adults [28, 29]. tially, perioral and paranasal areas are During pregnancy and infancy, exposure to mostly protected. Usually thin squamations wide-spectrum antibiotics and living with clinically similar to seborrheic dermatitis uncrowded families are related to the deve- may be observed in the scalp. In severe lopment of atopic dermatitis [8]. It is sugges- cases, yellowish sticky crusts may be present ted that exposure to infections in the early [5,36]. Persisting pruritus causes restless- stages of life has a preventative role in the ness in the infant. Thereafter, arms and legs development of atopic dermatitis. According can be affected. Typically, diaper region is to the hygiene hypothesis, a child with mul- protected. Lichenification is rare in infants. tiple siblings is constantly exposed to infec- In approximately 20-30% of cases, lesions di- tions in perinatal and postnatal period and sappear following the age of 2 [5, 8, 35].

Table 1. Environmental factors [2,8]

• Living in a region of low humidity and low UV exposure • Living in cities • High education level of families • Western style diet rich in polyunsaturated fatty acids and sugar • Exposure to wide-spectrum antibiotics during pregnancy and childhood • Living in uncrowded families • Frequent use of detergent, use of soap which increases the skin pH, hard water Page 4 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf

ii. Atopic Dermatitis in Childhood is observed more commonly with the increasing age. There is no pathognomonic evidence Atopic dermatitis in childhood defines the cli- in the differential diagnosis of atopic hand ec- nical features observed frequently in children zema from the irritant or allergic hand eczema between the ages 2-12. In this period, invol- [40, 41]. vement is observed in flexural region (antecu- bital fossa, neck, wrist, ankle), dorsum of the Eyelid eczema with pruritus accompanied by neck, hand, and foot. Reticular pigmentation erythema, edema and thin squamation can be also referred to as dirty neck is observed in observed in atopic dermatitis. With pruritus lateral neck. Dryness and fissures behind the becoming chronic, development of lichenifica- ear or on earlobe are typical. The lesions may tion is typical in the forthcoming period [42]. be new-onset lesions whereas they may be Chronic cheilitis with erythema, squams and lasting since infancy as well [5, 6, 34]. fissures in both lips and commissures can be iii. Atopic Dermatitis in Adulthood observed in atopic dermatitis [43]. Even though there are authors stating that v. Other Organ Symptoms Except Skin atopic dermatitis in adulthood is formed of Signs two separate subgroups with different clinical Atopic dermatitis is a part of the process re- features as cases with onset in the adulthood ferred to as the atopic walk and in the forth- and cases with onset in pre-adulthood, a con- coming periods, asthma and rhinitis can sensus has not been established yet [34]. develop in patients. Asthma, allergic rhinitis Hand, flexural region, head and neck involve- and IgE-mediated food allergies, which are ment is frequent in adulthood. Close relati- systemic atopic comorbidities, can be obser- onship with asthma, allergic rhinitis, hand ved in approximately 40% of patients with eczema and allergic contact dermatitis has atopic dermatitis [20,44]. Atopic dermatitis is been detected [37]. Xerosis is frequent being among the major risk factors for the develop- more significant particularly in winter time ment of asthma. It has been reported that, up .Head-neck dermatitis in this period is [5] to 3 years of age, at least one of asthma or al- typical and it should be noted that it may be lergic rhinitis has been observed in 66% of an indicator for sensitivity to Malassezia fur- children with atopic dermatitis. Besides, it fur yeast [6]. has been reported that patients were predis- iv. Types of Regional Atopic Dermatitis posed to animal, food, and drug allergies [44,45]. The severity of eczema has been Various regional atopic dermatitis types have found to be correlated with the prevalence been defined in children and adults. Genital and severity of atopic comorbidities (asthma, dermatitis is frequent in infancy; atopic foot, allergic rhinitis, and food allergy); patients nummular eczema and prurigo-like type in with atopic comorbidity in addition to eczema, childhood and eyelid eczema in adulthood it is more difficult to take the disease under [38]. control [45,46]. In patients with early-onset, Nummular eczema is a type of eczema with severe atopic dermatitis, food allergy usually inflamed patches or plaques having net mar- accompanies atopic dermatitis. IgE-mediated gins and the treatment thereof is difficult. food allergy has been reported in 35% of Nummular eczema is frequently secondarily children with atopic dermatitis [44]. infected with S. aureus. Typically, it is locali- In atopic dermatitis chronic pruritus and in- zed in extremities and gluteal region [6]. Ju- flammation cause sleep disorders and psychi- venile papular dermatosis shows a course atric symptoms. Neuropsychiatric disease with hypopigmented lichenoid smooth papu- risks, such as depression, attention deficit, les localized on knee and elbow and com- hyperactivity disorder, speech disorders in monly observed in spring and summer [6,39]. children, headaches and seizures, are increa- Atopic dermatitis is an endogenous risk factor sed [47]. Significant increase has been detec- for the development of hand eczema. Atopic ted in the risk of depression in individuals hand eczema frequently involves the volar with diseases such as asthma, eczema, and face of the wrist and dorsum of the hand and allergic rhinitis [48]. Depression and anxiety

Page 5 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf are commonly observed particularly in cases titis, it may be necessary to perform, when re- with severe atopic dermatitis [49]. Severe ec- quired, skin biopsy and serum IgE level mea- zema and female gender have been detected surement, potassium hydroxide test, patch as risk factors for depression and predisposi- test and various genetic tests. There is no tion for suicide [50]. data supporting, in disease diagnosis, the use It has been found that the individuals with of many different cytokines and chemokines, atopic dermatitis have an increased predispo- the role of which has been demonstrated in sition to vitiligo, alopecia areata, rheumatoid the pathogenesis of atopic dermatitis [2]. arthritis and inflammatory bowel diseases VII. Laboratory [51,52]. In recent years, even though the relationship of atopic dermatitis with cardiovas- Even though high serum IgE and eosinophil cular diseases is emphasized, no significant values are observed in atopic dermatitis, there relationship has been found [53]. is no pathognomonic laboratory finding. Ele- vated total and/or allergen-specific serum IgE VI. Diagnosis values are the most commonly observed labo- Clinical diagnosis is substantial in atopic der- ratory findings. These values are normal in matitis; there is no specific histological fin- approximately 20% of patients. Total IgE le- ding or laboratory test. Until today, various vels do not always correlate with the disease diagnostic criteria have been defined by many severity. IgE levels may increase in conditions different groups. With the revision performed such as parasitic diseases, some cancers and in 2003 on criteria determined by Hanifin and autoimmune diseases [2,54]. Rajka in 1980, diagnostic criteria appropriate Various allergens, mainly food, can be res- for clinical practice has been constituted for ponsible for the exacerbations in approxima- the diagnosis of atopic dermatitis in infancy, tely 30% of symptoms in children with atopic childhood and adulthood [2] (Table 2). dermatitis. Children under three years of age In order to exclude other diseases falling wit- with moderate-severe eczema should undergo hin the differential diagnosis of atopic derma- skin prick test or allergen-specific IgE tests

Table 2. Diagnostic Criteria for Atopic Dermatitis [2]

Main Characteristics; should be present: Accompanying characteristics; Characteristics that • Pruritus suggest the diagnosis of atopic dermatitis, whereas due • Eczema (acute, subacute, chronic): to their non-specific nature, that cannot be used for the Typical morphology and age-specific distributions* diagnosis of atopic dermatitis in scientific studies: Chronic or recurrent history • Atypical vascular responses (facial pallor, white der- • Face, neck and extensor region involvement in mographism, delayed blanch response) children • Keratosis pilaris (pitriasis alba/hyperlinear palm/ Lesion or history of lesion in flexural regions in any ichthyosis age group • Ocular/periorbital changes Preserved inguinal or axillary region • Other regional signs (perioral changes/periauricular lesions) • Perifollicular prominence/lichenification/prurigo lesions

Important characteristics; signs observed in most Excluding characteristics; conditions to be excluded cases, supporting diagnosis: before diagnosis • Age of early onset • Scabies • Atopy (Personal or familial history) • Seborrheic dermatitis • IgE reactivity • Contact dermatitis (allergic or irritant) • Xerosis • Ichthyoses • T-cell lymphoma of the skin • Psoriasis • Photosensitive dermatoses • Immunodeficiency conditions • Erythrodermas due to other causes

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with regard to egg white or cow milk allergies Table 3. Complications in Atopic Dermatitis along with other food allergies observed commonly in the population. Positive results should be confirmed with food provocation tests. Infective • Bacterial infections Food allergy tests are not recommended for • Viral infections children older than three years. This patient group can be investigated with regard to mite Ocular sensitivity and other common inhalant aller- • Keratoconjunctivitis • Blepharitis gens [55]. • Cataract VIII. Disease Severity Scales • Uveitis • Keratoconus There are many atopic dermatitis severity sca- • Retinal decollement les prepared for use in clinical studies. Among Others these, the statistical validity of Scoring Atopic • Growth and developmental delay Dermatitis (SCORAD) and Eczema Area and • Erythrodermia Severity Index (EASI) have been shown in the studies conducted [56]. lonization in lesions. Impetigo due to streptococci is frequent as well [36]. Staphylococci SCORAD index is calculated by taking into cause impetiginization of the lesions. Altho- account the extent, intensity and subjective ugh all regions can be affected, facial, parti- complaints it causes. The extent (A) is scored cularly perioral area involvement is typical. by applying the rule of nine, the intensity (B) Recently developed and rapidly spreading is determined by grading each of erythema, weepy sores and yellowish crusts are obser- edema, effects of scratching, weepy sores, lic- ved [5]. henification and dryness on a scale from 0 to The most serious infectious complication ec- 3 and subjective complaint (C) is scored by zema herpeticum is defined as disseminated grading pruritus and sleep disorder on a scale herpes simplex virus infection arising from from 0 to 10 followed by the calculation ac- eczema. Monomorphic vesicles and erosions cording to the A/5+7xB/2+C formula. Maxi- with sudden onset disseminating rapidly in 1 mum score is 103 [57]. When EASI score is or 2 weeks are observed in cases with severe calculated, disease extent and intensity eva- eczema. It is associated with grouped vesicles luated by the doctor is taken into account. As and extensive crusty plaques localized on distinct from the SCORAD index, subjective face, neck and sometimes on extremities. Se- complaints and signs of dryness, weepy sores condary bacterial infections and in severe and are not included in the assessment [58]. disseminated cases, meningitis and encepha- IX. Complications litis can develop. Mostly, fever, fatigue, lymphadenopathy and lymphopenia in blood Skin-barrier impairment, immunological di- accompany skin signs. Tzanck smear can be sorders, low antimicrobial peptide levels and used to support diagnosis [36, 60]. long-term topical steroid use observed in atopic dermatitis, establishes the basis for seri- Molluscum contagiosum with raised papules ous skin infections in these patients (Table in skin color is another viral infection develo- 3). Levels of LL-37, a cathelicidin, and b-de- ping in children with atopic dermatitis. Even fensin 2 (HBD-2) exerting antimicrobial acti- though localized on flexural regions mostly, it vity produced by keratinocytes in normal can be observed everywhere since it is easily people are decreased in atopic dermatitis. spread through autoinoculation [36]. Therefore, predisposition to bacterial, viral In lesions unresponsive to treatment or sho- and fungal infections is increased. Particu- wing peripheral spread gradually, superficial larly, the prevalence of skin infections deve- fungal infections should be considered. Tinea loping with S. aureus is significantly high. pedis and tinea faciale can be observed [36]. Clinically, bacterial and viral infections are Blepharitis, keratoconjunctivitis, keratoco- observed more commonly in atopic dermatitis nus, uveitis, cataract, and retinal decollement cases and have a sudden onset. In addition, and ocular herpes simplex are the ocular fungal infections have an insidious onset [36, complications of atopic dermatitis. The inci- 59].Impetigo is frequent due to S. aureus co-

Page 7 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf dence of ocular complications has been repor- serious manifestation and a common herpes ted as between 25% and 50%. Seasonal aller- simplex virus (HSV) infection, is observed in gic conjunctivitis, perennial allergic a ratio up to 3%. Predisposition to molluscum conjunctivitis, vernal keratoconjunctivitis, contagiosum infections is also increased in atopic keratoconjunctivitis, atopic blepharo- child and adult atopic dermatitis patients. It conjunctivitis, and giant papillary conjuncti- has been reported that colonization of Malas- vitis fall under the title of chronic allergic sezia sympodialis fungus is increased in pa- conjunctivitis. Seasonal and perennial allergic tients in whom dermatitis is observed in the conjun ctivitis are the most common allergic facial and neck region and that allergic sen- ophthalmologic diseases observed. sitivity develops against this fungus in patients [64,65]. In a recent meta-analysis in In general, severe pruritus, burning sensa- which studies investigating the association tion, watering and erythema are observed bi- between AD and lymphoma development wer laterally. Corneal involvement and permanent e reviewed, it has been observed that loss of vision are very rare. Vernal keratocon- lymphoma risk is somewhat increased in se- junctivitis and atopic keratoconjunctivitis are rious AD patients. In adult-type atopic der- more serious diseases with corneal involve- matitis patients, a mild clinic with generally ment and can cause loss of vision. Vernal k mild attacks and remissions, a course with eratoconjunctivitis is a disease observed usu- mild symptoms and sometimes with severe ally in prepubertal period in atopic children attacks, or a course with consistently severe in spring. It is associated with severe pruritus symptoms can be observed [66]. and when there is corneal involvement, pho- tophobia, foreign object feeling and watering XI. Risk Factors are observed. Atopic keratoconjunctivitis The development risk of atopic dermatitis starts at the age of twenties and is a conditio starts within the mother’s womb. The issue n causing vernal keratoconjunctivitis-like that cow milk, egg in the mother’s diet, expo- symptoms. As distinct from vernal keratocon- sure to house mites in a setting constitute a junctivitis, eyelid and periorbital skin involve- risk during pregnancy and lactation is still ment are more significant. Development of controversial. Despite the publications with cataract has been reported in 5-35% of pati- regard to the possibility that breast milk may ents [42,61]. be protective in infancy, there are controver- In severe cases, erythrodermia as well as sial results such as long-term lactation in- growth and develomental delay can be obser- creases the incidence of AD. In a Cochrane ved [6,7] review carried out in 2006, it has been emphasized in the studies conducted that foods X. Prognosis such as cow milk, eggs and nuts ingested du- Atopic dermatitis has a chronic course and af- ring pregnancy do not increase the risk of ato- fects the life of patients unfavorably. However, pic disease. Nevertheless, American Academy in some patients, it has also been observed of Pediatrics (AAP) recommends diet during that atopic dermatitis with early age onset re- lactation period and states that peanut, wal- mits with the advancing years. 10-30% of nut, egg, cow milk, and fish increase the risk those who have atopic dermatitis in childhood [64, 65, 67]. It has been stated in two studies have the disease at later ages [62]. It has been conducted that AD risk was low in a baby claimed that remission rates in patients app- whose mother did not ingest foods such as ropriately treated and followed up are higher. milk, egg, and fish during lactation. However, In addition, it has been reported that remis- the Cochrane review stated that there was no sion rates in patients with mild-moderate di- clear evidence regarding that protection from sease is higher than those in patients antigens during lactation period prevented experiencing a severe disease. Another prog- atopic dermatitis in breastfed babies. They nostic factor is that remission rates were stated that, in the diet of babies who have a lower in patients who were required to be hos- high risk of developing atopic dermatitis be- pitalized [63]. Predisposition to bacterial, viral fore six months of age, eating fish, eggs, nuts, and fungal infection is increased in patients and cow milk, which have a high allergic po- with atopic dermatitis. Eczema herpeticum, a tential, increases the risk. However, there is

Page 8 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf paucity of evidence as to the efficacy of diet in tosis should be considered in this age group. protection after six months of age. Even tho- Nummular eczema is important due its co- ugh protection from allergens is recommen- existence and being mistaken for the disease. ded in sensitive people, being protected from Also in this age group, impetigo, scabies, pyri- allergens during pregnancy may not be pre- doxine, niacin, riboflavin, essential fatty acids ventive since specific Th2 cells may develop and biotin deficiency, phenylketonuria, and in the baby in the postpartum period. It has nutritional deficiencies like acrodermatitis en- been emphasized that nutrition rich in antio- teropathica fall within differential diagnosis. xidants, fibers and minerals during preg- When we examine diseases falling within dif- nancy decreased the development of allergic ferential diagnosis in both children and rhinitis however, Ca, F, and Mg decreased the adults, irritant and allergic contact dermatitis risk of atopy. It has been detected that B-ca- are the diseases which rank first. In addition, rotene increased the risk of atopy. Smoking diseases like dermatophyte infections and increased sensitization in experimental ani- ichthyosis vulgaris may be mistaken for in mals [64, 65]. both child and adult patients. Diseases falling within differential diagnosis only in adults are Smoking and alcohol consumption elevates mycosis fungoides, xerotic eczema, lichen the level of IgE developing against respiratory simplex chronicus, and psoriasis [69, 70, allergens in humans. Smoking and alcohol 71]. The diagnosis is made by diagnostic cri- are accepted as factors increasing the risk of teria and in the case of a suspicion, in order atopic dermatitis. Atopic disease is high in ba- to differentiate it from other skin diseases, bies delivered via Caesarean section or who skin biopsy and laboratory tests such as IgE are premature or have low birth weight. Pro- are routine ly performed [64, 65]. However, in biotics reduce the antigen absorption by selected cases, apart from these tests, scree- changing the intestinal flora and support Th1 ning for mycosis, patch test and genetic tests immune response which decreases in AD. Re- can be performed. In most of the clinical and ceiving probiotics during pregnancy and in- experimental studies, it has been detected fancy decreases the incidence of AD between that there is a decrease in contact sensitiza- 2-4 years of age. Omega-3 and omega-6 oils tion in AD patients. However, it is recommen- have been investigated and no specific effects ded that skin patch test be performed to thereof have been detected. The subject regar- detect and avoid the related allergens in per- ding that natural life and avoiding chemical sistent cases. Causes of other erythematous- exposure decrease atopic dermatitis risk is squamous diseases, Langerhans cell controversial. Atopic dermatitis has been histiocytosis, collagenous tissue diseases and more commonly observed in children under erythrodermia and particularly T-cell five years and diagnosed with obesity for more lymphoma should be excluded [64, 65, 66, than 2,5 years [64,65,67,68]. 67, 68]. XII. Differential Diagnosis XIII. Treatment The age group of the patient is very important i. Non-pharmacological Methods in the differential diagnosis of AD. Since clinical symptoms differ according to age gro- a. Education and Support ups, diseases falling within the differential Atopic dermatitis is a common disease and af- diagnosis change considerably as well. Se- fects quality of life unfavorably in a significant borrheic dermatitis is the first disease mista- manner. The cost of AD is quite high both due ken for and it is sometimes impossible to to healthcare expenses required for treatment differentiate [69]. Even though axillary and and causing labor loss. Patients receive long- inguinal involvement is in favor of seborrheic term treatments owing to the fact that it is a dermatitis, in case this differentiation is not disease with a chronic course and there is no possible, some of the clinicians recommend curative treatment which also cause medicine that diagnosis of infantile dermatitis be made. expenses and a number of toxicities [64]. It In addition, syndromes with immune system can be considered that AD has preventable findings such as Netherton, Omenn, Hyper- characteristics since the disease has trigge- IgE, Wiskott-Aldrich and, although rare, ring factors. Triggers vary for different pati- lymphoproliferative diseases such as histiocy- ents and among these are various foods,

Page 9 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf aeroallergens, irritants and contactors, hor- fissuring, rhagade and lichenification as well. mones, stress, climate, house mites and mic- It is suggested that reinforcing the epidermal roorganisms like S. aureus. Eliminating the barrier with moisturizers prevents atopic allergens, diet, skin care and protection and walk, however this has not been proven [64, assessment of many proven or unproven con- 65, 67]. In infants in whom pre-natal atopy troversial subjects and performing the accu- risk has been calculated to be high, use of re- rate applications are critical [68]. The pat ient gular moisturizers decreased the chance of and family thereof should be well-informed in atopic dermatitis development in these in- order to ensure the most appropriate conditi- fants. This study demonstrated that moistu- ons in the follow-up of patients and minimize rizers not only decrease the symptoms in AD the medical treatment need. They should be but also have disease preventing effects and informed about the critically important mat- emphasized the importance of moisturizer ters that the disease can be triggered by use [74]. stress, the skin of patients is drier than nor- We can divide the moisturizers in three gro- mal and moisturizing has a critical importance, triggers such as chemicals and wool ups as emollients, occlusives and humec- having allergen characteristics should be tants. Emollients are comprised of glycol, avoided; cloth selection, bed and pillow choi- glycerol stearate, soy sterols and their main ces, minimizing the house mites and subjects effect is to ensure that the skin is softened. as such have critical importance. Other than Occlusives, on the other hand, are comprised these, particularly in children, the patient of vaseline, dimethicone and mineral oils and and the families should be informed about their main duty is to form a layer which pre- many subjects such as the benefits of diet, vents the evaporation of water. Preventing the choice of baby food and benefits of bathing evaporation of water enhances emollience as and, in order for bathing to not be harmful, well. Humectants are comprised of agents ideal bathing and what should be done after drawing and retaining water such as glycerol, the bath; and access to reliable sources regar- lactic acid, and urea [64, 73, 74]. Other than ding this information should be ensured. the classical classification, in order to en- Support programs and patient societies can hance the skin barrier repair, there are pro- be useful to consult and patient information ducts comprising ceramides, free fatty acids brochures and similar educational instru- and cholesterol which are present in the na- ments can be helpful as well [64, 65, 68]. tural structure of epidermis. Even though they have advantages for the epidermal re- b. Skin barrier repair pair, the superiority of these moisturizers over The most significant difference in the skin of the conventional ones has not been proven atopic dermatitis patients is that their skin is [75]. In fact, there is no data or study de- very dry. With this dryness, the barrier fun monstrating which type of moisturizer is ideal ction of epidermis is impaired. Barrier for which atopic dermatitis patient. Currently, dysfunction eases the entrance of allergens the most essential feature of a moisturizer is and irritants and dryness escalates pruritus that it is not an allergen. Since testing the [72, 73]. Therefore, the basis of treatment is moisturizers before use is not common, odor- to moisturize the skin and enhance the bar- less moisturizers with less preservative ratio rier functions. Regular daily use of moisturi- and less risk of sensitivity are ideal and these zers should be recommended to all patients. should be preferred. Ideal moisturizer varies In patients with mild symptoms, only moistu- for each patient and whether or not it is enti- rizers are sufficient, however in moderate and rely ideal is realized after use. Ease of use and severe patients they are used as adjuvants to cosmetic disturbances may be important in treatment. After the attacks are taken under moisturizer selection as well. Presenting vari- control with systemic and topical medicines, ous options to the patient and continuing moisturizers stand out in maintenance. Thus with the most satisfying one is the best app- toxicities to emerge are prevented by allowing roach. Using moisturizers comprising propy- us to lower the dose and duration of medica- lene glycol and urea should not be preferred tion, mainly the corticosteroids. When used in patients under the age of two and in child- alone, moisturizers increase hydration and ren, respectively. The application method of decrease pruritus. They decrease erythema, moisturizers is as essential as their type. It is

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recommended that they be used after bath is high, topical steroids with medium to low and 1-3 times/day depending on the need. potency should be preferred [65]. Concomitant use with topical medicines is not Compliance to treatment is reduced during recommended since it may cause dilution topical steroid use due to steroid phobia and problems and inactivity [64, 65, 67, 68]. the expected effect may not be achieved. The- ii. Topical Treatment refore, the families should be trained in terms of treatment and accurate topical steroid use. a. Topical Corticosteroids Efficacy: Their use is indicated in case non- Topical corticosteroids (TCS) have been the pharmacological methods are inadequate and basis of atopic dermatitis treatment for more the response is very goog when used conco- than 50 years. mitantly with moisturizers. Ointment forms Mechanism of Action: It is suggested that are used due to dryness of the skin, however, topical steroids suppress the release of proin- in exudative lesions other forms may be pre- flammatory cytokines by disrupting their an- ferred. The use of topical steroids also redu- tigen processing mechanisms [76, 77, 78]. ces the Staphylococcus aureus colonization on the skin [80]. Administration: Topical steroids are administered twice a day, in the morning and Side-effects: Well-known side-effects such as night, during the acute exacerbation period in skin atrophy, petechiae, striae, telangiectasia, the treatment of atopic dermatitis. When in- color changes, acneiform eruptions, and local flammation regresses or remission is ensured, infections may occur; additionally as a result it may be administered once a day. There are of sudden discontinuation of treatment, exa- many randomized, controlled studies and cerbations or, despite the treatment, loss of systemic reviews demonstrating that there is efficacy referred to as tachyphylaxis may de- no difference in efficacy between once or twice velop [65]. daily administration [79]. When acute period Topical steroids are safe during pregnancy regresses, side-effect frequency may be dec- and lactation, however, it should be of note reased with once daily administration. The that use on an extensive skin area may incur dose of administration should be gradually unfavorable effects on fetal growth. Steroid reduced or switched to intermittent adminis- should not be administered on breasts shortly tration (proactive treatment) when the treat- before lactation and should be cleaned if there ment dose is being reduced. In the acute is any. period, steroids with moderate-high potency Combination with topical antibiotics: for 3-6 days and in the maintenance period There is no data as to the superiority of topi- steroids with low potency are preferred. Prin- cal steroids plus antimicrobials to monoth ciples of using topical steroids in atopic der- erapy [65]. Therefore, topical steroids are suf- matitis are summarized in (Figure 1) [65]. ficient in AD as monotherapy. In the case of With regard to the choice of topical steroids infection on the involved area, infection treat- for infants and children, a topical steroid with ment principles should be complied with. a lower potency compared to that of adults is b. Topical Calcineurin Inhibitors preferred (Table 4). However, in case a response is not ensured, switching to a topical Topical calcineurin inhibitors (TCI), tacroli- steroid with higher potency is possible by ca- mus and pimecrolimus (Table 5) [76, 77], are reful monitoring. In some countries, only steroid-free agents with anti-inflammatory ef- hydrocortisone acetate and butyrate are the fects in both acute exacerbations and mai approved steroids for use in children under ntenance treatment of AD in adults and child- one year of age. Mometasone furoate and flu- ren above 2 years of age [76, 77]. ticasone propionate can only be used in chil Mechanism of Action: TCIs show their anti- dren older than 2 years. Other topical treat- inflammatory effects by suppressing the cal- ments can be used in patients above 12 years cineurin dependent T-cell activation hence of age. Since side-effects can develop in facial the production of proinflammatory cytokines and neck regions where the drug absorption and mediators. Antipruritic effects thereof de-

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Figure 1. Administration method of topical steroids in atopic dermatitis. **This medicine should be applied upon consultation with specialists. ∞Indicated so as to be discontinued within 3 months in patients aged >16 with very severe symptoms. *This drug should be administered according to the prescribing information [81].

Table 4. Topical steroid use according to the severity of eruptions [65]

Severity Eruption characteristics Topical steroid choice Severe Severe edema, lichenification with erythema Potent or very potent or infiltration Moderate Many papules, dry flakes, crusts, vesicles, ero- Potent or moderate sions, excoriations, and itchy nodules Mild Moderate erythema, dry flakes, few papules, Moderate, weak and excoriation Very Mild Pruritus, dry flakes, and mild erythema Agents, such as moisturizers, other than topical No dryness, no inflammation steroids

Recommendations

Topical steroids should be recommended taking into account the efficacy and safety profile.

Once or sometimes twice daily administration is sufficient, however, long-term use is not recommended.

Patient’s age, how extensive the lesion is and severity thereof should be considered in the choice of potency in steroids.

Babies and areas such as head-neck, skin folds and genital regions, which are problematic in terms of side-effects, should be monitored closely and occlusion should be avoided.

When remission is ensured, maintenance treatment twice a week is continued.

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Table 5. TCI Formulations [76,77]

Formulations for tacrolimus ointment in moderate-severe AD

• 0.03% formulation in children with ages 2-15

• 0.1% formulation in children with ages ≥16

Pimecrolimus 1% cream is indicated in mild-moderate AD patients ≥2 years

pend on inhibiting mast cell degranulation ted that lymphoma, other malignancy types [82]. Therefore, due to lack of side-effects and photo-carcinogenicity are unrelated with such as skin atrophy, TCI use is superior to TCI, however, that sunscreen can be applied TCS use in sensitive and thin skin areas [76, during TCI use considering the increased 77]. photo-carcinogenicity with systemic calcineurin inhibitors [78]. In 2011, FDA (US Food Administration: Twice daily administration and Drug Administration) reported that there of tacrolimus ointment or pimecrolimus was paucity of evidence supporting that tac- cream is effective in treating inflamed lesions rolimus ointment increased the risk of T-cell and resolving pruritus. In the administrations lymphoma [65]. of TCI, there are different restrictions than TCS. Tacrolimus ointment cannot be applied Even though there are publications regarding onto erosive or ulcerative surfaces and the ef- that TCI may increase the prevalence of local ficacy of the drug is limited [77, 83]. It is re- viral infections (eczema herpeticum or eczema commended that tacrolimus ointment be molluscatum) [83, 84], information is contra- applied once a day after bath and UV expo- dictory [76,78]. In case local viral infection sure be avoided afterwards. It is also recom- develops during the treatment, the treatment mended that tacrolimus ointment be applied should be discontinued. up to a maximum of twice daily with 12-hour It is recommended that age limitations should intervals [8]. be considered during TCI use. TCI can be in- Efficacy: It has been demonstrated in the dividually preferred in infants and babies who USA that application of TCI once-twice daily have severe facial and cheek eczema. In this per day or one to three times weekly onto the case, it is important to inform parents with recurring skin decreased relapses [76, 77]. regard to off-label use and effect-side effect Japanese and American guidelines reported profile [80]. that 0.03% or 0.1% forms of tacrolimus de- American guideline does not recommend rou- monstrated similar efficacy and safety profiles tine control of tacrolimus blood levels since in children and 0.1% form was superior in the systemic absorption amount after topical children. Anti-inflammatory potency of stero- application is very low so as to be ignored [6]. ids with moderate potency has been found si- However, in another guideline, in order to pre- milar to 0.1% tacrolimus ointment and higher vent the elevation of the drug in blood con- than 1.0% pimecrolimus cream [65, 79]. centration and protect the safety of the drug, TCI is not recommended in children younger the upper limit of the 0.1% form has been de- than two years old and in pregnant and lac- termined as 5 g in adults. Similarly, the upper tating women [65]. limit of the 0.03% form in children with ages 2-5 (<20 kg body weight), 6-12 (20-50 kg body Side-effects: The most common localized weight) and 13 years and above (≥50 kg body side-effects of TCI is generally burning and weight) has been determined as 1g, 2-4 g and stinging sensation and pruritus. In order to 5 g, respectively [65]. prevent early withdrawal, the patients should be informed about these potential side-effects c. Topical Antimicrobials and Antiseptics [76, 77]. Japanese and American guidelines In the studies conducted in the skin micro- reported a correlation between AD severity biome of AD patients [85], increase in S. au- and increased lymphoma risk regardless of reus gene copies and decrease in microbial TCI use. Whereas EADV eczema group repor- variation have been demonstrated. And this

Page 13 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf brings forefront the notion that TCS and an- dermatitis. This is particularly recommended timicrobial combinations might be effective in in patients with predisposition to Malassezia patients with high S. aureus colonization species [80]. [78]. Topical antiseptics are particularly re- d. Topical Antihistamines commended in acute AD exacerbations with clinical manifestation of bacterial impetigini- Topical antihistamines are not recommended zation characterized by leakage, pustules and in the treatment of AD due to absorption risk fissures [78]. and the risk of photoallergic contact dermatitis development [76]. Proactive antimicrobial bleach baths (twice a week with 0.005% sodium hydrochloride) can Recommendations be used in patients who have recurrent skin infection [76, 77]. In these group of patients, Topical antiseptics are particularly recom- intranasal mupirocin can be applied along mended in acute AD exacerbations with with bleach baths [7]. In case there is no res- clinical manifestation of bacterial impetigi- ponse to TCS and TCI and/or in the presence nization characterized by pustules and fis- of superinfection, addition of antimicrobial sures. therapy (topical antiseptic) may be considered Topical antibiotics should not be used for [84]. Even though chlorhexidine, octenidine, prolonged periods. 0.3% crystal violet, diluted potassium per- manganate baths (100 ml of 1% KmnO4 stock Clinically, antifungal treatment should be solution to an entire bathtub) are applied, considered in in cases of face-neck-shoul- there is no sufficient evidence as to their effi- der dermatitis. cacy [78]. Recommendations There is paucity of studies with regard to the efficacy of antiseptic baths. TCI is the first line option in acute and chronic treatment of AD patients who do not respond to topical treatments or in whom these treatments are not administered. e. Other topical agents 1) Coal Tar TCIs are recommended as first line treatment in “problematic areas” (face, intertriginous regions, Despite being one of the oldest therapies in genital region, scalp in babies) since they lack the treatment of AD, topical coal tar has fallen the adverse, side effects of glucocorticoids. into disfavor due to lack of controlled-randomized trials demonstrating its efficacy in tre- TCIs can be used in maintenance treatment for the prevention of recurrences. atment [76, 77]. Even though the evidence is inconsistent, there are publications recom- mending coal tar in AD with scalp involve- In recent years, the efficacy of antimicrobial ment or lichenification [77, 78, 80]. clothes covered with silver nitrate or a qua- Mechanism of Action: Coal tar can restore ternary ammonium composition is contradic- filaggrin expression by aryl hydrocarbon re- tory. Antimicrobial underwear (for example ceptor (AHR) activation and STAT6 dephos consisting of silver nitrate) can be considered phorylation and counteract Th2-mediated in chronic AD patients [80]. downregulation of skin barrier proteins thus In a meta-analysis published by Birnie et al., it has been demonstrated that topical corti- Recommendations costeroid preparations consisting of an antimicrobial or antifungal have no superiority Due to difficulty of cosmetic tolerance of over the ones not consisting them [86]. The tar, it can only be applied in selected cases general opinion does not favor long-term use where lichenification is observed. of topical antibiotics (including fucidic acid) [78, 80]. Use in babies is controversial. Clinically, antifungal treatment should be considered in cases of face-neck-shoulder

Page 14 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf diminish spongiosis, apoptosis and CCL-26 and laboratory values. The side-effects repor- expression [87]. ted are exacerbation of AD (3.1%), pain in the 2) Topical Phosphodiesterase Inhibitors application site (2.3%) and infection in the application site (1%) [90]. Various novel PDE4 inhibitors are under research in clinical trials of mild-moderate AD Crisaborole ointment 2% provided therapeu- treatment. tical benefit with its favorable safety profile and drug application was submitted to FDA Mechanism of Action: Crisaborole ointment in 2016 [92]. is a 2% boron-based benzoxaborole PDE4 inhibitor. It has been demonstrated that it re- 3) Application of Wet-wrap Dressing solved the severity of the disease in AD Application of wet-wrap dressing may be be- patients. Boron chemistry in this compound neficial in the treatment of resistant AD [76, mimics the phosphate in cAMP. Therefore, 77, 93]. In acute, oozing and erosive lesions, PDE4 inhibition and weakening of cellular in- wet-wrap dressing is recommended primarily flammation are targeted [88]. The fact that it during the period until oozing stops. On the has a small molecular structure, is a lypophy- other hand, caution should be exercised aga- lic compound and has unique physiochemical inst folliculitis, skin maceration and secon- properties, crisaborole can penetrate dermis dary infections that might develop due to and be active in the inflamed area. However, long-term use of wet-wrap dressing [78]. it is converted to its inactive metabolites AN7603 and AN8323 during its absorption to 4) Polydocanol systemic circulation [89, 90]. Crisaborole also It has an anesthetic and antipruritic effect. No has an inhibitory effect on Th2-originated systemic side-effect has been reported except cytokines such as IFN-γ, TNFα, IL-2, IL-5 and rare contact allergy. Since there are no con- IL-10 [91]. trolled trials, it can be used as an adjuvant Efficacy: Crisaborole ointment has achieved for antipruritic effect in AD [80]. a good efficacy profile in all studies for the treatment of mild-moderate AD. Two pioneer tri- 5) Tannins als, AD-301 and AD-302, were designed Their activity results from their astringent similarly and Phase 3 trials primarily researc- properties. Since there are no controlled tri- hed the efficacy of crisaborole ointment 2% als, it can be used as an adjuvant for antip- applied twice daily for 28 days on each atopic ruritic effect in AD [80]. lesion. Crisaborole ointment attained treatment success before the control group (pla- 6) Zinc cebo-treated patients) and resulted in the Albeit the astringent, anti-inflammatory and regression of IGA (Investigator's Global As- cooling effect of topical agents comprising sessment) severity scores in patients receiving zinc, there are no controlled trials demonstra- crisaborole treatment. Both trials set forth re- ting its efficacy in AD [80]. mission in disease severity based on diminished AD signs and symptoms including 7) Topical Non-steroidal Anti- pruritus, erythema, exudate, excoriation, in- inflammatory Drugs duration/papule and lichenification [90]. There is no publication demonstrating the ef- Side-effect: Crisaborole ointment demonstra- fect of non-steroidal anti-inflammatory drugs ted a favorable safety profile with regard to (NSAIDs) in the eczematous lesions of AD. treatment emergent adverse events (TEAEs) NSAIDs are not included in the AD treatment and application site reactions (pain, dermati- guidelines in Europe and USA [87]. tis) in most of the mild-moderate AD cases. iii. Phototherapy The incidence of these reactions in the treatment group is higher than that of the control Photo(chemo)therapy is a good therapeutic group whereas the side-effects are short-term. option to resolve skin lesions, pruritus and Additionally, no clinically significant diffe- insomnia in AD patients with remission du- rence has been observed in any treatment rations up to 6 months without serious short- group in vital findings, electrocardiograms term side-effects [94].

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Mechanism of Action: Various factors such place in the management of AD. On the other as suppression of the antigen-presenting hand, non-sedative antihistamines may con- function of Langerhans cells, stimulation of tribute to treatment in patients with additio- antimicrobial peptides, stimulation of apop- nal manifestations related to AD such as tosis in T-lymphocytes [95], decrease in S. a urticaria, allergic rhinitis or conjunctivitis[77, ureus and Malassezia spp. colonization, dimi- 102, 103]. Decision should be made accor- nished antigen presentation in phototherapy- ding to patient characteristics for short-term mediated stratum corneum thickening [96, adjuvant treatments targeting pruritus in 97]. acute AD attacks. Efficacy: Considering its low risk profile, re- In patients with sleep dysfunction due to se- lative efficacy, availability, and patient com- vere pruritus, even though short-term spora- fort level, db-UVB is emphasized as the most dic use of sedative antihistamines such as effective option. Additionally, UVA1 for acute hydroxyzine is appropriate, it should be of exacerbations, UVB for chronic AD and PUVA note that they affect sleep quality. Long-term only in severe, extensive AD are recommen- use thereof is not recommended particularly ded [76, 77]. The American guideline states in children [78, 104]. that phototherapy can be used as maintenance therapy in chronic disease. Recommendations

S2k AD guideline states that phototherapy There is no data as to the contribution of (UVA-1, db-UVB, broadband UVB, balneo- long-term use of oral H1 antihistamines to phototherapy) can be recommended as an ad- the management of AD. juvant therapy in AD patients above 18 years of age in the acute period. In the same guide- Short-term use according to patient cha- line, it has been expressed that phototherapy racteristics may be appropriate in the ma- might be considered in children ≥12 years nagement of severe AD attacks. [81]. It should be of note that TCI use along with phototherapy is still controversial [78]. b. Systemic Antimicrobials Side-effect: In the presence of oozing, early It is well known that genetic and environmen- lesions, UV therapy is not recommended due tal defects in the natural immune system of to poor treatment response [78]. In addition, the skin and insufficiencies in the local anti- use of TCS and emollients is recommended in microbial defense mechanism lead to coloni- order to prevent exacerbations before photot- zation of many pathogens, mainly S. aureus, herapy [78]. in AD patients. This incidence reaches 90% for S. aureus in moderate and severe AD pa- Recommendations tients [105]. Routine use of systemic antimicrobial treat- Phototherapy is recommended in the treatment is not recommended in the management ment of AD in chronic phase and resistant of AD. Oral antimicrobial treatment approp- to topical treatments. riate for active bacterial, viral, or fungal infe ctions defined with clinical findings contribu- Except for UVA1 effective in acute exacer- tes to the treatment of AD [106]. bations, phototherapy is rather recommended in chronic, lichenified AD cases. Microscopic examinations should be performed and cultures be taken to support the clinical signs. Superinfections of S. aures and iv. Systemic Agents beta-hemolytic streptococci on the bacterial a. Systemic Antihistamines side, herpes simplex on the viral and Malas- sezia on the fungal side should be the firsts In the controlled studies, there is no data de- that come to mind. Particularly a streptococ- monstrating that antihistamines contribute to cal infection should be investigated in a child the atopic dermatitis severity scores and di- suffering from an AD attack accompanied by minish pruritus significantly [98,99,100, intense, bright red erythema in skin folds 101]. Therefore, long-term treatment with se- [78]. Again, in resistant eczemas on face, dative or non-sedative antihistamines has no neck and shoulders, examination for Malas-

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ticularly nephrology tests be performed and basal creatinine levels be recorded [109]. Recommendations Optimal treatment duration should be consi- Systemic antibiotic treatment should be dered as 3-6 months in patients responding recommended only if clinical findings cle- well to treatment. It is known that with 3- to arly show that there is bacterial superin- 4-month treatments repeated intermittently, fection. the disease is well-controlled [11]. The intermissions can be determined according to se- Resistant eczemas of face, neck and sho- verity evaluation of the patient and other ulders should be evaluated in terms of features. In patients who tolerate the drug Malassezia superinfection and antifungal well and have a long history of severe disease treatment. before the treatment, treatment period can be prolonged to a maximum of 1-2 years with re- Herpes infections should be carefully eva- latively low maintenance doses, without inter- luated in terms of manifestation of ec- missions [116]. However, caution should be zema herpeticum and systemic antiviral exercised for side-effects that may occur du- treatment. ring the uninterrupted treatment particularly with high doses. sezia followed by oral or topical antifungal tre- In the routine monitoring of cyclosporine, atment may be necessary [107]. which is a drug with a narrow therapeutic index, close monitoring of blood pressure, In herpes infections with increased incidence creatinine, liver enzymes and lipid levels in and higher dissemination risk, if this disse- blood tests are important parameters. In ad- mination (eczema herpeticum) has occurred, dition, infections and increase in malignan- use of systemic anti-virals is mandatory. Cau- cies due to immunosuppression and other tion should be exercised with regard to ec- considerable side-effects such as gingival zema coxsackium or eczema vaccinatum hyperplasia and hypertricosis should be ca- manifestations as well [104,108]. refully monitored [104,109]. c. Immunomodulatory Agents Recommendations 1) Cyclosporine Cyclosporine is the first-line option for Cyclosporine, an immunosuppressive drug, is systemic treatment in the management of the first-line option for systemic treatment in extensive and severe AD. children, adolescents and adult patients with extensive and severe AD. Cyclosporine, a cal- A dose of 2.5-5 mg/kg/g can be selected as cineurin inhibitor, suppresses T-lymphocytes the starting dose. The treatment is maintai- strongly through proinflammatory cytokines ned as a dose reduction of 0.5-1 mg/kg/g including interleukin-2 [12]. Cyclosporin has every two weeks after disease control is en- been approved about 20 ago for use in adult sured which is usually 6 weeks. AD patients. It has been demonstrated in randomized, controlled studies and meta-analy- Optimal treatment duration is recommen- ses that cyclosporin reduced severity scores ded as 3-6 months. In patients who tolerate and increased quality of life [109, 110, 111, the drug well and have a long history of se- 112, 113, 114, 115]. vere disease before the treatment, treatment period can be planned as 1-2 years with the A dosing range of 2.5-5 mg/kg/g can be se- lowest dose possible, without intermissions. lected as the starting dose. The treatment a Patient follow-up is mandatory in uninter- dministered as being divided into two is m rupted treatment for side-effects. aintained as a dose reduction of 0.5-1 mg/kg/g every two weeks after disease con- Blood pressure control, nephrologic para- trol is ensured which is usually 6 weeks. It is meters and blood lipid levels are important essential that, along with general examination parameters of follow-up. before treatment, blood pressure control, par-

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Cyclosporine should not be administered in ractions is that the applicable dose should be combination with phototherapy due to increa- reduced up to its 1/4 in concurrent use with sed risk of carcinogenesis. Live vaccination is xanthine oxidase inhibitors like allopurinol. not recommended during cyclosporine use. Azathioprine should not be used in combina- The appropriate time is two weeks after the tion with phototherapy due to increased risk treatment is discontinued. The earliest restart of carcinogenesis [109]. It can be used very can be possible after 4-6 weeks [106,109]. cautiously during pregnancy in limited indi- cations with dose reduction [78]. 2) Azathioprine 3) Methotrexate In the treatment of disseminated and severe AD, in cases when cyclosporine is ineffective AMethotrexate can be evaluated as the third and contraindicated, azathioprine can be eva- option after cyclosporine and azathioprine in luated as a second-line option. Although its the treatment of extensive and severe AD. efficacy has been demonstrated in randomi- Even though its efficacy has been demonstra- zed, controlled trials, long-term efficacy and ted in limited number of studies, two of which safety data are limited [117,118]. Even tho- were randomized and controlled, carried out ugh it is not a licensed treatment in AD yet, it in adults and children, there is paucity of can be used in children as well [119,120]. data regarding its long-term efficacy and sa- Azathioprine, which is a purine analog, supp- fety [121, 122, 123, 124]. Although it is not resses both B- and T-lymphocytes that de- a licenced treatment for AD, it can be used in monstrate high proliferation in inflammatory children as well [78,122]. Methotrexate, conditions by inhibiting DNA synthesis [102]. which is a folic acid antagonist, shows immu- nosuppresive effect by inhibiting purine and The onset of action is slow and reaches the pyrimidine synthesis [104]. peak efficacy in 8-12 weeks. Although the optimal dose range is 1-3 mg/kg/g, the starting Its onset of action is slow and reaches peak does is usually selected as 50 mg/g in the efficacy in 8-12 weeks. The optimal dose first 1-2 weeks. The risk of myelosuppression range is between 7.5-25 mg/week in adults is high in individuals with low thiopurine and 0.2-0.7 mg/kg/week in children. Oral or methyltransferase (TPMT) activity [78,118]. subcutaneous forms can be used [78,102]. Even though controlling the enzyme activity In the follow-up of the drug which is usually can indicate that the person is under risk, well-tolerated, hepatotoxicity, bone marrow since access to this test is not common, low toxicity, pulmonary toxicity, gastrointestinal starting doses are selected and dose is esca- side-effects are prominent parameters. In lated in time. order to decrease the risk of these side-effects, Increase in the risk of leukopenia, gastrointestinal side-effects, elevations in liver enzyme levels, non-melanoma skin cancers and Recommendations lymphoma are the possible side-effects [102]. An important point with regard to drug inte- In case cyclosporine is ineffective or contraindicated, azathioprine can be selected in the treatment of extensive and severe Recommendations AD.

Methotrexate is the third option after Although the optimal dose range is bet- cyclosporine and azathioprine in the treat- ween 1-3 mg/kg/g, according to TMPT ment of extensive and severe AD. enzyme activity, use of lower doses may be required. If the enzyme activity cannot be Optimal dose is 7.5-25 mg/week in adults measured, the starting dose is low such as and 0.2-0.7 mg/kg/week in children. The 50 mg/g and the dose is incremented in 1- onset of action is slow and reaches peak 2 weeks. Its onset of action is slow and re- efficacy in 8-12 weeks. aches peak efficacy in 8-12 weeks.

Gastrointestinal side-effects, hepatotoxi- Myelosuppression and liver enzyme levels city, bone marrow toxicity are prominent are prominent parameters in patient fol- parameters in patient follow-up. low-up.

Page 18 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf folic acid support should be recommended. It There is no classic dose scheme due to stu- is contraindicated in pregnancy [78,106]. dies conducted in different dose schemes. Headache, fever and muscle pains have been 4) Mycophenolate Motefil /Mycophenolate reported as the most common side-effects Sodium [106]. Even the fact that it is among the last Mycophenolate motefil (MMF) or Mycopheno- options in systemic treatments due to high late sodium (MPS) is an option to be evaluated costs and side-effects is controversial [104, in patients unresponsive to phototherapy and 106]. other systemic treatments particularly in the treatment of adult patients with extensive and Recommendations severe AD. In a single, controlled trial, MPS has been found to have a similar efficacy with IFN-γ is among the last options in patients cyclosporine [125]. In addition, limited num- not responding to phototherapy or other ber of uncontrolled trials and case series sup- systemic treatments in the management of port its efficacy [126, 127]. MPS impairs severe and extensive AD. purine synthesis by inhibiting inosine monop- 6) Systemic Steroids hosphate dehydrogenase and affects B- and T-lymphocytes selectively [102]. Common clinical dermatology experiences support the only controlled trial reporting In adults, MMF and MPS can be used up to that corticosteroids, the first of immunosupp- their optimal doses of 2 gr/g and 1440 mg/g, ressive treatments which spring to mind, de- respectively. Onset of action is slower than monstrate similar efficacy in AD patients cyclosporine (78). It can be used in children [134]. However, well-known important side- in selected cases. The dose can be selected as effects make their use unadvisable when pro- 30-50 mg/kg/g [128]. fit-loss balance is considered. They can be As an immunosuppressive drug, its side-ef- evaluated in terms of short-term use in severe fect profile is more moderate. The most com- acute attacks in adult AD patients resistant mon reported side-effects are gastrointestinal to other treatments [78, 106]. effects such as nausea, diarrhea and hema- Methylprednisolone can be selected with an tological disorders. Its use in pregnant women initial dose of 0.5 mg/kg/g and the treatment is contraindicated [78]. duration may be a short attack treatment of one week or be extended to a maximum of one Recommendations month with a tapering schedule according to the severity of the disease. In uses where dose Mycophenolate motefil (MMF) or Mycophe- reduction is not possible, relapse/rebound nolate sodium (MPS) is an option to be risk is high [78, 106, 134]. It may serve as a evaluated in patients unresponsive to pho- bridge in order to switch to other systemic tre- totherapy and other systemic treatments atments in selected severe cases [102]. When particularly in the treatment of adult pati- compared to adults, it may be an option for a ents with extensive and severe AD. short-term with caution in children suffering 5) Interferon-γ Recommendations In the management of severe and disseminated AD, interferon-γ (IFN-γ) can be evaluated Systemic steroids can be evaluated in as an alternative treatment option in patients terms of short-term use in extensive and not responding to phototherapy or other severe acute attacks in adult AD patients. systemic treatments. However, the results of It should be used very cautiously in child relatively old, limited number of controlled tri- patients. als are controversial [129, 130, 131, 132]. A relatively new trial reporting a successful re- Methylprednisolone can be used in a star- sult is not a controlled trial [133]. IFN-γ is ting dose of 0.5 mg/kg/g. It can be discon- TH1 cytokine active in natural and acquired tinued complying with the tapering immune system by increasing natural killer scheme. cell proliferation and macrophage oxidation [102]. It is not recommended as a long-term treatment in in the treatment of AD.

Page 19 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf from extensive and severe attack. It is not re- phosphatidylcholines, and sphingomyelins. commended as a long-term treatment in the Namely, this drug seems to be more effective treatment of AD [106]. mainly in AD occurring due to immune dysregulation rather than skin barrier disorder. d. Biologic Agents Evaluating the metabolic profiles of lipids be- 1. Omalizumab fore treatment can guide to determine the appropriate omalizumab patient [141]. Omalizumab is a recombinant humanized IgG1 monoclonal antibody binding to free IgE Features Regarding the Drug in circulation from the Ce3 region of the Fc Drug dose: In distinct cases, omalizumab has fragment. Omalizumab binds to free IgEs in been administered in a dose of 150-600 circulation and prevents them from cross bin- mg/once in 2 weeks. It has been reported that ding to the high-affinity FcER-IgE complex on efficacy is better in high doses in some of the surface of mast cells and from being deg- these cases and it was emphasized that this ranulated. In addition, decreasing the level of is related to the amount of the drug to dec- IgE level in circulation, omalizumab decrea- rease the serum free IgE level [138]. However, ses the amount of high-affinity IgE receptors in some other studies, it has been demonstra- on mast cells and basophils, therefore supp- ted that omalizumab dose as low as 150 resses the activation of those cells and media- mg/once in 15 days is sufficient for the treat- tor release [135]. Omalizumab is indicated in ment of AD. It has been emphasized that this allergic asthma and chronic urticaria. Its use is an important evidence that main mecha- in atopic dermatitis is off-label and the num- nism of action of this drug is immune regula- ber of patients reported in literature is limited tion and it has even been emphasized that and efficacy results are controversial. When there should not be a target such as decrea- the literature is reviewed, it is emphasized sing the serum free IgE level in these patients that some features relating to the patients [142]. In a manner supporting this, in some and use of the drug are the factors determi- of the trials, even though total serum IgE level ning the efficacy of the drug [136, 137]. has been seriously suppressed with the oma- Patient Characteristics lizumab treatment, its clinical efficacy has not been demonstrated. It has been emphasized Age: Efficacy in children is higher than that, the main indicator demonstrating the adults. The reason for this might be that AD clinical efficacy is decreased serum IgE/IgG follows a natural course in passing from and IgE/IgG mRNA ratio rather than decrea- childhood to adulthood and during this co- sed IgE level [140]. urse it demonstrates some differentiations [138]. Treatment duration: It seems like one of the factors determining the efficacy of omalizu- Serum IgE levels: In patients with very high mab in AD is the treatment duration. In ge- baseline serum IgE level, inefficacy or limited neral, it is not possible to evaluate the efficacy efficacy is more common. The reason for this of treatment before 3 months. As the period might be that the dose adninistered may not progresses, treatment success increases. be sufficient to reduce the free IgE level in cir- Even in some studies, it has been demonstra- culation. Therefore, it is emphasized that hig- ted that main efficacy is achieved after a pe- her dose of omalizumab might be appropriate riod as long as 7-10 months. The cause for in these group of patients [139]. However, this has been shown as the prolonged time of contrary to this, there are cases with high IgE elimination of IgEs, which omalizumab binds level responding very well to the treatment. to, from serum and as incomplete efficacy as This may be due to the fact that omalizumab a result of insufficient elimination [143]. demonstrates some other immune regulating There is paucity of case presentations regar- functions regardless of IgE in AD. Even these ding the concurrent use of omalizumab with mechanisms can be ahead of IgE-mediated some other agents in AD. It is considered that mechanism [140]. these combinations both increase efficacy and Skin barrier disorders: Omalizumab is more reduce drug doses. One of these combinations effective in patients without filaggrin muta- is combination with ivig. Low dose omalizu- tion and with no disorders in lipid metabolites mab (150-300 mg) and very low dose ivig (10 such as fasting serum glycerophospholipids, g/week) have been found to be effective in AD

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[144]. Another combination is the combina- successful or use thereof is not recommended tion of omalizumab with extracorporeal pho- [148]. There is no study or data as to its use topheresis. An effective result has been in children. Therefore it cannot be used in achieved in a resistant AD patient in whom childhood AD. extracorporeal photopheresis has been admi- Efficacy: Dupilumab relieves both the skin nistered [145]. Due to the paucity in number signs and symptoms and improves the quality of patients in whom combination treatments of life index in AD with regard to general he- are administered, these treatments can only alth dose-dependently. Pruritus, that is the be applied in very resistant, severe cases. most important sign suffered from, attenua- Use of omalizumab in AD is safe. No signifi- ted in a ratio of 55.7% at the end of a 12-week cant side-effect has been reported with its use treatment and significant improvement has in these patients [146]. been observed in pruritus according to NRS Although omalizumab is not one of the stan- (pruritus numeric rating scale) and 5D pruri- dard treatments administered in AD, it may tus scale. Suppression of pruritus is the main be an effective treatment method in a group cause of increase in the quality of life. In ad- of patients. Further studies are required to dition, in patients receiving dupilumab, signi- determine the dosing of the drug and subty- ficant improvement has been observed in pes of patients in whom the drug can be used. EASI (Eczema Area and Severity Index), SCO- RAD (SCORing Atopic Dermatitis), IGA (Inve Recommendations stigator’s Global Assessment), PRO (patient- reported outcomes) sleep pattern, depression, Omalizumab’s use in atopic dermatitis is anxiety and quality of life index [149, 150]. off-label and the number of patients reported in literature is limited and efficacy results are controversial. It has been demonstrated that dupilumab achieved an improvement of %74+/-3.6 in EASI Omalizumab has been administered in a and 82,5-85%, 60-62% and 36% of patients dose of 150-600 mg/once in 2 weeks in AD reached EASI-50, EASI-75, and EASI-90, res- patients. pectively [149,151]. It is not possible to evaluate the efficacy of treatment before 3 months. As the period Also an acceptable improvement of 38-40% progresses, treatment success increases. has been detected in IGA score [152]. Despite the lack of one-to-one comparative trials with Use of omalizumab in AD is safe. No signi- regard to efficacy, dupilumab seems to be ficant side-effect has been reported with its more effective than cyclosporine [153]. use in these patients.

2) Dupilumab Dosage and Administration: In the studies Dupilumab is a human monoclonal antibody conducted, when 300 mg/week, 300 mg/2 that binds to and blocks the alpha subunit of weeks, 200 mg/2 weeks, 300 mg/ month and the IL-4 receptor found as a common struc- 100 mg/month are compared, it has been de- ture in IL-4 and IL-13 receptors. Inhibition of tected that efficacy increased with dose. Due this structure leads to the blockade of both of to the fact that the most effective doses are IL-4- and IL-13-mediated signalizations and 300 mg/week and 300 mg/2 weeks and there therefore to the suppression of Th2 inflamma- is no significant difference between these two tory response which has an important role in doses and this dose has been approved by the pathogenesis of AD [147]. FDA [150], the dosage was determined as 300 mg/2 weeks. Phase 1, 2 and 3 trials have been carried out with dupilumab regarding its use AD and it The initial dose is administered as 600 mg has been approved in Match 2017 by FDA to and repeated doses continue as 300 mg/2 be used in “moderate and severe AD in adult weeks. The administration is via subcuta- patients in whom topical treatments were not neous injection. It is a treatment that the pa-

Page 21 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf tients can administer at home once the route first 4 weeks; this even more rapid than of administration is taught to the patient. In cyclosporine [153]. case a dose is missed, it can be administered Evaluation of the efficacy of the drug ac- in 7 days without disrupting the protocol. Ho- cording to the factors related to patients: wever, in case the dose is missed for more Serum dupilumab concentrations has been than one week, that dose should be skipped found to be lower in overweight patients, ho- and the dosing is withheld until normal do- wever, dose regulation is not required accor- sing time on the 14th day [148]. ding to body weight in adults. Being elderly, Dupilumab can be used alone or in combina- child, one of two genders or concurrent use of tion with topical treatments. When used in topical corticosteroids do not affect the phar- combination, topical calcineurin inhibitors macokinetics of dupilumab [152]. should be restricted so as to be applied only Dupilumab is an effective and safe drug in the onto the problematic areas. When combined treatment of AD. Due to being common in with topical corticosteroids, the efficacy of the children, there is an urgent need for clinical drug increases [148, 154]. trials regarding the use in these patients and Side-effects: Dupilumab is a safe drug. The efficacy and safety of this drug [154]. side-effects are mild or moderate in severity and generally not different from those of pla- Recommendations sebo. The most common side-effects are na- sopharyngitis, exacerbation of the disease, Phase 1, 2 and 3 studies have been carried headache, injection reactions, conjunctivitis, out with dupilumab in AD and it has been blepharitis, oral herpes infection, keratitis, approved in Match 2017 by the FDA to be itching of the eyes, other herpes simplex virus used in “moderate and severe AD in adult infections and dry eye [148, 155]. Serious patients in whom “topical treatments were side-effects such as exacerbation of the di- not successful or use thereof is not recom- sease and skin infections are more common mended”. with placebo than dupilumab [149]. In many cases, conjunctivitis and keratitis Dupilumab is a safe drug. The side-effects ameliorate during the treatment or when the are mild or moderate in severity and gene- treatment is discontinued. Conjunctivitis rally not different from those of placebo. emerging with the use of dupilumab is an infectious conjunctivitis or a conjunctivitis of 3) Ustekinumab unknown origin and does not seem to be an allergic conjunctivitis. It is not common and Ustekinumab is a human monoclonal anti- even in some studies, the frequency has been body targeting the p40 subunit of IL-12/23. found even below 0.5% [148,156,157]. How ustekinumab acts in AD is not definite. However, it is considered that with the inhi- Herpes virus infections have not been detec- biton of IL-23, T17 and T22 cells are blocked. ted in all studies. In the studies it was detec- The pathways that these cells play a role on ted, the entire herpes simplex virus infections are important in the pathogenesis of AD[158]. are mild or moderate and observed in the form of herpes labialis [149]. Ustekinumab is an agent indicated only in psoriasis in dermatology and its use in AD is İnjection reactions are observed in 7% of pa- off-label. Data regarding the use of this agent tients. The incidence and severity is not dose- in AD is extremely limited and in which pati- dependent [149]. ents, in which dose and for how long this Laboratorically, no evidence was observed drug will be used are yet unknown. In current suggesting hepatic, renal or any organ toxi- studies and case reports, ustekinumab has city. The only laboratory disorder detected is only been used in patients who were resistant mild eosinophilia occurring in around Week to other treatments and who had severe AD. 12 in patients receiving dupilumab [157]. Efficacy: While in some patients good results Onset rate of efficacy: Dupilumab symptoms were achieved both clinically and laboratori- are taken under control rapidly. There is a cally, in some patients adequate responses significant improvement in symptoms in the were not achieved despite improvements in

Page 22 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf laboratory values. Also in another group of ment has become a current issue to prevent patients, no improvement has been achieved the development of new attacks or to lengthen either clinically or laboratorically and even the remission period It is considered that exacerbation of the disease has been observed there is a subclinical inflammation in skin [159, 160, 161]. A significant improvement areas without lesions since histopathologic has been observed in pruritus and lesions hyperkeratosis, epidermal hyperplasia, struc- after the second or third injection in almost tural changes such as intercellular and en- all patients in whom the drug was effective. dothelial edema on the treated skin or on the Namely, ustekinumab can be evaluated as an skin with normal appearance as well as epi- agent, the efficacy of which is not definitely dermal barrier dysfunction, dendritic cell po- predicted in AD, however as an agent that ac- pulation similar to that in lesional skin, local hieves rapid success in patients it has been proinflammatory cytokines, lymphocytic ineffective [161, 162]. filtration and RNA expression profile are observed [165]. Therefore, proactive approach Age: Ustekinumab has been used in children has become a current issue in the mainte- above 12 years and in adults [163]. There is nance treatment of AD. In proactive treat- no study demonstrating whether or not the ment, there is the matter of long-term age of the patient is important regarding effi- intermittent administration of topical antiin- cacy. flammatory treatments on areas where lesi- Dose: In most of the cases, dose regulation ons were formed along with moisturization of has been applied as 45 mg or 90 mg accor- the entire body including the skin areas wit- ding the weight of the patient as in psoriasis hout lesions [165]. In fact, maintenance tre- (164). However, 45 mg and 90 mg doses have atment in AD can be defined for two different been compared with each other independent conditions. According to this, the disease is of the weight of the patient and no difference divided into two as mild or moderate in seve- was observed between each other with regard rity. Patients whose disease is taken under to efficacy [160]. control with the main treatments are accepted as mild those who cannot be taken under Administration protocol and dose range: In control as moderate [166]. Maintenance tre- current cases, the treatment was administe- atment of mild AD includes appropriate skin red by following the protocol used in psoria- care and general precautions. It should be sis. However, 12-week interval was long even preferred that the moisturizers contain oil in patients in whom the drug was effective and additives with inactive ingredients to re- and the disease exacerbated in around Week pair the skin barrier and be applied to the 8. Therefore, probably, it will be more approp- moisturized skin taking into account the war- riate that the dose range in AD be shorter nings that glycerol additive is tolerated better [158, 163]. than urea, sodium chloride and propylene Side-effects: No serious side-effects have glycol can cause irritation in children under been detected in any cases reported in litera- 2 years of age and moisturizers containing ture [163, 164]. peanut can cause allergy and products containing urea can cause irritation in children. Recommendations In addition, bath with addition of 1 ml/L sodium hypochlorite (bleach) twice a week is Ustekinumab is an agent indicated in pso- also recommended for reducing Staphylococ- riasis and its use in AD is off-label. Data cus aureus colonization and not causing bac- regarding the use of this agent in AD is ext- terial resistance [64, 65, 76, 78, 82, 102, remely limited and in which patients, in 109, 167]. In the maintenance treatment of which dose and for how long this drug will moderate-severe atopic dermatitis, topical be used are yet unknown. calcineurin application 2-3 times a week V. Maintenance Treatment of Atopic upon the appearance of the first symptom or Dermatitis on skin areas appearing to be normal but predisposed to make an attack or regular appl Due to the fact that atopic dermatitis is a re- ication of moderately potent topical corticos- current chronic disease and affects the qu teroids not containing antimicrobials 1-2 ality of life unfavorably, maintenance treat- times a week are recommended [166]. TCS

Page 23 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf with low potency or primarily TCIs are recom- and easy application. It has been expressed mended for the facial region. In the clinical that, after 95% improvement during the ma- trials, no side-effects have been reported in intenance treatment, in the final dose it can the moderately potent maintenance treatment be applied once a week for 4 weeks, decrea- 2 times a week for 16 weeks. In literature, it sing the dose by 25% every two weeks for 4 has been reported that no side-effect has been week or decreasing the dose by 50% once a observed with 1-year proactive treatment with month [64,81,167]. Phototherapy is combi- TCIs [64, 65, 76, 78, 81, 102, 109, 167]. ned with other treatments except the TCIs; other guidelines do not recommend however, There are some differences with regard to re- in the Polish guideline it is stated that TCI- commendations for moisturizer, TCS and TCI phototherapy combination can be performed use in current treatment guidelines; for exam- but caution should be exercised. Proactive ple, in the Polish treatment guideline, TCS treatments in current treatment guidelines maintenance treatment has not been recom- are summarized in (Table 6) [64, 76, 81, mended; most of the guidelines do not men- 102, 109, 167]. tion any discrimination or superiority among TCIs whereas Japanese guideline only recommends tacrolimus and in the European gui- Vi. Adjuvant Treatment in Atopic deline it is stated that tacrolimus is more Dermatitis effective than pimecrolimus. Atopic dermatitis is a chronic disease affec- It has been stated in Japanese and Polish gui- ting the quality of life of patients unfavorably delines that phototherapy can be used in the in which epidermal barrier dysfunction, im- maintenance treatment. Narrow-band UVB is mune dysregulation and environmental fac- preferred due to its efficacy, low risk profile tors play a role. A search for alternative and Recommendations adjuvant treatments comes to forefront due to the chronic course of the disease, insuffici- Phototherapy, mainly narrowband-UVB, ency of topical or systemic treatments from can be used in maintenance treatments. time to time or development of side-effects. a. Diet Recommendations 1) Probiotics, Prebiotics and Simbiotics Daily moisturization of the body and protective Live microorganisms which are beneficial by measures comprised in the main treatment of regulating the microbial balance in a certain maintenance treatment of atopic dermatitis sho- concentration are called probiotics. Probiotics uld be considered. It is preferred that the mois- are microorganisms that are found naturally turizers contain oil and additives with inactive in human body or that resemble these micro- ingredients to repair the skin barrier. Products containing urea should not be preferred in organisms. “Pro” means “for” in Greek and children due to the possibility of irritation. “biotic” means “bios” i.e. “life”. Prebiotic is a non-digestible food ingredient that promotes Bath with addition of sodium hypochloride twice the growth of beneficial microorganisms and a week is also recommended for reducing increases the activity thereof selectively. Staphylococcus aureus colonization and not When taken alone, prebiotics provide the causing bacterial resistance growth of beneficial bacteria present in the natural flora of the colon. Simbiotics are pro- Tacrolimus ointment or pimecrolimus cream ducts comprised of both prebiotics and pre- can be applied for twice a week upon first symptom or on skin areas in normal appearance biotics [168,169]. with predisposition to have an attack. Normal intestinal flora both helps digestion and affects local and general immune system. Class I TCS can be applied in the facial areas It has been reported that lactobacilli are pre- upon the first symptom and Class II TCS, not dominant in a healthy child whereas in child- containing antimicrobials, can be applied on other body areas but it should not be preferred ren predisposed to allergies, Gram(-) bacteria primarily. and Staphylococcus aureus are increased. The aim is to reestablish this balance with

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probiotics in the intestinal flora of AD pati- les, Bacillus cereus, Clostridium butyricum, ents. In addition, it is suggested that probio- Lactococcus lactis. It is desired that oral pro- tics induce Th1-weighted lymphocytes more biotics show pathogenic or toxic effects in the than Th2 and decrease IgE production [168, host, hang on to the intestinal cells, grow, 169, 170]. produce antibacterial products, produce a Probiotics received with foods or for supple- mucosal and systemic immune response, be mentary purposes are bacteria and yeasts. colonied temporarily, and not replace but be Lactic acid bacteria are Lactobacilli acidophi- added to the existing natural flora. Their mec- lus, L. casei, L. fermentum, L. gasseri, L. hanism of action is to diminish the number of johnsonii, L. lactis, L. paracasei, L. planta- pathogenic and harmful bacteria, produce an- rum, L.reuteri, L. rhamnosus, L. salivarius, L. timicrobial components, compete for food ele- bulgaricus; bifidobacteria are Bifidobacterium ments and colonization regions, ensure the breve, B. bifidum, B. infantis, B. lactis, B. lon- activation of enzymes providing digestion, gum, B. adolescentis, B. animalis; yeasts are decrease the production of amine or toxic Saccaromyces boulardii and others are Ente- enzymes and improve immune system [168, roccocus faecalis, Streptoccocus thermophi- 169, 170].

Table 6. Comparison of Current Guidelines

Treatment Guidelines America Europe Japan German Polish Maintenance Eichenfield et al. ETFAD/EADV (Katayama et al. (Werfel T, et al. (Nowicki et al. Treatment (Pro- Section 2. Task Force (Wol- 2017) (Saeki et al 2016)80 2015)167 active) 2014)69 lenberg et 2016)65 (Sidbury et al. al.2016)78 Section3,4. 2014)64

Proactive treat- TCS or TCI appli- TCS or TCI appli- TCS or TCI appli- TCS application TCI use with cer- ment approach cation 1-3 times cation twice a cation 1-3 times twice a week or tain intervals a week to the week to the pre- a week on previ- TCI, average of 3 previously affec- viously affected ously affected months to the ted areas areas, concurrent areas, concurrent previously affec- with a moisturi- with a moisturi- ted areas zer for the whole zer for the whole body body

TCS Application to the Application to the 1-3 times a week Application to the Has no place in previously affec- previously affec- up to 6 months previously affec- maintenance tre- ted areas 1-2 ted areas twice a ted areas 1-2 atment times a week week times a week

Class II and III Lower efficacy are more approp- than Class III riate, Class I is not effective eno- ugh

There is data regarding 3-month use

TCI Application to the Tacrolimus is 0,03% and Compliance to To the previously previously affec- more effective 0,1% tacroli- age restriction affected areas ted areas 2-3 mus up to 6 times a week There is data re- months Combination Tacrolimus, twice garding its clini- with photothe- a week up to 12 cal use for one rapy is not re- months; pimecro- year commended, limus once a day concurrent use up to 3 months, with sunscreen longer if intermit- recommended tent

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Phototherapy Has no place in Not discussed Can be used in Not discussed db-UVB once a maintenance tre- maintenance week (For 4 atment weeks, same as the last dose, followed by reduction in the dose by 25% every 2 weeks – for 4 weeks, then once a month a dose equal to 50% of the highest dose. PUVA treatment can be applied as well.

Moisturizers can be combined with TCS, combination with calcineurin inhibitors is possible (however caution should be exercised) Anti-histamines Has no place in Not sufficient to They are conside- Since they are First-generation maintenance tre- resolve pruritus. red to be amelio- considered to be sedative antihista- atment Sedatives are pre- rating pruritus ineffective in nor- mines are prefer- ferred for helping since H1 receptors mal treatment, red; if there is sleep problems are on C nerve fib- they are not re- concurrent aller- however they have res. Contrary to commended in the gic rhinitis/con- no place in main- many guidelines, maintenance tre- junctivitis second tenance they are recom- atment generation is pre- mended in treat- ferred but has no Blockade against ment but has no place in the main- alternative recep- place in mainte- tenance treatment tors such as H4R nance. may be more beneficial Mast cell stabili- Not discussed Not discussed Not discussed Since they are Not discussed zers considered to be ineffective in normal treatment, they are not recommended in maintenance.

Bath with bleac- Effective due to 5% bleach, 100 ml Not discussed Not discussed Not discussed her addition Staphylococcus for 100L, full bath aureus decoloni- tub zation Moisturizers In the mainte- Emollients, bath It is recommended It is recommended Should be used nance treatment, oils, barrier cre- that hydrophilic that oily moisturi- for more than the frequency and ams are recom- oils be applied to zers be applied. once a day; the amount of use are mended skin after bath. ones with barrier recommended ac- Urea, lactate, col- Urea and glycerin properties are pre- cording to age; it lagen addition is additive may be ferred; glycerol ad- is recommended beneficial beneficial, howe- ditive is tolerated that oily moisturi- ver products com- better than urea zers be applied to prising urea is not and sodium chlo- moist skin after recommended in ride; propylene bath children due to ir- glycol may result ritation. in irritation under 2 years of age; moisturizers containing peanut should not be used for the possibility of allergy.

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Table 6. Comparison of Current Guidelines (Continued) Treatment Guidelines America Europe Japan German Polish Other treat- There is evidence ments regarding their safety and efficacy, however, which one, when, and which dose should be preferred are not clear Probiotic/pre- No sufficient evi- TThere is evi- Stating that there Lactobacilli can- Not discussed biotic dence to recom- dence however, are publications not be recommend when, in which as to their safety, mended dose and which however there is according to the should be prefer- no comment for studies red are not clear recommendation

Fatty acids Fish oil is rich in Not discussed Recommended in No sufficient Not discussed n-3 fatty acid, case n-6/n-3 study for any re- competes with n- ratio increases in commendation 6 fatty acid and blood has an anti-inflammatory effect, however there is paucity of data for their efficacy in AD Vitamin D No sufficient No sufficient Not discussed Not discussed No sufficient study for recom- study for recom- study for recommendation mendation mendation Elimination diet Diet if any food Diet if any food Diet if any food Diet if any food Not discussed allergy is detec- allergy is detec- allergy is detec- allergy is detected, ted, if not normal ted, if not normal ted, there is no diet diet “special AD diet” Supports a diagnostic elimination diet for 4-6 weeks and a controlled challenge Specific immu- Generally not re- Generally not re- Not discussed Recommended if Recommended if notherapy commended commended respiratory aller- respiratory allergic gic disease coe- disease coexists or In selected cases xists or any any allergen is de- in which severe allergen is detec- tected. disease and ted. patch test are positive, particularly against house dust mites, grass and pollen Chinese herbal No sufficient evi- Not discussed According to the Not discussed No sufficient evi- therapy dence for recom- guideline of the dence for recommendation previous year mendation (Saeki et al. 2016) it can be recommended; in this guideline herbal therapies are not recommended due to li- kelihood of severe side-effects

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Borage Oil No sufficient evi- Not discussed Generally herbal Not discussed Not discussed dence for recom- therapies are not mendation recommended

Primrose oil No sufficient evi- Generally herbal Not discussed Not discussed dence for recom- therapies are not mendation recommended

Environmental Against standard Not discussed No annex Detection of po- Avoiding allergens Factors approach such tential occupatio- and irritants (ciga- as protection nal triggering rette smoke, infec- against house factors, if any tions, wool dust mites or clothes, stress) special clothes routinely

Psychological Not discussed Not discussed Recommended Recommended Not discussed Approach Particularly in cases triggered by psychologic state

Probiotics are available in capsule, tablet, [170]. In a meta-analysis published in 2016, cachet or powder forms. They may be found it has been reported that oral probiotic admi- in various fermented foods, yoghurt and milk nistration for 8 weeks was effective in the tre- beverages. The most commonly used probio- atment of AD in children above 1 year of age. tics are Bifidobacterium lactis, Streptococcus [171]. In the same study, it has been reported termophilus, Lactobacilli reuteri, Lactobacilli that probiotic use longer than 8 weeks did not rhamnosus, and Lactobacilli acidophilus. provide an additional benefit. Mixtures con- Their side-effects are limited. Even though taining different probiotic and prebiotic bac- bronchitis, infections, intestinal ischemia are teria or lactobacillus species have been found mentioned among the side-effects, many stu- to be more effective than other probiotic alter- dies reported that side-effects are not different natives whereas due to low number of pati- from those of placebo [168,169]. ents enrolled in the randomized, controlled trials and presence of methodologic and bio- The efficacy of probiotics in prevention and logic differences between the trials suggest treatment of allergic diseases is controversial. that the results are very optimistic[172]. With Lactobacillus and Bifidobacterium species regard to current guidelines, it has been sta- have been investigated. There are studies and ted, in the current American [64] and German evidence supporting that probiotics may be [109] guidelines, that there was no sufficient beneficial in the treatment and prevention of evidence for them to be recommended; in the atopic dermatitis. They are necessary for the European guideline [78]. that there is some stimulation of intestinal flora intestine-related evidence as to their safety and efficacy w lymphoid tissues and a healthy immune hereas when, how much and which bacte- system in the newborn. The intestinal flora of ria/yeast should be preferred were not clari- the babies who have allergic diseases has fied; in the Japanese guideline [81]. that there been found to be more different and the vari- was some evidence with regard to their safety ety of the intestinal flora has been found low. and efficacy;and in the Polish guideline [167]. It is envisaged that the intervention on intes- Recommendations tinal flora by probiotics, prebiotics or simbiotics will regulate immune response, prevent According to current data, routine use of the development of allergic diseases and can probiotics is not recommended in the pre- contribute to the treatment of the disease. In vention of development of AD or its treat- a meta-analysis published in 2014, it has ment. On the other hand, they can be used been reported that mixture of different bacte- in selected cases due to the presence of rial products and bifidcobacterum species of evidence regarding their safety and effi- lactobacillus species have been found to be ef- cacy. fective in decreasing the AD SCOARD index

Page 28 of 37 (page number not for citation purposes) J Turk Acad Dermatol 2018; 12 (2): 18122r1. http://www.jtad.org/2018/1/jtad18122r1.pdf the subject was not discussed (Table 6) [64, in the treatment of childhood or adulthood 76, 78, 81]. AD [174, 175]. Side-effects such as diarrhea, elevation in transaminases, disease exacerba- 2) Fatty Acids tion and reversible cardiomyopathy along Delta-6-desaturase activity has been found to with very serious side-effects such as fatal he- be low in AD (173). Since decreased level of patic necrosis, nephropathy caused by CHT fatty acids has been found in the patients have been reported in literature [65, 81]. On with eczema, it has been suggested that es- the other hand, it has been pointed out that sential fatty acids play a role in the pathoge- there may be non-herbal ingredients along nesis of AD however, the efficacy of essential with herbal flowers and herbal seeds under n-6 fatty acid supplement has not been de- the name of CHT [175]. Although it has been monstrated in the studies carried out. Later, stated in 2016 Japanese Guideline that CHT n-3 fatty acid, considered to be demonstrating in combination with other treatments in re- antiinflammatory properties by competing sistant patients can be considered, in 2017 with n-6, has become a current matter [64, Japanese Guideline and Polish Guidelines, 168, 169, 173]. Fish oil is rich in n-3 fatty there is the opinion that there is no adequate acid. In case n-6/n-3 ratio increases in blood, evidence to recommend their use; it has not n-3 fatty acid supplement has been recom- been discussed in European and German mended [81]. Gamma linoleic acid (GLA) is a Guidelines (Table 6) [64, 76, 78, 81, 102, kind of essential fatty acid and a precursor of 109, 167]. some mediators such as prostaglandin E1. Even though it has been reported that it re- Recommendations solved inflammation and immunity in some of the trials regarding GLA, different sources There is no adequate evidence to recom- have been used for GLA in these studies; bo- mend CHT. rage oil (23% GLA) and primrose oil (8-10% GLA) (168,169). Oral supplement of these both oils has been evaluated as inert for ec- 4) Oral Vitamin D zema in Cochrane review[14]. Borage oil and There are various results achieved in the stu- primrose oil have not been recommended in dies conducted regarding the serum vitamin currentguidelines [64, 76, 78, 102, 109, D levels of SAD patients. In the studies, the 167]. effect of vitamin D replacement to disease ac- Recommendations tivity score varies in AD patients [168]. Vit amin D replacement has not been recom Standard use of fatty acids in AD treatment mended in current guidelines (Table 6) [64, is not recommended, however, in case n- 76, 78, 81, 102, 109, 167]. 6/n-3 ratio increases in blood, n-3 fatty Recommendations acid supplement has been recommended. Even though there is no adequate evidence to recommend vitamin D, replacement the- 3) Chinese Herbal Treatment reof is recommended in case of deficiency. Treatments of herbal origin can be administered as topical or systemic in AD. Among these, Chinese Herbal Treatments (CHT) are 5) Elimination Diet generally mixtures with special names in Food allergy is not rare in AD and food allergy which many herbs are combined. Along with test should be performed in suspected cases Zemaphyte, Xiano-Feng-San, Hochu-ekki-to, [65, 168]. Most of the current guidelines do the efficacies of which are demonstrated in not recommend a special diet if there is no randomized, controlled studies, there are food allergy detected. However, American gui- many other products prescribed in general deline supports a diagnostic elimination diet dermatology clinics in Japan [65,81]. 28 ran- and controlled elimination diet for 4-6 weeks domized, controlled trials have been reviewed if there is a suspected case and no positivity in 2013 Cochrane review and it has been stain the test [64, 76, 78, 81, 102, 109, 167]. ted that oral or topical CHT is not beneficial

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Recommendations Sleeping disorders in AD are characterized as diminished quality of sleep, waking up during Food allergy should be investigated in sus- the night and daytime sleepiness. A relations- pected cases in AD. If food allergy is not de- hip has been detected between sleeping prob- tected, in order to avoid malnutrition, lems and AD severity. It has been reported elimination diet is not recommended. that sleeping problem is the main factor affecting quality of life in childhood AD. Tiredness, fatigue and mental diseases such as depres- b. Environmental Factors sion can be observed in patients with sleeping problems [47, 176, 177]. One or more dep- It is considered that skin barrier function is ression symptoms are observed in one third impaired in AD and therefore allergens penet- of AD patients. Anxiety, impairment of con- rate through the skin and activate the i centration along with depression have been mmune system and this leads to the develop- reported in AD patients and even depression ment of atopic diseases such as hay fever, or injuries or fractures due to antihistamine asthma which is known as atopic walk. The- use could have been observed. Assessment of refore, it is suggested that long-term control systemic treatment alternatives such as of skin inflammation and barrier function will cyclosporine and methotrexate have been re- prevent the development of atopic diseases in commended in patients suffering from slee- the future. Moisturizing the skin is one of the ping problems [47, 176, 177]. In German and main treatments in AD. Again for the same Japanese guidelines which are the recent reasons, environmental factors that may im- ones, psychiatric consultation has been repair the barrier function of the skin should be commended in cases in which mental disea- avoided. The main allergens and irritants are ses play a role in etiology in AD patients soaps, detergents, house dust and mites, sol- (Table 6) [64, 76, 78, 81, 102, 109, 16]. vents such as formaldehyde and toluene, infections, cigarette, wool clothes. Since the threshold of AD patients are low, it is recom- Recommendations mended that they avoid these general allergens and irritants, use soaps with neutral pH, Psychiatric consultation should be reques- prefer soft and cotton clothes, wear the new ted with regard to comorbid mental disea- clothes after washing with liquid cleaners and ses in which psychological factors trigger rinsing very well and avoid extreme heat and AD. extreme moisture. In addition, it is recommended that, if any, occupational potential Systemic alternative treatments should be trigger functions be detected. Along with evaluated in patients suffering from slee- these precautions, patient-based approach is ping problems despite appropriate topical recommended [64, 76, 78, 81, 102, 109, treatment. 167] Recommendations References Avoiding irritants that may impair skin bar- 1. Flohr C, Mann J. New insights into the epidemiology rier function, detection of potential triggers of childhood atopic dermatitis. Allergy 2014; 69: 3- and patient-based approach is recommen- 16. PMID: 24417229 ded. 2. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab 2015; 66: 8-16. PMID: 25925336 c. Psychological Factors 3. Megna M, Patruno C, Balato A, Napolitano M, Balato As well as causing predisposition to atopic di- N. Adult Atopic Dermatitis: Less Certainty, More seases such as hay fever and asthma, AD Challenges. J Investig Allergol Clin Immunol 2017; causes sleeping problems not rarely due to 27: 276-277. PMID: 28731420 chronic pruritus and inflammation, and co- 4. Otsuka A, Nomura T, Rerknimitr P, Seidel JA, Honda T, Kabashima K. The interplay between genetic and morbid mental health problems such as spe- environmental factors in the pathogenesis of atopic ech disorder and hyperactivity disorder in dermatitis. Immunol Rev 2017; 278: 246-262. PMID: childhood [47]. 28658541

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