Advances in Atopic Dermatitis (Eczema) Treatments

Abstract

Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory skin disease that is characterised by intense itching and recurrent eczematous lesions. It predominantly starts in infancy where it affects up to 20% of children, but is also highly prevalent in adults.  AD inflicts a significant psychosocial burden on patients and their families, and increases the risk of food allergy, asthma, allergic rhinitis, other immune-mediated inflammatory diseases, and mental health disorders. It is lifelong condition associated with epidermal barrier dysfunction and altered immune function.

Currently, prevention and treatment focus on restoration of epidermal barrier function, which is best achieved through the use of emollients, and controlling intermittent flares with anti-inflammatory agents. Topical corticosteroids remain the preferred first-line therapy for acute flares, but they are also used proactively along with topical calcineurin inhibitors to maintain remission.  There remains a need and opportunity to improve AD care through future research directed toward an improved understanding of the heterogeneity of the disease and its subtypes, the role of autoimmunity in its pathogenesis, the mechanisms behind disease-associated itch and response to specific allergens, and the comparative effectiveness and safety of therapies.

Introduction

Atopic dermatitis (AD) is a common pruritic chronic inflammatory skin disease that presents with relapsing and remitting cycles and significantly burdens a patients’ quality of life (QoL).¹ AD affects over 20% of children and up to 3% of adults in many countries and its prevalence is on the rise, especially in the developing world.^2,3  AD prevalence appears to have plateaued in certain developed countries including New Zealand and the UK but continues to rise in lower-income countries including South East Asia and Latin America, specifically in young children aged 6-7 years of age.³ AD prevalence varies across race and region as evidenced by its higher incidence in African-American children (17.3%) compared to Caucasian children (10.4%); however, the role of race and ethnicity in the pathophysiology of AD remains unclear.^4-6  AD has a multifactorial etiology including immune system dysfunction, skin barrier disorders, genetic and environmental factors.^7,8 However, the interaction between these factors is poorly understood⁷. It is imperative to the success of AD management to treat both the epidermal barrier defect and inflammation present in many AD cases.⁹ Recent advances in the knowledge of the immunopathogenesis of AD are promising and expected to yield new therapeutic targets and opportunities for patients.¹⁰  This paper aims to explore recent advances in the treatment of AD and develop consensus on the topical treatment of mild-to-moderate atopic dermatitis (AD).

Methods

An expert panel of 9 dermatologists and paediatricians who commonly treat AD patients was convened on October 29, 2017 to develop evidence-based consensus treatment recommendations for the topical management of mild-to-moderate AD in pediatric and adult patient populations. The treatment of other forms of dermatitis such as irritant dermatitis and allergic contact dermatitis is not included in the scope of this work. Likewise, the treatment of severe AD and use of systemic treatment for atopic dermatitis were not included in the scope of this work.

Evidence coupled with the expert opinion and experience of the panel was used to define and address current clinical challenges in the clinical care of mild-to-moderate AD and to develop 15 key statements or recommendations for clinicians to optimize treatment and improve outcomes.  The consensus process consisted of a nominal group technique and a Delphi approach.¹¹ Statements were developed based on AD guidelines literature identified prior to the meeting. The panel reached unanimous consensus through 9 blinded reiterations and votes to define the 15 final statements and key points used for discussion in this paper.

Literature review

Literature describing current best-practice in AD treatment was identified in a search prior to the expert panel meeting.  Selected literature was clinically relevant  to the pre-established consensus statements, addressed multidisciplinary aspects of AD management and used validated AD classification systems such as Severity Scoring of atopic dermatitis, SCORAD¹²and Eczema Area and Severity Index, EASI.¹³ Guidelines included for discussion were the most current, dated from 2012-2016 (Table 1).

Results of the search indicate guidelines for the topical treatment of AD have not changed significantly over the past 10 years. Evidence from the review suggest there is more heterogeneity in topical treatment guidelines and practices for the pediatric AD population^14-16 than those for adult AD.  ^17,18,19-21  For example, TCIs are recommended by the American Academy of Dermatology (AAD)⁷ and European Academy of Dermatology and Venereology (EADV)^18,22 endorsed guidelines, but not by the Japanese Dermatological Association (JDA)¹⁴ guidelines .

Results of the panel discussions and consensus statements

Statement 1: AD is a common chronic inflammatory skin disease that presents with relapsing and remitting cycles and burdens patients’ quality of life (QoL).

AD diagnosis starts with a detailed patient history, including ascertainment of family history of atopy (atopic dermatitis, allergic rhinitis and asthma), known allergies and exposure profile.²³ This is followed by physical examination of the patient’s skin to determine the extent of the AD and estimating the percentage involvement, while severity is determined by grading specific signs of presenting eczema (e.g. oozing, scaling, crusting, erythema, edema, lichenification). ¹³ In addition, AD flare-ups significantly burden patients’ physical and psychosocial well-being and is associated with high levels of sleep deprivation, stigmatization, social withdrawal, anxiety, and depression.²⁴

In clinical practice, severity should take into account patient criteria such as how AD affects their ability to carry out daily activities and functions, impacts their QoL, and appears as lesions and affected body surface area.^21,23Anxiety in people with AD is of particular concern, as psychological stress has been found to trigger the itch-scratch cycle and can precipitate or exacerbate AD leading to flares and abnormal skin barrier function.^24,25 In a study involving 318 AD patients aged 4 to 70 years, patients were reported to have significantly lower vitality, social functioning and mental health than the general population.²⁵ In addition, study participants had statistically lower mental health scores than patients with other chronic illnesses including hypertension and diabetes. ²⁵ An international study involving 2002 patients aged 13 years and older with moderate to severe AD reported more than 33% of the patients have lower self-confidence because of their condition.²⁶ The same survey found approximately 50% of experience depression and unhappiness and anxiety about the next exacerbation even when in remission.²⁶ Patients reported on average 9 flares per year, with an average duration of 15 days per flare, resulting on average in 136 days of AD flare up days experienced per year and 107 nights of interrupted sleep.²⁶ 75% of patients and their caregivers feel that being able to effectively control AD would be the single most important improvement in their QOL.²⁶ For these reasons, it is important AD assessment focus on both physical and QoL aspects of the disease for optimal AD management.

Statement 2: Age, ethnicity, genetics, comorbidities, and burden of disease influence the experience of living with AD.

AD is a common condition in infancy which usually disappears by 3 years of age in most children.¹⁶ The prognosis is mostly determined by severity, exposure and sensitization to allergens, the presence of rhinitis, and a positive family history of atopy.²⁷ The early identification and avoidance of sensitizing allergens coupled with emollient therapy to improve skin barrier function at a young age? is therefore extremely important for limiting its progression and burden on the patient as well the population.

AD prevalence continues to vary and change in different regions of the world. Nigeria, the United Kingdom and New Zealand and, more recently, Latin America are currently the areas with the highest childhood prevalence, with a prevalence of about 20%, while China and India report the lowest prevalence of 0.2% and 0.9%, respectively.^3,28 Environmental risk factors associated with increased prevalence include higher socioeconomic status, higher level of family education, smaller family size and urban environment. (need reference)

Research indicates the adult prevalence of AD ranges from 2.1% to 4.9% across countries, is generally lower for males vs females, and decreases with age while severity varies by scale and region. However, regardless of age or region, the majority of AD cases in children and adults are mild, while severe cases average between 10-20% in children and are slightly higher in the adult population.^18,28

Statement 3: Itch, sleep disturbances, and secondary infections are important issues for patients with AD.

Patients with AD frequently experience sleep disturbances that have been shown to be directly related to the severity of pruritus. A 2006 study of 76 patients from general practitioner and dermatologist practices found that more than 50% of the patients suffered from sleep disturbance due to pruritus.²⁹  Pruritus and its associated lack of sleep can significantly decrease AD patients’ quality of life. A prospective cross-sectional and matched study³⁰of 1356 adult outpatients with chronic urticaria, psoriasis or AD showed AD significantly impedes sleep, physical comfort and daily activities. Of the 386 AD patients included in the study, 46% reported “often” having difficulty with sleep while 10% of patients experienced difficulties sleeping on a daily basis. AD was reported to impact physical comfort more than urticaria or psoriasis (p<0.001) and affect daily activities more than psoriasis (p<0.001).³⁰ 

Antihistamines have been used to relieve itching in AD patients in past decades, despite there being limited data to support their use.¹⁸ The few randomized trials that have been conducted with both first and second generation histamines show little or no effect in decreasing pruritus.^18,21 First generation antihistamines such as hydroxyzine,  may facilitate sleep better than newer, less sedating second generation histamines in acute situations during flares but do affect sleep quality. ²¹ As such, guidelines do not support their use for the treatment of pruritus and caution against long term use for sleep disturbances.^18,19

Statement 4: Patient and/or caregiver education is an essential aspect of AD management.

Patient and caregiver education is a key aspect of effective AD control and should be viewed as a type of intervention in itself that can improve therapeutic outcomes.  Although effective treatments for AD are available, outcomes are often limited by poor adherence to treatment plans. It is important for patients and caregivers to understand the chronic relapsing-remitting nature of AD, how to cleanse and hydrate skin, apply moisturizers and topical medications, when to seek medical advice, how to avoid irritants and triggers, when to step up or step down treatment for treatment to be successful.^19,31 Education should start with a clear, written treatment plan and continue with each follow up visit to ensure the plan is well understood and adhered to. ³¹ Discussion and individualized, written care plans should provide the opportunity for the patient to identify and plan ways to avoid their triggers and be actively involved in their care plan.¹⁹  Educational approaches that utilize a number of different methods and tools such as videos, pamphlets, support groups, to facilitate the transfer of knowledge and skills to patient and their caregivers have been demonstrated to improve outcomes such as AD disease severity, treatment adherence, QOL, and coping with itch.³²  These approaches are recommended as an essential adjunct to conventional therapy. Caregiver education programs such as atopy schools that incorporate varied educational approaches and tools are ideal however, while widely available in Europe, they are not so in Canada.

Statement 5: Most patients have mild-to-moderate disease, which usually responds to topical therapy.

Although information is limited on its severity, it is estimated that approximately two-thirds of AD patients have mild disease and 26% to 7% have moderate and severe disease.³³ Although it is common practice for pediatric patients to be referred and treated by dermatologists or pediatricians, most cases can be adequately treated by primary care physicians with the use of topical anti-inflammatory therapy. Whether or not patients are referred to a dermatologist, pediatrician, or allergist, family practitioners play a central role in AD care, follow up, and ongoing patient/caregiver education.³¹

Statement 6: Regular use of moisturizers and avoidance of triggers are recommended as the foundation of management for all patients with atopic dermatitis, regardless of disease severity.

Moisturizers remain the cornerstone of treatment for all severities of AD, to counter and control the xerosis, decrease epidermal water loss and improve the dysfunctional epidermal barrier.¹⁷ A Cochrane review³⁴with a focus on moisturizers that contained humectants, lipids and/or ceramides (or their precursors)³⁵ reported their daily use reduced the rate of flares and enhanced the efficacy of topical steroid treatment. The panel agreed with established guidelines ^14,17-23 supporting the daily use of moisturizers, alone or in combination with other therapy, for all AD patients to prevent itching, reduce flare frequency and restore the lipid balance of the skin. In accordance with established guidelines, the panel acknowledged the application of moisturizers should be liberal and frequent and the choice of moisturizer will be dependent on individual preference but ideally should be safe, effective, inexpensive, and free of additives, fragrances, perfumes, and other potentially sensitizing agents. Moisturizers should also be applied soon after bathing, to improve skin hydration.¹⁷ Although the frequency of bathing is controversial, short duration warm baths are recommended for all patients with AD as part of standard care, immediately followed by adequate application of moisturizer to damp skin.^{14,17,18,21,22} Dilute bleach baths (using 0.5cups sodium hypochorite per full bath or 1mL/L) twice weekly are recommended for patients with recurrent skin infections.^18,31

Statement 7: When routine moisturizing does not control symptoms, anti-inflammatory topical therapy should be added and continued until control is achieved.

Define control as clearance or near-clearance (ideally with photos).

If moisturizers and avoidance of triggers is not sufficient, topical anti-inflammatory agents, such as corticosteroids (TCSs) or calcineurin inhibitors (TCIs), are recommended and should be applied to involved skin daily or twice a day until clear, while moisturizers continue to be applied to all areas.^{14,17,18,22,23,36,37}  TCS are the most widely used first-line anti-inflammatory option and are available in a variety of strengths from mild (group I) to potent and very potent (group III and IV).²¹ Super potent TCS are not recommended for mild to moderate AD, especially in children. There seems to be no consensus regarding what agent, strength or dose of TCS to use for the treatment of flares as there are limited controlled, comparative studies with TCS products. Once daily use of a potent TCS for 3-6 days is usually sufficient for treatment of flares, followed by a quick taper in potency.^18,21 Another common practice is to use the lowest potency agent thought to be needed and adjust upward only if it fails.¹⁷

Treatment with topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI) for mild to moderate AD are both very effective in gaining control of AD.

If topical TCS or TCI treatment does not manage to control AD inflammation, phototherapy or a short course of systemic corticosteroids may be warranted to get the disease under control, while continuing the topical products.²¹ (Fig 1) (Anita add warning re rebound for systemic steroid use)

Statement 8:  Patient age, location/appearance/extent of lesions, response to previous therapy, and patient preferences should be considered when choosing a topical anti-inflammatory treatment for AD

There are a multitude of formulations of topical anti-inflammatory treatments. The broad categories are ointments, oils, creams, lotions, gels, foams, sprays. In general, for eroded lesions or non-intact skin, ointments or oils are preferred as they do not contain the preservatives required to stabilize other formulations that may cause burning or stinging of the patient’s skin. Ointments are also more potent than their equivalent in other formulations. Creams are more cosmetically acceptable than ointments, and are a good choice for patients who do not tolerate the sticky feel of an ointment. Cream and ointment formulations are commonly available in generic form and are thus the best options for patients with financial constraints. Lotions are optimal for hair-bearing sites but the alcohol in their formulation may produce a burning sensation on non-intact skin. Gels, foams, and sprays are more recent developments and may lead to enhanced medication delivery. Gels are oily and are best reserved for body sites. Foams, like lotions, are easy to apply to hair-bearing sites without soiling of the hair so are a good option for affected scalps. Sprays should be reserved for locations that might be widespread or difficult to reach, for patients with body or scalp involvement who can direct the spray appropriately (ie. not recommended in children).

Low potency TCS products are considered appropriate for face and folds and for the very young, while high potency TCS are generally not used in AD unless the lesions are very chronic and lichenified. TCI products, including tacrolimus ointment and pimecrolimus cream, are safe and effective for children over 2 years of age and can be used on all areas of the body and face.²¹ However, they may not be well tolerated on very inflamed skin.

Statement 9: Patient/caregiver concerns about topical anti-inflammatory therapies (e.g. steroid phobia, black box warning) should be addressed.

TCS are generally safe when used appropriately; however, potential side effects such as skin atrophy, purpura, telangiectasia, striae, focal hypertrichosis, impaired wound healing, allergic contact dermatitis and acneiform or rosacea-like eruptions on the face can occur, particularly if TCS are used inappropriately.  The potential for these and other side effects, however, may result in a patients’ fear to comply with TCS treatment and should be discussed with the patient to improve adherence and avoid under-treatment.²¹

Similarly, TCI usage may result in short term side effects that could negatively impact compliance such as cutaneous viral infections, skin burning and pruritus, especially when applied to acutely inflamed skin.^17,21 Patients should be advised of these potential side effects to avoid premature discontinuation of treatment.  The FDA issued black box warning on TCIs regarding a possible risk for lymphoma cancer should also be discussed with patients prior to start of treatment.¹⁸ Clinicians should assure patients that no causal relationship has been established between lymphoma cancer and TCI and that 5 year post-marketing surveillance data from 11,000 patients confirm there is no higher incidence of cancer in TCI-exposed patients than in the general population.³⁸

Statement 10: Maintenance therapy with topical anti-inflammatory agents may reduce flares and should be considered in patients with frequently relapsing disease.

TCS and TCI may be used intermittently to maintain control if moisturizers alone do not. TCS may be used proactively 1 – 2 times per week or TCI may be used 2 – 3 times per week after disease stabilization, to prevent recurrences in previously affected skin areas (Fig 1). ^{14,17-23,36,37,39}Data from several different trials show proactive therapy with TCS or TCI reduces number of flares and improves the QoL of AD patients and improves mild, moderate AD care. ⁴⁰ The occurrence of side-effects does not depend on the proactive or reactive use of the substances, but on the respective potency of TCI and TCS.⁴⁰ Proactive therapy allows the patient to actively control their disease, however, the additional cost associated with long-term maintenance therapy and the need for more frequent medical follow up may be of concern for some patients and health providers and warrants consideration, discussion and planning to ensure patient compliance and safety.

Statement 11: Patients on long-term TCS therapy should be periodically assessed for potential side effects.

The long-term safety of TCS is unknown as most studies conducted to date have been short-term and none have exceeded 1 year in duration.⁴⁰ Therefore, the continuous use of higher-potency products with higher risks for systemic side effects should be avoided, particularly in children, and patients monitored periodically for potential complications associated with long-term, even intermittent, TCS use. Cutaneous side effects and skin atrophy should be monitored for with regular physical examinations in both children and adults.^14,17-21

Statement 12: Secondary infections of AD should be treated with short-term topical or systemic antibiotic or antiviral therapy as per causative agent; antibiotics should not be used long-term.

Secondary infections are a common problem in patients with AD which may warrant short-term topical or systemic antibiotic treatment.^18,21 This is particularly important since bacterial infections can flare AD.   However, they should only be used for short periods and not long term to avoid antibiotic resistance.^18,21   Cultures should be done to confirm the bacterial infection and assess response to treatment.  For patients with repeat infections, bleach baths provide another effective therapy to control infection, using 100mL of 5% household bleach per full tub two to three times a week.²¹

Statement 13: Panel allergy testing and dietary modification are not routinely recommended for mild-to-moderate AD.

There is a perception that most patients with AD have food allergies. While atopic patients have more allergies than the rest of the population, the majority of mild /moderate AD patients do not. Patients with AD have a 10-15% risk of an IgE mediated food allergy.(reference?)  These patients will respond with symptoms such as hives, vomiting, diarrhea, and change in level of consciousness immediately after exposure. Patient who get hives can get itchy and scratch secondarily inducing eczema. Eczema increases IgE mediated food allergies. Food allergies rarely induce eczema.(add reference)

The patient history should be used to guide the determination of what role, if any, specific food and environmental allergens play in the patent’s AD. For example, some patients’ eczema may be worse in the spring and fall when pollen is around or there are abrupt changes in temperature, or react shortly after eating certain foods which may indicate a significant allergen. Patients should be assessed by an allergist for confirmation of an alleged food allergy and only employ restricted diets or food avoidance after allergies have been confirmed according to established National Institute of Allergy and Infectious Disease (NIAID) guidelines.⁴¹ Currently, there is no evidence that milk-or egg-free elimination diets or food restricted diets benefit patients with AD. ¹⁸

Statement 14: Many patients with AD have difficulty adhering to management recommendations, leading to poorer outcomes.

Patient outcomes and clinical improvement are closely related to topical medication adherence, and are especially important in chronic dermatological diseases such as AD.  Providers can help increase adherence with the selection of the correct medication, the involvement of family members or friends in the patient’s treatment plan, the use of simple and clear written treatment plans, by explaining likely side effects to the patient prior to use of the medication and through frequent, ongoing follow up clinic visits.⁴² Table 2 lists key elements providers should strive to provide in their patient interactions that improve patient adherence to prescribed therapy.²⁵

Statement 15: New therapies based on a better knowledge of the pathogenesis of AD,  may lead to improved outcomes.

There remains an opportunity and need to improve AD treatment with new approaches that treat the underlying disease and prevent the onset of new lesions by affecting pathogenic mechanisms. Recently, three new, nonsteroidal, barrier creams (Atopiclair, Mimyx, and Epiceram) have entered the marketplace and been shown to improve AD by repairing damaged skin barrier and providing some anti-inflammatory activity.⁴³ In addition, biologics that target immune responses and inhibit IgE cells, T cells, and target Th1, Th2, Th22, phosphodiesterase-4,  IL-4 and IL-31, such as rituxamib, pascolizumab, REGN668, and crisaborole, show promise for the treatment of AD and are being evaluated.⁴⁴ (add Echenfield 2017)

Discussion

Inconsistencies and differences between guidelines were acknowledged and addressed given they can have a negative impact on implementation and adherence and result in inconsistent, suboptimal patient care. It is hoped that this update and review of guidelines coupled with the expert opinion and clinical experience of the panel will help standardize and guide topical AD care. Recommendations contained in this paper aim to assist primary care  physicians, allergists, pediatricians and dermatologists in their treatment of mild-to-moderate AD and address clinical challenges and inconsistencies in treatment.

Limitations

Statements used in the position paper were based on a mix of data and expert opinion. While it is possible that alternatives for AD treatment guidelines could exist, the statements are suggestions for best practice developed from a panel of expert clinicians that are supported by peer-reviewed literature and other existing guidelines.

Conclusions

A multi-therapeutic approach that incorporates short-term management of flares and longer-term strategies to prolong the time between flares is needed for the treatment of AD. Clear, simple treatment plans, agreed upon jointly between the health provider and patient and close, frequent follow-up provide means to improve the poor adherence associated with chronic topical therapies. Patient preferences and cost of moisturizers and topical anti-inflammatories should both be considered when developing a treatment plan and plans should be adjusted and changed according to patient safety, effectiveness and compliance.

Table 1: Selected Guidelines and Clinical Care Pathways 

Association, Year, Country	Document Title	Contributors	Methodology
AAD   2014, US17	Section 2: Management and treatment of AD   with topical therapies	US/UK/Canada dermatologists	Literature search and classification of evidence and recommendations
EADV   2012, EU18,22	Guidelines for treatment of AD Part I   Guidelines for treatment of AD Part II	EU allergists and dermatologists
JDA   2016, Japan14	Clinical practice guidelines for the management   of AD	Japanese Dermatologists
Eczema Society of Canada/Société canadienne de l’eczéma.   2016, Canada19	Practical guideline to management of AD	Canadian Dermatologists
Not applicable   2016, Canada20	Case-Based Clinical Pathway	Canadian Dermatologists
ETFAD/EADV AD task force21	Position paper adult and paediatric AD patients, 2015	EU allergists and dermatologists

AAD, American Academy of Dermatology; EADV, European Academy of Dermatology and Venereology; JDA, Japanese Dermatological Association.

Table 2:  10 Steps to Improve Patient Compliance

1	Look patients in the eye; first impressions count
2	Allow patients to verbalize their story
3	Show you are interested and prepared to listen
4	Touch and feel their skin
5	Explain the condition and the rationale for treatment
6	Solicit input and questions
7	Demonstrate the application process
8	Keep the treatment regimen simple
9	Give patients contact information
10	Provide instruction sheets for later home reference and education

Provided by Steven Feldman et al. 2008, American Academy of Dermatology⁴²

Fig 1: Guidelines: Overview of Topical Treatment for AD

Mild: SCORAD <25/or transient AD; Moderate: SCORAD 25-50/or recurrent AD²⁶

Recommendations from guidelines^{14,17,18,22,37}, pathways^19,20 and a position paper²¹

EndNote Reference List

1. Garg N, Silverberg JI. Epidemiology of childhood atopic dermatitis. Clinics in dermatology. 2015;33(3):281-288.

2. Flohr C, Mann J. New insights into the epidemiology of childhood atopic dermatitis. Allergy. 2013;69(1):3-16.

3. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015;66 Suppl 1:8-16.

4. Kaufman BP, Guttman‐Yassky E, Alexis AF. Atopic Dermatitis in Diverse Racial and Ethnic Groups–Variations in Epidemiology, Genetics, Clinical Presentation, and Treatment. Experimental dermatology. 2018.

5. Williams H, Stewart A, von Mutius E, Cookson W, Anderson HR. Is eczema really on the increase worldwide? Journal of Allergy and Clinical Immunology. 2008;121(4):947-954. e915.

6. Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI. Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three. Journal of Allergy and Clinical Immunology. 2009;124(6):1251-1258. e1223.

7. Wen HJ, Chen PC, Chiang TL, Lin SJ, Chuang YL, Guo YL. Predicting risk for early infantile atopic dermatitis by hereditary and environmental factors. British Journal of Dermatology. 2009;161(5):1166-1172.

8. Leung DYM, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: Shifting paradigms in treatment approaches. Journal of Allergy and Clinical Immunology. 2014;134(4):769-779.

9. Gittler JK, Shemer A, Suárez-Fariñas M, et al. Progressive activation of TH2/TH22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. Journal of Allergy and Clinical Immunology. 2012;130(6):1344-1354.

10. Mayba JN, Gooderham MJ. Review of Atopic Dermatitis and Topical Therapies. Journal of Cutaneous Medicine and Surgery. 2017;21(3):227-236.

11. McMillan SS, King M, Tully MP. How to use the nominal group and Delphi techniques. Int J Clin Pharm. 2016;38(3):655-662.

12. Stalder JF, Taieb A, Atherton DJ, et al. Severity scoring of atopic dermatitis: the SCORAD index: consensus report of the european task force on atopic dermatitis. Dermatology. 1993;186(1):23-31.

13. Hanifin JM, Thurston M, Omoto M, et al. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. Experimental Dermatology. 2001;10(1):11-18.

14. Saeki H, Nakahara T, Tanaka A, et al. Clinical practice guidelines for the management of atopic dermatitis 2016. The Journal of dermatology. 2016;43(10):1117-1145.

15. Carbone A, Siu A, Patel R. Pediatric atopic dermatitis: a review of the medical management. The Annals of pharmacotherapy. 2010;44(9):1448-1458.

16. Galli E, Neri I, Ricci G, et al. Consensus Conference on Clinical Management of pediatric Atopic Dermatitis. Ital J Pediatr. 2016;42:26.

17. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: Section 2: Management and treatment of atopic dermatitis with topical therapies. Journal of the American Academy of Dermatology. 2014;71(1):116-132.

18. Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic eczema (atopic dermatitis) Part I. Journal of the European Academy of Dermatology and Venereology. 2012;26(8):1045-1060.

19. Atopic dermatitis: A practical guide to management. Eczema Society of Canada;2016.

20. Guenther LC, Andriessen A, Lynde CW, et al. Development of a Clinical Pathway for Atopic Dermatitis Patients: A Case-Based Approach. Journal of drugs in dermatology: JDD. 2016;15(12):1485-1494.

21. Wollenberg A, Oranje A, Deleuran M, et al. ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients. Journal of the European Academy of Dermatology and Venereology. 2016;30(5):729-747.

22. Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic eczema (atopic dermatitis) Part II. Journal of the European Academy of Dermatology and Venereology. 2012;26(9):1176-1193.

23. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis: Part 1: Diagnosis and assessment of atopic dermatitis. Journal of the American Academy of Dermatology. 2014;70(2):338-351.

24. Senra MS, Wollenberg A. Psychodermatological aspects of atopic dermatitis. Br J Dermatol. 2014;170 Suppl 1:38-43.

25. Carroll CL, Balkrishnan R, Feldman SR, Fleischer AB, Manuel JC. The burden of atopic dermatitis: impact on the patient, family, and society. Pediatric dermatology. 2005;22(3):192-199.

26. Zuberbier T, Orlow SJ, Paller AS, et al. Patient perspectives on the management of atopic dermatitis. Journal of Allergy and Clinical Immunology. 2006;118(1):226-232.

27. Peroni DG, Piacentini GL, Bodini A, Rigotti E, Pigozzi R, Boner AL. Prevalence and risk factors for atopic dermatitis in preschool children. Br J Dermatol. 2008;158(3):539-543.

28. Barbarot S, Auziere S, Gadkari A, et al. Epidemiology of atopic dermatitis in adults: Results from an international survey. Allergy. 2018.

29. Barbeau M, Bpharm HL. Burden of Atopic dermatitis in Canada. International Journal of Dermatology. 2006;45(1):31-36.

30. Grob JJ, Revuz J, Ortonne JP, Auquier P, Lorette G. Comparative study of the impact of chronic urticaria, psoriasis and atopic dermatitis on the quality of life. British Journal of Dermatology. 2005;152(2):289-295.

31. Eichenfield LF, Boguniewicz M, Simpson EL, et al. Translating Atopic Dermatitis Management Guidelines Into Practice for Primary Care Providers. Pediatrics. 2015;136(3):554-565.

32. LeBovidge J, Borok J, Udkoff J, Yosipovitch G, Eichenfield LF. Atopic dermatitis: therapeutic care delivery: therapeutic education, shared decision-making, and access to care. Semin Cutan Med Surg. 2017;36(3):131-136.

33. Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: A US population–based study. Journal of allergy and clinical immunology. 2013;132(5):1132-1138.

34. van Zuuren EJ, Fedorowicz Z, Arents BWM. Performance and Tolerability of the Moisturizers Cetaphil® and Excipial® in Atopic Dermatitis: What is the Evidence Based on Randomized Trials? Dermatology and Therapy. 2017;7(3):331-347.

35. van Zuuren EJ, Fedorowicz Z, Lavrijsen A, Christensen R, Arents B. Emollients and moisturisers for eczema. In: Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd; 2016.

36. Sidbury R, Tom WL, Bergman JN, et al. Guidelines of care for the management of atopic dermatitis part 4: Prevention of disease flares and use of adjunctive therapies and approaches. Journal of the American Academy of Dermatology. 2014;71(6):1218-1233.

37. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis part 3: Management and treatment with phototherapy and systemic agents. Journal of the American Academy of Dermatology. 2014;71(2):327-349.

38. Siegfried EC, Jaworski JC, Hebert AA. Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice. American journal of clinical dermatology. 2013;14(3):163-178.

39. Brouwers MC, Kho ME, Browman GP, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. Canadian Medical Association Journal. 2010;182(18):E839-E842.

40. Wollenberg A, Ehmann LM. Long term treatment concepts and proactive therapy for atopic eczema. Annals of dermatology. 2012;24(3):253-260.

41. Guidelines for the diagnosis and managment of food allergy in the United States: Summary for patients, families, and caregivers. National Institute of Allergy and Infectious Diseases;2011. 11-7699.

42. Feldman SR, Horn EJ, Balkrishnan R, et al. Psoriasis: improving adherence to topical therapy. Journal of the American Academy of Dermatology. 2008;59(6):1009-1016.

43. Simpson EL. Atopic dermatitis: a review of topical treatment options. Current medical research and opinion. 2010;26(3):633-640.

44. Guttman-Yassky E, Dhingra N, Leung DY. New era of biologic therapeutics in atopic dermatitis. Expert opinion on biological therapy. 2013;13(4):549-561.