Hindawi Dermatology Research and Practice Volume 2020, Article ID 1524293, 10 pages https://doi.org/10.1155/2020/1524293 Research Article Consensus on the Clinical Approach to Moderate-to-Severe Atopic Dermatitis in Spain: A Delphi Survey Joaquı́n Sastre ,1 Esther Serra Baldrich,2 José Carlos Armario Hita,3 L. Herráez,4 Ignacio Jáuregui,5 Ana Martı́n-Santiago,6 Javier Ortiz de Frutos,7 Juan Francisco Silvestre,8 and Antonio Valero9 1 Service of Allergy, Fundación Jiménez Dı́az, Madrid, CIBERES, Instituto Carlos III, Department of Medicine, Universidad Autónoma de Madrid, Madrid, Spain 2 Dermatology Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 3 Service of Dermatology, Hospital Universitario Puerto Real, University of Cádiz, Cádiz, Spain 4 Service of Allergy, Hospital Universitario 12 de Octubre, Madrid, Spain 5 Service of Allergy, Hospital Universitario Cruces, Barakaldo, Vizcaya, Spain 6 Service of Dermatology, Hospital Universitari Son Espases, Palma, Spain 7 Service of Dermatology, Hospital Universitario 12 de Octubre, Madrid, Spain 8 Service of Dermatology, Hospital General Universitario de Alicante, Alicante, Spain 9 Section of Allergy, Hospital Clinic i Provincial de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain Correspondence should be addressed to Joaquı́n Sastre; jsastre@fjd.es Received 3 December 2019; Accepted 18 February 2020; Published 7 April 2020 Academic Editor: Giuseppe Stinco Copyright © 2020 Joaquı́n Sastre et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. The purpose of this study was to gather information on the current assessment and management of patients with moderate-to-severe AD in routine daily practice. Methods. A cross-sectional two-round Delphi survey with the participation of dermatologists and allergologists throughout Spain was conducted. They completed a 46-item questionnaire, and consensus was defined when responses of ≥80% of participants coincided in the categories of a 5-point Likert scale for that item. Results. A total of 105 specialists (aged 40–59 years) completed the two rounds. Participants agreed regarding the consideration of AD as a multifaceted disease and the differences in clinical presentation of AD according to the patient’s age. It is recommendable to perform a skin biopsy to exclude early stage T-cell cutaneous lymphoma, psoriasis, or dermatitis herpetiformis, among others (99.1%). Also, consensus was reached regarding the use of the SCORAD index to quantify the severity of the disease (86.7%), the use of wet wraps to increase the effect of topical corticosteroids (90.4%), the usefulness of proactive treatment during follow-up (85.6%) and tacrolimus ointment (91.2%) to reduce new flares, and the fact that crisaborole is not the treatment of choice for severe AD (92.4%). AD was not considered a contraindication for immunotherapy in patients with allergic respiratory diseases (92.4%). In patients with severe AD, the use of immune response modifier drugs (97.6%) or phototherapy (92.8%) does not sufficiently cover their treatment needs. Consensus was also obtained regarding the role of the new biologic drugs (93.6%) targeting cytokines involved in the Th2 inflammatory pathway (92.0%) and the potential role of dupilumab as first-line treatment (90.4%) in moderate-to-severe AD patients. Conclusion. This study contributes a reference framework to the care of AD patients. There is no diagnostic test or biomarkers to direct treatment or to assess the severity of the disease, and many therapeutic challenges remain. 1. Introduction and, to a lesser extent, adults. Infants with AD may develop a typical progression of atopic disorders, including allergic Atopic dermatitis (AD) is a chronic, pruritic, relapsing rhinitis, food allergy, and asthma at certain ages, a sequence inflammatory skin condition, commonly affecting children commonly referred to as the atopic march [1, 2]. AD 2 Dermatology Research and Practice diagnoses are continuously on the rise, oscillating between patients with moderate-to-severe AD in conditions of 10% and 20% of the pediatric population. The disease affects routine clinical practice. The results of this study will be 1–10% of adults worldwide, and recent studies have sug- helpful to identify some of the unmet medical needs cur- gested that adult AD is more common than previously rently present in the care of these patients. thought [3, 4]. Although AD is not a life-threatening con- dition, it poses a significant social, psychological, and eco- 2. Methods nomic burden [5]. The negative psychosocial impact of AD on quality of life is well established [5, 6], with itching, 2.1. Study Design. A cross-sectional two-round Delphi scratching, sleep loss, and social embarrassment being survey was conducted over a 5-month period (between July among the most commonly reported difficulties contrib- 13 and December 5, 2017) with the participation of der- uting to school, work, and social struggles. Depression and matologists and allergologists throughout Spain. The ob- anxiety have been reported to be also more common in jective of the study was to develop a consensus document on adults with AD, with these psychiatric symptoms being the clinical approach to moderate-to-severe AD patients. influenced by AD disease severity and the degree of im- The aims of the consensus were as follows: (a) to help cli- pairment of quality of life [6]. nicians in the assessment and management of AD patients in The presentation of AD depends on age and ranges from daily practice, (b) to know the current status of the care of papulovesicles to lichenified plaques. The pathogenesis of patients with AD in Spain, and (c) to identify potential areas AD is multifactorial, including genetic, and environmental to improve outcomes, including early recognition of hall- factors. Also, AD is characterized by skin barrier defects, mark signs and symptoms to ensure correct diagnosis and immunologic dysfunction, and alterations in the skin use of evidence-based tools to determine disease impact and microbiome [7–9]. However, a number of cytokines and guide treatment decisions, and to promote patient en- mediators involved in Th2, Th22, Th17, and Th1 pathways gagement and adherence to therapies. appear to be important in AD pathogenesis, and there is The Delphi method is generally accepted as a powerful currently an increasing interest in developing targeted means of reaching consensus and generating ideas among therapies, especially for patients with moderate-to-severe responders on a number of issues related to health problems forms of the disease not responding to conventional treat- in conditions of low grade evidence, knowledge, or appli- ments [10–12]. Also, the disease is frequently associated with cation [22]. Briefly, the method involves sending a ques- other comorbid skin conditions and extracutaneous diseases tionnaire to the responders and analyzing their response. [13, 14]. The causative mechanisms underlying these asso- This is then used to develop a new questionnaire and the ciations are poorly understood, but treating physicians cycle is repeated. Three methodological aspects are impor- should be aware of these associations while seeking to al- tant in a Delphi study. First, responders or panelists are not leviate the burden for patients with AD [15]. aware of the identity of the other responders, to ensure that Available evidence on different aspects of the disease is their responses are independent. Second, participants re- uncertain and scarce at the population level. There are two spond individually to avoid group domination by certain studies on the prevalence of severe AD in adults in Spain, individuals. Third, mathematical voting procedures are used one in three different areas (Asturias, Catalonia, and the to permit the ranking of items. Likewise, there are no set Balearic Islands) in 2015-2016 and the other one in Madrid guidelines for deciding on the optimum number of Delphi in 2016-2017; the estimated prevalence was 0.08% and participants as this is likely to change depending on the 0.028% (0.015% for children), respectively [16, 17]. AD was purpose of the Delphi survey. The original Delphi method considered severe when the patient received a systemic involves three or more rounds, whereas the modified immunosuppressant or a biologic (omalizumab, rituximab) technique is limited to two rounds to avoid losses of ac- during follow-up or had been hospitalized because of AD ceptable response rates due to prolonged duration of the [16]. However, presently, there exists no gold standard for process and the negative influence on the interest of the evaluating the severity of AD [18]. panelists. In the present study, a modified Delphi method A study based on data from the 2016 National Health was used to reach consensus. and Wellness Survey conducted in France, Germany, Italy, Spain, and the United Kingdom revealed that AD is asso- ciated with a significant disease burden and higher preva- 2.2. Participants and Procedures. At the beginning of the lence of atopic and psychological comorbidities, impaired project, a scientific committee formed by nine specialists, health-related quality of life, lower work productivity, in- five dermatologists, and four allergologists with proven creased activity impairment, and increased healthcare uti- experience and interest in AD was established. Participants lization [19]. The Spanish Society of Allergology and Clinical were authors of relevant research publications and were Immunology carried out two wide-scale studies regarding renowned professionals in the care of allergic patients, with the epidemiologic, clinical, and socioeconomic factors of the expertise in AD. Two study coordinators (JS, ES) supervised main allergic disorders in Spain, including AD [20, 21]. the progression of the study, including recruitment of However, no previous studies have evaluated the clinical participants and results of analysis of data, as well as other approach to patients with AD at a national level in Spain. organizational and logistic aspects of the project. Therefore, a cross-sectional Delphi survey was designed to Items to be included in the study questionnaire were gather information on the assessment and management of selected by members of the scientific committee based on a Dermatology Research and Practice 3 search of the literature to identify previously conducted participants (6.5%) and there was discrepancy in 7 items studies with high level of evidence, such as systematic re- (15.2%). As shown in Table 1, the percentages of consensus views and meta-analyses, and key primary studies focused ranged between 50% and 100%, with the lowest percentages on the field of moderate-to-severe AD in adult patients. being in the sections of severity of AD and comorbidities and Candidates to participate in the study were proposed by the the highest percentages in the sections of differential diag- study coordinators and members of the scientific committee. nosis, etiology and physiopathology, and quality of life. They were specialists in dermatology or allergology involved in the care of patients with AD in public hospitals and some 3.3. Definition and Diagnosis of AD. Of the 14 items included private consultations throughout Spain, preferably with 5 or in this section, 12 (85.7%) achieved consensus, and there was more years of experience and attending at least 10 patients discrepancy in the remaining 2 (14.3%) (Table 2). Partici- with AD per month. The study questionnaire was lodged in pants agreed regarding the consideration of AD as a mul- an Internet microsite to which specialists who agreed to tifaceted disease derived from the interaction of multiple participate accessed via a weblink with the user’s password. factors, including the skin components (96.8%), the immune The initial draft included 47 items, two of which were system (97.6%), skin microbiome (89.6%), and genetic removed after the first round and a new item was added. (98.4%) and environmental (98.4%) factors. AD is diagnosed Therefore, the final questionnaire was composed of a set of clinically (97.6%) using the criteria of Hanifin and Rajka 46 items, in which questions were grouped into seven (94.3%), with the clinical presentation depending on the sections: definition and diagnosis (14 items), differential patient’s age (92.8%), and currently lacking validated bio- diagnosis (1 item), severity of AD (2 items), etiology and markers that can help in the diagnosis of AD (83.2%). There physiopathology (4 items), comorbidities of AD (4 items), were discrepancies in the usefulness of the classification of health-related quality of life (2 items), and treatment and intrinsic and extrinsic AD as the basis of specific avoidance follow-up (19 items). Questions were formulated so that they strategies (60%) and eosinophil count as a biomarker of AD could be answered using a 5-point Likert scale: 1: “strongly (37.1%). disagree,” 2: “disagree,” 3: “neither agree nor disagree,” 4: “agree,” and 5: “strongly agree.” The study questionnaire is described in the Supplementary Materials. 3.4. Differential Diagnosis. Participants agreed on the single item of this section, i.e., performing a skin biopsy to exclude other conditions, such as early stage T-cell cutaneous 2.3. Statistical Analysis. Only full completed questionnaires lymphoma, psoriasis, or dermatitis herpetiformis (99.1%) were considered. The consensus criteria included “una- (Table 3). nimity” when 100% of the participants agreed on the same category of the Likert scale, “consensus” when agreement involved ≥80% of the participants, “majority” when agree- 3.5. Severity of AD. Of the two items, consensus was reached ment involved ≥70% of participants, and “discrepancy” on one regarding the use of the SCORAD (scoring atopic when agreement involved <70% of the participants. For the dermatitis) index to quantify the severity of the disease purpose of the analysis, “unanimity” and “consensus” (86.7%). There was discrepancy about eczema area and groups were considered together as a consensus. Descriptive severity index (EASI) score as a validated scale that is not statistics included frequencies and percentages. The analysis used in routine clinical practice (58.1%) (Table 3). was carried out trough consultation and analysis of the answers in the database from the online platform. 3.6. Etiology and Physiopathology. Of the four items, con- sensus was reached in all of them with the highest percentages 3. Results regarding that “currently there is an unmet need in the treatment of moderate-severe AD” (98.4%) and the statement 3.1. Characteristics of Participants. Of a total of 200 der- that “a high percentage of patients with AD also present food matologists and allergologists who were invited to partici- allergy, allergic rhinitis, or asthma” (94.4%) (Table 3). pate in the study, 125 (62.5%) accepted and completed the first Delphi round, 105 (84%) of which completed the second round. The final participation rate was 52.5%. Of the 105 3.7. Comorbidities. Of the four items, two achieved con- participants, 59 (56.2%) were dermatologists and 46 (43.8%) sensus regarding the fact that DA in children is frequently allergologists. The general profile of participants included a associated with allergic comorbidities (91.4%) and that mean age between 40 and 59 years, 5 or more than 5 years of children with AD are more prone to suffer from mental experience in the care of patients with AD with at least 10 disorders (84.8%). There was no consensus about the as- patients with AD visiting per month (both children and sociation of AD in adults with allergic disorders (78.1%) and adults), and 46.7% working in public hospitals, with all of a higher relative risk for immune-mediated inflammatory them having available biologic drugs in the workplace. diseases (43.8%) (Table 3). 3.2. General Results. After the two Delphi rounds, consensus 3.8. Health-Related Quality of Life. Consensus was reached was reached on 36 of the 46 items (78.3%). There were 3 in the two items regarding AD as a cause of marked psy- items where the agreement involved ≥70% of the chological anxiety (91.2%) and the usefulness of patient- 4 Dermatology Research and Practice Table 1: General results obtained for the different sections of the questionnaire. Section Items n Consensus n (%) Majority n (%) Discrepancy n (%) 1. Definition and diagnosis 14 12 (85.7) 0 2 (14.3) 2. Differential diagnosis 1 1 (100) 0 0 3. Severity of AD 2 1 (50) 0 1 (50) 4. Etiology and physiopathology 4 4 (100) 0 0 5. Comorbidities of AD 4 2 (50) 1 (25) 1 (25) 6. Health-related quality of life 2 2 (100) 0 0 7. Treatment and follow-up 19 14 (73.7) 2 (10.5) 3 (15.8) AD: atopic dermatitis. Table 2: Results regarding definition and diagnosis of AD. Consensus Discrepancy Item (%) (%) (i) AD can also develop de novo in adults or young adults, or even in advanced age 93.6 (ii) AD is a multifaceted disease that is derived from the interactions of multiple factors, including the 96.8 skin components (cellular and extracellular components that form the skin barrier) (iii) AD is a multifaceted disease that is derived from the interactions of multiple factors, including the 97.6 immune system (innate and adaptative) (iv) AD is a multifaceted disease that is derived from the interactions of multiple factors, including the 89.6 skin microbiome (v) AD is a multifaceted disease that is derived from the interactions of multiple factors, including genetic 98.4 factors (vi) AD is a multifaceted disease that is derived from the interactions of multiple factors, including 98.4 environmental factors (vii) Currently, the diagnosis and assessment of the severity of AD are made on clinical grounds 97.6 (viii) The clinical criteria defined by Hanifin and Rajka are used for the clinical diagnosis of AD 94.3 (ix) The clinical presentation of AD depends on the age of the patients 92.8 (x) With greater frequency, children < 2 years of age and adults present involvement of the face and neck; 94.3 in addition, adults also present involvement of the flexor and extensor surfaces (xi) Some forms of presentation seen in adults include dermatitis of the head and neck, chronic eczema of 96.8 the hands, and multiple zones of lichenification or prurigo (xii) The classification of “intrinsic” AD (not associated with IgE) and “extrinsic” AD (associated with 60.0 IgE) has practical implications related to specific avoidance strategies in the management of the disease (xiii) The blood eosinophil count is not a useful biomarker in AD 37.1∗ (xiv) Currently there are no validated biomarkers that help in the diagnosis of AD 83.2 AD: atopic dermatitis; IgE: immunoglobulin E. ​ ∗ 37.1% of disagreement. oriented SCORAD (PO-SCORAD) for the self-assessment of consensus that there are no enough bibliographic references AD in children, integrating the perspectives of the physician supporting the use of antihistamines to alleviate pruritus and the patient in the management of the disease (91.2%) (85.7%) but there was discrepancy regarding the usefulness (Table 3). of antihistamines as systemic treatment of AD (64.8%). Most participants agreed on the positive effects of allergen-specific immunotherapy (SIT) in some sensitized patients (76.2%) 3.9. Treatment and Follow-Up. Of the 19 items regarding and reached consensus that the item of AD is not a con- different aspects of treatment and follow-up of patients with traindication for immunotherapy in patients with allergic AD, 14 (73.7%) obtained consensus, whereas most partic- respiratory diseases (92.4%). In patients with severe AD, the ipants agreed on 2 items (10.5%) and there were discrep- use of immune response modifier drugs (97.6%) or pho- ancies in 3 (15.8) (Table 4). In the presence of positive prick totherapy (92.8%) does not sufficiently cover their treatment tests, participants agreed on avoidance of suspected allergens needs. Participants agreed on the adequate risk-benefit ratio (83.8%) and dietary foods (91.4%). There was consensus on of cyclosporine (80.0%) but disagreed on the adequate risk- the use of wet wraps to increase the effect of topical cor- benefit ratio of phototherapy (69.5%). Finally, there was ticosteroids (90.4%), the usefulness of proactive treatment consensus on the role of the new biologic drugs (93.6%) during follow-up (85.6%) and tacrolimus ointment (91.2%) targeting cytokines involved in the Th2 inflammatory to reduce new flares, and the fact that crisaborole is not the pathway (92.0%) and the potential role of dupilumab as treatment of choice for severe AD (92.4%). Most of the first-line treatment (90.4%) in moderate-to-severe AD participants (72.4%) believed that the simultaneous com- patients. By contrast, there was discrepancy regarding the bination on the same location of topical glucocorticoids and position of Janus kinase (JAK) inhibitors in the treatment topical calcineurin inhibitors is not useful. Also, there was of AD (60.0%). Dermatology Research and Practice 5 Table 3: Results regarding differential diagnosis, severity of AD, etiology and physiopathology, comorbidities, and health-related quality of life. Consensus Majority Discrepancy Item (%) (%) (%) Differential diagnosis (i) In certain situations, skin biopsy should be considered to exclude other conditions, such 99.1 as early stage T-cell cutaneous lymphoma, psoriasis, or dermatitis herpetiformis Severity of AD (i) The SCORAD index is used to quantify the severity of the disease in order to assess the 86.7 comparative efficacy of treatments and progression of the disease in routine clinical practice (ii) The EASI score is a validated scale that is not used in routine clinical practice 58.1 Etiology and physiopathology (i) A high percentage of patients with AD also present food allergy, allergic rhinitis, or 94.4 asthma (ii) Treatments oriented to increase filaggrin expression can be useful in the management of 93.3 AD in a particular group of patients (iii)Currently there is an unmet need in the treatment of moderate-severe AD 98.4 (iv) Biologic drugs are especially promising for adult patients with moderate or severe forms 89.6 of the disease Comorbidities of AD (i) AD in adults is frequently associated with allergic comorbidities 78.1 (ii) AD in children is frequently associated with allergic comorbidities 91.4 (iii) The relative risk of suffering from immune-mediated inflammatory diseases such as rheumatoid arthritis and chronic inflammatory bowel disease is higher in patients with AD 43.8∗ than in the general population (iv) Children with AD are more prone to suffer from mental disorders such as depression, 84.8 anxiety, and behavior disorders Health-related quality of life (i) AD causes considerable psychological anxiety and results in a dramatic impact on the 91.2 quality of life for both patients and their families (ii) The usefulness of PO-SCORAD for the self-assessment of AD in children suggests the importance of integrating the perspectives of the physician and the patient in the 91.2 management of AD AD: atopic dermatitis; SCORAD: scoring atopic dermatitis; EASI: eczema area and severity index; PO-SCORAD: patient-oriented SCORAD. ​ ∗ 43.8% neither agree nor disagree. 4. Discussion depending on the characteristics of the study, including the number of experts, survey distribution methods, number of The aim of the Delphi method is to obtain an opinion, level rounds, and face-to-face meetings. The overall participation of agreement, or consensus on a current topic or concern rate in our study was 52.5%, but the percentage of partic- from among a group of specialists or experts. This is an ipants having completed the two Delphi rounds was 84%, iterative and anonymous process with controlled feedback being in the upper band of the range over 60–80% reported and analysis of the results widely used in health sciences. For in the literature [33, 34]. In addition, the total number of 46 this study, the percentage of unanimity, consensus, majority, items was adequate, as high number of items is associated and discrepancy has been decided taking into account the with significantly lower response rates [35]. standard percentages that are usually used for a Delphi In the opinion of the panelists, consensus was obtained questionnaire of these characteristics and by agreement of regarding the consideration of AD as a multifaceted disease the entire scientific committee. Although the Delphi caused by the interaction of multiple factors. Recent studies methodology has been applied in various dermatological of the etiopathogenesis of AD have highlighted the complex diseases [23–31], no previous studies comprising a con- interplay among skin barrier deficiency, immunological sensus of opinion have been published on AD using the derangement, which contributes to the development, pro- Delphi technique. In a multicenter international project, a gression, and chronicity of the disease [36]. Abnormalities in Delphi study was conducted to reach consensus between filaggrin, another stratum corneum constituent, and tight different stakeholders on a core set of domains and items for junctions induce and/or promote skin inflammation. This registries of atopic eczema patients to collect data for re- inflammation, in turn, can further deteriorate the barrier search focused on photo- and systemic immunomodulatory function by downregulating a myriad of essential barrier- therapies [32]. In this respect, given the paucity of Delphi maintaining molecules [36]. The panel also agreed that the studies on AD, the present survey fills a gap in the literature. diagnosis of AD remains clinical without a reliable bio- With respect to the percentages of panelists having marker to confirm the diagnosis or assess the severity of the completed the rounds of questions set, the data varies disease. Currently, biomarkers cannot be applied in daily 6 Dermatology Research and Practice Table 4: Results regarding treatment and follow-up of patients with AD. Consensus Majority Discrepancy Item (%) (%) (%) Substances that should be avoided (i) When the prick test is positive for any allergen with suspicion of clinical involvement, 83.8 avoidance of these allergens as far as possible may be a useful complementary measure (ii) Patients with moderate-to-severe AD should follow a diet that does not include foods testing positive in the prick test or prick-prick test and that are clinically relevant for the 91.4 patient Topical and anti-inflammatory treatment (i) The use of wet wraps increases the effect of topical corticosteroids 90.4 (ii) Proactive “treatment”, for example, application for two times per week in long-term 85.6 follow-up, can help reduce new flares (iii) Proactive “treatment” with application of tacrolimus ointment two times per week can 91.2 help reduce new flares (iv) Simultaneous combination on the same location of topical glucocorticoids and topical 72.4 calcineurin inhibitors does not seem to be useful (v) Based on results of clinical trials of crisaborole, this is not the treatment of choice for 92.4 severe AD Antipruritic treatment (i) There are no sufficient bibliographic references supporting the general use of first- and 85.7 second-generation antihistamines for treating pruritus in AD (ii) First- and second-generation antihistamines, in general, are not useful for systemic 64.8 treatment of AD Allergen-specific immunotherapy (allergen-SIT) (i) Allergen-SIT has positive effects in some sensitized patients with AD 76.2 (ii) AD is not a contraindication for the use of immunotherapy in patients with allergic 92.4 respiratory diseases (allergic rhinoconjunctivitis, allergic bronchial asthma) Systemic treatments (i) With the current immune response modifiers, the therapeutic needs of patients with 97.6 severe AD are not sufficiently covered (ii) In the treatment of severe AD, cyclosporine has an adequate risk-benefit ratio 80.0 (iii)With phototherapy, the therapeutic needs of patients with severe AD are not sufficiently 92.8 covered (iv) In the treatment of severe AD, phototherapy has an adequate risk-benefit ratio 69.5 New systemic treatments (i) Treatment with biologic drugs should be considered in patients with severe AD not 93.6 controlled with conventional systemic and topical treatment (ii) The objectives of these new biologic drugs should be targeting mainly cytokines involved 92.0 in Th2 allergic inflammation such as IL-4, IL-5, IL-13, and IL-31 (iii) Dupilumab has the potential to become the new first-line reference treatment for patients with moderate-to-severe AD who are candidates for systemic treatment (with or 90.4 without topical treatment) (iv) According to results of phase II studies, JAK inhibitors will be a future treatment of AD 60.0∗ ∗ AD: atopic dermatitis; SIT: specific immunotherapy; IL: interleukin; JAK : Janus kinase. ​ 60.0% neither agree nor disagree. practice for diagnosing AD, although they will play an in- physician-assessed instrument and symptoms measured creasingly important role in AD research and personalized with a patient-assessed instrument or control of flares, medicine [37]. There were discrepancies regarding the hampers comparison among studies [39]. Participants also usefulness of the classification of intrinsic and extrinsic AD agreed on the need to perform a skin biopsy to exclude other as the basis of specific avoidance strategies, eosinophil count conditions, including early stage T-cell cutaneous lym- as a biomarker of AD, and the use of EASI in clinical phoma, psoriasis, or dermatitis herpetiformis. In this re- practice. spect, the clinical characteristics and the hallmark of Sézary There was also consensus about differences in the clinical syndrome, a leukemia variant of T-cell cutaneous lym- presentation of AD according to the patient’s age. Even phoma, often share striking similarities with AD [40]. though many common features exist, there are significant In relation to comorbid conditions, allergic diseases in differences between the clinical characteristics of children, adults and depression, anxiety, and behavioral disorders in adolescents, and adult AD subgroups [38]. Moreover, the children were items for which consensus was obtained. A lack of standardization of outcome measures for clinical recent meta-analysis of 35 studies found that children and signs of AD, such as clinical signs measured with a adolescents with AD had significantly higher risk of total Dermatology Research and Practice 7 mental disorders than those without AD (odds ratio [OR] reference framework for the care of adult patients with 1.65; 95% confidence interval [CI] 1.46–1.86), with an ab- moderate-to-severe AD in clinical practice. solute risk of 12.6% [41]. Also, AD was recognized as the cause of considerable psychological anxiety. In fact, psy- Data Availability chological stress is a significant contributor to AD disease course through its direct and indirect effects on immune The data used to support the findings of this study are in- response, cutaneous neuropeptide expression, and skin cluded within the article. barrier function [42]. Consensus regarding treatment included the use of wet Conflicts of Interest wraps to enhance the effect of topical corticosteroids, the use of proactive treatment in the affected area to reduce Joaquı́n Sastre declares that he has received funding for his new flares, the recognition that crisaborole is not the collaboration as a consultant for Thermo Fisher, Hycor treatment of choice for severe AD, the adequate benefit-risk Biomedical, Novartis, Sanofi Genzyme, LETIPharma, ratio of cyclosporine in severe AD, the role of biologic Mundipharma Pharmaceuticals, ALK, and GSK. On the drugs, targeting cytokines involved in allergic inflamma- other hand, he declares that he has received fees for tion caused by Th2 helper lymphocytes, and the potential of conferences promoted by Novartis, GSK, Stallergenes, dupilumab to become the new first-line treatment in pa- Sanofi Genzyme, Circassia, LETIPharma, and Faes Farma. tients with moderate-to-severe AD [43, 44]. A consensus He also states that he has received research grants from was also reached on how to interpret skin prick test results. Thermo Fisher, Mundipharma Pharmaceuticals, ALK, and There was discrepancy in relation to the statement that Sanofi Genzyme. Esther Serra declares that she has received first- and second-generation antihistamines are generally fees for her collaboration as a consultant/speaker attending not useful in the systemic treatment of AD. Short-term, meetings and funding for her collaboration in different intermittent use of sedating antihistamines may be bene- research projects promoted by Novartis, Sanofi Genzyme, ficial in the setting of sleep loss secondary to itch [45] but GSK, LETIPharma, Faes Farma, MSD, Lilly, Amgen, they reduce rapid eye movement (REM) sleep, produce AbbVie, and Pfizer. José Carlos Armario has received fees daytime somnolence, impair learning, and reduce work as a speaker and funding for meetings, congresses, and efficiency [46]. It has been postulated that second-gener- course attendance as well as for participating in a research ation antihistamines may have anti-inflammatory effects. project, promoted by AbbVie, Almirall, Galderma, ISDIN, In human keratinocytes, histamine decreases the formu- Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, and lation of tight junctions and the expression of filaggrin, a Sanofi Genzyme. Lys Herráez declares that she has received gene responsible for AD, via histamine H1 receptor (H1R) fees for her collaboration as a speaker and/or consultant for [47]. Furthermore, histamine regulates IL-31, a cytokine advisory boards, research projects, congresses, and course involving the skin barrier and pruritus, through H1R and attendance for Novartis, Sanofi, GSK, AstraZeneca, ALK- induces the production of thymus and activation-regulated Abello, and Mundipharma. Ignacio Jáuregui declares that chemokine (TARC) via H4R [47]. Recently, in a ran- he has received funding from Sanofi Genzyme and Novartis domized, double-blind, placebo-controlled, parallel-group for his collaboration in different meetings, as well as fees as study, a novel selective H4R antagonist, ZPL-3893787, speaker in online courses on atopic dermatitis and urti- showed significant reductions of EASI and SCORAD scores caria. He also declares that he has received funding from as compared with placebo, but a nonsignificant difference LETIPharma and Sanofi Genzyme for attending AAAAI in the reduction of pruritus [48]. Congress in 2019. On the other hand, he declares that he The results of the present study should be interpreted has received fees as a speaker from Sanofi and MSD. In taking into account the fact that responses to the ques- respect of his participation in different research projects, he tionnaire reflect what the specialists would do in the different declares that he has received funding as a member of an scenarios posed by each question, which may differ slightly advocacy group for Sanofi Genzyme (atopic dermatitis) from their clinical practice. However, the Delphi method and Novartis (chronic urticaria); furthermore he has allowed exploring systematically different clinical, diag- worked as a consultant for Faes Farma and has been in- nostic, and treatment aspects of patients with AD, based on volved in several observational studies for Novartis. Ana the qualified opinion of dermatology and allergology experts Martı́n declares that she has received fees as a speaker in the in the field. There is no diagnostic test or biomarkers to conferences “Nonpharmacological Treatment for Atopic direct treatment or to assess the severity of the disease, and Dermatitis” and “Management of Patients with Atopic many therapeutic challenges remain. The extent to which Dermatitis,” both promoted by Sanofi Genzyme. She also activation of immune pathways in addition to Th2 signaling declares that she has received funding for her collaboration contributes to AD pathogenesis remains unknown [49], as as a consultant in research and for her assistance in the well as whether new medications directed against targets ESPD Congress, both promoted by Sanofi Genzyme. Javier believed to lead to AD will prove to be effective without Ortiz declares that he has received funding for his col- significant risk. laboration in different research projects promoted by In summary, this was a Delphi survey study of a sample Sanofi Genzyme, Novartis, Astellas Pharma, MSD, Uriach, of dermatology and allergology experts in the care of patients and Laboratorios Viñas. Juan Francisco Silvestre has re- with AD. The present consensus document contributes as a ceived fees as a speaker and funding for meetings, 8 Dermatology Research and Practice congresses, and course attendance as well as participating advice during the study and Marta Pulido, MD, PhD, for in a research project, all promoted by Sanofi Genzyme. the help in writing the manuscript and for the editorial Antonio Valero declares that he has received funding for assistance. This work was supported by a grant from meetings, congresses, and course attendance from LETI- Sanofi Genzyme SA. Pharma, Novartis, Allergy-Therapeutics, and ALK and for his collaboration in different research projects promoted by Novartis, AstraZeneca, GSK, and Menarini. He also de- Supplementary Materials clares that he has participated in presentations promoted Study questionnaire. Section 1: definition and diagnosis. by Sanofi Genzyme, GSK, Novartis, Uriach, and Chiesi. Section 2: differential diagnosis. Section 3: severity of AD. Section 4: etiology and physiopathology. Section 5: Acknowledgments comorbidities of AD. Section 6: health-related quality of life. Section 7: treatment and follow-up. (Supplementary The authors would like to thank the experts who have Materials) participated as panelists: Águeda Pulpillo Ruiz, Alejandro Joral Badas, Alicia Enrı́quez Matas, Almudena Hernández Nuñez, Almudena Mateu, Amalia Pérez Gil, Amparo References Pérez Ferriols, Ana Beristain Urquiza, Ana Batalla Cebey, [1] S. K. Bantz, Z. Zhu, and T. Zheng, “The atopic march: pro- Ana Bauza Alonso, Ana Isabel Tabar Purroy, Ana Marı́a gression from atopic dermatitis to allergic rhinitis and Delgado Márquez, Ana Martı́n-Santiago, Ana Rosado asthma,” Journal of Clinical & Cellular Immunology, vol. 5, Ingelmo, Angela Hernández Martı́n, Antonio Valero, no. 2, p. 202, 2014. Antonio Vélez Garcı́a-Nieto, Araceli Sánchez, Arancha [2] E. Serra-Baldrich, J. O. de Frutos, I. 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