1002979 research-article20212021 TAJ0010.1177/20406223211002979Therapeutic Advances in Chronic DiseaseG Girolomoni, M de Bruin-Weller Atopic Dermatitis Special Collection Therapeutic Advances in Chronic Disease Review Nomenclature and clinical phenotypes Ther Adv Chronic Dis 2021, Vol. 12: 1–20 of atopic dermatitis DOI: 10.1177/ https://doi.org/10.1177/20406223211002979 https://doi.org/10.1177/20406223211002979 20406223211002979 © The Author(s), 2021. Article reuse guidelines: Giampiero Girolomoni , Marjolein de Bruin-Weller, Valeria Aoki, Kenji Kabashima, sagepub.com/journals- permissions Mette Deleuran, Luis Puig, Ashish Bansal and Ana B. Rossi Abstract: Atopic dermatitis is a heterogeneous disease and resists classification. In this review, we discuss atopic dermatitis nomenclature and identify morphologic phenotypes, which will facilitate correct diagnoses and development of treatment strategies. We support using the term ‘atopic dermatitis’ rather than eczema, because it describes the allergic background and inflammation (‘itis’) as drivers of the disease. Atopic dermatitis has many morphologic manifestations that vary by topographic area affected, age, or race and require consideration in differential diagnosis. Different phenotypes based on morphology and topographic location, ethnicity, and age are discussed. A better-defined phenotype identification for atopic dermatitis will facilitate earlier and correct diagnosis of this complex Correspondence to: Giampiero Girolomoni condition and inform selection of the most appropriate treatment choice in an era in which Department of Medicine, targeted therapies may generate more individualized patient care. Section of Dermatology and Venereology, University of Verona, Piazzale A. Stefani 1, Keywords: atopic, dermatitis, eczema, nomenclature, phenotype, treatment Verona, 37126, Italy giampiero.girolomoni@ univr.it Received: 5 February 2021; revised manuscript accepted: 25 February 2021. Marjolein de Bruin-Weller National Expertise Center of Atopic Dermatitis, Department of Dermatology and Introduction often present. Diagnosis of AD is largely based on Allergology, University Atopic dermatitis (AD) is a chronic inflamma- the morphology and distribution of lesions,2,3,9 Medical Center, Utrecht, Netherlands tory skin condition affecting both children (15– but also on the patient’s clinical course, comorbid Valeria Aoki 20%) and adults (2–5%).1–3 Its prevalence is conditions, and family history. Our understand- Department of increasing, particularly in lower-income coun- ing of the pathogenesis of AD in part reflects the Dermatology, University of São Paulo School of tries, and it occurs in a variety of geographic and complex interplay between genetic and environ- Medicine, São Paulo, ethnic patterns.3,4 Previously classified as either mental factors.9 Brazil Kenji Kabashima early-onset [i.e. infantile (aged <2 years), child- Department of hood (aged 2–12 years), adolescent (aged 12– Many genes have been linked to AD across dif- Dermatology, Kyoto University Graduate School 18 years)], or adult-onset (aged >18 years), a ferent populations, but the extent of genetic risk of Medicine, Kyoto, Japan separate subgroup of elderly-onset AD (aged for AD is yet to be fully defined. However, can- Mette Deleuran ⩾60 years) has recently been described.5–7 AD didate gene studies, genome-wide association Department of Dermatology, Aarhus can therefore be regarded as a lifelong disease, studies, and genetic sequencing studies have University Hospital, and clinical and laboratory differences observed shown that genetic susceptibility is associated Aarhus, Denmark in these subtypes contribute to the heterogenous with epidermal barrier dysfunction and type 2 Luis Puig Department of nature of the disease.8 dominated immune responses.9–13 Indeed, type Dermatology, Hospital de 2 inflammation plays a key role in both acute la Santa Creu i Sant Pau, Universitat Autònoma de Traditionally, clinical lesions in eczema are classi- and chronic phases of the disease.14–17 However, Barcelona, Barcelona, fied as ‘acute’ (oozing, oedema, and erythema) or an incomplete understanding of the underlying Spain ‘chronic’ (dyspigmentation, xerosis, and lichenifi- immunologic mechanisms of AD and its hetero- Ashish Bansal Regeneron cation) (Figure 1). However, as AD is a chronic geneous manifestations has resulted in a thera- Pharmaceuticals, Inc., relapsing condition, both types of lesions can peutic approach based more on disease severity Tarrytown, NY, USA Ana B. Rossi coexist during flares. Pruritus is a hallmark of than on phenotype or its underlying specific bio- Sanofi Genzyme, AD, and excoriations secondary to scratching are logic pathways (endotype). Cambridge, MA, USA journals.sagepub.com/home/taj 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Chronic Disease 12 Figure 1. Clinical signs of atopic dermatitis. Objectives The term ‘dermatitis’ was excluded from early First, we discuss the nomenclature associated discussions of hereditary and clinical presentation with AD. Second, we identify and illustrate differ- of allergic sensitization because it was considered ent morphologic phenotypes seen in patients of difficult to define.19,23 An electronic survey of different age ranges or races and in different ana- experts from the International Eczema Council tomic locations. To guide appropriate treatment led to a consensus (97.2%) on the need to include decisions, it is critical that the different AD phe- the prefix ‘atopic’ in all descriptions of the dis- notypes are diagnosed efficiently and correctly ease, regardless of a preference for ‘eczema’ or and in a timely manner. ‘dermatitis’.18 We agree that use of the term ‘atopic’ provides important mechanistic informa- tion and helps group AD with other diseases with AD nomenclature the same aetiology. Atopy, which is Greek for ‘out of place’, entered the medical lexicon in 1923, with ‘atopic derma- Differences in nomenclature create potential for titis’ following a decade later, soon after the term confusion and for issues with the quality of epi- ‘atopic eczema’ had first been used.18–21 The demiologic data24 given that AD and eczema are American Academy of Asthma and Immunology represented by different codes in the International defines atopy as ‘the genetic tendency to develop Classification of Diseases, Tenth Revision (ICD- allergic diseases such as allergic rhinitis, asthma, 10), system. Besides the ICD-10 codes for AD and AD’ (or ‘eczema’, depending on the termi- (L20.x; Table 1), other ICD-10 codes can be nology used).22 Most individuals with AD are used in diagnosis. sensitized to allergens and have a coexisting aller- gic disease, and allergen exposure can have an Thus, the heterogeneity of AD presentation may effect on AD symptoms, severity, and flares. be a source of the varied terminology used to 2 journals.sagepub.com/home/taj G Girolomoni, M de Bruin-Weller et al. Table 1. ICD-10 codes that can be used for AD and its different morphologic phenotypes. L20 Atopic dermatitis L29 Pruritus L20.0 Besnier’s prurigo L29.0 Pruritus ani L20.8 Other atopic dermatitis L29.1 Pruritus scroti    L20.81 Atopic neurodermatitis L29.2 Pruritus vulvae    L20.82 Flexural eczema L29.3 Anogenital pruritus, unspecified    L20.83 Infantile (acute) (chronic) eczema L29.8 Other pruritus    L20.84 Intrinsic (allergic) eczema L29.9 Pruritus, unspecified    L20.89 Other atopic dermatitis L30 Other and unspecified dermatitis L20.9 Atopic dermatitis, unspecified L30.0 Nummular dermatitis L26 Exfoliative dermatitis L30.1 Dyshidrosis [pompholyx] L28 Lichen simplex chronicus and prurigo L30.2 Cutaneous autosensitization L28.0 Lichen simplex chronicus L30.8 Other specified dermatitis L28.1 Prurigo nodularis L30.9 Dermatitis, unspecified L28.2 Other prurigo L53 Other erythematous conditions L53.8 Other specified erythematous conditions L53.9 Erythematous condition, unspecified AD, atopic dermatitis; ICD, International Classification of Diseases, Tenth Edition. describe AD. Consensus within the medical com- must be present along with at least three of five munity is necessary to avoid confusion, bias, and major criteria: history of flexural involvement, his- errors in epidemiologic data. We argue for the use tory of dry skin, onset of AD before 2 years of age, of ‘atopic dermatitis’ over ‘atopic eczema’ because history of any other atopic condition, and flexural it more fully captures the inflammatory aetiology dermatitis.25 The AAD guidelines comprise essen- of the disease, an important feature when consid- tial, important, and associated clinical features. For ering use of new targeted therapies. Education of a positive diagnosis of AD, essential features (pruri- the lay community will be a key next step to ensur- tus and eczema) must be present, and important ing use of consistent terminology. features (early AD onset, history of atopy and xero- sis) are usually present, lending further support to the diagnosis; evidence of associated features (e.g. Diagnosis of AD facial pallor, lichenification), while suggestive of The diagnostic criteria used for AD have been thor- AD, are not a mandatory requirement.27 The oughly reviewed by Andersen et al.19 Diagnostic Millennium Criteria were the first to require the guidelines from the UK Working Party25 and the presence of antigen-specific immunoglobulin E American Academy of Dermatology (AAD)26,27 are (IgE) as a mandatory criterion for the diagnosis of established for paediatric and adult diagnoses. AD.29 The presence of IgE antibodies is also These guidelines are refinements of the Hanifin– required for some definitions of atopy, such as that Rajka criteria, first introduced in 1980 and compris- of the World Allergy Organization.18 However, this ing four major and 23 minor clinical features, of criterion is controversial because it excludes as which at least three major and three minor criteria many as two-thirds of patients with AD who do not must be present to confirm an AD diagnosis.28 The display this type of response30 and is generally not UK Working Party Criteria mandate that pruritus used as a diagnostic criterion in practice. journals.sagepub.com/home/taj 3 Therapeutic Advances in Chronic Disease 12 Several challenging clinical phenotypes of AD AD,48 but no agreement exists as to whether num- exist that display peculiar morphologic features or mular dermatitis is AD in all cases. In most cases, topographic distributions, and some of these phe- nummular dermatitis is idiopathic, and no allergic notypes have difficult-to-discern aetiologies or or irritant cause can be discerned. It is more com- may mimic or coexist with other dermatologic mon in children (although not infants) and adult- conditions. These challenging phenotypes can be onset AD,49 and coexists in some individuals with defined morphologically [nummular dermatitis, typical flexural AD or elevated serum IgE (or prurigo nodularis (PN)-like lesions, erythro- both).50,51 As occurs in AD, staphylococcal supe- derma, lichenified dermatitis, follicular/papular rantigen-producing Staphylococcus aureus coloniza- dermatitis and pompholyx (dyshidrosis)]4,31–43 tion is commonly present in nummular dermatitis.52 (Figure 2) and topographically (flexural or perior- Nummular dermatitis may be considered AD ificial or occurring on the face, lips [eczematous when other features of AD (e.g. typical flexural cheilitis], eyelid, head and neck, hand and foot, or eczematous lesions), elevated IgE, and atopic nipple)34,36,38,39,41–46 (Figure 3). Figures 4 and 5 comorbidities (history of asthma, rhinoconjuncti- show histologic samples of AD. vitis, food allergy) are currently or have been pres- ent and when no evidence exists for other diseases No consensus exists on whether some of these (e.g., stasis dermatitis) that are also known to cause challenging phenotypes represent exclusive forms nummular dermatitis.31,32 of AD, and this lack of consensus is further com- plicated by the availability of separate ICD-10 Prurigo nodularis. PN (Figure 2b) is a condition codes for these manifestations (Table 1). There is distinct from AD, but PN secondary to AD can a need to confirm which of, and when, these con- occur. PN is characterized by single to multiple ditions should be considered forms of AD and excoriated hyperkeratotic and intensely itchy pap- which are independent diagnoses. We propose ules and nodules that occur predominantly on the that nummular dermatitis, PN-like AD, erythro- extremities.33,53 Pruriginous lesions are persistent derma, pompholyx, lichenified dermatitis, flex- and tend to be symmetrically distributed in areas ural dermatitis, facial dermatitis, eczematous accessible to scratching, with normal or lichenified cheilitis, eyelid dermatitis, head and neck derma- skin between the lesions, and a characteristic ‘but- titis (HND), hand and foot dermatitis, and nipple terfly’ sign on the back where no lesions are present dermatitis should be considered part of the spec- in areas inaccessible to scratching. PN is com- trum of AD when other AD features (e.g. typical monly located on the extensor surfaces of the flexural eczematous lesions), elevated IgE, or extremities and rarely affects the face.54 Pruritus atopic comorbidities (history of asthma, rhino- may be accompanied by burning, stinging, pain, conjunctivitis, food allergy) are present, especially and other symptoms. There is often neuronal sen- when there is no evidence of other diseases known sitization, demonstrated by allokinesis (light touch- to cause these phenotypes. evoked itch) and hyperkinesis (exaggerated itch response to a pruritic stimulus).55 The key immune mediators and mechanisms behind atopic itch in Morphologic AD phenotypes AD have been reviewed and include histamine, Nummular or discoid dermatitis. The term ‘num- TSLP and type-2 cytokines.56 The key role of type mular’ derives from the coin-like appearance of 2 cytokines in PN is emphasized by the very good lesions that form rapidly by the merging of papules therapeutic response to dupilumab.57 and papulovesicles into circinate and ovoid plaques (Figure 2a).34,40 Lesions are typically 1.5–3 cm in AD has been identified as an underlying or con- diameter and progress from a highly inflammatory tributing cause in nearly one-half of PN cases.58,59 acute phase characterized by marked erythema, PN secondary to AD is more common in adults crusty appearance, and oozing/weeping to a and in individuals of South-East Asian or African smoother, scaly phase that may become annular origin.4,59,60 In an AD registry study performed in because of central clearing and peripheral exten- Japan, the prevalence of prurigo nodules in 300 sion. Lesions are predominantly present on lower patients with AD was high: 30.9% in patients extremities but can also appear on upper extremi- with moderate AD and 56.3% in patients with ties and the trunk.47 Nummular dermatitis is the severe AD.61 Itch is a cardinal symptom in AD, most common atypical morphologic variant of and the itch–scratch cycle could lead to secondary 4 journals.sagepub.com/home/taj G Girolomoni, M de Bruin-Weller et al. palms of the hands and soles of the feet tend to be spared, along with the nose (nose sign) in some cases.62,63 Scaling of the skin follows, with large scales in acute cases and small scales in chronic cases.62 Erythrodermic AD is more common in adolescents and adults (aged 12–60 years) in East Asia, particularly those with a longer disease course.4,64,65 Erythroderma is not specific to AD and a differential diagnosis must consider numer- ous causes, but AD has been reported to be the underlying cause of erythroderma in 5%–24% of cases.66 Erythrodermic AD is a serious condition because it is associated with a high rate of hospi- talization, skin infections, and potential life- threatening complications.67 Lichenified dermatitis. Lichenified dermatitis (Fig- ure 2d) refers to a thickening of the skin, which appears elevated, with accentuated creases and a leathery appearance due to prolonged scratching and rubbing. In an analysis of AD clinical trial data, lichenification was found to be more common in patients from South-East Asia or Africa than in Caucasian patients.4 The condition is most com- mon in young people (median age 7 years).35 Along with pronounced greater lichenification, individuals from Africa or of African descent can present with perifollicular accentuation and post-inflammatory depigmentation, which can complicate the diagno- sis.60 People from Asia or of Asian descent with AD exhibit increased epidermal hyperplasia (increased epidermal thickness and Ki67 counts) on lesional biopsy specimens, which is associated with increased gene expression of T helper (Th)17- and Th22- related markers.60,65 Figure 2. Morphologic phenotypes. (a) Nummular (discoid) dermatitis. (b) Prurigo nodularis. (c) Follicular/papular dermatitis. Follicular and Erythrodermic. (d) Lichenoid dermatitis. (e) papular dermatitis is a morphological subtype Follicular/papular dermatitis. (f) Dyshidrosis or Pompholyx. more commonly identified in darker skin photo- types (Figure 2e). An analysis of AD feature prevalence reported among clinical studies by region found that studies from Africa reported a PN lesions. Accordingly, PN can coexist with AD higher prevalence of papular lichenoid lesions or persist after cessation of AD.33 (22%) compared with the overall prevalence from all studies (22%).4 Erythroderma. Erythroderma (Figure 2c), also known as exfoliative dermatitis, is the presence of erythema on >90% of the body surface area. Topographical phenotypes Erythroderma typically begins with the appear- AD typically affects the face, neck, and flexural ance of erythemato-pruritic lesions of varied pri- zones.27 Many of the morphologic variants show mary morphology, most often on the head, trunk, predisposition for certain areas of the body. Some and genital region, and rapidly spreads to all or topographical phenotypes of AD are described as most of the body within days or a few weeks. The follows. journals.sagepub.com/home/taj 5 Therapeutic Advances in Chronic Disease 12 Typical flexural dermatitis. A tendency for AD to guidelines.12,25,27,64,71 The signs most frequently affect flexural areas was first noted in Roman seen with flexural involvement are erythema, Emperor Augustus by Suetonius,68–70 and remains oedema or papulation, excoriation, lichenification, a prominent feature of both US and UK diagnostic and oozing or crusting (Figure 1). Flexural areas Figure 3. (Continued) 6 journals.sagepub.com/home/taj G Girolomoni, M de Bruin-Weller et al. Figure 3. Topographic phenotypes of AD. (a) Typical flexural dermatitis. (b) Face. (c) Eczematous cheilitis. (d) Eyelid dermatitis. (e) Head and neck dermatitis. (f) Hand dermatitis. (g) Nipple dermatitis. †Inadequate treatment of eyelid dermatitis can lead to severe chronic inflammation with scarring or ‡ocular surface diseases such as atopic keratoconjunctivitis (picture shows sclerosis and symblepharon of conjunctiva). typically affected by AD include the neck, cubital flexural involvement is common in adolescent and popliteal fossae, wrists, and ankles (Figure 3a). and adult Caucasians, extensor involvement appears to be more common in infants and Asians The extent of flexural involvement appears to and can occur in those of African descent35,43,73,74 vary with disease course and differs by racial ori- (Figure 3a, right two panels). gin. Flexural involvement is more common in patients with early-onset AD and a chronic per- Face. Facial involvement (Figure 3b) is common sisting course.72 There may be sparing of flexural in AD, not only in children and infants,27 but also involvement in patients aged >60 years.5 Whereas in adolescents and adults. In many individuals, journals.sagepub.com/home/taj 7 Therapeutic Advances in Chronic Disease 12 Figure 4. Atopic dermatitis: histology. (a) Normal skin. (b) Atopic dermatitis. (c) Dyshidrosis. (d) Acute dermatitis. (e) Chronic dermatitis. AD may involve the face alone; in infants aged scalp.73 Periorificial lesions of the head tend to <1 year, AD is typically restricted to the face, occur in AD during childhood.5 where it is characterized by erythematous and highly pruritic lesions alongside moist, oozing Eczematous cheilitis. Eczematous cheilitis (Fig- papulovesicles that sometime form crusts or ure 3c) can be a manifestation of AD and presents scales45,73 and can be concentrated in the perioral as red, dry lips, and sometimes with a median fis- region,5,75 on the cheeks, or, in some cases, the sure of the lower lip, alongside lateral fissures 8 journals.sagepub.com/home/taj G Girolomoni, M de Bruin-Weller et al. Figure 5. Histology: subacute chronic dermatitis, psoriasiform dermatitis. (a) Sub-acute-chronic dermatitis. (b) Psoriasiform dermatitis. Histological images generously provided by Dr Maria Teresa Fernández-Figueras. (angular cheilitis).76 In nearly one-fifth of cases, inflammation with scarring and subsequent cheilitis is a manifestation of AD.77 Chronic chei- complications like ectropion or entropion as litis can be the result of exposure to irritants or well as to ocular surface diseases such as kerato- allergic contact dermatitis to sensitizers such as conjunctivitis (Figure 3d). nickel, fragrances, Balsam of Peru, chromium salts and manganese salts present in cosmetics, Similar to eczematous cheilitis, eyelid dermatitis dental materials, and oral hygiene products.77 In is a common manifestation of AD.45,64 Eyelid der- contrast, angular cheilitis (Figure 3c) is usually matitis is more common in childhood and may infectious in nature. also be more common in people of Asian descent, particularly females.4,81 Onset after 6 months of Eyelid dermatitis. Substantial eyelid involve- age and a personal history of atopy are the main ment was highlighted as a key feature in the first risk factors for eyelid dermatitis in AD.82 Of note, description of AD, but eyelid involvement is long-term use of potent topical steroids to treat common in several forms of dermatitis (Figure eyelid dermatitis can cause eyelid skin atrophy 3d).19,73 Itching, burning, and crusting of the due to the thin skin of the eyelid, as well as serious eyelids is common, and scaling may occur at the adverse events such as glaucoma and cataracts, base of the eyelashes, along with depigmenta- which are also associated with use of systemic tion, lichenification, and loss of lashes.39,78 AD corticosteroids.83–85 is associated with ocular diseases, including conjunctivitis and cataracts.79,80 Inadequate Head and neck dermatitis. In adolescents and treatment of eyelid dermatitis, blepharitis, or adults, facial AD, often seen as xerotic, scaly, ery- periocular eczema can lead to severe chronic thematous, and sometimes lichenified plaques journals.sagepub.com/home/taj 9 Therapeutic Advances in Chronic Disease 12 affecting the face and neck and eventually the scalp, dupilumab and development of new regional der- is one of the causative factors of HND (Figure 3e). matoses, with a predilection for the face, head, and neck regions.95–97 This rare phenomenon has yet to There are many other potential causes for HND, be fully clinically characterized and a unifying phe- such as aeroallergen sensitization, allergic contact notype has not been identified. These reports may dermatitis to topical products, rosacea, sebor- represent disparate rashes with multiple underly- rheic dermatitis, topical corticosteroid (TCS) ing aetiologies. It is possible that dupilumab treat- withdrawal syndrome, and sensitization to ment potentially unmasks previously undiagnosed Malassezia furfur,37,38,76,81,86 and these may coexist ACD or seborrheic like-dermatitis, which had with AD in the same person. been kept at bay prior to dupilumab initiation. A recent case report suggests that topical ketocona- Allergic contact dermatitis (ACD) commonly zole is successful in treating facial rashes refractory involves the lips, eyelids, and neck, among other to dupilumab.98 regions, and may be mistaken for or complicate AD.87 The delayed hypersensitivity reaction Elevated serum levels of Malassezia-specific IgE observed with ACD following prior sensitization are characteristic of HND in contrast to sebor- to an allergen results in highly pruritic erythema- rheic dermatitis or pityriasis versicolor.99–101 In tous plaques. AD treatments may be implicated 2000, Devos and Van der Valk investigated in ACD, and allergens with higher rates of sensi- whether positive prick tests to P. ovale were asso- tization among patients with AD include formal- ciated with a specific localization in the head and dehyde releasers, metal allergens, cocamidopropyl neck region in a cohort of 589 patients. They betaine, and fragrances. ACD should also be found that serum levels of Malassezia-specific investigated in paediatric patients; although rates IgE were elevated in all patients with AD and of sensitization are comparable with the general HND but in only 13.6% of patients with AD population, ACD is a highly relevant diagnosis in without HND.100 children, and paediatric skin with an immature barrier function is more susceptible to toxicity.88 A positive response to oral itraconazole may In a UK retrospective case study of 114 children support the clinical diagnosis of HND. aged 3–15 years who were patch-tested over a Randomized, placebo-controlled trials have 3-year period, findings on patch test were positive shown significant clinical improvement of sus- in 33% of patients with facial dermatitis, 40% pected HND in patients with AD treated with with perioral dermatitis, and 86% with eyelid der- systemic antifungals.102–104 matitis.89 Paediatric patients with moderate-to- severe and early-onset AD have a higher incidence Hand and foot dermatitis. AD of the hand (Figure of sensitization to topical products, most com- 3f) presents usually as xerotic, scaly, lichenified, monly to emollients and antiseptics.90 Sunscreens and fissured skin, mainly on the dorsal hands.105 can also be a cause of ACD on the face and neck, This phenotype predominates in adulthood, and both sensitization and photosensitization although specific manifestations do occur in chil- should be investigated when suspected.91,92 dren (juvenile palmoplantar dermatitis or derma- titis plantaris sicca).4,73 In adults, the lifetime HND can be induced by TCS withdrawal. In par- prevalence of hand dermatitis is 15%,106 and it is ticular, overuse of potent TCS on the face can twice as common in females as in males.106,107 In lead to many adverse events upon withdrawal, a study of Swedish children, approximately 70% including burning, itching, and facial redness.93,94 of those with hand dermatitis at age 16 years had A retrospective analysis of 55 people in Australia a history of AD, and the risk of hand dermatitis suspected to be undergoing TCS withdrawal was greater in children with persistent or more found that 100% of patients experienced redness severe AD.108 In a French study that evaluated and itch. Of these patients, TCS were initially the benefit of therapeutic patient education in 72 prescribed for AD (76%), contact dermatitis adults with chronic hand eczema, 43.7% had a (15%), or other rashes (9%).93 personal history of AD.109 A retrospective review and clinical examination of 725 German adoles- In addition, recent reports have suggested an asso- cent and adults with AD found that two-thirds of ciation between treatment of AD with the biologic patients whose dermatitis developed after infancy 10 journals.sagepub.com/home/taj G Girolomoni, M de Bruin-Weller et al. and then persisted into adulthood had hand der- that manifests as vesicles and blisters on the palms matitis.75 A systematic review and meta-analysis and soles; it accounts for <10% of all cases of of 35 studies in 12 countries showed that patients hand and foot dermatitis35 (Figures 2f, 6). This with AD have a 3- to 4-fold increased incidence condition is very itchy and disabling. Complications of hand dermatitis when compared with con- can lead to or include secondary infection.118,119 trols,110 and that hand dermatitis in schoolchil- dren with AD frequently affects only the dorsa.111 Hyperkeratotic, dry fissured hand eczema, pulpi- tis, and nummular hand eczema are other clinical Hand dermatitis is often associated with occupa- manifestations of hand dermatitis (Figure 6).120 tional or domestic exposure to irritants and can be aggravated by daily tasks that necessitate con- Nipple dermatitis. AD-related nipple dermatitis tact with water, such as dishwashing, laundry, presents symmetrically, typically involving both and childcare. However, a history of childhood the nipples and areolas (Figure 3g).64 Nipple der- AD appears to be the main risk factor for devel- matitis can be aggravated or triggered by breast- opment of hand dermatitis.105 Approximately feeding121,122 and is found in 11–23% of individuals 29% of people with hand dermatitis have a his- with AD, most commonly in postpubertal girls tory of AD.112 A Norwegian study found that and young adults.4,114 Despite being described as 90% of school children with hand eczema also a minor diagnostic feature of the Hanifin–Rajka reported AD, which suggests that hand eczema criteria,30 the specificity of nipple eczema as a in children is closely associated with AD.111 In symptom of AD remains unclear.27,29,123,124 most cases, distinguishing between contact der- matitis and AD of the hand caused by endoge- nous factors is impossible by clinical presentation AD in the elderly: a new phenotype alone, and patch testing is warranted to deter- Phenotyping and stratification of AD type by mine whether any concomitant contact dermati- both age-related clinical picture and age at onset tis is present. Nevertheless, the presence of have been reviewed by Bieber and colleagues.5 lesions at the wrist is indicative of an underlying Elderly-type AD (AD in patients aged ⩾60 years) endogenous cause.105 A 7-year follow-up study has been suggested to be a distinct age-related in patients with hand dermatitis found that 45% phenotype alongside previously recognized infan- of patients also had concomitant AD lesions on tile, childhood, and adult phenotypes.5–7,125 other parts of their body during the follow-up period.112 As in adult-type AD, lichenified lesions are com- mon, but tend to be localized to the cubital and Unlike hand dermatitis, foot dermatitis is pre- popliteal extensor areas rather than the flexural dominantly caused by allergens in footwear.113 areas, as is typical of adult-type AD.5,126,127 Three Foot dermatitis may also be associated with forms of elderly-type AD are apparent – elderly AD.113 In most cases, the condition is found con- onset, relapsing, and continuous – and are subdi- comitantly with hand dermatitis.114 A dorsal pat- vided by age at onset.126–132 A comparison of stud- tern similar to that found in hand dermatitis ies carried out in various geographic locations suggests an allergic aetiology.115 The prevalence indicates that the prevalence of AD in those aged of foot dermatitis in patients with AD is approxi- >60 years is relatively stable at 2–5%.127,130,133 mately 30%.116 Immune system changes due to aging (immunose- nescence), such as increased type 2 cytokine pro- Juvenile palmoplantar dermatitis is a distinct duction [mainly interleukin (IL)-4 and IL-13], subtype of AD. As the name suggests, it affects may play a key role in the pathogenesis of elderly- the palms and plantar surfaces of the hands onset AD,127,134 as they do in chronic idiopathic and feet, rather than the dorsal surfaces. In pruritus of the elderly.135 Additional considera- affected children, symptoms are most common tions in the elderly include changes in the compo- in winter and tend to resolve between the ages sition of the cornified envelope with aging that may of 12 and 16 years.64,117 lead to impaired barrier function,136 and the effects of medications, including calcium channel blocker- Dyshidrosis, also called dyshidrotic eczema or induced dermatitis137 and statin-exacerbated pompholyx, may be a clinical phenotype of AD xerotic/asteatotic dermatitis.138 journals.sagepub.com/home/taj 11 Therapeutic Advances in Chronic Disease 12 Figure 6. Most common phenotypes of hand eczema: dyshidrotic and hyperkeratotic. (a) Dyshidrotic eczema. The main component of dyshidrotic eczema is the presence of multiple vesicles containing clear fluid; the hands are usually wet. Sometimes due to the thick stratum corneum, vesicles do not come out of the skin surface and are only visible on close examination. (b) Hyperkeratotic eczema. Features include skin thickening (hyperkeratosis), fissures and bleeding, desquamation, and scaling. The hands are usually very dry. Guidelines are lacking on the differential diagnosis used commonly for HND,142 with narrowband of AD versus other skin conditions in the elderly, UVB phototherapy as another approved option. and diagnosis relies on persistence of symptoms Patients with severe AD can also be treated with for 6 months after excluding other causes such as traditional systemic immunosuppressive medica- comorbidities, treatment-related adverse events, tion, such as cyclosporine A or oral glucocorti- cutaneous T-cell lymphoma, and nonbullous vari- coids, with off-label use of azathioprine, ants of bullous pemphigoid.51,126,127,139 methotrexate or mycophenolate mofetil sometimes considered.140 However, use of these systemic immunosuppressants can be limited by their Treatment of atopic dermatitis adverse effects and tolerability, particularly for Preventive skin hygiene, including barrier-stabiliz- long-term treatment.27,142,143 Novel biologic thera- ing topical treatment, hydration, and monitoring pies include the approved therapy dupilumab, and treatment for superinfections are critical in the which targets the underlying inflammatory mecha- care of patients with AD. Guidance exists on the nism of AD by selectively blocking type 2 inflam- treatment of AD in adults and children,140 and mation.144–147 Many novel systemic and topical typical treatment strategies for AD include treating treatments are also under investigation, including visible skin lesions with topical anti-inflammatory the JAK inhibitors baricitinib, upadacitinib, and medications such as corticosteroids and calcineu- abrocitinib, the dual JAK-SYK inhibitor ASN002, rin inhibitors in combination with frequently as well as antagonists of histamine and TSLP, applied emollients to minimize the impact of skin which are each implicated in the pathogenesis of barrier dysfunction.140,141 TCS are an effective first AD.148 The implementation and success of these line of anti-inflammatory treatment when applied agents in treating AD relies, however, on further to skin lesions of patients with AD, and they and elucidation of the various phenotypes and appro- are associated with minor side effects.99,140 Steroid- priate diagnosis of the disease. sparing topical agents that are licensed for the treatment of AD include the calcineurin inhibitors tacrolimus ointment and pimecrolimus cream and Conclusions the phosphodiesterase 4 inhibitor crisaborole; Lack of consensus on AD terminology may these are preferred for sensitive locations and are lead to confusion and result in erroneous data 12 journals.sagepub.com/home/taj G Girolomoni, M de Bruin-Weller et al. and flawed epidemiologic assumptions. Efforts Conflict of interest statement continue to address this issue, and the increasing Dr. Giampiero Girolomoni has been principal use of the consensus term ‘atopic dermatitis’ in investigator in sponsored clinical trials and the literature and in medical records, may be a received personal fees from AbbVie, Abiogen, sign of progress. Wider use of the term ‘atopic Almirall, Amgen, Biogen, Boehringer Ingelheim, dermatitis’ for diagnosis should help generate Bristol-Myers Squibb, Celgene, Celltrion, LEO more accurate epidemiologic data and improve Pharma, Lilly, Menlo Therapeutics, Merck, evaluation of disease burden, outcome meas- Merck Sharp & Dohme, Novartis, OM Pharma, ures, and reimbursement decisions, as well as Pfizer, Regeneron, Samsung, Sandoz, Sanofi development of new treatments. Genzyme and UCB Pharma. AD is a heterogeneous condition that continues to Dr. Marjolein De Bruin-Weller has been principal frustrate attempts at classification based on age, investigator, advisory board member, and consult- morphology, and topographic location. This ant for Regeneron, Sanofi Genzyme; principal inves- review considers the clinical characteristics of tigator, and advisory board member for AbbVie, morphologically (nummular dermatitis, PN-like Pfizer, and Leo Pharma; and advisory board mem- lesions, erythroderma, pompholyx, papular/follic- ber for Lilly, UCB, Galderma, and Janssen. ular and lichenified dermatitis) and topographi- Dr. Valeria Aoki has received honoraria for lec- cally defined (flexural, facial, including eczematous turing from Sanofi. cheilitis and eyelid dermatitis, head and neck, hand and feet, or nipple) phenotypes of AD, which Dr. Kenji Kabashima has received consulting we consider to be a practical guide to discerning fees, honoraria, grant support, and lecturing fees the distinct manifestations of this heterogenous from Japan Tobacco, LEO Pharma, Maruho, disease. The subtyping of AD by phenotype may Mitsubishi Tanabe, Ono, Procter & Gamble, be important to identify the more appropriate Sanofi, Taiho, and Torii. treatment for patients, and a protocol has been Dr. Mette Deleuran has received research support, developed for a systematic review of phenotypes in honoraria for lecturing and is on consulting/advisory AD.149 Given the diversity of AD phenotypes, this board agreements with AbbVie, Almirall, Galapagos, reference will facilitate earlier and correct diagno- LEO Pharma, Lilly, Meda Pharma, Pfizer, Pierre ses of AD, leading to better treatment decisions Fabre, Regeneron, and Sanofi Genzyme. and management of the disease. Dr. Luis Puig has received research support, Acknowledgements honoraria for lecturing, and is on consulting/ Microphotographs in Figure 5 have been gener- advisory board agreements with AbbVie, ously provided by Dr. Maria Teresa Fernández- Almirall, Amgen, Baxalta, Biogen, Boehringer Figueras, Department of Pathology, Hospital Ingelheim, Celgene, Gebro, Janssen, LEO Universitari General de Catalunya, Universitat Pharma, Lilly, Merck Serono, Merck Sharp & Internacional de Catalunya, Sant Cugat del Dohme, Pfizer, Mylan, Novartis, Roche, Sandoz, Vallès (Barcelona), Spain. The authors espe- Samsung Bioepis, Sanofi, and UCB. Dr Puig is cially thank the patients who provided written also an Associate Editor of Therapeutic Advances agreement for the use of their photographs in in Chronic Disease and, therefore, the peer review scientific publications, and Noah Levit process was managed by alternative members of (Regeneron Pharmaceuticals, Inc.) for critical the Board and the submitting Editor had no feedback on the manuscript. involvement in the decision-making process. Dr. Ashish Bansal is an employee and shareholder of Regeneron Pharmaceuticals, Inc. Author contributions GG conceived the manuscript, MdB, ABR, KK, Dr. Ana B. Rossi is an employee and may hold and AB performed literature review references, stock and/or stock options in Sanofi Genzyme. ABR analyzed data, ABR, GG, MdB, VA, MD, and LP provided clinical photos, MdB and ABR Funding contributed to writing. 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