Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis

INTRODUCTION — Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease that commonly affects both children and adults. AD is often associated with an elevated serum level of immunoglobulin E (IgE) and a personal or family history of atopy, which describes a predisposition to a group of disorders that includes eczema, asthma, and allergic rhinitis [1,2]. Although sensitization to environmental or food allergens is clearly associated with AD, it does not seem to be a causative factor in most patients but may be a contributory factor in a subgroup of patients with severe disease or seasonal flares [3]. (See "Role of allergy in atopic dermatitis (eczema)".)

The epidemiology, pathophysiology, clinical manifestations, and diagnosis of AD are reviewed here. The treatment of AD and the role of allergy in AD are discussed separately.

●(See "Treatment of atopic dermatitis (eczema)".)

●(See "Management of severe, refractory atopic dermatitis (eczema) in children".)

●(See "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults".)

●(See "Role of allergy in atopic dermatitis (eczema)".)

EPIDEMIOLOGY

Prevalence and incidence — AD affects approximately 2 to over 20 percent of children worldwide, with large variations among countries and ethnic groups [4]. Countries in Africa, Oceania, and the Asia-Pacific region have higher rates of AD than countries in the Indian subcontinent and Northern/Eastern Europe [5]. In the United States, the prevalence of AD in children is approximately 13 percent, with the highest rates reported in African American children (22 percent) [6-9].

Data on the prevalence of AD in adults are limited. Population-based studies from Scandinavian countries report prevalence rates of 10 to 14 percent among adults [10-12]. In the United States, two cross-sectional studies independently found that the prevalence of AD was approximately 7 percent [13,14].

While the incidence remains high in urban areas and high-income countries, an increasing trend in incidence and prevalence of atopic eczema has been reported in the last few decades in Africa, East Asia, Western Europe, and parts of Northern Europe [5,15].

In the vast majority of cases, AD has an onset before the age of five years, and prevalence data in children show a slight female preponderance [16,17]. Persistent AD beyond infancy may affect approximately 50 percent of patients diagnosed with AD during childhood [12,18]. In addition, approximately 25 percent of adult patients with AD report adult onset of disease [19].

Risk factors — Risk factors for AD include multiple genetic and environmental factors.

●Genetic risk factors – A family history of atopy (eczema, asthma, or allergic rhinitis) is the strongest risk factor for AD. Approximately 70 percent of patients have a positive family history of atopic diseases. Children with one atopic parent have approximately a two- to threefold increased risk of developing AD, and the risk increases to three- to fivefold if both parents are atopic [2,20].

Loss-of-function variants in the FLG gene, resulting in defective epidermal barrier, are a major risk factor for AD and other skin and allergic diseases, including allergic contact dermatitis, asthma, and food allergy [21-23]. Multiple other genes have been proposed as potential contributors to the risk of AD, including genes involved in the regulation of innate host defenses and T cell function [24]. (See 'Genetic factors' below.)

●Environmental exposures – Environmental factors, including climate, urban versus rural setting, air pollution, early exposure to nonpathogen microorganisms, and water hardness, may influence the risk of AD [25,26]. Examples of studies linking environmental factors to AD are shown below:

•The "hygiene hypothesis" – Two systematic reviews provided evidence to support an inverse relationship between AD and exposure to endotoxin, early daycare, helminth infestation, number of siblings, farm animals, and pet dogs in early life [27,28]. There was no protective effect associated with viral or bacterial infections.

•Water hardness – Epidemiologic evidence from ecologic studies linked high hardness (high levels of calcium carbonate) of domestic water with increased prevalence of AD in children [29-34]. A 2021 meta-analysis of seven observational studies that included nearly 386,000 participants found a modest increase of risk of AD in children exposed to hard water (odds ratio [OR] 1.28, 95% CI 1.09-1.50) [34]. However, the authors considered the certainty of this estimate to be very low due to high risk of bias and heterogeneity in the definition of "hard water." Moreover, a randomized controlled trial found no efficacy of ion exchange water softeners installed in the home of children with eczema [35]. These negative results further suggest that water hardness may not play a major role in AD.

PATHOPHYSIOLOGY — A multiplicity of mechanisms are involved in the pathogenesis of AD, including epidermal barrier dysfunction, genetic factors, T helper type 2 (Th2) cell-skewed immune dysregulation, altered skin microbiome, and environmental triggers of inflammation [36-40]. Whether skin inflammation is initiated by skin barrier dysfunction ("outside-in" hypothesis) or by immune dysregulation ("inside-out" hypothesis) is still debated. It is increasingly recognized that combinations of different mechanisms may result in multiple "endotypes" and phenotypes of AD [40].

Epidermal barrier dysfunction — The epidermal barrier function primarily resides in the stratum corneum, which consists of vertical stacks of anucleate corneocytes packed with keratin filaments embedded in a matrix of filaggrin breakdown products, ceramides, cholesterol, and free fatty acids [41,42]. The stratum corneum provides the first line of defense against the environment, including pathogens and allergens, and controls water homeostasis. An altered stratum corneum, therefore, results in increased transepidermal water loss, increased permeability, reduced water retention, and altered lipid composition [43-45].

Epidermal barrier dysfunction is the key abnormality in the pathophysiology of AD [45], hence the importance of moisturizers and emollients in the management of AD. (See "Treatment of atopic dermatitis (eczema)", section on 'Emollients and moisturizers'.)

Epidermal barrier dysfunction is caused by multiple factors, including reduced filaggrin production, imbalance between stratum corneum protease and antiprotease activity, tight junction abnormalities, altered composition and lamellar organization of epidermal lipids, microbial colonization, itch-scratch cycle, and release of proinflammatory cytokines.

●Filaggrin – Filaggrin deficiency is a major determinant of defective barrier function [21]. It is associated with disruption of keratinocyte differentiation, impaired corneocyte integrity and cohesion, impaired tight junction formation, decreased water retention, altered lipid formation, and enhanced susceptibility to cutaneous infection. The filaggrin precursor profilaggrin is encoded by the FLG gene, located in the epidermal differentiation complex on chromosome 1q21.3. Following its synthesis, profilaggrin undergoes extensive phosphorylation; is stored in keratohyalin granules; and, subsequently, dephosphorylated and cleaved by several endoproteases into filaggrin monomers that have keratin filament-aggregating properties [46,47]. Further degradation of filaggrin monomers in the upper stratum corneum releases hygroscopic amino acids and their derivatives (eg, pyrrolidone carboxylic acid, trans-urocanic acid) that, together with sodium and chloride ions, urea, and lactate, compose the natural moisturizing factor (NMF) [48]. The NMF maintains skin hydration and water retention within the stratum corneum in conditions of low environmental humidity.

●Other factors that can result in skin barrier breakdown include:

•Imbalance between stratum corneum protease (eg, kallikrein, stratum corneum chymotryptic enzyme) and antiprotease activity (eg, lymphoepithelial Kazal-type related inhibitor [LEKTI]).

•Abnormalities of the tight junction function. Tight junctions are located in the granular layer of the epidermis below the stratum corneum and are thought to seal the intercellular space to prevent the free diffusion of macromolecules [49]. Defective tight junctions may contribute to skin barrier impairment. Tight junctions are composed of a number of transmembrane proteins, such as proteins of the claudin family, junctional adhesion molecule (JAM)-A, occludin, and tricellulin. A reduced expression of the tight junction protein claudin-1 has been demonstrated in nonlesional skin of individuals with AD [50].

•Microbial colonization and release of proinflammatory cytokines [51]. (See 'Alteration of cutaneous microbiome' below.)

•Inflammatory cytokines, such as interleukin (IL) 4, IL-13, IL-17A, IL-22, IL-25, and IL-31, have also been shown to suppress filaggrin expression in the skin, resulting in additional barrier impairment [52].

Genetic factors — A genetic basis for AD was initially suggested by twin studies that found concordance rates of 80 percent for monozygotic twins compared with 20 percent for dizygotic twins [53-55]. Subsequently, multiple linkage studies and genome-wide association studies (GWAS) implicated loci associated with skin barrier abnormalities, in particular the epidermal differentiation complex on chromosome 1q21, which includes FLG, and new loci, including candidate genes involved in the regulation of innate host defenses and T cell function [23,24,56]. However, these genetic susceptibility loci account for less than 20 percent of the total heritability of AD, with most of it remaining largely unexplained [24].

FLG variants — Loss-of-function variants in FLG, located in the epidermal differentiation complex on chromosome 1q21.3 and encoding profilaggrin, cause ichthyosis vulgaris [57], the most common single-gene inherited disorder of keratinization (see "Ichthyosis vulgaris"), and are also the strongest genetic risk factor for AD [21,56]. In meta-analyses, loss-of-function variants in FLG are associated with a three- to fourfold increased risk of AD [22,23,58].

●Prevalence by geographic area/ethnic groups – The prevalence of loss-of-function FLG variants in patients with AD varies among geographic areas and ethnic groups. Prevalence rates of up to 50 and 27 percent have been reported in patients of European and Asian descent, respectively. In contrast, loss-of-function variants in FLG appear to be uncommon in African patients with AD, with prevalence rates of <1 percent [59-61]. FLG variants appear to be relatively higher among African American patients. In a United States cohort of 741 children from the Pediatric Eczema Elective Registry (PEER), the prevalence of any FLG variants was 31.5 percent in White children and 15.3 percent in African American children [62].

The prevalence of specific FLG variants also varies across different populations. The most prevalent variants are R501X, 2282del4, S3247X, and R2447X in European patients; S2889X in patients from the Indian subcontinent; 3321delA in East Asian patients; K4022X in Korean and Northern Chinese patients; and S2554X, S2889X, S3296X, and Q1701X in Japanese patients [63].

●Association with specific AD phenotypes – FLG variants are associated with specific AD phenotypes, including early-onset and persistent disease; increased risk of asthma, allergic rhinitis, and food allergy; increased prevalence and persistence of hand and foot dermatitis during adulthood; and multiple contact allergies [64-68]. The FLG genotype may also influence the response to treatment. In a cohort study of 842 children enrolled in the PEER and followed up for an average of 7.6 years, patients with homozygous, loss-of-function FLG variants were less likely to report any period of skin clearance and more likely to report frequent steroid use than patients with wild-type FLG or heterozygous FLG variants [69].

Other genes — In addition to FLG, other potential susceptibility genes for AD have been found, including genes involved in the regulation of innate host defenses and T cell functions [70,71]. A meta-analysis of 26 GWAS that included over 21,000 cases and 95,000 controls found 31 loci associated with AD [24]. These comprised widely replicated loci, such as the epidermal differentiation complex on 1q21.3 (including FLG); the cytokine cluster on 5q31.1 (including genes encoding IL-13 and IL-4); the locus on chromosome 11q13.5, between two candidate genes, EMSY and LRRC32; as well as new loci, including candidate genes involved in the regulation of innate host defenses and T cell function.

Immune dysregulation and inflammation — Both the innate and acquired immune responses have a role in the pathogenesis of type 2 inflammation in AD [36,72]. (See "An overview of the innate immune system" and "The adaptive cellular immune response: T cells and cytokines" and "The adaptive humoral immune response" and "Role of allergy in atopic dermatitis (eczema)".)

Keratinocytes and antigen-presenting cells in the skin express a number of innate immune receptors called pattern recognition receptors, which include toll-like receptors (TLRs). Stimulation of TLRs by tissue damage or microorganisms leads to the release of a wide range of danger signals (alarmins), including antimicrobial peptides (AMPs); cytokines, such as IL-1A, thymic stromal lymphopoietin (TSLP), IL-25, and IL-33; proteases (kallikreins, cathepsins); and extracellular matrix (ECM) proteins, such as periostin [73].

The release of alarmins triggered by epithelial barrier disruption activates inflammatory dendritic epidermal cells and type 2 immune cells, including Th2 cells, skin-resident group 2 innate lymphoid cells (ILC2s), mast cells, and basophils. Activated Th2 cells release IL-4 and IL-13, which promote inflammation as well as B cell IgE class switching, the latter resulting in the production of antigen-specific IgE molecules via the signal transducer and activator of transcription (STAT) pathway [45].

In addition to their role in promoting inflammation, Th2 cytokines (IL-4, IL-13, IL-31, and IL-22) affect the epidermal barrier function by suppressing the expression of terminal keratinocyte differentiation genes (eg, FLG, loricrin, involucrin), inhibiting the production of AMPs, and promoting epidermal hyperplasia [74].

Neuroimmune interactions — Chronic itch is a defining symptom of AD. Itch is mediated by the transmission of signals along unmyelinated, histamine-sensitive and non-histamine-sensitive peripheral C-nerve fibers that originate from cell bodies of primary sensory neurons (pruriceptors) located in the dorsal root ganglia [75]. The nerve endings in the epidermis, papillary dermis, and skin appendages are activated by endogenous and exogenous pruritogens, including histamine, cytokines, and proteases and their respective receptors. (See "Pruritus: Etiology and patient evaluation".)

In AD, chronic itch results from complex interactions among non-histamine-sensitive peripheral C-nerve fibers, keratinocytes, and Th2 immune cells. Type 2 cytokines, including IL-4, IL-13, TSLP, and IL-31, are thought to be relevant mediators of chronic itch in AD. In mouse models, sensory neurons that innervate the skin were found to express IL-4, IL-13, and IL-31 receptors [76]. Although, in these models, IL-4 did not directly trigger itch, it sensitized dorsal root ganglia neurons to a variety of pruritogens, eliciting an itch response to otherwise subthreshold amounts of pruritogens.

In contrast, IL-31 appears to directly trigger itch in patients with AD [77]. The responsiveness of itch to inhibition of the IL-4 receptor (dupilumab) and IL-31 receptor (nemolizumab) and downstream IL-4, IL-13, and IL-31 signaling (Janus kinase [JAK] inhibitors) supports the relevance of these neuroimmune interactions in the pathogenesis of chronic atopic itch [78,79]. (See "Treatment of atopic dermatitis (eczema)", section on 'Controlling pruritus'.)

Alteration of cutaneous microbiome — Most patients with AD have substantial alteration of the skin microbiome, characterized by reduced diversity of the bacterial community and overgrowth of Staphylococcus aureus, especially in lesional skin [80]. A meta-analysis of 95 observational studies found that 70 percent of patients with AD carried S. aureus on lesional skin (95% CI 66-74), and 39 percent carried S. aureus on nonlesional skin (95% CI 31-47) [81].

A skin microbiome study using high-throughput deoxyribonucleic acid (DNA) sequencing of the bacterial 16S ribosomal ribonucleic acid (rRNA) gene in patients with moderate to severe AD and healthy controls found a striking decrease in the skin microbial diversity during flares, with reduction of Streptococcus, Corynebacterium, and Propionibacterium genera and increase in S. aureus density [82]. Of note, the microbiome diversity reverted to normal after treatment.

A multiplicity of bacterial proteins that act as virulence factors, including clumping factor B, fibronectin-binding proteins, proinflammatory proteins, toxins, enterotoxins, and proteases, contribute to the pathogenesis of AD [80]. Toxic shock syndrome toxin-1 (TSST-1) and the staphylococcal enterotoxin serotypes SEA, SEB, SEC, SED, SEE, or SEG are superantigens that bind to major histocompatibility class II (MHCII) molecules on the surface of antigen-presenting cells and T cell receptors on T cells, resulting in excessive production of T cell cytokines. Moreover, superantigens are also allergens that can elicit an IgE response and trigger mast cell degranulation [80].

PATHOLOGY — Histologically, AD is characterized by epidermal changes, including spongiosis (epidermal edema), with varying degrees of acanthosis and hyperkeratosis, accompanied by a lymphohistiocytic infiltrate in the dermis. In the acute phase, the histologic picture is dominated by spongiosis, an intercellular epidermal edema that leads to stretching and eventual rupture of the intercellular attachments, with the formation of vesicles.

CLINICAL MANIFESTATIONS

Common features — Dry skin and severe pruritus are the cardinal signs of AD. However, the clinical presentation is highly variable, depending upon the patient's age, ethnicity, and disease activity (figure 1).

Acute eczema is characterized by intensely pruritic, erythematous papules and vesicles with exudation and crusting (picture 3B), whereas subacute or chronic lesions present as dry, scaly, or excoriated, erythematous papules (picture 6C). Skin thickening from chronic scratching (lichenification) and fissuring may develop over time (picture 1A). In many patients, lesions in different stages may be present at the same time.

In children and adults with deeply pigmented skin, erythema may appear dark brown or violaceous instead of pink or red, as typically seen in patients with lighter complexions (picture 1J). The typical erythematous and scaly lesions of eczema may appear as lesions with a grayish, violaceous, or dark brown hue (picture 1A-B). Dry skin may have a whitish or ashy color and a reduction in skin shininess (picture 2). Lichenified areas typically appear hyperpigmented (picture 1A, 1C). Postinflammatory hyper- and hypopigmentation are also common (picture 1I and picture 1F). (See "Postinflammatory hyperpigmentation".)

In children, AD occurs in the first year of life in 60 percent of cases and by the age of five years in nearly 85 percent of cases. The clinical presentation at various ages is outlined below [83]:

●Infants and young children – In infants and young children (zero to two years), AD typically presents with pruritic, red, scaly, and crusted lesions on the extensor surfaces and cheeks or scalp (picture 3A-E) but may be diffuse (picture 3A, 3F). There is usually sparing of the diaper area (picture 4) [83]. Acute lesions can include vesicles, and there can be serous exudates and crusting in severe cases.

●Older children and adolescents – In older children and adolescents (2 to 16 years), AD is characterized by less exudation and often demonstrates lichenified plaques in a flexural distribution, especially of the antecubital and popliteal fossae, volar aspect of the wrists, ankles, and neck (picture 1A, 1D-E) [83]. The sides of the neck may show a reticulate pigmentation, the so-called "atopic dirty neck" (picture 1B, 1F).

●Adults – In adults, the skin flexures are commonly involved (picture 5 and picture 1C, 1G-I), though adults may have less flexural involvement than children with AD [84]. Frequently, the dermatitis may involve the face, neck (picture 1B, 1F), or hands (picture 6A-B) [83,85].

In all age groups, any area of the body can be involved in severe cases, although it is uncommon to see lesions in the axillary, gluteal, or groin area. Lesions in these locations should prompt consideration of other diagnoses, such as psoriasis, allergic contact dermatitis, or seborrheic dermatitis. (See 'Differential diagnosis' below.)

Associated features — Patients with AD may present a variety of cutaneous findings, so-called "atopic stigmata," which include [86]:

●Centrofacial pallor

●White dermographism

●Keratosis pilaris (picture 7A-B)

●Palmar hyperlinearity (picture 8A-B)

●Pityriasis alba (picture 9)

●Periorbital darkening ("allergic shiners") and Dennie-Morgan infraorbital folds (picture 10A-D)

●Thinning or absence of the lateral portion of the eyebrows (Hertoghe's sign)

●Infra-auricular and retroauricular fissuring

●Nipple eczema (picture 11)

Although considered minor diagnostic criteria, these findings are frequently seen and may be supportive of the diagnosis of AD in some patients (figure 1). (See 'Diagnosis' below.)

Clinical variants — Regional and morphologic variants of AD have been described in both children and adults [86,87]. They may be the only manifestation of AD or occur in association with the classic age-related manifestations.

Regional variants include:

●Atopic hand eczema – Atopic hand eczema typically involves the volar wrists and dorsum of the hands (picture 6A-C). It is most common in adults with a history of AD who no longer have dermatitis in typical areas (eg, flexural), especially in those who are exposed to "wet work" environments [88]. Concurrent foot eczema has been reported in approximately one-third of patients with atopic hand eczema [89]. (See "Chronic hand eczema".)

●Eyelid eczema – Eyelid dermatitis is a common feature of AD and may be the only manifestation in some patients (picture 12A-D) [90]. It is often associated with lichenification and presence of Dennie-Morgan lines (picture 10B-D). (See "Eyelid dermatitis".)

●Atopic cheilitis – Lip eczema or "cheilitis sicca" is a common manifestation of AD, characterized by dryness, peeling, and fissuring of the lips (picture 13). The clinical appearance may be indistinguishable from irritant or allergic cheilitis. (See "Cheilitis".)

Morphologic variants include [87,91]:

●Nummular dermatitis (see "Nummular eczema")

●Prurigo nodularis type (see "Prurigo nodularis")

●Follicular type

Laboratory findings — Up to 80 percent of patients with AD have increased serum IgE levels, often with eosinophilia. The IgE level tends to vary with disease severity, although some patients with severe disease have normal IgE values.

Most patients with AD have a cutaneous hyperreactivity to various environmental stimuli, including exposure to food and inhalant allergens, irritants, changes in physical environment (including pollution, humidity, etc), microbial infection, and stress [51].

Clinical course and complications

●Clinical course – AD follows a chronic, relapsing course over months to years. Patients with mild disease may experience intermittent flares with spontaneous remission, but patients with moderate to severe dermatitis rarely clear without treatment.

Many children with eczema develop extended periods of eczema clearance by late childhood, but the disease may persist or recur in adolescents and adults in a variable proportion of cases [10,12,92-95].

A pooled analysis of 45 studies including over 110,000 subjects found that 20 percent of cases of childhood AD had persistent disease eight years after the diagnosis and less than 5 percent had persistent disease 20 years after the diagnosis [96]. The age of onset was the main factor associated with persistence of AD. The hazard ratio was 2.65 (95% CI 2.54-2.75) for onset at age 2 to 5 years, 4.22 (95% CI 3.86-4.61) for onset at age 6 to 11 years, and 2.04 (95% CI 1.66-2.49) for onset at age 12 to 17 years compared with age of onset <2 years. Other risk factors for persistence were disease severity and duration and female sex. Hypersensitivity to one or more allergens did not seem to influence the persistence of AD.

●Infectious complications – Patients with AD are predisposed to the development of bacterial and viral skin infections. Because S. aureus colonizes nearly 100 percent of patients, impetiginization of lesions of AD is frequent and is associated with disease exacerbation. However, infection from community-acquired, methicillin-resistant Staphylococcus aureus (MRSA) is uncommon among children with AD [97-99].

Eczema herpeticum, also called Kaposi's varicelliform eruption, is the rapid dissemination of a herpes simplex viral infection on the affected skin of patients with AD (picture 14A-C). Eczema herpeticum is a rare complication, occurring in less than 3 percent of patients with AD, and can occasionally be recurrent [100]. Severe eczema, high levels of serum IgE, and history of food allergy or asthma appear to be predisposing factors [101].

In children with AD, atypical hand, foot, and mouth disease (HFMD; caused by coxsackievirus A6) lesions tend to appear in areas previously or currently affected by the dermatitis, similar to eczema herpeticum ("eczema coxsackium") (picture 15). (See "Atypical exanthems in children".)

COMORBIDITIES — Comorbidities and disorders associated with AD are reviewed separately. (See "Atopic dermatitis: Comorbidities and associated diseases".)

RISK OF CANCER

Lymphoma — The association between AD and lymphoma remains controversial [102,103].

●A 2015 systematic review and meta-analysis of 4 cohort studies and 18 case-control studies found a modest increase in the risk of lymphoma in patients with AD compared with the general population [104]. The risk increase was significant in the meta-analysis of the cohort studies (relative risk [RR] 1.43, 95% CI 1.12-1.81) but not in the case-control studies (odds ratio [OR] 1.18, 95% CI 0.94-1.47). However, the large heterogeneity of case-control studies in study design and diagnostic criteria does not allow any definite conclusion.

Three of the studies included in this meta-analysis reported a significant association between severity of AD and cutaneous T cell lymphoma (CTCL) [105-107]. However, this finding must be interpreted with caution because a misclassification bias cannot be excluded. Due to overlapping clinical features, CTCL cases may have initially been misdiagnosed and treated as severe AD.

●A 2023 United Kingdom study that included a pediatric cohort of 409,431 children with AD and 1,809,029 children without AD aged four to nine years followed for a median follow-up time of five to seven years found that the overall risk of hematologic malignancies was not different in the two groups (hazard ratio [HR] 1.07, 95% CI 0.91-1.25) [108]. However, among children with severe AD, there was a statistically significant greater risk of all noncutaneous lymphomas (HR 3.18, 95% CI 1.41-7.16).

In the adult cohort that included 625,083 patients with AD and 2,678,888 patients without AD, patients with moderate or severe disease had a slightly increased risk of all hematologic malignancies (HR 1.09, 95% CI 1.03-1.14; and HR 1.44, 95% CI 1.27-1.64, respectively), mainly driven by lymphomas. In particular, the risk of CTCL increased with worsening severity of AD (HR 1.73, 95% CI 1.21-2.47; HR 5.60, 95% CI 4.34-7.23; and HR 18.09, 95% CI 12.43-26.32 for mild, moderate, and severe disease, respectively). An increased risk of CTCL was found in all severity categories after excluding patients receiving systemic immunosuppressive treatments.

Skin cancer and other cancers — The association of AD with skin cancer and internal cancers is controversial.

●A 2020 systematic review and meta-analysis of eight population-based cohort studies (n = 5,726,692) found a higher incidence rate of keratinocyte carcinomas (five studies, pooled standardized incidence ratio [SIR] 1.46, 95% CI 1.20-1.77) and cancers of the kidney (two studies, pooled SIR 1.86, 95% CI 1.14-3.04), central nervous system (two studies, pooled SIR 1.81, 95% CI 1.22-2.70), and pancreas (one study, SIR 1.90, 95% CI 1.03-3.50) among patients with AD [109]. However, the authors concluded that because of methodologic and quality heterogeneity across the included studies and variation in the definition of AD, no firm conclusions can be drawn about these associations. Moreover, detection bias cannot be excluded due to increased medical surveillance of patients with AD.

●In contrast, two large cohort studies performed in England (471,970 individuals with AD and 2,239,775 without AD) and Denmark (44,945 individuals with AD and 445,673 without AD) did not find an association between AD and overall risk of cancer [110]. However, in the English cohort, individuals with AD had a 20 percent higher risk of non-Hodgkin lymphoma (HR 1.20, 99% CI 1.07-1.34) and a nearly 50 percent higher risk of Hodgkin lymphoma (HR 1.48, 99% CI 1.07-2.04). A similar increased risk of non-Hodgkin lymphoma and Hodgkin lymphoma, although nonstatistically significant, was found in the Danish cohort.

DIAGNOSIS

History and clinical examination — In the vast majority of cases, the diagnosis of AD is clinical, based on history, morphology and distribution of skin lesions, and associated clinical signs (figure 1) [2]. (See 'Common features' above and 'Associated features' above.)

Because of the high variability of clinical presentation, related to age, ethnicity, and severity, the diagnosis may be difficult, especially in infants and older adults. Moreover, in patients with highly pigmented skin, the clinical signs of dermatitis differ from those seen in patients with lightly pigmented skin [111].

●Dry skin may appear a whitish or gray color (picture 2).

●Erythema may appear violaceous or may not be visible at all (picture 1J). Presence of edema or scale and increased skin temperature to the touch are signs of underlying erythema and inflammation.

●Lichenified areas from chronic scratching may appear hyperpigmented (picture 1I).

●Postinflammatory hyper- and hypopigmentation are common (picture 1F).

Diagnostic criteria — Several sets of criteria have been proposed for the diagnosis of AD. Although they are generally used in epidemiologic studies, they provide guidance to the diagnostic approach in clinical settings.

The United Kingdom Working Group on AD criteria include one mandatory and five major criteria but do not include allergy criteria as originally proposed by Hanifin and Rajka [112,113]:

●Evidence of pruritic skin, including the report by a parent or caregiver of a child rubbing or scratching

In addition to itchy skin, three or more of the following are needed to make the diagnosis:

●History of skin creases being involved. These include antecubital fossae, popliteal fossae, neck, areas around eyes, and fronts of ankles.

●History of asthma or hay fever (or history of atopic disease in a first-degree relative for children <4 years of age).

●The presence of generally dry skin within the past year.

●Symptoms beginning in a child before the age of two years. This criterion is not used to make the diagnosis in a child who is under four years old.

●Visible dermatitis involving flexural surfaces. For children under four years of age, this criterion is met by dermatitis affecting the cheeks or forehead and outer aspects of the extremities. (See 'Common features' above.)

The American Academy of Dermatology criteria for the diagnosis of AD include three sets of essential, important, and associated features [2,114].

●Essential features (any three required)

•Mild to severe pruritus

•Eczema (acute, subacute, chronic) with typical morphology and age-specific patterns:

-Facial, neck, and extensor involvement in infants and children up to four years of age

-Current or previous flexural lesions in any age group

•Chronic or relapsing course

●Important features (two or more required)

•Onset before two years of age

•Personal and/or family history of allergic rhinitis, asthma, food allergies, or AD

•Dry skin within the last year

●Associated features (one or more required)

•Atypical, vascular responses (eg, facial pallor, white dermographism, delayed blanch response)

•Keratosis pilaris, pityriasis alba, hyperlinear palms, ichthyosis

•Periocular changes (periorbital darkening or lichenification, bilateral periorbital eczema, Dennie-Morgan lines under the lower eyelids)

•Perioral eczema, bilateral periauricular eczema lesions, prurigo nodules or papules

•Perifollicular accentuation or lichenification

•Sparing of groin or axilla

Skin biopsy and laboratory tests — Skin biopsy and laboratory testing, including IgE levels, are not used routinely in the evaluation of patients with suspected AD and are not recommended. However, in selected patients, histologic examination of a skin biopsy or other laboratory tests (eg, serum IgE, potassium hydroxide preparation, patch testing, genetic testing) may be helpful to rule out other skin conditions [2]. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of AD includes:

●Allergic or irritant contact dermatitis – Allergic or irritant contact dermatitis may be difficult to differentiate from AD (picture 16). Moreover, allergic contact dermatitis may coexist with AD [115,116]. The localization of dermatitis to a specific skin area, history of exposure to irritants or potential sensitizers, and a relevant patch test positivity suggest the diagnosis of contact dermatitis. A skin biopsy is not useful to distinguish irritant or allergic contact dermatitis from AD, as they share identical histopathologic features. (See "Clinical features and diagnosis of allergic contact dermatitis".)

●Seborrheic dermatitis – Seborrheic dermatitis is the most common differential diagnosis in infants (picture 17A-C). The two conditions may also coexist. The presence of salmon-red, erythematous skin patches with greasy scale, involvement of the scalp, and little or no pruritus support the diagnosis of seborrheic dermatitis. (See "Seborrheic dermatitis in adolescents and adults" and "Cradle cap and seborrheic dermatitis in infants".)

●Psoriasis – In contrast with AD, psoriasis often involves the diaper area with well-demarcated, erythematous patches with little scale in infants and young children (picture 18A-B and figure 1). (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

●Scabies – Scabies may present as a diffuse eruption mimicking AD (picture 19). The involvement of the skin folds (and of the diaper area in infants) and the presence of vesicopustules on the palms and soles suggest the diagnosis of scabies. The demonstration of mites or eggs by skin scraping, dermoscopy, or adhesive tape test can confirm the diagnosis. (See "Scabies: Epidemiology, clinical features, and diagnosis".)

●Less common conditions that may be confused with AD include:

•Drug reactions (picture 20) (see "Exanthematous (maculopapular) drug eruption")

•Primary immunodeficiencies, including Wiskott-Aldrich syndrome (picture 21) and hyperimmunoglobulin E syndrome (picture 22) (see "Wiskott-Aldrich syndrome" and "Autosomal dominant hyperimmunoglobulin E syndrome")

•Nutritional deficiencies, acrodermatitis enteropathica (picture 23) (see "Zinc deficiency and supplementation in children")

•Netherton syndrome (picture 24A-B) (see "Netherton syndrome")

•Cutaneous T cell lymphoma (see "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides")

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atopic dermatitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Eczema (atopic dermatitis) (The Basics)")

●Beyond the Basics topics (see "Patient education: Eczema (atopic dermatitis) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors – Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease that commonly occurs in children and adults, with an estimated worldwide prevalence in children of 2 to over 20 percent. A family history of atopy (eczema, asthma, or allergic rhinitis) and the loss-of-function mutations in the filaggrin (FLG) gene, involved in the skin barrier function, are major risk factors for AD. (See 'Epidemiology' above and 'Risk factors' above.)

●Clinical manifestations – The cardinal features of AD are dry skin and severe pruritus. Erythema, papulation, oozing and crusting, excoriation, and lichenification vary with the patient's age, ethnicity, and stage of lesions (picture 1A, 3B, 6C and figure 1). In children and adults with deeply pigmented skin, the typical erythematous and scaly lesions of eczema may appear with a grayish, violaceous, or dark brown hue (picture 1A-B, 1I-J). (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of AD is clinical, based upon history, morphology and distribution of skin lesions, and associated clinical signs (figure 1). Diagnostic criteria for the clinical diagnosis include:

•Pruritus

•Eczema (acute, subacute, chronic) with typical morphology and age-specific patterns:

-Facial, neck, and extensor involvement in infants and children

-Current or previous flexural lesions in any age group

-Sparing of the groin and axillary regions

•Chronic or relapsing history

Skin biopsy and laboratory testing, including IgE levels, are usually not necessary in patients felt clinically to have AD. (See 'Diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William L Weston, MD, who contributed to earlier versions of this topic review.