INTRODUCTION — Atopic dermatitis is a chronic, pruritic, inflammatory skin disease that occurs most frequently in children but also affects adults. Atopic dermatitis is often associated with an elevated serum level of immunoglobulin E (IgE) and a personal or family history of atopy, which describes a group of disorders that includes eczema, asthma, and allergic rhinitis [1,2]. Although sensitization to environmental or food allergens is clearly associated with the atopic dermatitis phenotype, it does not seem to be a causative factor but may be a contributory factor in a subgroup of patients with severe disease . (See "Role of allergy in atopic dermatitis (eczema)".)
The epidemiology, pathophysiology, clinical manifestations, and diagnosis of atopic dermatitis are reviewed here. The treatment of atopic dermatitis and the role of allergy in atopic dermatitis are discussed separately.
Prevalence and incidence — Atopic dermatitis affects approximately 5 to over 20 percent of children worldwide, with large variations among countries and ethnic groups [4,5]. Countries in Africa, Oceania, and the Asia-Pacific region have higher rates of atopic dermatitis than countries in the Indian subcontinent and Northern/Eastern Europe . In the United States, the overall prevalence is approximately 16 percent, with the highest rates reported in African American children (19 percent) [6-9].
Data on the prevalence of atopic dermatitis in adults are limited. Population-based studies from Scandinavian countries report prevalence rates of 10 to 14 percent among adults [10-12]. In a United States, cross-sectional study including nearly 1300 adults, the prevalence of atopic dermatitis was 7.3 percent (95% CI 5.9-8.8) .
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, as well as in parts of Northern Europe [5,14].
In the vast majority of cases, atopic dermatitis has an onset before the age of five years, and prevalence data in children show a slight female preponderance [15,16]. Persistent atopic dermatitis beyond infancy may affect approximately 50 percent of patients diagnosed with atopic dermatitis during childhood [12,17]. Onset in the first six months of life appears to be associated with severe disease.
Risk factors — Risk factors for atopic dermatitis 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 atopic dermatitis . Approximately 70 percent of patients have a positive family history of atopic diseases. Children with one atopic parent have a two- to threefold increased risk of developing atopic dermatitis, and the risk increases to three- to fivefold if both parents are atopic .
Loss-of-function variants in the FLG gene, resulting in defective epidermal barrier, are a major risk factor for atopic dermatitis and other skin and allergic diseases, including allergic contact dermatitis, asthma, and food allergy [18-20]. Multiple other genes have been proposed as potential contributors to the risk of atopic dermatitis, including genes involved in the regulation of innate host defenses and T cell function . (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 atopic dermatitis [22,23]. Examples of studies linking environmental factors to atopic dermatitis are shown below:
•The "hygiene hypothesis" – Two systematic reviews provided evidence to support an inverse relationship between atopic dermatitis and exposure to endotoxin, early daycare, helminth infestation, number of siblings, farm animals, and pet dogs in early life [24,25]. 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 atopic dermatitis in children [26-31]. A 2021 meta-analysis of seven observational studies that included nearly 386,000 participants found a modest increase of risk of atopic dermatitis in children exposed to hard water (odds ratio [OR] 1.28, 95% CI 1.09-1.50) . 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."
PATHOPHYSIOLOGY — A multiplicity of mechanisms are involved in the pathogenesis of atopic dermatitis, including epidermal barrier dysfunction, genetic factors, Th2 cell-skewed immune dysregulation, altered skin microbiome, and environmental triggers of inflammation [32-36]. 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 result in multiple "endotypes" and phenotypes of atopic dermatitis .
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 [37,38]. 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 [39-41].
Epidermal barrier dysfunction is the key abnormality in the pathophysiology of atopic dermatitis , hence the importance of moisturizers and emollients in the management of atopic dermatitis. (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 . 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 1q23.3. 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 [42,43]. 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) . 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 . 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 atopic dermatitis .
•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 .
Genetic factors — A genetic basis for atopic dermatitis was initially suggested by twin studies that found concordance rates of 80 percent for monozygotic twins compared with 20 percent for dizygotic twins [49-51]. 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 [20,21,52]. However, these genetic susceptibility loci account for less than 20 percent of the total heritability of atopic dermatitis, with most of it remaining largely unexplained .
FLG variants — Loss-of-function variants in FLG, located in the epidermal differentiation complex on chromosome 1q23.3 and encoding profilaggrin, cause ichthyosis vulgaris , the most common single-gene, inherited disorder of keratinization (see "Ichthyosis vulgaris"), and are also the strongest genetic risk factor for atopic dermatitis . In meta-analyses, loss-of-function variants in FLG are associated with a three- to fourfold increased risk of atopic dermatitis [19,20,54].
The prevalence of loss-of-function FLG variants in patients with atopic dermatitis 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 atopic dermatitis, with prevalence rates of <1 percent [55-57]. 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 .
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 .
FLG variants are associated with specific atopic dermatitis 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 [60-64]. 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 .
Other genes — In addition to FLG, other potential susceptibility genes for atopic dermatitis have been found, including genes involved in the regulation of innate host defenses and T cell functions [66,67]. A meta-analysis of 26 GWAS that included over 21,000 cases and 95,000 controls found 31 loci associated with atopic dermatitis . 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 atopic dermatitis [32,68]. (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 .
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 .
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 .
Neuroimmune interactions — Chronic itch is a defining symptom of atopic dermatitis. 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 . 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 atopic dermatitis, 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 atopic dermatitis. In mouse models, sensory neurons that innervate the skin were found to express IL-4, IL-13, and IL-31 receptors . 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. The responsiveness of itch to inhibition of the IL-4 receptor (dupilumab) and downstream IL-4 signaling (Janus kinase [JAK] inhibitors) supports the relevance of these neuroimmune interactions in the pathogenesis of chronic atopic itch [73,74]. (See "Treatment of atopic dermatitis (eczema)", section on 'Controlling pruritus'.)
Alteration of cutaneous microbiome — Most patients with atopic dermatitis have substantial alteration of the skin microbiome, characterized by reduced diversity of the bacterial community and overgrowth of Staphylococcus aureus, especially in lesional skin . A meta-analysis of 95 observational studies found that 70 percent of patients with atopic dermatitis carried S. aureus on lesional skin (95% CI 66-74), and 39 percent carried S. aureus on nonlesional skin (95% CI 31-47) .
A skin microbiome study using high-throughput DNA sequencing of the bacterial 16S rRNA gene in patients with moderate to severe atopic dermatitis 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 . 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 atopic dermatitis . 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 .
PATHOLOGY — Histologically, atopic dermatitis 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.
Common features — Dry skin and severe pruritus are the cardinal signs of atopic dermatitis. 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 4B), 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. The typical erythematous and scaly lesions of eczema may appear as lesions with a grayish, violaceous, or dark brown hue (picture 1A-C). Dry skin may have a whitish or ashy color and a reduction in skin shininess (picture 2). Lichenified areas typically appear hyperpigmented (picture 1A, 1D). Postinflammatory hyper- and hypopigmentation are also common (picture 3A-B). (See "Postinflammatory hyperpigmentation".)
Atopic dermatitis 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 :
●In infants and young children (zero to two years), atopic dermatitis typically presents with pruritic, red, scaly, and crusted lesions on the extensor surfaces and cheeks or scalp (picture 4A-E) but may be diffuse (picture 4A, 4F). There is usually sparing of the diaper area (picture 5) . Acute lesions can include vesicles, and there can be serous exudates and crusting in severe cases.
●In older children and adolescents (2 to 16 years), atopic dermatitis 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, 1E-F) . The sides of the neck may show a reticulate pigmentation, the so-called "atopic dirty neck" (picture 1B, 3B).
●In adults, atopic dermatitis is considerably more localized and lichenified. The areas involved are, in most cases, the skin flexures (picture 1D, 1G-I, 3A). Less frequently, the dermatitis may involve the face, neck (picture 1B, 3B), or hands (picture 6A-B) [78,79].
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 atopic dermatitis may present a variety of cutaneous findings, so-called "atopic stigmata," which include :
●Keratosis pilaris (picture 7A-B)
●Palmar hyperlinearity (picture 14B)
●Pityriasis alba (picture 8)
●Periorbital darkening ("allergic shiners") and Dennie-Morgan infraorbital folds (picture 9A-D)
●Thinning or absence of the lateral portion of the eyebrows (Hertoghe's sign)
●Infra-auricular and retroauricular fissuring
Clinical variants — Regional and morphologic variants of atopic dermatitis have been described in both children and adults [80,81]. They may be the only manifestation of atopic dermatitis 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 atopic dermatitis who no longer have dermatitis in typical areas (eg, flexural), especially in those who are exposed to "wet work" environments . Concurrent foot eczema has been reported in approximately one-third of patients with atopic hand eczema . (See "Chronic hand eczema".)
●Eyelid eczema – Eyelid dermatitis is a common feature of atopic dermatitis and, in some patients, may be the only manifestation (picture 10A-D) . It is often associated with lichenification and presence of Dennie-Morgan lines (picture 9B-D). (See "Eyelid dermatitis (eczema)".)
●Atopic cheilitis – Lip eczema or "cheilitis sicca" is a common manifestation of atopic dermatitis, characterized by dryness, peeling, and fissuring of the lips (picture 11). The clinical appearance may be indistinguishable from irritant or allergic cheilitis. (See "Cheilitis".)
Laboratory findings — Up to 80 percent of patients with atopic dermatitis 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 atopic dermatitis 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 .
Clinical course and complications — Atopic dermatitis 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.
The majority of patients are clear of eczema by late childhood, but the disease may persist into adolescence and adulthood in a variable proportion of cases [10,12,86-89].
A pooled analysis of 45 studies including over 110,000 subjects found that 20 percent of cases of childhood atopic dermatitis had persistent disease eight years after the diagnosis and less than 5 percent had persistent disease 20 years after the diagnosis . The age of onset was the main factor associated with persistence of atopic dermatitis. 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 atopic dermatitis.
Patients with atopic dermatitis are predisposed to the development of bacterial and viral skin infections. Because S. aureus colonizes nearly 100 percent of patients, impetiginization of lesions of atopic dermatitis is frequent and is associated with disease exacerbation. However, infection from community-acquired, methicillin-resistant Staphylococcus aureus (MRSA) is uncommon among children with atopic dermatitis [91-93].
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 atopic dermatitis (picture 12A-C). Eczema herpeticum is a rare complication, occurring in less than 3 percent of patients with atopic dermatitis, and can occasionally be recurrent . Severe eczema, high levels of serum IgE, and history of food allergy or asthma appear to be predisposing factors .
In children with atopic dermatitis, 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 13). (See "Atypical exanthems in children".)
Allergic rhinitis, asthma, and food allergy — Patients with atopic dermatitis and a genetic predisposition to produce IgE following exposure to allergens may develop a typical sequence of atopic dermatitis, allergic rhinitis, asthma, and food allergy at certain ages (the "atopic march") [1,96,97]. (See "Role of allergy in atopic dermatitis (eczema)".)
Multiple studies indicated that the risk of progression to atopic march is inversely associated with the age of onset of atopic dermatitis:
●A cohort study including nearly 4000 children with at least three years of follow-up found that the cumulative incidence of seasonal allergies and asthma during the follow-up was higher among children with atopic dermatitis onset before age 2 than among those with onset at ages 3 to 7 or 8 to 17 (39, 32, and 30 percent, respectively) . However, since the age at onset was self-reported, a misclassification bias cannot be excluded.
●In a Canadian cohort of 2311 children with atopic dermatitis, allergic sensitization detected by skin prick testing at age one year was associated with a sevenfold increased risk of asthma at age three compared with absence of allergic sensitization (relative risk [RR] 7.04, 95% CI 4.13-11.99) .
Whether there is a cause-effect relationship between atopic dermatitis and subsequent development of respiratory allergy is still debated. It has been hypothesized that epicutaneous sensitization to allergens can occur in early life in children with atopic dermatitis due to the defective skin barrier, therefore increasing the risk of other forms of allergic disease during childhood [100,101]. Several trials are underway to evaluate whether the enhancement of a defective skin barrier with daily application of emollients during the first months of life, which has been shown to halve the incidence of atopic dermatitis in infants, also reduces the risk of early allergic sensitization and, therefore, the incidence of respiratory allergy later in life [102-104]. (See "Treatment of atopic dermatitis (eczema)", section on 'Skin barrier enhancement'.)
Patients with atopic dermatitis also have an increased risk of food-induced urticaria/anaphylaxis [105,106], eosinophilic esophagitis, and chronic rhinosinusitis/nasal polyps . Studies suggest that environmental exposure to food allergens through an impaired skin barrier is a plausible route for food sensitization and allergy [108,109]. In one study of 512 children younger than 15 months with a history of atopic dermatitis, exposure to peanut antigen in household dust was associated with a twofold increased risk of peanut sensitization and peanut allergy .
However, although the rate of food sensitization is high in infants and young children, ranging from approximately 30 to 60 percent, depending upon the population and diagnostic test, the actual rate of confirmed food allergy is much lower [105,111-115]. Therefore, serum IgE should not be used for the diagnosis of food allergy in the absence of clinical reactions to the ingestion of a certain food. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)
Ichthyosis vulgaris — Loss-of-function variants in the filaggrin gene (FLG), which causes ichthyosis vulgaris, confer an increased risk of developing atopic dermatitis and are associated with early-onset, moderate to severe, and persistent eczema [19,52,116]. (See "Ichthyosis vulgaris".)
It is estimated that approximately 10 to 30 percent of patients with atopic dermatitis also have ichthyosis vulgaris [117,118]. These patients usually show palmar hyperlinearity (picture 14A-B) and keratosis pilaris (picture 7A-B). (See "Overview and classification of the inherited ichthyoses", section on 'Ichthyosis vulgaris' and "Keratosis pilaris".)
Eye diseases — Ocular comorbidities occurring in patients with atopic dermatitis include atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). AKC is a chronic, allergic, ocular disease that most often occurs in adults with a history of atopic dermatitis . VKC most commonly occurs in children living in warm, dry, subtropical climates . Ocular itching, burning, tearing, and mucus discharge are common symptoms. Complications include keratoconus, infectious keratitis, and blepharitis. (See "Atopic keratoconjunctivitis" and "Vernal keratoconjunctivitis".)
Psychiatric disorders — There is a growing body of evidence that a number of psychiatric disorders and symptoms, including impaired psychosocial functioning, attention deficit hyperactivity disorder (ADHD), learning disability, depression, and anxiety disorders, are more common among adults and children with atopic dermatitis than in the general population [121-124]. The association of atopic dermatitis with psychosocial distress and other psychiatric disorders may be influenced by the perceived disease severity and other factors that negatively affect quality of life, such as the loss of sleep, disabling pruritus, and social embarrassment .
Attention deficit hyperactivity disorder — The results of a 2010 systematic review of 20 studies including over 170,000 individuals and several subsequent, observational studies suggest an association between atopic dermatitis and attention deficit hyperactivity disorder (ADHD) in children as well as in adults [121,125-129]. The mechanisms underlying ADHD and atopic dermatitis are unknown. Sleep disturbance secondary to nocturnal pruritus, elevated levels of psychologic stress, and the effects of proinflammatory cytokines on brain development are the leading hypotheses to explain this association [128,130,131]. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis" and "Attention deficit hyperactivity disorder in adults: Epidemiology, pathogenesis, clinical features, course, assessment, and diagnosis" and "Attention deficit hyperactivity disorder in children and adolescents: Epidemiology and pathogenesis".)
Depression and anxiety disorder — Several cohort studies and meta-analyses have found an association between atopic dermatitis and anxiety disorder, depression, suicidal ideation, and attempted suicide in adults and children [121,132-137]:
●An analysis of data on over 90,000 children from the 2007 National Survey of Children's Health in the United States found that among children with atopic dermatitis, the prevalence of depression and anxiety disorders was significantly higher than among their peers without atopic dermatitis (6.5 versus 3.4 percent, and 7.3 versus 4.1 percent, respectively) and showed an increasing trend with increasing parent- and caregiver-reported severity of dermatitis .
●A large, longitudinal, cohort study using data from the Taiwan National Health Insurance Research Database from 1998 to 2008 assessed the risk of developing major depression or anxiety disorders later in life among more than 8000 adolescents and adults with atopic dermatitis and age- and sex-matched controls . This study found that patients with atopic dermatitis had an increased risk of developing major depression (hazard ratio [HR] 6.56, 95% CI 3.64-11.84), any depressive disorder (HR 5.44, 95% CI 3.99-7.44), and anxiety disorders (HR 3.57, 95% CI 2.55-4.98).
●A 2019 meta-analysis of 37 observational studies found a nearly twofold increased risk of depression in patients with atopic dermatitis compared with individuals without atopic dermatitis (odds ratio [OR] 1.71, 95% CI 1.48-1.98). Based on data from 14 studies, patients with atopic dermatitis were also more likely to have suicidal ideation (OR 1.97, 95% CI 1.19-3.25) .
●The association between atopic dermatitis and suicidality was examined in another meta-analysis of 15 observational studies including over 310,000 patients with atopic dermatitis and nearly 4.5 million controls . Compared with persons without atopic dermatitis, patients with atopic dermatitis were found to have an increased risk of suicidal ideation (pooled OR 1.44, 95% CI 1.25-1.65) and suicide attempts (pooled OR 1.36, 95% CI 1.09-1.70). Two of the included studies reporting on the risk of completed suicide among patients with atopic dermatitis provided conflicting results [138,139].
The results of these studies emphasize the need for a multidisciplinary approach to the management of atopic dermatitis that includes patient and parent/caregiver education and psychologic and behavioral support (see "Treatment of atopic dermatitis (eczema)"). Clinicians treating atopic dermatitis should be vigilant for depressive symptoms, especially in patients with severe disease who may need psychiatric referral.
Obesity and metabolic syndrome — The association between atopic dermatitis and obesity in children and adults is controversial [140-144]:
●In a multicenter, case-control study, 132 children aged 4 to 17 years with moderate to severe atopic dermatitis were compared with 143 children with other skin problems . Children with atopic dermatitis were more likely than controls to have a body mass index (BMI) in the 97th percentile or higher and a waist circumference in the 85th percentile or higher (OR 2.64, 95% CI 1.15-6.06, and OR 3.92, 95% CI 1.50-10.26, respectively). In addition, atopic dermatitis was associated with a higher percentile of systolic and diastolic blood pressure after controlling for age, sex, and family history of hypertension.
●A cross-sectional analysis of data from the Canadian Partnership for Tomorrow Project including nearly 260,000 Canadian residents aged 30 to 74 years, of whom approximately 21,000 had a history of atopic dermatitis, found that atopic dermatitis was associated with a mild reduction in the risk of hypertension (OR 0.87, 95% CI 0.83-0.90), type 2 diabetes (OR 0.78, 95% CI 0.71-0.84), myocardial infarction (OR 0.87, 95% CI 0.75-1.00), and stroke (OR 0.79, 95% CI 0.66-0.95), after adjusting for age, sex, ethnic background, BMI, smoking 100 cigarettes, weekly alcohol intake, average daily sleep, and weekly physical activity .
●A 2015 systematic review and meta-analysis of 30 observational studies found that being overweight and obese were associated with increased prevalence of atopic dermatitis in Asia and North America (OR 1.23, 95% CI 1.11-1.41, and OR 1.47, 95% CI 1.21-1.79, respectively) .
However, the mechanisms underlying this association are largely unknown.
Cardiovascular disease — Previous studies evaluating the association between atopic dermatitis and cardiovascular (CV) disease provided conflicting evidence:
●A 2017 meta-analysis using adjusted data from 13 studies did not find an association between atopic dermatitis and myocardial infarction (pooled OR 1.03, 95% CI 0.88-1.21), stroke (OR 1.12, 95% CI 0.95-1.32), or hypertension (OR 1.10, 95% CI 0.97-1.24) but found a nearly 50 percent increased risk of angina pectoris (OR 1.48, 95% CI 1.23-1.79) .
●A subsequent, large, population-based study using 1998 to 2015 data from the United Kingdom Clinical Practice Research Datalink compared the data from nearly 400,000 adult patients with atopic dermatitis and 1.5 million controls matched by age, sex, calendar time, and age and date at cohort entry . This study found that patients with atopic dermatitis and, in particular, those with severe disease (as defined by treatment with systemic immunosuppressants, phototherapy, or specialist referral) had an increased risk of CV disease, including myocardial infarction (HR 1.37, 95% CI 1.12-1.68), unstable angina (HR 1.41, 95% CI 1.02-1.95), heart failure (HR 1.67, 95% CI 1.36-2.05), atrial fibrillation (HR 1.35, 95% CI 1.14-1.59), and CV death (HR 1.30, 95% CI 1.10-1.53). Although known confounding factors (eg, BMI, smoking, hypertension, hyperlipidemia, diabetes) had been adjusted for, the possibility that the results were driven by residual confounding cannot be excluded. In addition, this study could not determine whether atopic dermatitis per se or treatments for atopic dermatitis confer an increased risk of CV disease. Despite these caveats, this study indicates that in adults presenting with severe atopic dermatitis, screening for CV disease and known risk factors for CV disease may be appropriate.
Anemia — An analysis of caregiver-reported and self-reported data on over 200,000 children and adolescents from the 1997 to 2013 United States National Health Interview Survey found that children with a history of atopic disorders, including eczema, asthma, hay fever, or food allergy, have an increased risk of anemia (for eczema, OR 1.83, 95% CI 1.58-2.13) . The risk was much higher in children with all four disorders (adjusted OR 7.87, 95% CI 5.17-12). Using laboratory data from the 2014 to 2015 National Health and Nutrition Examination Survey on over 30,000 children, the authors found that children with a current history of atopic eczema had a twofold increased risk of anemia, particularly microcytic anemia (OR 2.03, 95% CI 1.20-3.46).
Whether anemia in children with atopic dermatitis is related to chronic inflammation or malnutrition secondary to dietary restrictions in patients suspected to have food allergies is unknown. Further ad hoc-designed studies are needed to confirm this association and clarify the underlying mechanisms.
RISK OF CANCER
Lymphoma — The association between atopic dermatitis and lymphoma remains controversial [150,151]. 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 atopic dermatitis compared with the general population . 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 atopic dermatitis and cutaneous T cell lymphoma [153-155]. However, this finding must be interpreted with caution because a misclassification bias cannot be excluded. Due to overlapping clinical features, cutaneous T cell lymphoma cases may have initially been misdiagnosed and treated as severe atopic dermatitis.
Finally, this meta-analysis did not find a significant association between the use of topical calcineurin inhibitors and risk of lymphoma in patients with atopic dermatitis, although one included cohort study reported a significant fivefold increased risk of lymphoma associated with the use of topical tacrolimus (RR 5.44, 95% CI 2.51-11.79) . The use of high-potency topical corticosteroids was also associated with increased risk of lymphoma (OR 1.73, 95% CI 1.52-1.97) .
Skin cancer and other cancers — The association of atopic dermatitis with skin cancer and internal cancers is controversial:
●A systematic review and meta-analysis of eight population-based, cohort studies (n = 5,726,692) found among patients with atopic dermatitis 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) . However, the authors concluded that because of methodologic and quality heterogeneity across the included studies and variation in the definition of atopic dermatitis, no firm conclusions can be drawn about these associations. Moreover, detection bias, due to increased medical surveillance of patients with atopic dermatitis, cannot be excluded.
●In contrast, two large, cohort studies performed in England (471,970 individuals with atopic eczema and 2,239,775 without atopic eczema) and Denmark (44,945 individuals with atopic eczema and 445,673 without atopic eczema) did not find an association between atopic dermatitis and overall risk of cancer . However, in the English cohort, individuals with atopic dermatitis had a 20 percent higher risk of non-Hodgkin lymphoma (hazard ratio [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.
History and clinical examination — In the vast majority of cases, the diagnosis of atopic dermatitis is clinical, based upon history, morphology and distribution of skin lesions, and associated clinical signs (figure 1) . (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 light skin types :
●Dry skin may appear whitish or ashy color (picture 2).
●Erythema may appear violaceous or may not be visible at all (picture 1C). 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 3A).
●Postinflammatory hyper- and hypopigmentation are common (picture 3B).
Diagnostic criteria — Several sets of criteria have been proposed for the diagnosis of atopic dermatitis. Although they are generally used in epidemiologic studies, they provide guidance to the diagnostic approach in clinical settings.
The United Kingdom Working Group on atopic dermatitis criteria include one mandatory and five major criteria but do not include allergy criteria as originally proposed by Hanifin and Rajka [160,161]:
●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 atopic dermatitis include three sets of essential, important, and associated features :
•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
•Early age of onset
•Personal and/or family history of atopy, IgE reactivity
•Atypical, vascular responses (eg, facial pallor, white dermographism, delayed blanch response)
•Keratosis pilaris, pityriasis alba, hyperlinear palms, ichthyosis
•Perioral changes, periauricular lesions
•Perifollicular accentuation, lichenification, prurigo-like lesions
Skin biopsy and laboratory tests — Skin biopsy and laboratory testing, including IgE levels, are not used routinely in the evaluation of patients with suspected atopic dermatitis 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 . (See 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of atopic dermatitis includes:
●Allergic or irritant contact dermatitis – Allergic or irritant contact dermatitis may be difficult to differentiate from atopic dermatitis (picture 15). Moreover, allergic contact dermatitis may coexist with atopic dermatitis [162,163]. 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 atopic dermatitis, 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 16A-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 atopic dermatitis, in infants and young children, psoriasis often involves the diaper area, with well-demarcated, erythematous patches with little scale (picture 17A-B and figure 1). (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)
●Scabies – Scabies may present as a diffuse eruption mimicking atopic dermatitis (picture 18). The involvement of the skin folds (and, in infants, of the diaper area) 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 atopic dermatitis include:
•Primary immunodeficiencies, including Wiskott-Aldrich syndrome (picture 20) and hyperimmunoglobulin E syndrome (picture 21) (see "Wiskott-Aldrich syndrome" and "Autosomal dominant hyperimmunoglobulin E syndrome")
•Netherton syndrome (picture 23A-B) (see "Overview and classification of the inherited ichthyoses", section on '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 5th to 6th 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 10th to 12th 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 is a chronic, pruritic, inflammatory skin disease that occurs most frequently in children but also affects adults, with an estimated worldwide prevalence in children of 5 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 atopic dermatitis. (See 'Epidemiology' above and 'Risk factors' above.)
●Clinical manifestations – The cardinal features of atopic dermatitis 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, 4B, 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-C, 3A). (See 'Clinical manifestations' above.)
●Diagnosis – The diagnosis of atopic dermatitis is clinical, based upon history, morphology and distribution of skin lesions, and associated clinical signs (figure 1). Diagnostic criteria for the clinical diagnosis include:
•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 immunoglobulin E (IgE) levels, are usually not necessary in patients felt clinically to have atopic dermatitis. (See 'Diagnosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William L Weston, MD, who contributed to earlier versions of this topic review.
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