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In Atopic Dermatitis, Looks Can Be Deceiving
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In Atopic Dermatitis, Looks Can Be Deceiving

Burden of AD


AD is a common, chronic, inflammatory skin disease.1 It is associated with immune dysregulation and skin barrier dysfunction.2

Prevalence and Age of Onset

AD affects millions in the United States and it is one of the most common dermatoses.3,4 The number of individuals affected has been increasing in industrialized countries.4 Up to 10% of adults have eczema, and an estimated 3.2%, or 7 to 8 million US adults, have AD.3,5 It is estimated that 1.6 million adults who have been diagnosed and treated for moderate-to-severe disease remain uncontrolled.6-8 Up to 25% of children experience AD, and it is the top diagnosis at dermatologist visits in children 4 years and younger.9,10

However, AD is not just a pediatric disease.2 The onset of symptoms spans all ages (Figure 111).2,11 AD may be a persistent, life-long disease. The Pediatric Eczema Elective Registry follow-up examined the natural history of children with mild-to-moderate AD (N = 7157).12 Figure 212 demonstrates the proportion of individuals with at least 5 years of follow-up at a given age who ever reported a 6-month symptom-free and medication-free period (N = 2416). It was not until 20 years of age that 50% of patients experienced at least one 6-month symptom-free interval.12

Signs and Symptoms of AD

Patient-reported signs and symptoms of AD can occur on a daily basis. Baseline data for 380 adults with moderate-to-severe AD recruited into a randomized treatment study showed that 91% experienced dry or rough skin 5 to 7 days per week. A total of 78% reported flaking skin, 67% had cracking skin, 51% experienced bleeding, and 34% reported oozing at least 5 days per week (Figure 313).13

The presentation of AD differs in its acute, subacute, and chronic forms. Acute and subacute lesions are intensely pruritic and are characterized by erythema, papulovesicles, excoriations, and serous exudate. Chronic lesions are characterized by lichenification, papules, plaques, and excoriations. Patients with moderate-to-severe AD can experience acute and chronic lesion simultaneously.14

In addition to causing dermatologic lesions, patients with AD are susceptible to skin infections and colonization with Staphylococcus aureus. In a study of 687 patients with AD, Staphylococcus aureus colonization rates of 74% and 38% were reported in acute (n = 97 of 131) and chronic lesions (n = 211 of 556), respectively, versus 3% from the skin of patients with urticaria (n = 8 of 247).15 Other studies

have shown that AD causes exaggerated clinical manifestations of viral infections and an increased susceptibility to dermatophyte fungal infections.16

Effects of Symptoms on Daily Life

In patients with moderate-to-severe AD, itch is the most common and persistent burden. Eighty-six percent of patients enrolled in one study reported the daily presence of itch, and more than one-third (41.5%) reported itching at least 18 hours per day.13 In another study, approximately 40% of participants who completed an internet-based questionnaire had more than 10 episodes of itch per day, and 35% had experienced itching for over 20 years.17 In a separate study, more than 50% of participants who completed an internet-based questionnaire reported pain sensation associated with itch.18

Sleep disruption is also a problem for patients with moderate-to-severe AD. Nearly 9 of 10 patients with moderate-to-severe AD report disrupted sleep at least 1 night a week and slightly more than half have their sleep disrupted at least 5 nights a week.13 Sleep disruptions are often doubled in patients with eczema than in those with no disease. In a 2012 US population-based survey (N = 34,613) conducted by the National Health Interview Study, individuals with eczema were more likely than those with no disease to experience fatigue (adjusted OR 2.23; 95% CI, 1.93-2.58), daytime sleepiness (OR 2.04; 95% CI, 1.75-2.38), insomnia overall (OR 1.83; 95% CI, 1.59-2.12), insomnia and fatigue (OR 2.74; 95% CI, 2.28-3.29), and insomnia and daytime sleepiness (OR 2.47; 95% CI, 2.04-2.99) (all significant [P <.0001]).19

AD occurs in relapsing and remitting cycles.20 In the International Study of Life with Atopic Eczema (ISOLATE), patients (>13 years) and caregivers (of children 2-13 years) underwent in-depth telephone interviews. The study included a minimum of 150 patients recruited from 8 countries; all patients had moderate-to-severe AD. The 1371 patients with moderate AD reported an average of 8.3 episodes of exacerbated symptoms per year, totaling 113 symptomatic days per year and 33 nights of sleep disruption per year (calculated by multiplying the number of flares per year by the number of nights sleep was affected during a flare). For the 631 patients with severe AD, exacerbated symptoms occurred nearly once per month, an average of 11.1 episodes each year. These patients experienced exacerbated symptoms for more than half the year (192 days) and sleep disruption nearly half the nights in a year (162 nights).21

Psychosocial dysfunction is increased among patients with AD. Patients of the ISOLATE study reported that the AD flare caused concern about their appearance, affected their self-confidence, and led to feeling unhappy or depressed. Patients with moderate-to-severe AD report feelings of embarrassment and low self-confidence, problems with personal and social relationships, and problems with work.21 In a study of 102 patients who self-rated their AD as severe, 47% reported being frustrated by the disease, 39% were embarrassed by their appearance, and 35% were angry about their appearance.22 A cross-sectional study of  patients (N = 266) with moderate-to-severe AD and their partners revealed that 58% experienced a decrease in sexual desire at least occasionally. In addition, 55% said that the appearance of skin affects their sex life, and 47% said that the disease treatment affects their sex life.23

Behavioral, emotional, and psychological disorders are also increased in patients with AD. AD is independently associated with stress-related, behavioral, affective, and schizophrenic disorders.24 Anxiety, as measured by different clinical scales, is increased in patients with AD.25-27 Depressive symptoms are also increased in patients with AD.26

Disease Assessment

Disease assessment is largely based on clinical judgment. A plethora of instruments are used to assess severity in clinical trials. However, they are rarely used in clinical practice. Clinicians should ask patients general questions about the impact of AD on daily activity and use available scales mainly when practical.9 More than 25 disease severity scales are available, including:

Severity Scoring of Atopic Dermatitis (SCORAD)

Eczema Area and Severity Index (EASI)

Investigators’ Global Assessment (IGA)

Six-Area, Six-Sign Atopic Dermatitis (SASSAD)

Leicester Sign Score (LSS)

Total Severity Score (TSS)

Atopic Dermatitis Severity Index (ADSI)

Total Body Severity Assessment (TBSA)

Three-Item Severity Scale (TISS)9,28

Two commonly used quality-of-life scales across AD and other diseases include:

Dermatology Life Quality Index (DLQI)

36-Item Short-Form Health Survey (SF-36)28,29

The Role of Inflammation in AD


AD is a systemic, immune-driven disease. Researchers have proposed 2 hypotheses in AD pathogenesis: an epidermal-based model (“outside-in”) and an immune-based model (“inside-out”). Regardless of initiation, in either model, the result is a state of disease.1

Epidermal-Based Model

In the epidermal-based model (“outside-in”), AD is initiated by an epidermal barrier defect that occurs either through a genetic or acquired basis, with subsequent systemic immune activation mediated by memory Th2 cells.30,31 An abnormal skin barrier leads to antigen penetration and subsequent immune activation.32 The epidermal-based model is supported by mutations in structural proteins such as filaggrin, envelope precursor proteins, and claudin.31,32

Immune-Based Model

In the immune-based model (“inside-out”), AD is considered an immunologic disorder, with contributing barrier dysfunction.33 AD is initiated by activated memory Th2 cells that secrete several systemic cytokines, leading to widespread activation of the immune system.34 Activation of Th2 cells and downstream signaling pathways result in epidermal hyperplasia.33,34

Drivers of Inflammation in AD

Interleukins (ILs) are cytokines secreted by white blood cells that regulate the function of the immune system. IL-4 and IL-13 are key drivers in the underlying inflammatory process that drives itch and lesions.35,36 IL-4 and IL-13 represent key upstream drivers in the Th2 pathway that modulate multiple downstream mediators—including IL-5, IL-31, and immunoglobulin E—setting in motion the chronic underlying inflammation of AD (Figure 435-40).36,37

In acute and chronic lesions, the combined effects of IL-4 and IL-13 create a positive feedback loop. Increased expression of IL-4 and IL-13 decreases the production of structural proteins and antimicrobial proteins, resulting in a weakened skin barrier and increased susceptibility to infection. Keratinocytes are also affected, resulting in decreased keratinocyte differentiation. The number of infiltrating immune cells increases, in turn causing increased expression of IL-4 and IL-13.40 Increases in IL-4 and IL-13 activity correlate with the appearance of acute lesions; expression of these cytokines is also elevated in chronic disease.36

Elevated cytokine expression is persistent in skin lesions. In 1 study, expression of IL-4 and IL-13 was measured with reverse transcriptase-polymerase chain reaction testing of intrapersonal biopsy samples from acute and chronic skin lesions and nonlesional skin of  patients with moderate-to-severe AD (N = 17).36 Expression of IL-4 was significantly higher in acute lesions than in nonlesional skin (P <.05), and expression of IL-13 was significantly higher in chronic lesions than in nonlesional skin (P <.01) (Figure 536).36

Abnormalities in Atopic Skin

 
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