Atopic dermatitis is a chronic inflammatory skin disease that is characterized by intense itch and acute, subacute, or chronic eczematous skin lesions.1 The disease course can be chronic or relapsingremitting. Lesions typically present with an age-related morphology and distribution.1 The prevalence of atopic dermatitis is high, affecting up to 13% of children and 4% to 10% of adults in the United States.2-4 The burden of atopic dermatitis on the quality of life (QOL) of patients and their families is substantial, encompassing physical and psychological well-being, social functioning, and economic costs.5
The pathophysiology of atopic dermatitis is complex and involves genetic susceptibility, environmental factors, microbiome effects, and immune dysregulation.6 Traditional treatments for atopic dermatitis include the use of moisturizers to improve barrier integrity; topical anti-inflammatory medications when good skin care (such as bathing and moisturizing) is inadequate; and phototherapy, systemic immunosuppressants, or short-course systemic corticosteroids for recalcitrant or severe disease.7 Impaired barrier function, which permits irritants to penetrate the skin surface and affects the local microbiome, is caused by the disease and may also contribute to the disease.8 The recent development and approval of several new classes of medication for the treatment of atopic dermatitis has added variety to the treatment landscape.9-11
The objective of this article is to describe the current diagnostic criteria, treatment landscape, and burden of atopic dermatitis to highlight the challenges that this disease presents to the wider healthcare community.
Diagnosis of Atopic Dermatitis
There is no objective test to confirm a diagnosis of atopic dermatitis, and clinicians diagnose the disease based on the patient’s clinical features and historical characteristics.1,12 Diagnostic criteria are included in the atopic dermatitis practice parameters from the American Academy of Dermatology (AAD)1 and the Joint Task Force on Practice Parameters of the American Academy of Allergy, Asthma & Immunology (AAAAI) and American College of Allergy, Asthma & Immunology (ACAAI).12 According to both guidelines, the essential features of atopic dermatitis include pruritus and chronic or relapsing eczematous lesions that present with age-related typical morphology and distribution.1,12
A history of allergic diseases or immunoglobulin (Ig) E reactivity (ie, atopy) is considered essential to the diagnosis of atopic dermatitis by the AAAAI/ACAAI guidelines and an important feature by the AAD guidelines.1,12 These guidelines agree that a firm diagnosis of atopic dermatitis requires the exclusion of other skin conditions that have a similar appearance,1,12 such as other inflammatory skin conditions (eg, seborrheic dermatitis, psoriasis, contact dermatitis), infections (eg, impetigo, molluscum dermatitis, candidiasis), and conditions including scabies, keratosis pilaris, and ichthyosis vulgaris.13 A number of rare disorders can also mimic atopic dermatitis, including Letterer-Siwe disease, cutaneous T-cell lymphoma, X-linked recessive ichthyosis, lamellar ichthyosis, IgA or IgM deficiency, and graftversus-host disease.13
Although atopic dermatitis is historically considered a pediatric disease, with approximately 50% of individuals having symptoms within the first year of life and 95% of patients with disease onset at age under 5 years,14 the prevalence of atopic dermatitis is considerable in adults (approximately 4%-10% globally).2,4
The morphology of atopic dermatitis varies, depending on the age of the patient (Figure 1).8,15 In infantile atopic dermatitis (aged 3 months-2 years), lesions are acute and appear mainly on the face, extensor surfaces of the limbs, and trunk.8 Childhood atopic dermatitis (aged 2-12 years) is characterized by acute and chronic lesions that appear primarily at the flexural folds and periorificial areas. In adolescents or adults (aged >12-60 years), atopic dermatitis is characterized by chronic lichenified (ie, thickened) or excoriated lesions that occur in typical areas, such as the head, neck, and flexural areas, but it can also affect the hands and periorbital areas. Finally, in older (aged >60 years) patients, atopic dermatitis is characterized by extensive lesions with a strong pruritic component that often spare flexural areas.8
In addition to age-specific phenotypes, the range of atopic dermatitis severity is wide.15 Many disease severity scoring tools (such as the Eczema Area and Severity Index and Investigator’s Global Assessment) do not assess the impact of atopic dermatitis on patient QOL, which is measured using other scales (such as the Dermatology Life Quality Index and Skindex).16 Although these scoring tools are used frequently in clinical trials, their use in daily practice is still limited.15,16 There is a discrepancy in the way patients and physicians rate the severity of atopic dermatitis, with physicians focusing primarily on sleep disturbance and patients focusing more on skin-related QOL.17
Treatments for Atopic Dermatitis
Despite the heterogeneity of the clinical phenotype of atopic dermatitis, this condition is largely considered a single disease and is usually treated as such.15 The AAD, AAAAI/ACAAI, and consensus European treatment guidelines recommend a stepwise approach that depends on disease severity.12,18-22 Basic treatment for atopic dermatitis involves the use of moisturizers to improve the skin’s hydration and barrier function. Topical antiinflammatory medications, such as topical corticosteroids and topical calcineurin inhibitors, are used to treat flares or as maintenance therapy, whereas phototherapy, systemic immunosuppressants, and systemic corticosteroids are recommended for recalcitrant or severe disease.12,18-22
The guidelines provide detailed and largely comparable treatment recommendations with a common goal of maintaining the skin barrier, reducing the inflammatory response, and eliminating atopic dermatitis triggers23; however, these recommendations have several limitations. The most recent AAD and AAAAI/ACAAI guidelines were published approximately 10 years after the previous publication of guidelines, which necessitated the inclusion of a decade’s worth of therapeutic and scientific advances.7 The process of updating the guidelines, however, does not allow for the timely incorporation of novel therapies.16 The guidelines are extensive, which is problematic for primary care physicians who need more accessible information.7
A number of changes to the treatment paradigm have occurred since the publication of the AAD and AAAAI/ACAAI guidelines in 20144,18,19 and 2013,12 respectively, including the US Food and Drug Administration’s approval of crisaborole ointment, 2%, for the treatment of mild-to-moderate atopic dermatitis and of dupilumab for the treatment of moderate-to-severe atopic dermatitis.9,10 The AAAAI has recently published a multidisciplinary consensus statement regarding the current and emerging therapies for moderate-to-severe atopic dermatitis.16 The statement highlights that atopic dermatitis is a systemic disease, provides a definition for moderate-to-severe disease, and recommends dupilumab as first-line systemic treatment for adults with moderate-to-severe atopic dermatitis when the disease does not respond to topical treatment.16
To make recommendations more practical, the Atopic Dermatitis Yardstick was developed (Figure 2).20 Written to complement the treatment guidelines, the Atopic Dermatitis Yardstick includes mention of recently approved therapies such as crisaborole and dupilumab.20 Crisaborole is a nonsteroidal, phosphodiesterase-4 inhibitor for the treatment of mild-to-moderate atopic dermatitis.24,25 Dupilumab is a human monoclonal antibody against interleukin-4 receptor alpha for the treatment of moderate-to-severe atopic dermatitis.26
A number of anti-inflammatory agents have been approved or are currently in late-phase clinical development for the treatment of atopic dermatitis (Table 1).11,24-29,41 The majority of novel treatments for atopic dermatitis target moderate-to-severe disease.28
As with many chronic diseases, poor adherence is a significant impediment to the successful treatment of atopic dermatitis.42,43 Medication adherence can be categorized into 3 distinct phases, which include initiation (filling a prescription and starting treatment), implementation (using therapy according to directions), and persistence (continuing treatment).43,44 Patient nonadherence can be intentional or unintentional, and represents obstacles such as medication cost and formulary access, and limitations such as the inability to execute the treatment plan as prescribed, perhaps as a result of age, unclear instructions, or cognitive abilities.44 For example, among the real-world population of US patients with atopic dermatitis who are eligible for topical corticosteroid or topical calcineurin inhibitor treatment, the annual prescription cost per patient ranged from $53 to $1465.45
Adherence to topical treatments for atopic dermatitis is particularly poor, with patients vastly overestimating their adherence.42 Patient adherence to the topical treatment of atopic dermatitis tends to be greatest at the start of treatment (>90%) and decreases with extended duration (approximately 30% at 8 weeks),42 which is a trend for many dermatitis conditions, including psoriasis and acne.46
Poor medication adherence can also be confused with poor response to therapy, which can result in unnecessary treatment escalation.47 Adherence may be better with oral medications than with topical treatment for skin disease.47 Although it is generally accepted that oral medications are preferable to frequent injections, at least one study that was conducted to explore adherence to oral drugs versus injectable agents in patients with psoriasis showed greater adherence to injectable medications.48
Poor medication adherence can also result from complex treatment regimens for atopic dermatitis.49 For example, atopic dermatitis regimens can include up to 3 emollient therapies (cream or ointment, bath oil, and soap substitute), 2 topical corticosteroids (eg, specific to face and body), and wet dressings. In addition, patients often must keep track of many different topical preparations, which can lead to treatment mistakes.49
Safety concerns associated with atopic dermatitis treatments may also negatively affect treatment adherence. Steroid phobia refers to patients and caregivers’ negative feelings and beliefs (from mild apprehension to irrational fear) regarding topical corticosteroid treatment.50 The prevalence of steroid phobia ranges from 21% to 83.7%.50 Steroid phobia has been correlated with poor adherence to treatment.51 In studies of steroid phobia that identified where patients obtained information about topical corticosteroids, physicians and healthcare workers were listed as a top source, which suggests that careful counseling and education may assist in alleviating patient concerns.50
Impact of Atopic Dermatitis on Quality of Life
Atopic dermatitis has a substantial detrimental effect on the QOL of patients and their families.5 In children, the physical impact includes itching and scratching, which can result in significant sleep disturbance.5,52,53 The emotional impact of atopic dermatitis in children includes behavioral problems, irritability, crying, and embarrassment.5,53 Social isolation is also a serious concern.52 In a comparative study of QOL in children with chronic diseases, generalized eczema was identified as the condition with the second greatest impact on QOL, exceeded only by cerebral palsy.54 Atopic dermatitis reduces the QOL of families of patients with atopic dermatitis, with sleep disturbance as one of the primary domains affected.5,53 Physical and emotional domains are most affected in adults, with less impact on social functioning.5,55
The comorbidities most often associated with atopic dermatitis are related to atopy (eg, food allergies, asthma, and allergic rhinitis or allergic conjunctivitis).56,57 Individuals with atopic dermatitis are at increased risk for other allergic conditions (eg, hand eczema and contact dermatitis) and cutaneous infections.56,57 Increased cardiovascular risks and cancer comorbidities are also associated with atopic dermatitis.57,58 Mental health comorbidities are common in patients with atopic dermatitis, with links found between the disease and attention-deficit/hyperactivity disorder, depression, anxiety, suicidal ideation, and autism.56,59
Economic Impact of Atopic Dermatitis
Although novel therapies for atopic dermatitis provide more treatment options for patients, they also provide unique challenges for providers and payers. As previously discussed, updates to guidelines can lag behind practice by as much as 10 years.7 This places providers and payers in the position of needing to assess evolving levels of evidence for new therapies, to incorporate them within current treatment paradigms, and to take into account the cost of the therapy and distribution.60
Atopic dermatitis is associated with substantial economic burden for patients and their families, payers, and society.61 Table 2 discusses studies that show the economic impact of atopic dermatitis.45,61-67 Direct costs can include prescriptions, over-the-counter treatments, physician and emergency department visits, and hospitalizations.68 Individuals with atopic dermatitis use more healthcare resources than controls without atopic dermatitis.62 An analysis of data from the 2013 US National Health and Wellness Survey indicated that the mean annual direct cost for an individual with atopic dermatitis is $24,401 compared with $14,619 for controls without atopic dermatitis (difference, $9782; including healthcare provider visit, hospitalization, and emergency department visit costs).62
The out-of-pocket costs for adults with atopic dermatitis are estimated to be from $371 to $489 higher than for adults without atopic dermatitis.63 The indirect costs associated with atopic dermatitis include absenteeism, loss in productivity, and costs related to decreased QOL.68 Individuals with atopic dermatitis report higher absenteeism, presenteeism (ie, impairment as a result of health problems while working), and overall work impairment than individuals with no atopic dermatitis.55 The mean annual indirect cost for employed individuals with atopic dermatitis was $2400 higher than for individuals without atopic dermatitis.55 The most comprehensive analysis regarding the total annual burden of atopic dermatitis in the United States identified a cost of $4.228 billion (in 2004 US dollars).5,64
Budget impact analyses can assist with fiscal projections when new therapies come to market, and have been conducted for crisaborole and dupilumab in the United States.45,65,69 The crisaborole model was developed according to guidelines from the Academy of Managed Care Pharmacy, using current topical corticosteroid and topical calcineurin inhibitor use in patients aged ≥2 years to estimate the budget impact of crisaborole over 2 years for a 1-million-member plan.45,69
Two atopic dermatitis populations were evaluated: (1) patients receiving a topical calcineurin inhibitor or topical corticosteroid alone or in combination (combination population) and (2) patients receiving a topical calcineurin inhibitor alone or in combination with a topical corticosteroid (topical calcineurin inhibitor population, which excluded patients receiving a topical corticosteroid alone).45 The total budget impact of crisaborole over 2 years in the combination population was $350,946 ($0.015 per health plan member, per month [PMPM]), and a decrease of $22,871 (−$0.001 PMPM) in the topical calcineurin inhibitor population (excluding the topical corticosteroid alone population).45
The dupilumab budget impact model was based on a cost-effectiveness model and evaluated a population with moderate-to-severe atopic dermatitis in which topical therapy was ineffective. The net cost associated with dupilumab treatment was compared with the net cost for usual care (which was assumed to include emollients but not phototherapy or systemic immunomodulatory agents).65 The estimated budget impact of adding dupilumab results in an annual average increase of $22,348 per patient treated over a 5-year time horizon.65
Cost-effectiveness analyses are often used in conjunction with budget impact analyses to help determine the clinical benefit-to-cost ratio of interventions and assist with the identification of high-benefit therapies, including treatments that affect QOL.70 Using the model described above for deriving budget impact, dupilumab has estimated annual costs of $30,516 to $43,726 for $100,000 to $150,000 per quality-adjusted life-year (QALY) cost-effectiveness threshold65; the cost estimates for the same threshold were $24,665 to $34,946 for patients with moderate atopic dermatitis and $38,460 to $55,646 for patients with severe atopic dermatitis.65 A separate analysis estimated the costs from the US payer perspective to be $28,769 to $39,941, for a threshold of $100,000 to $150,000 per QALY gained compared with standard of care with an annual wholesale acquisition cost of $37,000.66
As treatment options for atopic dermatitis expand, payers must effectively manage cost and healthcare resource utilization.60,71 In addition to supporting guideline-recommended approaches to therapy to maintain costs,60 payers may institute programs, such as prior authorization and preferred-drug formulary status, to manage costs.60,71 For example, dupilumab has paved the way for the use of biologics in the treatment of atopic dermatitis, while also introducing specialty pharmacies to the distribution channels. Previous experience with the introduction of biologics and anti-inflammatory agents for the treatment of psoriasis may assist providers and payers with adjusting to the use of new treatments for atopic dermatitis.
Atopic dermatitis is a chronic disease that affects a large proportion of the US population, and is associated with a heavy disease burden that affects patients, their families, payers, and society. The current treatment paradigm is complex, with multiple different active drugs (for various parts of the body times in the disease course, or levels of disease severity), along with moisturizers, bathing recommendations, and other lifestyle recommendations. The available treatment options for atopic dermatitis have limitations related to efficacy, tolerability, and safety concerns. The approval of 2 novel medications for atopic dermatitis within the past 2 years, and the clinical development of additional drugs, have begun to revitalize the treatment landscape for this chronic disease.
Editorial and medical writing support under the guidance of the authors was provided by Jennifer M. Kulak, PhD, and Corey Mandel, PhD, of ApotheCom.
Author Disclosure Statement
Dr Feldman has received grant and consulting honoraria from Pfizer, and is a consultant to and has received grants from Regeneron and Sanofi; Dr Cox is a consultant to Pfizer; Dr Strowd has received a grant from Pfizer; Dr Gerber and Dr Cappelleri are employees and stockholders of Pfizer; Dr Faulkner is an employee of Pfizer; Dr Sierka is a former employee and stockholder of Pfizer, and is now an employee of Sanofi; Mr Smith is an employee and shareholder of Pfizer; Dr Levenberg is an employee of and holds stock in Pfizer.
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