For the past 40 years, the topical corticosteroids (alongside antihistamines) have been the mainstay of topical treatment of the management of atopic dermatitis (AD; Leung & Barber, 2003; Stone, 2002). However, in 2000, a new class of prescription drugs called topical immune modulators (TIMs) and now called calcineurin inhibitors (CIs) was approved for clinical use by the Food and Drug Administration (FDA). Tacrolimus ointment (Protopic) was the first developed TIMs and also the first nonsteroidal prescription drug developed specifically for the treatment of AD. Shortly after the FDA approval of Protopic in 2001, pimecromulis cream (Elidel) was approved for the treatment of mild to moderate AD.
Calcineurin inhibitors were a long-awaited alternative to topical corticosteroids because they offered a safe and effective option for both the short- and long-term treatment of AD for cases that range from mild to severe in adult and pediatric patient populations alike. Moreover, CIs lack the cadre of side effects associated with topical corticosteroids that often limit the latter's use and effectiveness, such as atrophy, tachyphylaxis, pigmentary disturbances, and the development of allergic contact dermatitis (Charman, 1999). The purpose of this article was to discuss and review the current standard of care and to disseminate an updated standard of care based on research findings and the observed discussions.
Atopic dermatitis is a cutaneous inflammatory disease characterized by hallmark signs and symptoms of pruritus, erythema, excoriation, and erosions accompanied by serous exudates, fibrotic papules, lichenification, dry skin, and susceptibility to skin infections (Reitamo et al., 2000; Shainhouse & Eichenfield, 2003). Secondary bacterial infection is common, and when it occurs, the atopic affected skin weeps and can become impetiginized; later plaques and pustules may also develop in the flaring skin (Halbert, 1996).
Atopic dermatitis is one of the most common skin diseases affecting young children (Halbert, 1996), presenting within the first 5 years in 85% of cases (Rudikoff & Lebwohl, 1998). The disease persists into adulthood in approximately 60% of children with AD. This is especially true for patients with early onset, severe disease, associated allergic rhinitis or asthma, and a strong family history of AD (Williams, 2000).
The prevalence of AD has risen steadily since the 1960s (Stone, 2002), with an estimated 10%-15% of the population affected in the United States (Rudikoff & Lebwohl, 1998; Schultz, Diepgen, & Svensson, 1996). In fact, approximately 20% of children have the disease (Ellis, Drake, & Prendergast, 2002), and the impact on their quality of life and their families is significant. For example, the intense pruritus and subsequent associated excoriations of AD can lead to sleep deprivation (Leung & Soter, 2001), chronic fatigue, school absences, impaired performance, and irritability (Hanifin, 2003; Kristal & Klein, 2000). Often, children with AD become the focal point of the family, which can lead to problems with family dynamics and relationships (Eichenfield, Hanifin, Luger, Stevens, & Pride, 2003; Hanifin, 2003). Furthermore, severe disease can lead to social isolation as children with AD may be ridiculed and ostracized by peers (Kristal & Klein, 2000).
The etiology of AD is currently under investigation; however, several factors have been elucidated to be playing a role in its pathogenesis. Various hypotheses, including abnormalities of skin barrier function, immunologic dyscrasias, and the induction and exacerbation by exogenous and endogenous factors, are currently under investigation.
One of the most heavily investigated theories for the pathogenesis of AD is that there is an underlying abnormality in skin barrier function, causing increased permeability and skin dryness (Yoshiike et al., 1993). For example, dysfunction of filaggrin, a key molecule in maintaining stability of the stratum corneum, has been shown to play a role in the development and exacerbation of AD. Seguchi et al. (1996) demonstrated that patients with AD had decreased production of filaggrin. Since that time, loss-of-function mutations in the gene encoding for filaggrin have been mapped and were found to be associated with an early age of onset of AD and with disease that persists into adulthood (Barker et al., 2007). In addition, some patients with AD have decreased levels of ceramides in their stratum corneum (Imokawa et al., 1991). Ceramides, the most abundant lipid present in the skin, are crucial for water retention. Lower levels of these lipids lead to increased permeability and decreased skin barrier function. Furthermore, overexpression of sphingomyelin deacylase, an enzyme responsible for degrading ceramide, has been shown in those with AD and may contribute to the low ceramide levels observed in those with AD (Imokawa et al., 1991).
Immunologic factors also play a role in the pathogenesis of AD. These factors include the pattern of local cytokine expression, the differentiation of helper T cells, and multiple roles for immunoglobulin (Ig)E, skin-directed cell responses, infectious agents, and superantigens (Leung & Soter, 2001). An immune defect is present, involving an abnormal overproduction of TH2 cells that interact with Langerhans cells and result in increased production of interleukin (IL)-4, IL-5, IL-6, IL-10, and IL-13 (Krafchik, 2006). With this increase of IL production in the presence of immune irregularity, plasma cells are erroneously signaled to differentiate into IgE versus IgG. Increased numbers of inflammatory cells are attracted to the epidermis due to interaction with TH2 cell surface receptors (Akdis, Akdis, Simon, & Blaser, 1999). High IgE and low gamma interferon levels are also observed. The imbalance of TH2 cells occurs in the acute process, with a swing toward TH1 cells signaling the presence of the chronic stages of the disease (Akkoc et al., 2008).
Another contributing factor to the development and maintenance of AD involves exogenous factors. Irritant contact dermatitis can be induced by many environmental triggers, such as daily washing with soap (Hogan, Dannaker, & Maibach, 1994) and contact with wool (Marks & DeLeo, 1992). This irritation in turn leads to scratching and a further decrease in the already susceptible skin barrier. Food allergies have also been shown to worsen the dermatitis, and several studies have demonstrated that elimination of the relevant food allergen will result in improved skin condition (Sicherer & Sampson, 1999). Environmental antigens from food (the gut) and dust mites (the lungs) react with antibodies to produce increased levels of IgE and, possibly, increased histamine reactions from mast dells (Krafchik, 2006).
In addition, it is important to recognize that, recently, it has been reported that a number of patients who have AD have also been found to have concomitant contact allergy (Militello, Jacob, & Crawford, 2006). Furthermore, it has also been reported that a number of these children with AD have demonstrated clinically relevant patch test results to ingredients in their lotions, creams, and the medicaments used to treat them (Jacob, Brod, & Crawford, 2008; Jacob, Burk, & Connelly, 2008, Jacob, Steele, Brod, & Crawford, 2008). In fact, Hogeling and Pratt (2008) reported that 7% of their pediatric patch-tested population had positive reactions to both fragrance and neomycin, two ingredients commonly found in products applied to the skin of patients with AD.
For example, a recent article by Jacob, Burke, et al. (2008) illustrated several cases of children with recalcitrant moderate to severe AD presenting with undiagnosed allergic contact allergy. Each of these children had developed allergy to a component in the steroid creams or lotions being used to treat them (lanolin in Aquahpor, isopropyl myristate in steroid creams, etc.). This resulted in a severe, disabling dermatitis in one patient even complicated by superinfection requiring hospitalization. When the relevant allergen was elucidated and avoided, each patient experienced significant improvement in his or her dermatitis (Jacob, Burke, et al., 2008).
This year marked the first published multicenter trial on clinically relevant contact allergens in pediatric populations (Jacob, Brod, et al., 2008). These authors reported that contact allergy was as likely in pediatric patients as adults in the United States, with nickel and fragrance-related chemicals being the most significant allergens in pediatric populations (Jacob, Brod, et al., 2008). Contact allergy to the active ingredients in the steroid (hydrocortisone and triamcinolone) as well as preservatives (formaldehyde releasers and benzyl alcohol) and emulsifiers (sorbitans) were also identified. Importantly, Hogeling and Pratt (2008) found that 41% were also diagnosed with AD. Given this information, we feel that any patient (especially) in the pediatric population who has significant recalcitrant dermatitis should receive a patch test (Jacob, Steele, et al., 2008).
In addition to the aforementioned exogenous triggers, emotional stress has been a well-documented endogenous trigger for flares of AD and resultant superinfection. Stressful events have been reported to occur before exacerbations of AD (Brown, 1972). In addition, a recent study evaluating the result of physiological stress on skin barrier function showed that stress-induced high levels of glucocorticoids led to inhibited epidermal lamellar body secretion and decreased lipid synthesis (Aberg et al., 2007). Decreased lamellar body secretion and lipid synthesis have been shown in turn to result in decreased epidermal antimicrobial peptides (encapsulated in lamellar bodies) and increased severity of group A Streptococcus pyogenes skin infections in murine models (Aberg et al., 2007). These findings may explain why patients with AD experience bacterial superinfections as the most common complication of their disease (Kristal & Klein, 2000).
Regarding genetics, children are more likely to develop the disease if one or both parents have had AD (Uehara & Kimura, 1993) and there is a high prevalence among siblings (Schultz Larsen, 1993). Often, children with AD may have what is termed atopic diatheses, an association with allergic rhinitis and asthma (Reitamo et al., 2000). In fact, the three conditions are so closely linked that they are often referred to as the atopic triad and should be considered as part of the overall pathogenesis.
In infants and young children, AD most commonly involves the scalp and face (Kristal & Klein, 2000). Extensor surfaces of the extremities and trunk may also be affected. Weeping or oozing lesions occur more often in children than in adults. Typically, children and adolescents have ill-defined, erythematous, scaly patches, but they can also have acute inflammatory flares. It is not uncommon to see both chronic and acute lesions present.
Because of constant scratching and rubbing, lichenification often develops and is reflection of both the severity and chronicity of the disease (Kristal & Klein, 2000). Flexural involvement tends to be more common in older children and adults (Hanifin, Leung, Paller, & Rico, 2003). Facial lesions are more diffuse. Pigmentary changes, including hypopigmentation or hyperpigmentation, may occur.
In adults, lichenification occurs in the flexural and facial areas (Rudikoff & Lebwohl, 1998). Often, the extremities are involved as well. In dark-skinned individuals, the disease tends to involve more lichenification, a follicular prominence of lesions, and postinflammatory pigmentary changes. Lesions are classified as acute, subacute, or chronic. Acute lesions are characterized by intensely pruiritic, erythematous papules; papulovesicles; or weeping skin (Kristal & Klein, 2000). Subacute lesions are erythematous-scaling papules or plaques. Pigmentary changes are often associated with chronic lesions that are characterized by prominent scaling and lichenification (Eigenmann, 2001). Patients typically present with a variation of the three types of lesions.
The gold-standard diagnostic criteria for AD were first recommended by Hanifin and Rajka (1980). They suggested that at least three major and three minor features must be present for a diagnosis of AD (Table 1). Then, in 2003, the Consensus Conference on Pediatric Atopic Dermatitis made modifications (Table 2). The panel had suggested that pruritus and eczema, acute, subacute, and chronic, are the essential clinical features to diagnose AD (Eichenfield et al., 2003). The differential diagnosis includes a wide range of eczematous dermatoses and genetic disorders (Table 3).
Until recently, topical corticosteroids have been the mainstay of AD therapy. Their effectiveness depends largely on the potency and frequency of the topical corticosteroid used and the degree of absorption through the skin [dose]. The Dalton rule serves as a reminder that molecules with a molecule weight equal to or less than 500 are able to easily penetrate normal and abnormal skin barrier. Topical steroids, as a rule, have a molecular weight ∼200 and thus account for the systemic adverse events associated with overuse and improper and prolonged use. Although greater potency may correlate with an expedited clearance of inflammation, there is also a greater potential for adverse effects both local and systemic (Nicol, 2000). The most common side effects of topical corticosteroids include skin atrophy, striae, and telangiectasias (Hanifin et al., 2004). Tachyphalaxis may also occur in some recalcitrant patients, particularly after long-term use (Boguniewicz, 2003; Nicol, 2000). Other adverse effects include bruising, hypopigmentation, and secondary infections (Abramovits, Goldstein, & Stevenson, 2003; Stone, 2002).
When topical corticosteroids are applied over large areas and for prolonged periods, systemic side effects may occur due to the large degree of absorption (Abramovits et al., 2003). Children experience much higher absorption than do adults because of their higher ratio of skin surface area to body mass (Shainhouse & Eichenfield, 2003) Consequently, systemic side effects are of particular concern in children (Shainhouse & Eichenfield, 2003).
Although systemic corticosteroid therapy is effective, the rapid rate of disease recurrence after discontinuation and the high risk for potential side effects make its use impractical (Paller, 2001). Consequently, mild topical corticosteroids are often recommended for children with AD, although they are not efficacious for moderate to severe disease. More potent topical corticosteroids should be avoided on areas of naturally thin skin, including the face, neck, and intertriginous areas, because of potential side effects (Leung & Barber, 2003; Shainhouse & Eichenfield, 2003).
Other treatments for AD include antihistamines. Antihistamines can provide symptomatic relief when administered at bedtime because of their tranquilizing and sedative effects (Nicol, 2000). Antihistamines also may be useful for treatment of coexisting allergic conditions, such as rhinoconjunctivitis, contact urticaria, and food allergies (Sidbury & Hanifin, 2000). Recently, topical formulations of anti-itch medications such as Mimyx (Stiefel Laboratories, Coral Gables, FL) and Atopiclair (Graceway Pharmaceuticals, Bristol, TN) have been introduced into the marketplace; their efficacy is limited and best suited in combination therapy.
Antibiotics may be indicated for secondary bacterial colonizations and infections as these may exacerbate and complicate flares (Leung & Barber, 2003). However, there is concern for the development of resistance to antibiotics (Hanifin et al., 2004). Therefore, long-term use of antibiotics for disease recalcitrant to standard therapy is not recommended (Eichenfield et al., 2003). Chlorine baths have been effective in eradicating the overgrowth of Staphylococcus aureus and returning the skin flora to a more balanced state, without the need for antibiotics.
Approved by the FDA for clinical use in December 2000 and 2001, Protopic and Elidel CIs are known for their ability to temporarily modulate the immune response without significant systemic immunosuppression (Bernard & Eichenfield, 2002). Formulated in concentrations of 0.03% and 0.01%, tacrolimus ointment was released for dispensing in February 2001 under the registered trademark Protopic for the treatment of moderate to severe AD. Pimecromulis 1% cream was released for dispensing in 2001 under the registered trademark Elidel for the treatment of mild to moderate AD.
According to the package inserts for both Protopic and Elidel, the exact mechanism of action of tacrolimus in AD is not known. In pivotal FDA clinical trials, it was demonstrated that tacrolimus inhibits T-lymphocyte activation (Madan & Griffiths, 2007). The mechanism of action is thought to be exerted by interfering and inhibiting dephosphorylation of calmodulin and calcineurin. Blocking this dephosphorylation, in turn, inhibits nuclear factor of activated T cell, which is responsible for regulating DNA and MRNA transcription and translation. This down-regulation helps to normalize the hyperstimulation of T helper cells, primarily TH2 cells, within the skin.
A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin then forms, and the phosphatase activity of calcineurin is inhibited (Madan & Griffiths, 2007). This effect has been shown to prevent the dephosphorylation and translocation of nuclear factor of activated T cells, a nuclear component thought to initiate gene transcription for the formulation of lymphokines such as IL-2 and gamma interferon (Madan & Griffiths, 2007).
Tacrolimus has also been shown to inhibit the release of preformed mediators from skin mast cells and basophils and to down-regulate the expression of high-affinity IgE receptors on Langerhans cells (Sperr et al., 1996). Tacrolimus ointment does not have the same side effects as those observed with the topical corticosteroids. There are several reasons for this. For one, because it has a higher molecular weight of 800 Da than that of topical corticosteroids, tacrolimus ointment will penetrate into the dermis but not beyond, allowing for topical efficacy but minimal systematic absorption. Furthermore, because its depth of penetration is limited, collagen synthesis is unaffected (Abramovits et al., 2003).
As treatment continues, tacrolimus ointment is less penetrating because the larger molecular weight prevents it from being absorbed through intact stratum corneum (Shainhouse & Eichenfield, 2003). This is in contrast to corticosteroids, which penetrate down into the subcutaneous tissue and into the circulatory system. In addition, tacrolimus ointment has been found to be effective for use anywhere on the body, including the eyelids, face, neck, and intertriginous areas, of both adults and children with AD (Reitamo et al., 2000; Stone, 2002).
EFFICACY OF TACROLIMUS OINTMENT
Tacrolimus ointment has been studied extensively for both safety and efficacy in the United States and Europe in trials involving more than 16,000 adult and pediatric patients (Kapp, Allen, & Rietamo, 2003). Two 12-week randomized, double-blind studies involving 632 patients demonstrated that tacrolimus ointment was an effective treatment of moderate to severe AD in patients (Hanifin, Ling, Langley, Breneman, & Rafal, 2001; Paller, Eichenfield, Leung, Stewart, & Appell, 2001). A 90% or greater improvement from baseline in disease status was observed for 6.6%, 27.5%, and 36.8% of patients in the vehicle group, 0.03% tacrolimus ointment, and 0.1% tacrolimus ointment group, respectively (Hanifin et al., 2001). Moreover, there was no need for the use of concomitant therapies that are typically used in this patient population.
In an open-label study with more than 7,900 patients, monotherapy with tacrolimus ointment was found to be a safe and effective treatment of AD (Koo, Prose, Fleischer, & Rico, 2002). More than 50% of patients enrolled to participate in this study were moderate to severe AD, half of which were children aged 2 to 15 years.
Similarly, long-term studies (Reitamo et al., 2000) have shown tacrolimus ointment to be safe and well tolerated in the treatment of patients with moderate to severe AD. In one such study, marked or excellent improvement or clearance of disease was reported in 54%, 81%, and 86% of patients at Week 1, Month 6, and Month 12, respectively (Reitamo et al., 2000). In another study, approximately 50% of patients had at least 2 years of exposure to treatment with tacrolimus ointment without any indication of an increased risk for any adverse event (Paller, Caro, Weinstein, & Rico, 2002).
In children, the long-term studies, ranging from 1 to 3 years, have demonstrated that tacrolimus ointment is safe and effective for the treatment of moderate to severe AD in children aged 2 to 15 years (Hanifin et al., 2003, Kang, Lucky, Pariser, Lawrence, & Hanifin, 2001). Moreover, it is particularly beneficial for children with persistent disease, for whom long-term treatment with topical corticosteroids would be inappropriate because of side effects (Reitamo, Van Leent, et al., 2002).
Compared with other treatments, tacrolimus ointment was significantly more effective than 1% hydrocortisone acetate in the treatment of moderate to severe AD in children (Reitamo, Van Leent, et al., 2002). Tacrolimus was also demonstrated to be comparable with 0.1% hydrocortisone butyrate ointment, a mid to potent topical corticosteroid, in the treatment of adults (Reitamo, Rustin, et al., 2002). Tacrolimus ointment has been shown to be more effective than pimecrolimus cream, another TIM, according to the results of three studies presented at the 2004 American Academy of Dermatology (AAD) 62nd annual meeting (AAD symposium; Paller, 2004). These studies represent the first direct comparative trials examining these two agents for the treatment of AD in the same patient population.
A total of 837 patients with mild to severe AD were evaluated in 36-week, randomized, investigator-blinded studies (Paller, 2004). End points of this multicentered trial included the percentage change from baseline in the eczema area and severity index, the physician-rated body surface area assessment, patient assessment of itch, and the six-point Investigator's Global Atopic Dermatitis Assessment. All efficacy end points indicated that treatment with tacrolimus ointment was superior to pimecrolimus cream, whereas both TIMs demonstrated similar safety profiles with no statistical difference in cutaneous or systemic adverse events (Paller, 2004).
A significant difference between the two TIMS is that pimecrolimus is indicated only for the treatment of mild to moderate AD, whereas tacrolimus ointment is indicated for moderate to severe disease. Also, pimecrolimus is available in a 1% concentration cream, whereas tacrolimus ointment is available in two concentrations, 0.03% and 0.1%. As the first TIM on the market, tacrolimus ointment has been studied longer; therefore, longer term safety and efficacy data are available for that agent.
BENEFITS of CIS
A significant benefit of TIMs is that they do not cause skin atrophy, the most common side effect associated with the use of topical corticosteroids (Tomi & Luger, 2003). In addition, long-term treatment with TIMs (specifically tacrolimus ointment) does not increase the risk of secondary infections in patients with AD (Fleischer et al., 2002). One explanation is that the use of tacrolimus ointment improves the epidermal barrier function, resulting in a decreased risk of local infection (Shainhouse & Eichenfield, 2003). In fact, long-term treatment of adults with AD was associated with decreased colonization by S. aureus (Shainhouse & Eichenfield, 2003).
Studies suggest that the quality of life has improved for patients using tacrolimus ointment. In one study, more than 60% of the 985 adult and pediatric patients observed improvements in symptoms, feelings, daily activities, sleep, and treatment impact (Drake et al., 2001). In another study, patients reported having fewer physician visits, fewer prescription medications for AD, and lower out-of-pocket expenses, as well as improved quality of life (Boguniewicz et al., 2004).
The most frequent adverse event reported with the use of tacrolimus ointment is the sensation of skin burning (Nghiem, Pearson, & Langley, 2002). This has occurred in approximately 33% to 45% of those treated with 0.03% tacrolimus ointment and 31% to 61% of those treated with 0.1% tacrolimus ointment, depending on the study. The stinging and burning directly correlate with the severity of the disease. The burning sensation may be due to the release of substance P and mast cell degranulation induced by the topical application of tacrolimus (Stander, Stander, Seeliger, Luger & Steinhoff, 2007). Typically mild to moderate, the burning sensation usually resolves within the first few days of treatment (Soter, Fleischer, Webster, Monroe, & Lawrence, 2001) presumably because of improvement in the disease status and skin healing (Kang et al., 2001, Reitamo et al., 2002).
ATOPIC DERMATITIS AWARENESS, PREVENTION, AND TREATMENT RECOMMENDATIONS
At the June 2003 conference, the Atopic Dermatitis Awareness, Prevention, and Treatment (ADAPT) panel developed a consensus of care for the management of AD that represents a new treatment paradigm for patients to proactively control the disease. Because the consensus is that the causes of AD are multifactorial, the following ADAPT recommendations should be tailored to each patient's specific symptoms. As part of its treatment regimen, ADAPT recommends palliative care, including bathing and moisturizing, along with the proper use of CI.
In patients with AD, the outer epidermal barrier layer of the skin is impaired. Thus, the skin's ability to lose water is increased and its ability to bind water is decreased (Nicol, 2000). The most effective method of hydrating the skin is to soak in water.
However, a common misconception in the treatment of recalcitrant and persistent AD is a lack of regard for the role of bathing and moisturizing. This notion is fueled by two true, but opposing, facts about bathing:
- Bathing dries the skin through the evaporation of water from wet skin, which then causes contraction of the stratum corneum and fissures, thus impairing the epidermal barrier.
- Bathing especially hydrates the skin, when moisturizer is applied immediately afterward, retaining hydration and keeping the barrier soft and flexible (Tofte & Hanifin, 2001). Applying moisturizers after bathing is critical to preventing damage to the stratum corneum and consequent inflammation and needs to be done immediately on damp skin, within a matter of minutes, or the value of hydration is lost (Stone, 2002; Tofte & Hanifin, 2001).
Bathing daily is preferable because it cleanses and hydrates the skin as well as enhances penetration of topical treatment (Hanifin & Tofte, 1999). For patients with extensive involvement or very dry skin, ADAPT had recommended bathing for 15 to 20 minutes or until the skin on fingertips has a pruned appearance twice daily. Use comfortable warm temperature, but avoid hot water. In addition, although no studies have been published regarding their efficacy, bleach baths are often recommended without the presence of an active skin infection and have been anecdotally reported to decrease the risk of S. aureus skin infections and the need for antibiotics (Krakowski & Dohil, 2008). When lesions are severe and bathing is painful, the tried and true "soak-and-smear" regiment may be useful. Use wet compresses (such as moisturization followed by application of damp pajamas under a dry pair until the skin heals enough that bathing is better tolerated). Showering is acceptable when the AD is under control or lesions are mild; however, to prevent incremental drying of the skin, drugs and moisturizer must be applied on damp skin (Hanifin & Tofte, 1999).
While bathing, avoid scrubbing the skin with wash clothes or other potentially abrasive bathing utensils. Use a mild, nonfragrance soap-free hydrating cleanser or glycerin-based soap sparingly. After bathing, partially dry the skin by patting it with a towel. Do not rub the skin. Rubbing is abrasive and can further irritate the skin. The skin should not be dried completely, allowing for moisturization to "lock in" the remaining water on the skin surface to further assist in hydration. It is important to avoid antibacterial cleansers due to the risk of inducing bacterial resistance (Eichenfield et al., 2003).
Emollients are a standard of care useful for both prevention and maintenance therapy, according to the AAD's guidelines (Hanifin et al., 2004). The more occlusive the moisturizer, the more effective it is at retaining moisture. The moisturizers should be applied within 3 minutes of pat drying to temporarily trap water in the stratum corneum, help maintain the skin's pliability, and decrease further transepidermal water loss to the environment (Abramovits et al., 2003, p. 2; Halbert, 1996).
Ointments and creams provide greater barrier function than do lotions (Eichenfield et al., 2003). Lotions are less effective moisturizers because they typically contain water, alcohol, preservatives, and fragrances, all of which dry out the skin and the latter of which may produce contact allergy (Leung & Barber, 2003; Nicol, 2000). Emollients with a water-in-oil or fatty-hydrophobic base seal most effectively (Nicol, 2000). Extremely dry, chapped skin benefits from more greasy preparations. Patients should avoid moisturizers that contain unnecessary ingredients such as fragrances, vitamin E, aloe vera, and malaleuka because of their irritancy and sensitizing potential (Halbert, 1996).
Ceramides, as discussed previously, are known to be decreased in the skin of patients with AD (Imokawa et al., 1991). Recently, new skin cleansers and moisturizers have been formulated to contain synthetic ceramides, in the hope that application of these products will decrease skin permeability and partially restore the skin integrity in patients with AD. A recent study showed that the use of these cleansers and moisturizers, in replacement of regular bar soap, can increase the affectivity of steroid creams in areas of mild to moderate eczema (Draelos, 2008). Nevertheless, more studies are indicated to accurately gauge the benefits of using such products.
Reapplying moisturizer often throughout the day is important in the management of AD for two reasons: (a) The maximum duration of action for emollients is 6 hours (Eichenfield et al., 2003), and (b) dry skin may provide a portal of entry for allergens, irritants, and skin pathogens (Leung & Soter, 2001). Frequent application of moisturizers three or four times throughout the day helps to maintain a high level of hydration in the stratum corneum (Leung & Barber, 2003; Nicol, 2000).
This regiment has the potential to be time consuming and overwhelming to the patient and the parent. It is important to provide clear instructions on order of application, amount of drug, and frequency to drive compliance and maximize outcomes. Below is algorithm for moderate to severe patients focusing on topical treatments and palliative care.
The morning routine is as follows:
- Bathe if instructed.
- If there is no bathing, apply drug to affected skin.
- Cover remaining skin with moisturizer.
The daytime routine is as follows:
- Moisturize throughout day.
- The evening regiment is as follows:
- Bathing either once or twice a day is dependent on severity of flare.
- Use recommended soaps or cleansers; avoid abrasive bathing utensils.
- Remove from bath when fingertips are pruned or after 15-20 minutes.
- Gently pat skin semidry with soft cotton towel.
- Immediately apply recommended drugs to areas of affected skin.
- Cover remaining skin and affected skin with moisturizer.
This article discussed and reviewed the current standard of care for AD and provided a newer standard of care based on research findings, discussions, and consensus. Although proactive use of tacrolimus ointment is a prophylactic monotherapy that can reduce the incidence of flares (Kapp et al., 2003), some practitioners may continue to prescribe topical corticosteroids concomitantly. Successfully managing and controlling moderate to severe AD presents many challenges. Patient direction and education are key components. The observed recommendations from Dermatology Clinical Advisory Board aim to give clarity direction and set an evidence-based standard of care into motion. With all these being said, future research, novel therapies, and further investigation into the role of contact allergy in AD are needed still to meet a variety of patient needs in the treatment of moderate to severe AD.
Aberg, K. M., Radek, K. A., Choi, E. H., Kim, D. K., Demerjian, M., Hupe, M., et al (2007). Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. Journal of Clinical Investigation, 117
Abramovits, W., Goldstein, A. M., & Stevenson, L. C. (2003). Changing paradigms in dermatology: Topical immunomodulators within a permutational paradigm for the treatment of atopic and eczematous dermatitis. Clinics in Dermatology, 21
Akdis, C. A., Akdis, M., Simon, H. U., & Blaser, K. (1999). Regulation of allergic inflammation by skin-homing T cells in allergic eczema. International Archives of Allergy and Immunology, 118
Akkoc, T., deKoning, P. J., Ruckert, B., Barlan, I., Akdis, M., & Akdis, C. A. (2008). Increased activation-induced cell death of high IFN-gamma-producing T(H)1 cells as a mechanism of T(H)2 predominance in atopic diseases. Journal of Allergy and Clinical Immunology, 121
Barker, J. N., Palmer, C. N., Zhao, Y., Liao, H., Hull, P. R., Lee, S. P., et al (2007). Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis
that persists into adulthood. Journal of Investigative Dermatology, 127
Bernard, L. A., & Eichenfield, L. F. (2002). Topical immunomodulators for atopic dermatitis
. Current Opinion in Pediatrics, 14
Boguniewicz, M. (2003). Treatment options and new therapeutic approaches in atopic dermatitis
. Dermatology Nursing, Suppl.
Boguniewicz, M., Abramovits, W., Whitaker-Worth, D., & Paller, A. (2004). Treatment, resources, and impact of atopic dermatitis
: The triad study. Journal of the American Academy of Dermatology, 50
Brown, D. G. (1972). Stress as a precipitant factor of eczema. Journal of Psychosomatic Research, 16
Charman, C. (1999). Clinical evidence: Atopic eczema. British Medical Journal, 318
Drake, L., Prendergast, M., Maher, R., Breneman, D., Korman, N., Satoi, Y., et al (2001). The impact of tacrolimus ointment on health-related quality of life of adult and pediatric patients with atopic dermatitis
. Journal of the American Academy of Dermatology, 44
(1 Suppl.), S65-S72.
Draelos, Z. D. (2008). The effect of ceramide-containing skin care products on eczema resolution duration. Cutis, 81
Eichenfield, L. F., Hanifin, J. M., Luger, T. A., Stevens, S. R., & Pride, H. B. (2003). Consensus conference on pediatric atopic dermatitis
. Journal of the American Academy of Dermatology, 49
Eigenmann, P. A. (2001). Clinical features and diagnostic criteria of atopic dermatitis
in relation to age. Pediatric Allergy and Immunology, 12
(Suppl 14.), 69-74.
Ellis, C. N., Drake, L. A., & Prendergast, M. M. (2002). Cost of atopic dermatitis
and eczema in the United States. Journal of the American Academy of Dermatology, 46
Fleischer, A. B. Jr., Ling, M., Eichenfield, L., Satoi, Y., Jaracz, E., Rico, M. J., et al (2002). Tacrolimus ointment for the treatment of atopic dermatitis
is not associated with an increase in cutaneous infections. Journal of the American Academy of Dermatology, 47
Halbert, A. R. (1996). The practical management of atopic dermatitis
in children. Pediatric Annals, 25
Hanifin, J. M. (2003). An overview of atopic dermatitis
. Dermatology Nursing, Suppl.
Hanifin, J. M., Cooper, K. D., Ho, V. C., Kang, S., Krafchik, B. R., Margolis, D. J., et al (2004). Guidelines of care for atopic dermatitis
, developed in accordance with the American Academy of Dermatology (AAD)/American Academy of Dermatology Association "Administrative Regulations for Evidence-Based Clinical Practice Guidelines." Journal of the American Academy of Dermatology, 50
Hanifin, J. M., Leung, D. Y., Paller, A., & Rico, J. (2003). Tacrolimus ointment monotherapy is safe and effective for the long-term treatment (more than 3 years) of atopic dermatitis
in pediatric patients. Journal of Allergy & Clinical Immunology, 111
Hanifin, J. M., Ling, M. R., Langley, R., Breneman, D., & Rafal, E. (2001). Tacrolimus ointment for the treatment of atopic dermatitis
in adult patients; Part I, efficacy. Journal of the American Academy of Dermatology, 44
Hanifin, J. M., & Rajka, G. (1980). Diagnostic features of atopic dermatitis
. Acta Dermato-Venereologica, Supplementum, 92
Hanifin, J. M., & Tofte, S. J. (1999). Update on therapy of atopic dermatitis
. Journal of Allergy and Clinical Immunology, 104
(3 Pt. 2), S123-S125.
Hogan, D. J., Dannaker, C. J., & Maibach, H. I. (1994). Contact dermatitis: Risk factors, and rehabilitation. Seminars in Dermatology, 31
Hogeling, M., & Pratt, M. (2008). Allergic contact dermatitis in children: The Ottawa hospital patch-testing clinic experience, 1996 to 2006. Dermatitis, 19
Imokawa, G., Abe, A., Jin, K., Higaki, Y., Kawashima, M., & Hidano, A. (1991). Decreased level of ceramides in stratum corneum of atopic dermatitis
: An etiologic factor in atopic dry skin? Journal of Investigative Dermatology, 96
Jacob, S. E., Brod, B., & Crawford, G. H. (2008). Clinically relevant patch test reactions in children-a United States based study. Pediatric Dermatology, 25
Jacob, S. E., Burk, C. J., & Connelly, E. A. (2008). Patch testing: Another steroid-sparing agent to consider in children. Pediatric Dermatology, 25
Jacob, S. E., Steele, T., Brod, B., & Crawford, G. H. (2008). Dispelling the myths behind pediatric patch testing-experience from our tertiary care patch testing centers. Pediatric Dermatology, 25
Kang, S., Lucky, A. W., Pariser, D., Lawrence, I., & Hanifin, J. M. (2001). Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis
in children. Journal of the American Academy of Dermatology, 44
(1 Suppl.), S58-S64.
Kapp, A., Allen, B. R., & Reitamo, S. (2003). Atopic dermatitis
management with tacrolimus ointment (Protopic). Journal of Dermatological Treatment, 14
(Suppl. 1), 5-16.
Koo, J., Prose, N., Fleischer, A., & Rico, M. J. (2002). Safety and efficacy of tacrolimus ointment monotherapy in over 7,900 atopic dermatitis
patients: Results of an open-label study. Annales de Dermatologie et de Venereologie, 129
(Suppl. 1), S414-S415.
Krakowski, A. C., & Dohil, M. A. (2008). Topical therapy in pediatric atopic dermatitis
. Seminars in Cutaneous Medicine and Surgery, 27
Kristal, L., & Klein, P. A. (2000). Atopic dermatitis
in infants and children. An update. Pediatric Clinics of North America, 47
Leung, A. K., & Barber, K. A. (2003). Managing childhood atopic dermatitis
. Advances in Therapy, 20
Leung, D. Y., & Soter, N. A. (2001). Cellular and immunologic mechanisms in atopic dermatitis
. Journal of the American Academy of Dermatology, 44
(1 Suppl.), S1-S12.
Madan, V., & Griffiths, C. E. (2007). Systemic ciclosporin and tacrolimus in dermatology. Dermatologic Therapy, 20
Marks, J. G., & DeLeo, V. A. (1992). Evaluation and treatment of the patient with contact dermatitis. In J. G. Marks & V. A. DeLeo (Eds.), Contact and occupational dermatology
(pp. 18-19). St. Louis, MO: Mosby Year Book.
Militello, G., Jacob, S. E., & Crawford, G. H. (2006). Allergic contact dermatitis in children. Current Opinions in Pediatrics, 18
Nghiem, P., Pearson, G., & Langley, R. G. (2002). Tacrolimus and pimecrolimus: From clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis
. Journal of the American Academy of Dermatology, 46
Nicol, N. (2000). Managing atopic dermatitis
in children and adults. Nurse Practitioner, 25
(4), 58-59, 63-64, 69-70, 80-81.
Paller, A. S. (2001). Use of nonsteroidal topical immunomodulators for the treatment of atopic dermatitis
in the pediatric population. Journal of Pediatrics, 138
Paller, A. (2004). Three prospective studies comparing tacrolimus ointment with pimecrolimus creas in atopic dermatitis
patients. Presented at X World Congress of Dermatology. Rome.
Paller, A., Caro, I., Weinstein, G. G., & Rico, M. J. (2002). Long-term (over 2 years) safety and efficacy of tacrolimus ointment monotherapy in atopic dermatitis
patients: Open-label study results. Annales de Dermatologie et de Venereologie
, (Suppl. 1, Pt. 1), 1245.
Paller, A., Eichenfield, L. F., Leung, D. Y., Stewart, D., & Appell, M. (2001). A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis
in pediatric patients. Journal of the American Academy of Dermatology, 44
(1 Suppl.), S47-S57.
Reitamo, S., Rustin, M., Ruzicka, T., Cambazard, F., Kalimo, K., Friedmann, P. S., et al (2002). Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis
. Journal of Allergy and Clinical Immunology, 109
Reitamo, S., Wollenberg, A., Schopf, E., Perrot, J. L., Marks, R., Ruzicka, T., et al (2000). Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis
. The European Tacrolimus Ointment Study Group. Archives of Dermatology, 136
Reitamo, S., Van Leent, E. J., Ho, V., Harper, J., Ruzicka, T., Kalimo, F., et al (2002). Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis
. Journal of Allergy and Clinical Immunology, 109
Rudikoff, D., & Lebwohl, M. (1998). Atopic dermatitis
. Lancet, 351
Schultz Larsen, E. (1993). Atopic dermatitis
: A genetic-epidemiologic study in a population-based twin sample. Journal of the American Academy of Dermatology, 28
Schultz Larsen, E., Diepgen, T., & Svensson, A. (1996). The occurrence of atopic dermatitis
in North Europe: An international questionnaire study. Journal of the American Academy of Dermatology, 34
(5 Pt. 1), 760-764.
Seguchi, T., Cui, C. Y., Kusuda, S., Takahashi, M., Aisu, K., & Tezuka, T. (1996). Decreased expression of filaggrin in atopic skin. Archives of Dermatological Research, 288
Shainhouse, T., & Eichenfield, L. F. (2003). Long-term safety of tacrolimus ointment in children treated for atopic dermatitis
. Expert Opinion on Drug Safety, 2
Sicherer, S. H., & Sampson, H. A. (1999). Food hypersensitivity and atopic dermatitis
: Pathophysiology, epidemiology, diagnosis, and management. Journal of Allergy and Clinical Immunology, 104
Sidbury, R., & Hanifin, J. M. (2000). Old, new, and emerging therapies for atopic dermatitis
. Dermatologic Clinics, 18
Soter, N. A., Fleischer, A. B. Jr., Webster, G. F., Monroe, E., & Lawrence, I. (2001). Tacrolimus ointment for the treatment of atopic dermatitis
in adult patients: Part II, safety. Journal of the American Academy of Dermatology, 44
(1 Suppl.), S39-S46.
Sperr, W. R., Agis, H., Czerwenka, K., Virgolini, I., Bankl, H. C., Müller, M. R., et al (1996). Effects of cyclosporin A and FK-506 on stem cell factor-induced histamine secretion and growth of human mast cells. Journal of Allergy and Clinical Immunology, 98
Stander, S., Stander, H., Seeliger, S., Luger, T. A., & Steinhoff, M. (2007). Topical pimecrolimus and tacrolimus transiently induce neuropeptide release and mast cell degranulation in murine skin. British Journal of Dermatology, 156
Stone, K. D. (2002). Atopic diseases of childhood. Current Opinion in Pediatrics, 14
Tofte, S. J., & Hanifin, J. M. (2001). Current management and therapy of atopic dermatitis
. Journal of the American Academy of Dermatology, 44
(1 Suppl.), S13-S16.
Tomi, N. S., & Luger, T. A. (2003). The treatment of atopic dermatitis
with topical immunomodulators. Clinics in Dermatology, 21
Uehara, M., & Kimura, C. (1993). Descendant family history of atopic dermatitis
. Acta Dermato-Venereologica, 73
Williams, H. C. (2000). Epidemiology of atopic dermatitis
. Clinical and Experimental Dermatology, 25
Yoshiike, T., Aikawa, Y., Sindhvananda, J., Suto, H., Nishimura, K., Kawamoto, T., et al (1993). Skin barrier defect in atopic dermatitis
: Increased permeability of the stratum corneum using dimethyl sulfoxide and theophylline. Journal of Dermatological Science, 5