FEATURE ARTICLE

APractical Management of Atopic DermatitisV Palliative Care to Contact Dermatitis

D iane M. H anna, Jessica M oennich, S haron E. J a c o b
ABSTRACT: Atopic dermatitis (AD) is one of the most com mon inflammatory skin diseases a m o n g c h ildre n a n d a d ults. This ch ronic disea se can h a ve a dramatic n e ga tive imp a c t on th e patients a n d fam ilys q u a lity of life. For most of the last four d e c a d e s, there were no new the ra p ies approved b y the Food a n d Drug Administration for the tre a tm e n t of this d ise a se , a n d p alliative c a re w a s u nd e rutilized . In 2000, a new cla ss of drugs, the topical immune m o d ula tors, m ore re c e n tly c om m o nly c a lle d c a lcine u rin inhibitors, re c eive d Food a n d Drug Administra tion indic a tion for the long-term treatm ent a n d management of AD. With this, a group of the nations lea d ing experts in AD c a m e tog e the r for the form a tion o f Atop ic Dermatitis Awareness, Prevention, a n d Tre a tm e nt (ADAPT) for formula ting a c o m pre h e nsive tre a tm e n t a lgorithm for m o d e r a te to se ve re AD, utilizing top ica l the ra p ies a n d p a llia tive c a re a s the core for tre a tm e n t. In 2003, ADAPT h e ld a c o nfe re n c e to fin a lize a c o n se n su s of c a r e for th e m a n a g e m e n t of AD, incorp ora tin g th e use of topical im m u ne m odulators, other topic a l therapies, a n d p a llia tive skin care. ADAPTs
Diane M. Hanna, MSN, ARNP-c, School of Nursing, University of Kansas, and Midwest Modern Dermatology, Overland Park, Kansas. Jessica Moennich, BS, The Ohio State University, College of Medicine, Columbus, Ohio. Sharon E. Jacob, MD, Department of Medicine and Pediatrics (Dermatology), Rady Childrens Hospital, University of California, San Diego, California. The authors declared no sponsorship, no disclosures, and no conflicts of interest. Correspondence concerning this article should be addressed to Diane M. Hanna, MSN, ARNP -c, 5244 W. 127th Terrace, Leawood, Kansas 66209. E-mail: dianehanna@me.com

guidelines are con sistent with th e E vide n ce -Ba sed Guidelines of C a re for Atopic Dermatitis recently issued by th e A m e rica n A ca d e m y of D e rm atolog y a s well a s th e Aca d e m ys Consensus Conference on P e diatric Atop ic D e rm a titis p u blishe d in the Jou rn al o f th e American Academy o f De rm a tology in 2004. T he p urpose of this article was to disc uss a n d review the current sta nd a rd of c a re a n d to d isse minate an u p d a te d standard of c a re b a sed on rese arc h find ings a n d d iscussions. Key words: Atopic Dermatitis, Topical Immune M odu lators, ADAPT (Atopic Dermatitis Awareness, Prevention, a n d T re a t m e n t)

or 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 latters use and effectiveness, such as atrophy, tachyphylaxis, pigmentary

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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. EPIDEMIOLOGY 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% Y 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). PATHOGENESIS 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
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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 T H 2 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 T H 2 cell surface receptors (Akdis, Akdis, Simon, & Blaser, 1999). High IgE and low gamma interferon levels are also observed. The imbalance of T H 2 cells occurs in the acute process, with a swing toward T H 1 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
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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 patchtested 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 superinfecVOLUME 1 | NUMBER 2 | MARCH/APRIL 2009

tions 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. CLINICAL FEATURES 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. DIAGNOSIS 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
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TABLE 1. Major and Minor Criteria for Diagnosis of AD

Major Criteria (n e e d th r e e or m ore) Facial and exten sor in vo lvem en t in in fants a n d ch ild r en Pruritus D erm atitisV ch ron ically or ch ron ica lly relap sin g Typical m orp h olog y a n d d istrib ution P ersonal or family history of a to p y (a sth m a , allergic rhinitis, and A D ) Flexural lichen ification in ad ults Minor criteria (n eed th ree or m o re) C a ta ra c ts Infections (c u ta n eo u s) Cheilitis ConjunctivitisV recu rrent Im mu noglob ulin EV e le va te d Facial pallor or eryth em a F o o d in to lera n ce H an d derm atitisV n on allergic Ichthyosis E cze m a V perifollicular a c c e n tu a tion Im m ediate (Typ e I) skin test reactivity Dennie-M organ infraorbital fold Itch in g w h en sw eatin g P alm ar hyp erlinearity Pityriasis a lb a K eratoconu s Keratosis pilaris W ool intoleran ce N ipp le dermatitis Orb ital d arken ing W h ite d erm o gra ph ism Xerosis
Note. AD = a t o p i c de rm atitis. A d a p te d from Hanifin and R ajk a (1980) (first pu blishe d in 1977 by Hanifin e t al., the di agn osis of AD c a n b e m a d e by fulfillin g m ajo r an d minor crite ria). Anothe r set of guide line s, e stablishe d a t t h e 2003 co n se n su s co n fe re n ce on pe di at ri c AD, m a y also be u se d i n the di agno sis of AD (E iche nfie ld et al., 2003).

roid 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

TABLE 2. Diagnostic Criteria Established at the 2003 Consensus Conference on Pediatric AD

I. Essential features (must be present for a n AD d iagnosis) Pruritus Chron ic, relapsing h istory E c z e m a (a c u te, su b a cu te, a n d ch r on ic ) 1. Typical m orp h olog y a n d a ge -s p ecific p a ttern 2. Sparing of groin a n d axillary region 3. C urrent or prior flexural lesions a t a n y a g e 4. S calp in infants 5. Facial, extensor, a n d n e ck involvem en t in ch ild ren II. Im p o rtant featu res (seen in m ost c a s e s a n d supp orts th e dia gn osis) Early a g e of on set Xerosis Atop y 1. P ersonal or family history 2. Im mun oglobulin E reactivity III. A sso ciated featu res (m a y su pp ort th e d iagn osis b u t are to o n on sp ec ific to b e su p p o rte d b y res ea rch or ep idem io lo gical stu dies) A typ ical va scu lar resp onses Keratosis pilaris, hyp erlin ear palm s, a n d ichthyosis O cu lar, p eriorbital ch a n g e s Oth er regional find ings: perioral a n d periauricular ch an ges

includes a wide range of eczematous dermatoses and genetic disorders (Table 3). TREATMENT OPTIONS Until recently, topical corticosteroids have been the mainstay of AD therapy. Their effectiveness depends largely on the potency and frequency of the topical corticoste100

Perifollicular a c c e n tu a tio n , lichen ification, and prurigo lesion s

Note. AD = a t o p i c de rm atitis. From Eichenfield et al. (2003). The p a n e l h a d s u g ge s te d th a t pruritus a n d e c z e m a , a c u t e , su b a c u te , an d ch ro n i c, are t he e sse ntial clinical fe atu re s to d i a g n o se AD. The diffe rential diagnosis include s a w i d e r a n ge o f e cz e m at o u s de rm at ose s and ge ne ti c disorde rs.

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TABLE 3.

Differential Diagnoses

Lichen simplex ch ronicus Seborrheic derm atitis N um m ular eczem a X erotic ecze m a D y sh id rotic e c z e m a C o n ta c t derm atitis Drug rea ction s Hyp erim mu noglobu lin E sy nd ro m e N eth erton syndro me Photosensitivity rash es Wiskott-Aldrich syn dro m e
Note. From Krafchik (2006).

ever, there is concern for the development of resistance to antibiotics (Hanifin et al., 2004). Therefore, longterm use of antibiotics for disease recalcitrant to standard therapy is not recommended (Eichenfield et al., the overgrowth of Staphylococcus aureus and returning the skin flora to a more balanced state, without the need for antibiotics. CALCINEURIN INHIBITORS Approved by the FDA for clinical use in December 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 downregulation helps to normalize the hyperstimulation of T helper cells, primarily TH 2 cells, within the skin. A complex of tacrolimusY 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 highaffinity 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).
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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
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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% hydro102

cortisone 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 Investigators 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
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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 patients specific symptoms. As part of its treatment regimen, ADAPT recommends palliative care, including bathing and moisturizing, along with the proper use of CI. Bathing In patients with AD, the outer epidermal barrier layer of the skin is impaired. Thus, the skins 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: 1. 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. 2. 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 AADs 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 skins 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 fattyhydrophobic base seal most effectively (Nicol, 2000). Extremely dry, chapped skin benefits from more greasy preparations. Patients should avoid moisturizers that
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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: 1. Bathe if instructed. 2. If there is no bathing, apply drug to affected skin. 3. Cover remaining skin with moisturizer. The daytime routine is as follows: 1. Moisturize throughout day.The evening regiment is as follows: 2. Bathing either once or twice a day is dependent on severity of flare. 3. Use recommended soaps or cleansers; avoid abrasive bathing utensils. 4. Remove from bath when fingertips are pruned or after 15Y minutes. 20 5. Gently pat skin semidry with soft cotton towel. 6. Immediately apply recommended drugs to areas of affected skin. 7. Cover remaining skin and affected skin with moisturizer. CONCLUSION 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 evidencebased 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. h
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